Novel compound as mas-related g-protein coupled receptor member x2 (mrgprx2) antagonists and pharmaceutical composition comprising same

Abstract

The present invention relates to a compound having a novel structure represented by chemical formula I or chemical formula II, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an MRGPRX2 antagonist, a pharmaceutical composition comprising same, and a method and use for preventing or treating diseases using same. <Chemical formula (I)> <Chemical formula (II)>

Description

[0001] Description of the Invention

[0002]

Title of invention

[0003] Novel compound as MRGPRX2 (Mas-related G-protein coupled receptor member X2) antagonist and pharmaceutical composition containing same

[0004]

Technical Field

[0005]

Background Technology

[0006] 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 endogenous peptides, allergens, infectious agents, toxins, and FDA-approved drugs, including receptors for basophils and eosinophils.

[0007] 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 (Al lergy 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 lower 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

[0008] (0001) Allergy Asthma Immunol Res. 2021 May; 13(3): 498-506

[0009] (0002) Neuron. 2019 Feb 6; 101(3): 412-420

[0010]

Contents of the invention

[0011]

Technical Problem

[0012]

Technical Solution

[0013] <Chemical Formula 1>

[0014] <Chemical Formula 1 1> with H, halogen, CN, - N02,

[0015] C1-C6 alkyl, C1-C6 haloalkyl, -0-(Cl- C6 alkyl), -C(=O)-OH, -C(=0)-(Cl- C6 alkyl), -C(=0)-0-(Cl- C6 alkyl), -NCC1-C6 alkyl)(Cl- C6 alkyl) or C3-C12 cycloalkyl

[0016] — H or C1-C6 alkyl), or

[0017] Ri is H, C1-C6 alkyl or - C(=0)- 0-(Cl- C6 alkyl);

[0018] R2 is H or halogen; in each of formulae I and II,

[0019] Li is -(CH2)X- (x is an integer from 1 to 3), -0-, -N(Rg)- (Rg is H or C1-

[0020] C6 alkyl) or - 0-(CH2)y- (y is an integer from 1 to 3), and Rs and R4 are each a functional group defined below, or are connected to each other to form a ring group containing at least one syl group,

[0021] R3 is H, C1-C6 alkyl or 3- to 12-membered heterocycloalkyl containing one or more heteroatoms selected from N, 0 and S, wherein one or more of the C1-C6 alkyl groups may be independently substituted with OH, CN, -0-CC1-C6 alkyl) or C3-C12 cycloalkyl, Y3 are each independently CH2, 0, S or pattern

[0022] X으 〕. Indicates), Y7— Y S (Y4 to Y6 are each independently CH2, 0, S, C (=0) or A 5- to 12-membered heteroaryl group containing a terephthalic acid atom, wherein one or more of R4's groups are independently selected from the group consisting of halogen, -CN, -N02, -OH, C1-C6 alkyl (wherein one or more of C1-C6 alkyl's groups may be independently substituted with -0-(Cl- C6 alkyl)), C1-C6 haloalkyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -0-(Cl- C6 alkyl), -0-CC1-C6 haloalkyl), -S-CC1-C6 haloalkyl), -NH2, -N(C1-C6 alkyl)(Cl- C6 is 0 or 1, y is 0 or 1, and at this time, one or more of Rj's complements may be independently substituted with halogen, C1-C6 alkyl or C1-C6 haloalkyl), or -

[0023] S(=0)『 N(R m )R n (Rm and Rn are each independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocycloalkyl or C6-C12 aryl containing one or more heteroatoms selected from N, 0 and S, and one or more of each of Rm and Rn may be independently substituted with 0H or - 0- (Cl- C6 alkyl);

[0024] The ring formed by connecting R3 and R4 is each independently represents CH2, NH or 0, and Wi and W2 are not CH2 at the same time). One or more of the above ring groups are independently selected from the group consisting of halogen, CN, OH, N02, C1-C6 alkyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, alkyl) or -S(=O)2-N(C1-C6 alkyl)(Cl- C6 alkyl). In the present invention, "Cm- Cn" (wherein m and n are each independently an integer of 1 or more, 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, "a-b membered" (wherein a and n are each independently an integer of 1 or more, and a < b) means the number of atoms forming a ring, for example, "4-12 membered ring" means that the ring is a 4- to 12-membered ring. For example, a 4- to 12-membered heterocycloalkyl is a ring forming a 4- to 12-membered member, and the atoms forming the ring may include not only carbon but also one or more heteroatoms such as N, 0, and S. In the present invention, unless otherwise specified, "alkyl" means a straight-chain or branched-chain saturated hydrocarbon group represented by - CnH2n+l (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" means a divalent functional group derived from alkyl as defined above. In the present invention, unless otherwise specified, "alkenyl" means an unsaturated hydrocarbon group containing at least one double bond between carbons in alkyl. Examples of alkenyl include -CH=CH2, -CH2CH=CH2, -CH=CH-CH3, etc. In the present invention, unless otherwise stated, "alkenylene" means a divalent functional group derived from alkenyl as defined above. In the present invention, unless otherwise stated, "alkynylene" means an unsaturated hydrocarbon group containing at least one triple bond between carbons in alkyl.Examples of alkynylene include - CH = CH, - CH2OCH, - OCH- CH3, etc. In the present invention, unless otherwise specified, "cycloalkyl" means 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 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, but is not limited thereto. 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, "heterocycloalkyl" means a cyclic group in which at least one carbon atom forming a ring in the cycloalkyl is independently substituted with a heteroatom selected from the group consisting of N, 0, and S. In heterocycloalkyl, the heteroatom may include one or more of the same heteroatoms, and two or more types of heteroatoms may each independently include one or more. Examples of heterocycloalkyl include oxiranyl, oxetanyl, Hereinafter, one or more selected from the group consisting of, but not limited to, "heterocycloalkylene" as used herein, unless otherwise specified, means a divalent functional group derived from heterocycloalkyl as defined above. "aryl" as used herein, unless otherwise specified, means an aromatic monocyclic or polycyclic ring group. Examples of aryl include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indenyl, and andracenyl. "Heteroaryl" as used herein, unless otherwise specified, means an aromatic monocyclic or polycyclic ring group containing 1 to 3 heteroatoms selected from the group consisting of N, 0, and S. Examples of heteroaryl include , thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isooxazolyl, pyrazolyl, triazolyl, pyridinyl, indolyl, 2H-pyrazolo[3,4-b]pyridinyl, 2H-pyrazolo[3,4-c]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, benzothiazolyl, benzoxazolyl, benzothiophenyl, benzofuranyl, benzopyrrolyl, benzoimidazolyl, benzoisoxazolyl, benzopyrazolyl, benzotriazolyl,

[0025] N=\

[0026] A woman N Benzopyridinyl, G NH However, it is not limited thereto. In the present invention, unless otherwise stated, “haloalkyl” means a functional group in which at least one of the H of the alkyl defined above is independently substituted with a halogen. Examples of haloalkyl include -CF3, -CH2-CF3, -CH2CF2H, -CF2H, -ecu, -CH2-

[0027] CC13, -CCI2H, -CF2CI, -CFH-CH3, -CF2-CH3, -CFCI2, etc. can be mentioned, but are not limited thereto. In the invention, "halogen" can be F, Cl, Br or I. In addition, the terms and abbreviations used in this specification have their original meanings unless otherwise defined.

[0028] (2) In the above (1), in each of Formula I and Formula

[0029] II according to an embodiment of the present invention, a is an integer from 0 to 3),

[0030]

[0031] One or more of R4 are each independently halogen, -CN, -NO₂, -OH, C1-C6 alkyl (where one or more of the C1-C6 alkyl may each independently be substituted with -O-(C1-C6 alkyl)), C1-C6 haloalkyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl), -S-(C1-C6 haloalkyl), -NH2, -N(C1-C6 alkyl)(C1-C6 alkyl),

[0032] Ap

[0033] -C(=O)-Rg (Rg is C1-C6 alkyl, -NH2, -O-(C1-C6 alkyl), -OH, 0 , tx Rgi (Rgi is H or C1-C6 alkyl), or oetc.), -[(C1-C6 alkylene)]z-NH-S(=O)₂Rh (Rh is C1-C6 alkyl, C3-C6 cycloalkyl, -N(C1-C6 alkyl)(C1-C6 alkyl) and z is 0 or 1), -O-S(=O)₂R₁ (R₁ is C1-C6 alkyl or C6-C12 aryl, and in this case one or more of the C6-C12 aryl may each independently be substituted with C1-C6 alkyl Go, eu is 0 or 1, y is 0 or 1, and at this time, one or more of Rj may be independently substituted with halogen, C1-C6 alkyl or C1-C6 haloalkyl), or -

[0034] S(=0)2- N(R m )Rn (Rm and Rn are each independently H, C1-C6 alkyl, C1-C6 haloalkyl,

[0035] C3-C12 cycloalkyl, or C6-C12 aryl, and each of Rm and Rn may be independently substituted with 0H or - 0- (Cl- C6 alkyl); One or more of the above ring groups are independently selected from the group consisting of halogen, CN, OH, N02, C1-C6 alkyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, H or C1-C6 alkyl) or - S(=0)『 N(C1- C6 alkyl) (Cl- C6 alkyl).

[0036] (3) In the above (1) or (2), in the compound represented by the chemical formula I according to the present invention, the compound including the ring group formed by R3 and R4 is represented by the following chemical formula

[0037] It can be expressed as III.

[0038] <Chemical Formula 111>

[0039] In Formula I, Rs and R4 represent a ring formed by connecting each other, and each independently represents an integer from 0 to 3), W2 each independently represents CH2, NH or 0, and W1 and W2 are not CH2 at the same time). Each of the above independently represents halogen, CN, OH, N02, C1-C6 alkyl, C1-C6 haloalkyl,

[0040] C3-C12 cycloalkyl, (Rp is H or C1-C6 alkyl) or — S(=0)2—

[0041] NCC1-C6 alkyl) (Cl- C6 alkyl) can be substituted.

[0042] (4) In the above (1) or (2), in the compound represented by the chemical formula II according to the present invention, the compound including the ring group formed by R3 and R4 can be represented by the following chemical formula IV. It represents a ring formed by bonding, Each independently represents an integer between 0 and 3 each independently represents CH2, NH or 0, and W1 and W2 are not CH2 at the same time). Each of the above independently represents halogen, CN, OH, N02, C1-C6 alkyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, H or C1-C6 alkyl) or -S(=0)2-

[0043] NCC1-C6 alkyl) (Cl- C6 alkyl) can be substituted.

[0044] (5) In any one of the above (1) to (3), the compound represented by the chemical formula I according to the present invention may include a compound represented by the following chemical formula la.

[0045] <Chemical Formula Ia> Each independently H, halogen, CN,

[0046] C1-C6 alkyl, C1-C6 haloalkyl, - CF3, -0-CC1-C6 alkyl), - C(=0)- OH, - C(=0)- (Cl- C6 alkyl), -C(=0)-0-(Cl-C6 alkyl), -N(C1-C6 alkyl) (Cl- C6 alkyl) or C6-C12 cycle

[0047] Rs and R4 are each a functional group defined below, or are connected to each other to form a ring group containing at least one cyclic group,

[0048] R3 is H or C1-C6 alkyl, wherein one or more of the C1-C6 alkyl groups may be independently substituted with CN,

[0049] Each independently H, halogen, -CN, -N02, -OH, C1-C6 alkyl (wherein, one or more of C1-C6 alkyl may be independently substituted with -0- (Cl- C6 alkyl)), -CHs, -

[0050] CH(CH3)(CH3), -CH(CHS)-0-CH3, C1-C6 haloalkyl, -CFs, - OC- CH3, C3-C6 cycloalkyl, - 0- (Cl- C6 alkyl), -O-CHs, -0-CC1-C6 haloalkyl), -0-CF3, -O-CHF2, - S- (Cl- C6 haloalkyl), -S-CFs, -NH2, - MCH3XCH3), or - C(=0)- Rg (Rg is C1-C6 alkyl, -

[0051] Any one of the selected heteroaryls, wherein at least one of the heteroaryls may be substituted with C1-C6 alkyl, C1-C6 haloalkyl or -CF3;

[0052] The ring formed by R3 and R4 connecting to each other (C and each independently represent an integer from 0 to 3, and R7 is H, halogen, 0H,

[0053] N02, C1-C6 alkyl, C1-C6 haloalkyl, -CF3, or -S(=O)2-N(C1-C6 alkyl)(Cl- C6 alkyl) (W1 and W2 each independently represent CH2, NH, N(C1-C6 alkyl) or 0, W1 and W2 are not CH2 simultaneously, and R8 is H, halogen, CN, OH, NO2, C1-C6 alkyl, C1-C6 haloalkyl or -CF3), C1-C6 alkyl or C3-C12 cycloalkyl), (Rio and Rii each independently

[0054] H, C1-C6 alkyl, C1-C6 haloalkyl, Rp is H or C1-C6 alkyl), there is.

[0055] (6) In any one of the above (1) to (3), the compound according to the present invention may include a compound represented by the following formula lb, formula Ic or formula Id.

[0056] <Formula Ib> In each of formula lb, formula Ic and formula Id, (Ra, Rb and so on each independently represent H, halogen, CN, NO2, C1-C6 alkyl, C1-C6 haloalkyl, -CF3, -O-C(C1-C6 alkyl)), -C(=O)-(C1-C6 alkyl) or

[0057] -C(=O)-O-(C1-C6 alkyl)), (Rd and Re each independently represent H or halogen), (wherein, Rf is H or C1-C6 alkyl);

[0058] R3 is H or C1-C6 alkyl;

[0059] L2 is -NH- or -O-, and e and f each independently represent 0 or 1;

[0060] R12 is H, halogen, C1-C6 alkyl or -O-(C1-C6 alkyl);

[0061] R13 is C1-C6 alkyl, C3-C6 cycloalkyl, C6-C12 aryl (wherein the eighth group of C6-C12 aryl

[0062] 1 or more of which may each be independently substituted with C1-C6 alkyl) 8 (Y8 is CH2 or 0, b is 0 or 1, y is 0 or 1, and wherein at least one of these complements may be independently substituted with halogen, C1-C6 alkyl, C1-C6 haloalkyl or - CH2F) or - N (R m )R n (wherein, Rm and Rn are each independently H, C1-C6 alkyl (wherein, at least one of H of C1-C6 alkyl may be independently substituted with -0-(Cl-C6 alkyl) or 0H), -CHs, -CH2CH3, -CH(CH3)(CH3), -CH2CH2-O-CH3, -CH2-C(CH3)2(0H),

[0063] C1-C6 haloalkyl, - CH2CH2F, -CH2-CF2H, C3-C12 cycloalkyl, or C6- C12 aryl).

[0064] (7) 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.

[0065] (8) In any one of the above (1) to (6), 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. In the present invention, "stereoisomer" includes diastereomers and optical isomers, and includes a single enantiomeric isomer, a mixture of enantiomeric isomers including a racemic mixture, a single diastereoisomer, and a mixture of diastereoisomers. Such isomers can be separated by resolution using a conventional technique, for example, column chromatography or HPLC. Alternatively, they can be stereospecifically synthesized using optically pure starting materials and / or reagents of a known arrangement. Specifically, the isomers may be optical isomers. In the present invention, "pharmaceutically acceptable" may mean physiologically acceptable and, when administered to a subject, does not typically cause an allergic reaction such as gastrointestinal disorder or dizziness or a similar reaction. 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 a 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 a novel structure of the present invention (the compound represented by Chemical Formula I or Chemical Formula II 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 a novel structure of the present invention, a stereoisomer thereof or a pharmaceutically acceptable salt thereof can effectively inhibit calcium mobilization in cells and 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 described above, and therefore, redundant detailed descriptions are omitted. Hereinafter, the “compound having a novel structure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof” according to the present invention may be a compound according to any one selected from (1) to (8), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.The present invention provides a pharmaceutical composition for the prevention or treatment of a disease including at least one selected from allergic diseases, inflammatory bowel disease, arthritis, and migraine, comprising a compound having a novel structure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. In the present invention, the allergic disease may include chronic urticaria, anaphylaxis, non-histaminergic pruritus, psoriasis, asthma, atopic dermatitis, or rosacea. The pharmaceutical composition of the present invention may further comprise at least one pharmaceutically acceptable carrier 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 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, but are not limited thereto. In addition to the above components, the pharmaceutical composition of the present invention may further include 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, liquids, 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 placing them in multi-dose containers. The formulations may be manufactured by a conventional method used in formulation in the art or by a method described in Remington's Pharmaceutical Science (19. thed., 1995) and can be formulated into various preparations depending on each disease or component. 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 of 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. The compound having the novel structure of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof may exhibit a preventive or therapeutic effect on diseases including at least one selected from allergic diseases, inflammatory bowel diseases, arthritis, and migraines.In the present invention, "prevention" means any act of suppressing or delaying the onset of a disease including at least one selected from among allergic diseases, inflammatory bowel diseases, arthritis, and migraines 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. In the present invention, "treatment" means any act of improving or beneficially changing the symptoms of a disease including at least one selected from among allergic diseases, inflammatory bowel diseases, arthritis, and migraines 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 allergic diseases, inflammatory bowel diseases, arthritis, and migraines, comprising a 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 comprising the same. In the present invention, "administration" means introducing a predetermined substance to a subject by an appropriate method. In the present invention, the "subject" means all animals including rats, mice, and livestock, including humans, which have developed or are capable of developing a disease, and may specifically be mammals including humans, but is not limited thereto. The method for preventing or treating an allergic disease of the present invention may be a method for administering a therapeutically effective amount of the compound of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.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 can be determined by those skilled in the art based on factors including the patient's sex, age, weight, health status, 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 concurrently, 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, weight, general health status, sex and diet, administration time, administration route and excretion rate of the composition, treatment period, drugs used in combination or concurrently with the specific composition, and similar factors well known in the medical field. The present invention provides a 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 a 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.

[0066] (9) 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 a step of administering a compound according to any one of (1) to (8), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0067] (10) The present invention provides a use of a compound according to any one of (1) to (8), 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.

[0068] (11) The present invention provides the use of a compound according to any one of (1) to (8), 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. Matters mentioned in the compound according to the present invention, the pharmaceutical composition comprising the same, the method using the same, and the use thereof are equally applicable unless they are contradictory.

[0069]

Effect of the invention

[0070]

Form for carrying out the invention

[0071] (Waters, SQD2 or Agi lent, LC / MSD) analysis was confirmed.

[0072] <Manufacturing Example>Compound Synthesis Method and NMR Analysis

[0073] [Example 1]

[0074] Scheme 1 Synthesis of phenyl (5-(3-fluorobenzyl)thiazol-2-yl)carbamate

[0075] 1 equivalent of 5-(3-fluorobenzyl)thiazol-2-amine was dissolved in 10 mL / g of tetrahydrofuran, 1.5 equivalents of pyridine were added, and the temperature was lowered to 0 °C. 1.2 equivalents of phenyl chloroformate were slowly added, the temperature was slowly raised to room temperature, and the mixture was stirred for 16 hours. After completion of the reaction, the mixture was extracted with ethyl acetate and water. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The precipitated solid was washed with methylene chloride and filtered. The product obtained by filtration was dried to obtain phenyl (5-(3-fluorobenzyl)thiazol-2-yl)carbamate.

[0076] Synthesis of 1-(5-(3-fluorobenzyl)thiazol-2-yl)-3-(4-(trifluoromethyl)phenyl)urea (Example 1) 1 equivalent of phenyl (5-(3-fluorobenzyl)thiazol-2-yl)carbamate was dissolved in 10 mL / g of tetrahydrofuran, and 2 equivalents of N,N-diisopropylethylamine and 2 equivalents of 4-(trifluoromethyl)aniline as reactant A1 were added. The mixture was raised to 80°C and stirred for 16 hours. After completion of the reaction, the mixture was extracted with methylene chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The title compound, Example 1, was obtained by purification and separation using column chromatography (hexane:ethyl acetate).

[0077] [Example 2-11] The compound of Example 2-11 was synthesized using substantially the same method as that described in the method for preparing the compound of Example 1 (Scheme 1), using the reactant A1 of Table 2 instead of the reactant A1 of the method for preparing the compound of Example 1. The structure, reactant A1, and analytical data of the compound of Example 1-11 are shown in Table 2.

[0078] [Table 2]

[0079] [Example 12]

[0080] Scheme 2 Synthesis of 5—(3—fluorophenoxy)thiazol—2—amine

[0081] 3-Fluorophenolic acid 1.3 equivalents were dissolved in 30 mL / g of acetone, and 2 equivalents of cesium carbonate were added. After stirring for 10 minutes, 1 equivalent of 5-bromothiazol-2-amine was added and heated at 65°C for 12 hours. After completion of the reaction, the mixture was filtered through Celite with acetone, concentrated, and extracted with ethyl acetate and water. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography (hexane:ethyl acetate) to obtain 5-(3-fluorophenoxy)thiazol-2-amine. 3-(5-(3-Fluorophenolic acid thiazol-2-yl)-1-methyl-1-(4-(trifluoromethyl)phenyl)urea 0 Synthesis of}(3—(5—(3— f luorophenoxy)thiazol— 2— yl)—l—methyl—l—(4— (trif luoromethyl)phenyl)urea)(Example 12)

[0082] 1 equivalent of 5-(3-fluorophenoxy)thiazol-2-amine was dissolved in 10 mL / g of tetrahydrofuran, 1.5 equivalents of pyridine were added, and the temperature was lowered to 0°C. 1.2 equivalents of phenyl chloroformate were slowly added, and the temperature was slowly raised to room temperature and stirred for 4 hours. In situ, 1.5 equivalents of N-methyl-4-(trifluoromethyl)aniline and 2 equivalents of N,N-diisopropylethylamine were added as reactant B1 and heated to 80°C. After completion of the reaction, the ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography (hexane:ethyl acetate) to obtain the title compound, Example 12. [Table 3]

[0083] [Example 13] Scheme 3 Synthesis of phenyl (5-(3-fluorophenoxy)thiazol-2-yl)carbamate

[0084] 5-(3-Fluorophenoxy)thiazol-2-amine was dissolved in 10 mL / g of tetrahydrofuran, 1.5 equivalents of triethylamine was added, and the temperature was lowered to 0°C. 1.2 equivalents of phenyl chloroformate was slowly added, the temperature was slowly raised to room temperature, and the mixture was stirred for 4 hours. After completion of the reaction, the mixture was extracted with ethyl acetate and water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified and separated by column chromatography (hexane:ethyl acetate) to obtain phenyl (5-(3-fluorophenoxy)thiazol-2-yl)carbamate.

[0085] Synthesis of 3-(5-(3-fluorophenoxy)thiazol-2-yl)-1-methyl-1-(4-(trifluoromethoxy)phenyl)urea) (Example 13) 1 equivalent of phenyl (5-(3-fluorophenoxy)thiazol-2-yl)carbamate was dissolved in 10 mL / g of 1,4-dioxane. 1.5 equivalents of N-methyl-4-(trifluoromethoxy)aniline and 2 equivalents of N,N-diisopropylethylamine as reactant C1 were added and heated to 80°C. After completion of the reaction, the ethyl acetate layer was extracted with water. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified and separated by column chromatography (hexane:ethyl acetate) to obtain the title compound, Example 13.

[0086] [Example 14-137] In a method substantially identical to that described in the method for preparing the compound of Example 13 (Scheme 3), the reactant of Table 4 was used instead of the reactant C1 of the method for preparing the compound of Example 13.

[0087] Compound Example 14-137 was synthesized using C1. The structure, reactant C1, and analytical data of compound Example 13-137 are shown in Table 4.

[0088] [Table 4]

[0089] [Example 138] Swick screw乂

[0090] Scheme 4 3-chloro-4-fluoro-N-methyl 0}aniline (3-chloro-4-fluoro-N-methylaniline)

[0091] (As a synthetic reactant of reactant D2), 1 equivalent of 3-chloro-4-fluoroaniline was dissolved in 10 mL / g of 1,4-dioxane. 2.5 equivalents of methylboronic acid, 2.5 equivalents of copper acetate, and 3.5 equivalents of pyridine were added, and the mixture was refluxed with stirring until the reaction was completed. After completion of the reaction, it was filtered through celite with ethyl acetate and then concentrated. The organic layer was extracted with ethyl acetate and brine. The ethyl acetate layer was dried over magnesium sulfate and then concentrated under reduced pressure and purified by column chromatography (hexane:ethyl acetate) to obtain 3-chloro-4-fluoro-N-methylaniline.

[0092] 1-(3-chloro-4-fluoro-phenyl)-3-(5-(3-fluoro-phenoxy)thiazol-2-yl)-1-methylurea (1-(3-chloro-4-fluoro-phenyl)-3-(5-(3-fluoro-phenoxy)thiazol-2-yl)-1-methylurea) (Synthesis of Example 138) 1 equivalent of phenyl (5-(3-fluoro-phenoxy)thiazol-2-yl)carbamate in 1,4-dioxane

[0093] It was dissolved in 10 mL / g. 1.5 equivalents of 3-chloro-4-fluoro-N-methylaniline and 2 equivalents of N,N-diisopropylethylamine were added as reactant D2, and stirred at 90°C for about 1 hour. After confirming the completion of the reaction, water was added, and the organic layer was extracted using ethyl acetate and brine. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified and separated by column chromatography (hexane:ethyl acetate) to obtain the title compound, Example 138.

[0094] [Examples 139-141] Compounds of Examples 139-141 were synthesized in substantially the same manner as described in the preparation method of compound of Example 138 (Scheme 4), using reactants D1 and D2 of Table 5 instead of reactants D1 and D2 of the preparation method of compound of Example 138. The structures, reactants DI, D2, and analytical data of compounds of Examples 138-141 are shown in Table 5.

[0095] [Table 5]

[0096] [Example 142]

[0097] Scheme 5 Synthesis of 4-(difluoromethoxy)-N-methylaniline (Reactant E2) As a reactant mixture, 1 equivalent of 4-(difluoromethoxy)aniline was dissolved in 10 mL / g of ethanol, then 1.5 equivalents of 37% aqueous formaldehyde solution was added, and the mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was dissolved in 10 mL / g of tetrahydrofuran, then 2 equivalents of sodium borohydride was added, and the mixture was stirred at room temperature for 18 hours. After confirming the completion of the reaction, water was added, and the organic layer was extracted using ethyl acetate and brine. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure, and then purified and separated by column chromatography (hexane:ethyl acetate) to obtain 4-(difluoromethoxy)-N-methylaniline. Synthesis of 1-(4-(difluoromethoxy)phenyl)-3-(5-(3-fluorophenoxy)thiazol-2-yl)-1-methylurea (Example 142) 1 equivalent of phenyl (5-(3-fluorophenoxy)thiazol-2-yl)carbamate and 2 equivalents of N,N-diisopropylethylamine were dissolved in 10 mL / g of 1,4-dioxane, then 1.5 equivalents of 4-(difluoromethoxy)-N-methylaniline as Reactant E2 was added, and the mixture was stirred at 80 °C for 18 hours. After confirming the completion of the reaction, water was added, and the organic layer was extracted using ethyl acetate and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, and then purified and separated by column chromatography (hexane:ethyl acetate) to obtain the title compound, the compound of Example 142.

[0098] [Examples 143-147] Compounds of Examples 143-147 were synthesized in substantially the same manner as described in the preparation method of compound of Example 142 (Scheme 5), using reactants E1 and E2 of Table 6 instead of reactants E1 and E2 of the preparation method of compound of Example 142. The structures, reactants El, E2 and analytical data of compounds of Examples 142-147 are shown in Table 6.

[0099] [Table 6]

[0100] [Example 148]

[0101] Scheme 6

[0102] Synthesis of N-methyl-3-(pyrrolidin-1-ylsulfonyl)aniline (N-methyl-S-Cpyrrolidin-1-ylsulfonyl)aniline) (reactant F2) 1 equivalent of 3-(pyrrolidin-1-ylsulfonyl)aniline as reactant F1 and 2 equivalents of potassium carbonate were dissolved in 10 mL / g of tetrahydrofuran, 2 equivalents of methyl iodide were added, and the mixture was stirred at room temperature for 16 hours. After confirming the completion of the reaction, water was added, and the organic layer was extracted using ethyl acetate and brine. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified and separated by column chromatography (hexane:ethyl acetate) to obtain N-methyl-3-(pyrrolidin-1-ylsulfonyl)aniline.

[0103] 3-(5-(3-fluorophenoxy)thiazol-2-yl)-1-methyl-1-(3-(pyrrolidin-1-ylsulfonyl)phenyl)urea 0}(3—(5—(3— f luorophenoxy) thi azol— 2— yl)—l—methyl—l—(3—(pyrrol idin— 1—yl sul fonyl)phenyl)urea)(Example 148) Synthesis of phenyl (5-(3 -fluorophenoxy)thiazol- 2 -yl)carbamate 1 equivalent of 1 , 4 -dioxane

[0104] After dissolving in 10 mL / g, 1.5 equivalents of N-methyl-3-(pyrrolidin-1-ylsulfonyl)aniline, which is the reactant F2, and 2 equivalents of N,N-diisopropylethylamine were added, and the mixture was stirred at 80°C for 2 hours. After confirming the completion of the reaction, water was added, and the organic layer was extracted using ethyl acetate and brine. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified and separated by column chromatography (hexane:ethyl acetate) to obtain the title compound, Example 148.

[0105] [Table 7] [Examples 149-151] Compounds of Examples 149-151 were synthesized in substantially the same manner as described in the manufacturing method of Example 148 (Scheme 6), except that 10 mL / g of dimethylformamide was used instead of 10 mL / g of tetrahydrofuran, 1 equivalent of methyl iodide was used instead of 2 equivalents, and reactants F3 and F4 of Table 8 were used instead of reactants F1 and F2 of the manufacturing method of the compound of Example 148. The structures, reactants F3, F4, and analytical data of compounds of Examples 149-151 are shown in Table 8. [Table 8] [Example 152]

[0106] Scheme 7

[0107] Synthesis of N-methyl-3-(piperidin-1-ylsulfonyl)aniline (N-methyl-S-Cpiperidin-1-ylsulfonyl)aniline) (reactant G2) As reactant G1, 1 equivalent of 3-(piperidin-1-ylsulfonyl)aniline was dissolved in 30 mL / g of methanol, 5 equivalents of sodium methoxide and 1.4 equivalents of paraformaldehyde were added, and the mixture was stirred at room temperature for 2 hours and then at 70°C for 30 minutes. After that, 1 equivalent of sodium borohydride was added at 0°C, the temperature was raised to 70°C, and the mixture was stirred for 2 hours. After confirming the completion of the reaction, water was added, and the organic layer was extracted using ethyl acetate and brine. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified and separated by column chromatography (hexane:ethyl acetate) to obtain N-methyl-3-(piperidin-1-ylsulfonyl)aniline.

[0108] 3-(5-(3-fluorophenoxy)thiazol-2-yl)-1-methyl _j_(3_(piperidin-1-ylsulfonyl) phenyl)urea 0 Synthesis of {3—(5—(3— f luorophenoxy) thiazol— 2— yl)—l—methyl—l—(3—(piperidin—l— ylsulfonyl)phenyl)urea) (Example 152) 1 equivalent of phenyl (5-(3 -fluorophenoxy)thiazol- 2 -yl)carbamate was dissolved in 10 mL / g of 1,4-dioxane. 1.5 equivalents of N-methyl-3-(piperidin- 1-ylsulfonyl)aniline and 2 equivalents of N, N-diisopropylethylamine as reactant G2 were added and heated to 80°C. After completion of the reaction, the mixture was extracted with ethyl acetate and water. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified and separated by column chromatography (hexane:ethyl acetate) to obtain the title compound, Example 152.

[0109] [Examples 153-167] Compounds of Examples 153-167 were synthesized in substantially the same manner as described in the preparation method of compound of Example 152 (Scheme 7), using reactants G1 and G2 of Table 9 instead of reactants G1 and G2 of the preparation method of compound of Example 152. The structures, reactants G1, G2, and analytical data of compounds of Examples 152-167 are shown in Table 9. [Table 9]

[0110] [Example 168]

[0111] Scheme 8 Synthesis of N-(2-fluoroethyl)-3-nitrobenzenesulfonamide As a reactant H1, 1 equivalent of 3-nitrobenzenesulfonyl chloride was dissolved in 10 mL / g of methylene chloride. At 0°C, 1.2 equivalents of 2-fluoroethylamine hydrochloride and 3 equivalents of triethylamine were added to the reactants H2 and stirred. After confirming the completion of the reaction, water was added, and the organic layer was extracted using methylene chloride and brine. The moisture remaining in the organic layer was completely removed with magnesium sulfate 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 N-(2-fluoroethyl)-3-nitrobenzenesulfonamide.

[0112] Synthesis of 3-amino-N-(2-fluoroethyl)benzenesulfonamide

[0113] 1 equivalent of N-(2-fluoroethyl)-3-nitrobenzenesulfonamide was dissolved in 10 mL / g of ethanol and 10 mL / g of tetrahydrofuran. 10 wt% of palladium / carbon was added, and the reaction was carried out by hydrogen substitution. The reaction mixture was stirred at room temperature for 16 hours. After confirming the completion of the reaction, it was filtered through Celite. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography and concentrated in vacuo to obtain 3-amino-N-(2-fluoroethyl)benzenesulfonamide.

[0114] Synthesis of N-(2-fluoroethyl)-3-(methylamino)benzenesulfonamide (N-(2- f luoroethyl)-3-(methylamino)benzenesu 1 f onam i de)

[0115] 1 equivalent of 3-amino-N-(2-fluoroethyl)benzenesulfonamide was dissolved in 10 mL / g of methanol. 1.5 equivalents of paraformaldehyde and 5 equivalents of sodium methoxide were added, and the mixture was refluxed and stirred for about 1 hour. 1 equivalent of sodium borohydride was added at 0°C, and the mixture was stirred for about 30 minutes. After adding water, the organic layer was extracted using ethyl acetate and brine. The remaining moisture in the organic layer was completely removed with magnesium sulfate, 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 N-(2-fluoroethyl)-3-(methylamino)benzenesulfonamide.

[0116] Synthesis of N-(2-fluoroethyl)-3-(3-(5-(3-fluorophenoxy)thiazol-2-yl)-1-methylureido)benzenesulfonamide (Example 168) One equivalent of phenyl (5-(3-fluorophenoxy)thiazol-2-yl)carbamate was dissolved in 10 mL / g of 1,4-dioxane. 1.5 equivalents of N-(2-fluoroethyl)-3-(methylamino)benzenesulfonamide and 2 equivalents of N,N-diisopropylethylamine were added, and the mixture was stirred at 90 °C for about 1 hour. After confirming the completion of the reaction, water was added, and the organic layer was extracted using ethyl acetate and brine. The remaining moisture in the organic layer was completely removed with magnesium sulfate 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, Example 168.

[0117] [Examples 169-177] Compounds of Examples 169-177 were synthesized in substantially the same manner as described in the preparation method of compound of Example 168 (Scheme 8), using reactants H1 and H2 of Table 10 instead of reactants H1 and H2 of the preparation method of compound of Example 168. The structures, reactants H1, H2 and analytical data of compounds of Examples 168-177 are shown in Table 10.

[0118] [Table 10]

[0119] [Example 178]

[0120] Scheme 9

[0121] Synthesis of 3-fluoro-1-((3 ■nitrophenyl)sulfonyl)azetidine (3- f luoro-1-((3-nitrophenyl)sulfonyl)azetidine)

[0122] 3-Nitrobenzenesulfonyl chloride 1 equivalent, 3-fluoroazetidine hydrochloride 1.5 equivalents as reactant II were dissolved in 5 mL / g of methylene chloride, 2 equivalents of triethylamine were added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the mixture was extracted with methylene chloride and water. The methylene chloride layer was dried over magnesium sulfate and the next reaction was carried out without further purification.

[0123] Synthesis of 3-((3-fluoroazetidin-1-yl)sulfonyl)aniline (3-((3-f luoroazet idin-l- yl)sulfonyl)ani 1 ine)

[0124] 1 equivalent of 3-fluoro-1-((3-nitrophenyl)sulfonyl)azetidine was dissolved in 25 mL / g of dimethylformamide, and 3 equivalents of tetrahydroxydiboron were added. 5 mol% of 4,4-dipyridine was dissolved in 10 mL / g of dimethylformamide, and then slowly added dropwise to the solution at 0°C, followed by stirring for 1 minute. After completion of the reaction, the mixture was extracted with ethyl acetate and water. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and the next reaction was carried out without further purification.

[0125] Synthesis of 3-((3-fluoroazetidine-1-yl)sulfonyl)-N-methylaniline (3~((3~ f luoroazet idin—l—yl )sulfonyl )—N— methyl ani l ine)

[0126] 1 equivalent of 3-((3-fluoroazetidin-1-yl)sulfonyl)aniline was dissolved in 40 mL / g of methanol, 1.4 equivalents of paraformaldehyde and 5 equivalents of sodium methoxide were added, and the mixture was stirred at room temperature for 16 hours. After that, 1 equivalent of sodium borohydride was added at 0°C and the mixture was stirred at 60°C for 1 hour. After completion of the reaction, the mixture was extracted with ethyl acetate and water. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. 3-((3-fluoroazetidin-1-yl)sulfonyl)-N-methylaniline was obtained by purification and separation by column chromatography (hexane:ethyl acetate).

[0127] 1- (3- ( (3 -fluoroazetidin- 1-yl)sulfonyl)phenyl )-3- (5- (3 -fluorophenoxy )thiazol- 2 -yl)- 1-methylurea (1- (3- ((3- f luoroazet idin- 1- yl ) sulfonyl ) phenyl )-3 -

[0128] Synthesis of (5-(3-fluorophenoxy)thiazol-2-yl)-1-methylurea) (Example 178) 1 equivalent of phenyl (5-(3-fluorophenoxy)thiazol-2-yl)carbamate was dissolved in 10 mL / g of 1,4-dioxane, and then 1.2 equivalents of 3-((3-fluoroazetidin-1-yl)sulfonyl)-N-methylaniline and 3 equivalents of N,N-diisopropylethylamine were added as reactant 12, and stirred at 80°C for 3 hours. After completion of the reaction, the mixture was extracted with methylene chloride and water. The methylene chloride layer was dried over magnesium sulfate and concentrated under reduced pressure. The title compound, Example 178, was obtained by purification and separation by column chromatography (hexane:ethyl acetate).

[0129] [Examples 179-180] Compounds of Examples 179-180 were synthesized in substantially the same manner as described in the preparation method of compound of Example 178 (Scheme 9), using reactants II and 12 of Table 11 instead of reactants II and 12 of compound of Example 178. The structures, reactants II, 12 and analytical data of compounds of Examples 178-180 are shown in Table 11. [Table 11]

[0130] [Example 181]

[0131]

[0132] Scheme 10

[0133] Synthesis of 2-((tert-butyldimethylsilyl)oxy)-2-methylpropan-1-amine

[0134] 1 equivalent of 1-amino-2-methylpropan-2-ol was dissolved in 10 mL / g of methylene chloride. 1.5 equivalents of tert-butyldimethylsilyl chloride and 2 equivalents of imidazole were added at 0°C, and the mixture was stirred at room temperature for about 2 hours. After confirming the completion of the reaction, water was added, and the organic layer was extracted using methylene chloride and brine. The moisture remaining in the organic layer was completely removed with magnesium sulfate 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 2-((tert-butyldimethylsilyl)oxy)-2-methylpropan-1-amine.

[0135] Synthesis of N-(2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)-3-nitrobenzenesulfonamide

[0136] 3-Nitrobenzenesulfonyl chloride 1 equivalent was dissolved in 10 mL / g of methylene chloride. 1.2 equivalents of 2-((tert-butyldimethylsilyl)oxy)-2-methylpropan-1-amine and 1.5 equivalents of triethylamine were added at 0°C and stirred. After confirming the completion of the reaction, water was added and the organic layer was extracted using methylene chloride and brine. The remaining moisture in the organic layer was completely removed with magnesium sulfate 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 N-(2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)-3-nitrobenzenesulfonamide.

[0137] Synthesis of 3-amino- N- (2-((tert-butyldimethylsilyl)oxy)- 2-methylpropyl)benzenesulfonamide

[0138] 1 equivalent of N-(2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)-3-nitrobenzenesulfonamide was dissolved in 10 mL / g of ethanol and 10 mL / g of tetrahydrofuran. 10 wt% of palladium / carbon was added, and the reaction was carried out by hydrogen substitution. The mixture was stirred at room temperature for 16 hours. After confirming the completion of the reaction, it was filtered through Celite. The filtrate was concentrated under reduced pressure, and the crude product obtained was purified by column chromatography and concentrated in vacuo to obtain 3-amino-N-(2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)benzenesulfonamide.

[0139] N-(2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)-3-(methylamino)benzenesulfonate 0Synthesis of white {N-(2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)-3-(methylamino)benzenesulfonamide}

[0140] 1 equivalent of 3-amino-N-(2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)benzenesulfonamide was dissolved in 10 mL / g of methanol. 1.5 equivalents of paraformaldehyde and 5 equivalents of sodium methoxide were added, and the mixture was refluxed with stirring for about 1 hour. 1 equivalent of sodium borohydride was added at 0 °C, and the mixture was stirred for about 30 minutes. After adding water, the organic layer was extracted using ethyl acetate and brine. The remaining moisture in the organic layer was completely removed with magnesium sulfate 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 N-(2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)-3-(methylamino)benzenesulfonamide.

[0141] Synthesis of N-(2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)-3-(3-(5-(3-fluorophenoxy)thiazol-2-yl)-1-methylureido)benzenesulfonamide One equivalent of phenyl(5-(3-fluorophenoxy)thiazol-2-yl)carbamate was dissolved in 10 mL / g of 1,4-dioxane. 1.5 equivalents of N-(2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)-3-(methylamino)benzenesulfonamide and 2 equivalents of N,N-diisopropylethylamine were added and stirred at 90°C for about 1 hour. After confirming the completion of the reaction, water was added and the organic layer was extracted using ethyl acetate and brine. The moisture remaining in the organic layer was completely removed with magnesium sulfate 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 N-(2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)-3-(3-(5-(3-fluorophenoxy)thiazol-2-yl)-1-methylureido)benzenesulfonamide.

[0142] 3-(3-(5-(3-fluorophenoxy)thiazol-2-yl)-1-methylureido)-N-(2-hydroxy— 2—methylpropyl)benzenesulfone 6}White} 0 Synthesis of 1-(3—(3—(5—(3—f luorophenoxy)thiazol—2—yl)—1—methylureido)—N—(2—hydroxy—2—methylpropyl)benzenesulfonamide) (Example 181)

[0143] 1 equivalent of N-(2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)-3-(3-(5-(3-fluorophenoxy)thiazol-2-yl)-1-methylureido)benzenesulfonamide in tetrahydrofuran

[0144] It was dissolved in 10 mL / g. 1.2 equivalents of tetrabutylammonium fluoride were added and the mixture was refluxed for about 1.5 hours. After confirming the completion of the reaction, water was added and the organic layer was extracted using ethyl acetate and brine. The remaining moisture in the organic layer was completely removed with magnesium sulfate 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, Example 181.

[0145] [Table 12] [Example 182]

[0146] Scheme 11

[0147] N—methyl [1, 1'—biphenyl]—3—a ■amine(N— methyl— [1, 1 1 — biphenyl ]~3~amine)(synthesis of 3-bromo-N-methylaniline, 1 equivalent of reactant J1, 2 equivalents of phenylboronic acid, 4 equivalents of potassium carbonate and 0.1 equivalent of palladium acetate were added to 50 mL / g of dimethylformamide and 50 mL / g of water. The resulting mixture was stirred under reflux for 16 hours. After confirming the completion of the reaction, the mixture was filtered through Celite with ethyl acetate, concentrated and extracted with ethyl acetate and water. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure and purified by column chromatography (hexane:ethyl acetate) to obtain N-methyl[1, 1'-biphenyl]-3-amine. Re 0}( 1—([ 1 , 1 1— bi pheny 1 ] — 3— y 1) — 3— ( 5— ( 3— f 1 uor ophenoxy) th i azo 1 — 2— y 1)— 1— methylurea)(Example 182) Synthesis of phenyl (5-(3 -fluorophenoxy)thiazol- 2 -yl)carbamate was dissolved in 10 mL / g of 1, 4-dioxane. 1.5 equivalents of N-methyl[1 , 1' -biphenyl] -3 -amine and 2 equivalents of N, N-diisopropylethylamine were added as reactant J2 and heated to 80°C. After completion of the reaction, the mixture was extracted with ethyl acetate and water. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified and separated by column chromatography (hexane:ethyl acetate) to obtain the title compound, Example 182.

[0148] [Example 183] Compound Example 183 was synthesized using reactants J1 and J2 of Table 13 instead of reactants J1 and J2 of the method for preparing compound Example 182 in substantially the same manner as described in the method for preparing compound Example 182 (Scheme 11). The structure, reactants JI, J2, and analytical data of compounds of Examples 182-183 are shown in Table 13.

[0149] [Table 13]

[0150] [Example 184]

[0151] Scheme 12

[0152] Synthesis of N—methyl-3—(prop— l—yn~!~y Dani line)

[0153] 3-Bromo-N-methylaniline 1 equivalent, cuprous iodide 0.1 equivalent, bis(triphenylphosphine)palladium chloride 0.1 equivalent, and triphenylphosphine 0.1 equivalent were dissolved in dimethylformamide 1.45 mL / g. After nitrogen replacement, 1.5 equivalents of triethylamine and 3 equivalents of propane were added. The resulting mixture was stirred under reflux for 16 hours. After confirming the completion of the reaction, the residue was filtered through Celite with ethyl acetate, concentrated, and extracted with ethyl acetate and water. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography (hexane:ethyl acetate) to obtain N-methyl-3-(prop-

[0154] 1-yn-1-yl)aniline was obtained. 3-(5-(3-fluorophenoxy)thiazol-2-yl)-1-methyl-1-(3-(prop-1-yn-1-yl)phenyl)urea 0} (3— (5— (3— f luorophenoxy)thiazol— 2— yl )—1— methyl— 1— (3— (prop— 1—yn— l— yl) phenyl) urea) (Example 184) Synthesis of 1 equivalent of phenyl (5- (3 -fluorophenoxy) thiazol- 2 -yl) carbamate was dissolved in 10 mL / g of 1,4-dioxane. 1.5 equivalents of N-methyl- 3- (prop- 1-yn- 1-yl) aniline and 2 equivalents of N, N-diisopropylethylamine were added and heated to 80°C. After completion of the reaction, the ethyl acetate layer was extracted with water. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified and separated by column chromatography (hexane: ethyl acetate) to give the title compound, Example 184 compound. Obtained. [Table 14]

[0155] [Reactants KI, K2]

[0156] Scheme 13 Synthesis of tert-butyl 4-(3-(methylamino)phenyl)- 3,6-dihydro(pyridine)- 1(2H)-carboxylate (reactant KI) 1 equivalent of 3-bromo-N-methylaniline, 1.2 equivalents of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 3,6-dihydro(pyridine)- 1(2H)-carboxylate, 4 equivalents of potassium carbonate and 0.1 equivalent of tetrakis(triphenylphosphine)palladium(0) were added to 1,4-dioxane 50 mL / g and 10 mL / g of water were added. The mixture was stirred under reflux for 16 hours. After confirming the completion of the reaction, the mixture was filtered through celite with ethyl acetate, concentrated, and extracted with ethyl acetate and water. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified and separated by column chromatography (hexane:ethyl acetate) to obtain tert-butyl 4-(3-(methylamino)phenyl)-3,6-dihydro(pyridine)-1(2H)-carboxylate. Tert-butyl 4-(3-(methylamino)phenyl)piperidine-1-carboxylate (tert-butyl

[0157] 4—(3—(methylamino)phenyl)piperidine—l— carboxylate) (Reactant K2) As a synthetic reactant, 1 equivalent of tert-butyl 4-(3-(methylamino)phenyl)- 3, 6-dihydro(pyridine)- 1(2H)-carboxylate was added to 10 mL / g of methanol, and 10 wt% of palladium / carbon was added to proceed with hydrogen substitution. The mixture was stirred at room temperature for 16 hours. After confirming the completion of the reaction, the mixture was filtered through celite with ethyl acetate, concentrated, and extracted with ethyl acetate and water. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography (hexane:ethyl acetate) to obtain tert-butyl 4-(3-(methylamino)phenyl) piperidine- 1-carboxylate.

[0158] [Example 185]

[0159] Scheme 14 Synthesis of tert-butyl 4-(3-(3-(5-(3-fluorophenoxy)thiazol-2-yl)-1-methylureido)phenyl)-3,6-dihydro(pyridine)-1(2H)-carboxylate One equivalent of phenyl (5-(3-fluorophenoxy)thiazol-2-yl)carbamate was dissolved in 10 mL / g of 1,4-dioxane. As reactant K1, 1.5 equivalents of tert-butyl 4-(3-(methylamino)phenyl)-3,6-dihydro(pyridine)-1(2H)-carboxylate and 2 equivalents of N,N-diisopropylethylamine were added and heated to 80°C. After completion of the reaction, the ethyl acetate layer and water were extracted. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography (hexane:ethyl acetate) to obtain tert-butyl 4-(3-(3-(5-(3-fluorophenoxy)thiazol-2-yl)-1-methylureido)phenyl)-3,6-dihydro(pyridine)-1(2H)-carboxylate.

[0160] 3-(5-(3-fluorophenoxy)thiazol-2-yl)-1-methyl-1-(3-(1,2,3,6-tetrahydropyridine—4—yl)phenyl)urea 0} Hydrochloride (1:1)(3—(5—(3—oh11101~013116110\7)111gog701—2—71 )— 1— methyl— 1—(3— ( 1 ,2,3 , 6— tetrahydropyr idin— 4— y 1 )pheny 1 )urea hydrochloride(l:l) )(Example 185) Synthesis of reactant K3, tert-butyl 4-(3-(3-(5-(3 -fluorophenoxy)thiazol-2 -yl)-1-methylureido)phenyl )- 3 , 6 -dihydro (pyridine)- 1(2H)-carboxylate, was added to 5 equivalents of 4 molar hydrochloric acid, and the mixture was stirred at room temperature for 16 hours. After confirming the completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent. Recrystallization was performed under hexane and tetrahydrofuran conditions to obtain the title compound, Example 185.

[0161] [Table 15]

[0162] [Example 186] Compound Example 186 was synthesized using reactant K2 of Table 16 instead of reactant K2 of the method for preparing compound Example 185 in substantially the same manner as described in the method for preparing compound Example 185 (S Company ieme 14).

[0163] [Table 16]

[0164] [Example 187]

[0165] 3-(5-(3-fluorophenoxy)thiazol-2-yl)-1-methyl-1-(3-(1,2, 3, 6-tetrahydropyridine— 4 —yl)phenyl)urea 0} (3— (5— (3— f luorophenoxy)thiazol— 2— yl)— 1— methyl— 1—

[0166] Synthesis of (3- (1,2,3,6-tetrahydropyridin- 4-yl)phenyl)urea) (Example 187) In Example 185, 1 equivalent of the compound 3- (5- (3 -fluorophenoxy)thiazol- 2 -yl) - 1-methyl- 1- (3- (1 , 2 , 3 , 6 -tetrahydropyridin- 4 -yl) phenyl) urea hydrochloride (1:1) was dissolved as a reactant in 50 mL / g of methylene chloride, and 50 mL / g of a saturated sodium bicarbonate solution was added. The mixture was stirred at room temperature for 16 hours. After confirming the completion of the reaction, water was added, and the organic layer was extracted using methylene chloride. The moisture remaining in the organic layer was completely removed with magnesium sulfate and then filtered. The crude product obtained by concentrating the filtrate under reduced pressure was purified and separated by column chromatography (hexane:ethyl acetate) to obtain the title compound, Example 187.

[0167] [Table 17]

[0168] [Example 188] Compound Example 188 was synthesized using the compound Example 186 of Table 18 instead of the compound Example 185, which is a reactant of the method for preparing compound Example 187, in a method substantially the same as that described in the method for preparing compound Example 187 (Scheme 15). [Table 18]

[0169] Scheme 16

[0170] Synthesis of N-methyl-3~(!~methyl-1,2,3,6—tetrahydropyridin-4—yl)aniline (N~methy!~3~(1— methyl— 1,2,3,6— tetrahydropyridin— 4— yl)aniline)

[0171] 1 equivalent of 3-iodo-N-methylaniline, 1.05 equivalents of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine, 3 equivalents of potassium carbonate, and 0.1 equivalent of tetrakis(triphenylphosphine)palladium(0) were added to 2 mL / g of 1,4-dioxane and 1 mL / g of water. The mixture was stirred under reflux for 16 hours. After confirming the completion of the reaction, the mixture was filtered through Celite with ethyl acetate, concentrated, and extracted with ethyl acetate and water. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified and separated by column chromatography (hexane:ethyl acetate) to obtain N-methyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)aniline.

[0172] Synthesis of 3-(5-(3-fluorophenoxy)thiazol-2-yl)carbamate (Example 189) 1 equivalent of phenyl (5-(3-fluorophenoxy)thiazol-2-yl)carbamate was dissolved in 10 mL / g of 1,4-dioxane and then N-methyl-3-(1-methyl- 1,2,3,6-tetrahydropyridin-4-yl)aniline 1.1 equivalents and N,N-diisopropylethylamine 2 equivalents were added, and the mixture was stirred at 80°C for 2 hours. After confirming the completion of the reaction, extraction was performed with ethyl acetate and water. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified and separated by column chromatography (hexane:ethyl acetate) to obtain the title compound, Example 189.

[0173] [Table 19]

[0174] [Example 190]

[0175] Scheme 17

[0176] Synthesis Example 25 of 3-(3-(5-(3-fluorophenoxy)thiazol-2-yl)-1-methylureido)benzoic acid (3-(3(5—(3—fluorophenoxy)thiazol—2—yl)—1—methylureido)benzoic acid) (Example 190) 1 equivalent of methyl 3-(3-(5-(3-fluorophenoxy)thiazol-2-yl)-1-methylureido)benzoate was dissolved in 50 mL / g of methanol, then 10 equivalents of sodium hydroxide was added, and the mixture was stirred at room temperature for 16 hours. After confirming the completion of the reaction, extraction was performed with ethyl acetate and water. Hydrochloric acid (1N) was added to the aqueous layer, and the obtained solid was filtered with water to obtain the compound of Example 190, the title compound. [Table 2

[0177] [Example 191] Scheme 18

[0178] Synthesis Example 25 of 3-(3-(5-(3-fluorophenoxy)thiazol-2-yl)-1-methylureido)benzamide (3—(3—(5—(3—fluorophenoxy)thiazol—2—yl)—1—methylureido)benzamide (Example 191) 1 equivalent of methyl 3-(3-(5-(3-fluorophenoxy)thiazol-2-yl)-1-methylureido)benzoate, which is the compound of Example 25, was added to 50 mL / g of saturated ammonium hydroxide solution, and the mixture was stirred at 60 °C for 12 hours. After confirming the completion of the reaction, extraction was performed with ethyl acetate and water. The ethyl acetate layer was dried over magnesium sulfate and then concentrated under reduced pressure, and purified and separated by column chromatography (methylene chloride:methanol) to obtain the compound of Example 191, the title compound. [Table 21 [Example 192]

[0179] Scheme 19

[0180] 3-(5-(3-fluorophenoxy)thiazol-2-yl)-1-methyl-1-(3-(morpholin-4-carbonyl)phenyl)urea 0} Synthesis of (3— (5— (3— f luorophenoxy)thiazol— 2— yl )—l—methyl—l—(3—(morphol ine—4— carbonyl )phenyl )urea) (Example 192) In Example 190, 1 equivalent of compound 3- (3- (5- (3 -fluorophenoxy)thiazol- 2 -yl )-1-methylureido)benzoic acid was dissolved in 10 mL / g of dimethylformamide, and then 2 equivalents of tetramethyluronium hexafluorophosphate azabenzotriazole and 3 equivalents of triethylamine were added, and stirred at room temperature for 5 minutes. 1.5 equivalents of morpholine as reactant L1 was added to the reaction mixture, and stirred for 3 hours. After confirming the completion of the reaction, extraction was performed with ethyl acetate and water. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified and separated by column chromatography (methylene chloride:methanol) to obtain the title compound, Example 192.

[0181] [Examples 193-194] Compounds of Examples 193-194 were synthesized in substantially the same manner as described in the preparation method of compound of Example 192 (Scheme 19), using reactant L1 of Table 22 instead of reactant L1 of the preparation method of compound of Example 192. The structures, reactant L1 and analytical data of compounds of Examples 192-194 are shown in Table 22.

[0182] [Table 22]

[0183] [Example 195] oh

[0184] Scheme 20

[0185] 3-(5-(3-Fluorophenoxy)thiazol-2-yl)-1-methyl-1-(3-nitrophenyl)urea(3 -

[0186] (5-(3-Fluorophenoxy)thiazol-2-yl)-1-methyl-1-(3-nitrophenyl)urea) synthesis Phenyl (5-(3-fluorophenoxy)thiazol-2-yl)carbamate (1 equivalent) was dissolved in 1,4-dioxane (10 mL / g), and then 2 equivalents of N-methyl-3-nitroaniline and 2 equivalents of N,N-diisopropylethylamine were added. The mixture was stirred at 80 °C for 2 hours. After confirming the completion of the reaction, it was extracted with ethyl acetate and water. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. It was purified and separated by column chromatography (hexane:ethyl acetate) to obtain 3-(5-(3-fluorophenoxy)thiazol-2-yl)-1-methyl-1-(3-nitrophenyl)urea.

[0187] Synthesis of 1-(3-Aminophenyl)-3-(5-(3-fluorophenoxy)thiazol-2-yl)-1-methylurea((3-aminophenyl)-3-(5-(3-fluorophenoxy)thiazol-2-yl)-1-methylurea)(Example 195)

[0188] 3-(5-(3-Fluorophenoxy)thiazol-2-yl)-1-methyl-1-(3-nitrophenyl)urea (1 equivalent) was dissolved in dimethylformamide (25 mL / g), and then 3 equivalents of tetrahydroxydiboron were added. 4,4-Dipyridine (0.05 equivalent) was dissolved in dimethylformamide (10 mL / g) and slowly added dropwise to the above solution at 0 °C, followed by stirring for 1 minute. After completion of the reaction, it was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. It was purified and separated by column chromatography (hexane:ethyl acetate) to obtain the title compound, the compound of Example 195.

[0189] [Table 23]

[0190] [Example 196]

[0191] N-(3-(3-(5-(3-fluorophenoxy)thiazol-2-yl)-1-methylureido)phenyl)cyclopropanesulfone 6 Synthesis of {White}ide (N— (3— (3— (5— (3— fluorophenoxy) thiazol-2-yl)-1-methylurea) (Example 196) As Example 195, 1 equivalent of 1-(3-aminophenyl)-3-(5-(3-fluorophenoxy)thiazol-2-yl)-1-methylurea was dissolved in 12 equivalents of pyridine, and then 1.2 equivalents of cyclopropanesulfonyl chloride (Ml of the reactant) were added, followed by stirring at 40°C for 16 hours. After completion of the reaction, the mixture was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The title compound, Example 196, was obtained through purification and separation by column chromatography (hexane:ethyl acetate). [Example 197] Compound Example 197 was synthesized in substantially the same manner as described in the method for preparing compound Example 196 (Scheme 20), using the reactant Ml of Table 24 instead of the reactant Ml of the method for preparing compound Example 196. The structures, reactant Ml, and analytical data of compounds of Examples 196-197 are shown in Table 24.

[0192] [Table 24] [Example 198]

[0193] Scheme 21

[0194] Synthesis of 3-(5-(3-fluorophenoxy)thiazol- 2-yl)-1-(3-hydroxyphenyl)-1-methylurea °}(3—(5—(3— f luorophenoxy)thiazol— 2— yl)—1—(3— hydroxyphenyl)—1— methylurea) One equivalent of phenyl (5-(3-fluorophenoxy)thiazol- 2-yl)carbamate was dissolved in 10 mL / g of 1,4-dioxane. 1.5 equivalents of 3-(methylamino)phenol and 2 equivalents of N,N-diisopropylethylamine were added, and the mixture was stirred at 90°C for about 1 hour. After confirming the completion of the reaction, water was added, and the organic layer was extracted using ethyl acetate and brine. The moisture remaining in the organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified and separated by column chromatography (hexane:ethyl acetate) to obtain 3-(5-(3-fluorophenoxy)thiazol-2-yl)-1-(3-hydroxyphenyl)-1-methylurea.

[0195] Synthesis of 3-(3-(5-(3-fluorophenoxy)thiazol-2-yl)-1-methylureido)phenyl 4-methylbenzenesulfonate (Example 198) Example 32 1 equivalent of 3-(5-(3-fluorophenoxy)thiazol-2-yl)-1-(3-hydroxyphenyl)-1-methylurea was dissolved in 10 mL / g of methylene chloride. 1.2 equivalents of 4-toluenesulfonyl chloride and 2 equivalents of triethylamine as reactant N1 were added, and the mixture was stirred at room temperature for about 1 hour. After confirming the completion of the reaction, the mixture was extracted with ethyl acetate and water. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified and separated by column chromatography (hexane:ethyl acetate) to obtain the title compound as Example 198 compound.

[0196] [Example 199] Compound Example 199 was synthesized in substantially the same manner as described in the method for preparing compound Example 198 (Scheme 21), using reactant N1 of Table 25 instead of reactant N1 of the method for preparing compound Example 198. The structures, reactant N1, and analytical data of compounds of Examples 198-199 are shown in Table 25.

[0197] [Table 25]

[0198] [Example 200] Scheme 22

[0199] N ' ~( (3- (3- (5- (3 -fluorophenoxy )thiazol- 2 -yl )-1 -methylureido)phenyl)sulfonyl)-dimethylformimidamide (N 1 - Synthesis of (3- (3- (5- (3-fluorophenoxy)thiazol- 2-yl)- 1— methyl thylure i do) phenyl )sulfonyl )— N,N— dimethylformimidamide) 1 equivalent of phenyl (5- (3 -fluorophenoxy)thiazol- 2 -yl)carbamate was dissolved in 10 mL / g of 1,4-dioxane, and then 1.2 equivalents of N,N-dimethyl- N' - ((3- (methylamino)phenyl )sulfonyl )formimidamide and 3 equivalents of N,N-diisopropylethylamine were added and stirred at 80°C for 2 hours. After completion of the reaction, the mixture was extracted with methylene chloride and water. The methylene chloride layer was dried over magnesium sulfate and concentrated under reduced pressure. Column chromatography (hexane:ethyl acetate) was used to purify and separate the residue, yielding N'-((3-(3-(5-(3-fluorophenoxy)thiazol-2-yl)-1-methylureido)phenyl)sulfonyl)-N,N-dimethylformimidamide.

[0200] Synthesis of 3-(3-(5-(3-fluorophenoxy)thiazol-2-yl)-1-methylureido)benzenesulfonamide (3—(3—(5—(3—f luorophenoxy)thiazol—2—yl)—1—methylureido)benzenesulfonamide) (Example 200)

[0201] N'-((3-(3-(5-(3-fluorophenoxy)thiazol-2-yl)-1-methylureido)phenyl)sulfonyl)-N,N-dimethylformimidamide 1 equivalent was dissolved in 15 mL / g of ethanol, 10 equivalents of hydrazine hydrate were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was extracted with ethyl acetate and water. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The title compound, Example 200, was obtained by recrystallization with diethyl ether and hexane.

[0202] [Table 26]

[0203] [Example 201]

[0204] Scheme 23

[0205] Synthesis of N—(3—fluorophenyl)oxetan— 3—amine (N—(3— f luorophenyl)oxetan— 3— amine) (Reactant 02)

[0206] 1 equivalent of 3-fluoroaniline was dissolved in 10 mL / g of methanol. 2.5 equivalents of oxetan-3-one and 2 equivalents of acetic acid were added to the reaction mixture at 0°C, and the mixture was stirred at room temperature for about 3 hours. After confirming that the starting material had disappeared, 2 equivalents of sodium cyanoborohydride were slowly added at 0°C, and the mixture was stirred at room temperature for 1 hour. The reaction was quenched using saturated sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate and water. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography (hexane:ethyl acetate) to obtain N-(3-fluorophenyl)oxetan-3-amine.

[0207] 3-(5-(3-fluorophenoxy)thiazole-2-yl)-1-(3-fluorophenyl)-1-(oxetan-3-yl)urea 0 Synthesis of {3—(5—(3— f luorophenoxy)thiazol— 2— yl)—1—(3— f luorophenyl)— 1—(oxetan— 3— yl)urea) (Example 201) One equivalent of phenyl (5-(3 -fluorophenoxy)thiazol- 2 -yl)carbamate was dissolved in 10 mL / g of 1, 4-dioxane. 1.5 equivalents of N-(3 -fluorophenyl)oxetan- 3 -amine and 2 equivalents of N, N-diisopropylethylamine were added to the reaction mixture, and the mixture was stirred at about 80°C for 2 hours. After confirming the completion of the reaction, the mixture was extracted with ethyl acetate and water. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified and separated by column chromatography (hexane: ethyl acetate) to obtain the title compound, Example 201. [Table 27]

[0208] [Example 202] Scheme 24

[0209] N—(cyclopropylmethyl)-1 3—fluoro 6}Synthesis of nyline (N~(cyclopropylmethy!)~3~ f luoroani 1 in)

[0210] 1 equivalent of 3-fluoroaniline was dissolved in 10 mL / g of methanol. 1.2 equivalents of cyclopropanecarbaldehyde and 1.5 equivalents of acetic acid were added, and the mixture was stirred at 0°C for about 1 hour. 1.5 equivalents of sodium borohydride were added to the reaction mixture, and the mixture was stirred at 0°C for about 1 hour. After confirming the completion of the reaction, the mixture was extracted with ethyl acetate and brine. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography (hexane:ethyl acetate) to obtain N-(cyclopropylmethyl)-3-fluoroaniline. 1-(Cyclopropylmethyl)-3-(5-(3-fluorophenoxy)thiazol-2-yl)-1-(3-fluorophenyl)urea 0} Synthesis of (1—(cyclopropylmethyl)— 3—(5—(3— f luorophenoxy)thiazol— 2— yl)— 1-(3- f luorophenyl)urea)(Example 202) One equivalent of phenyl (5-(3 -fluorophenoxy)thiazol- 2 -yl)carbamate was dissolved in 10 mL / g of 1, 4-dioxane. N-(cyclopropylmethyl)- 3 -fluoroaniline was added to the reaction mixture.

[0211] 1.5 equivalents of N,N-diisopropylethylamine and 2 equivalents of N,N-diisopropylethylamine were added, and the mixture was stirred at about 90°C for 1 hour. After confirming the completion of the reaction, extraction was performed with ethyl acetate and brine. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified and separated by column chromatography (hexane:ethyl acetate) to obtain the title compound, Example 202.

[0212] [Table 28]

[0213] [Example 203]

[0214] Scheme 25

[0215] Synthesis of 3—fluoro— N—(2—methoxyethyl)aniline(3— f luoro— N—(2— methoxyethyl)ani 1 in)(reactant 02)

[0216] 3-Fluoroaniline 1 equivalent was dissolved in 10 mL / g of dimethylformamide. 1.2 equivalents of 1-bromo-2-methoxyethane and 2.5 equivalents of potassium carbonate as reactant 01 were added, and the mixture was stirred under reflux for about 24 hours. After confirming the completion of the reaction, extraction was performed with ethyl acetate and brine. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified and separated by column chromatography (hexane:ethyl acetate) to obtain 3-fluoro-N-(2-methoxyethyl)aniline.

[0217] 3-(5-(3-fluorophenoxy)thiazol-2-yl)-1-(3-fluorophenyl)-1-(2-methoxyethyl)urea 0 Synthesis of {3—(5—(3— f luorophenoxy)thiazol— 2— yl)—1—(3— f luorophenyl)— 1—(2— methoxyethyl) urea) (Example 203) 1 equivalent of phenyl (5-(3 -fluorophenoxy)thiazol- 2 -yl) carbamate was dissolved in 10 mL / g of 1, 4 -dioxane. 1.5 equivalents of 3 -fluoro- N -(2 -methoxyethyl) aniline and 2 equivalents of N , N -diisopropylethylamine as reactant 02 were added, and the mixture was stirred at 80°C for about 1 hour. After confirming the completion of the reaction, the mixture was extracted with ethyl acetate and water. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified and separated by column chromatography (hexane:ethyl acetate) to obtain the title compound as Example 203 compound.

[0218] [Example 204] Compound Example 204 was synthesized using reactants 01 and 02 of Table 29 instead of reactants 01 and 02 of the method for preparing compound Example 203 in substantially the same manner as described in the method for preparing compound Example 203 (Scheme 25). The structure, reactants 01, 02, and analytical data of compounds of Examples 203-204 are shown in Table 29.

[0219] [Table 29]

[0220] [Example 205]

[0221] Scheme 26 Synthesis of methyl 2-amino-5-(3-fluorophenoxy)thiazole-4-carboxylate

[0222] 3-1 equivalent of fluorophenol was dissolved in 10 mL / g of tetrahydrofuran. 1.5 equivalents of sodium hydride were slowly added to the reaction mixture at 0°C and stirred for about 20 minutes. 1 equivalent of methyl 2-amino-5-bromothiazole-4-carboxylate was added as reactant P1 and stirred for about 1 hour at 0°C. After confirming the completion of the reaction, water was slowly added at 0°C. Extraction was performed with ethyl acetate and water. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified and separated by column chromatography (hexane:ethyl acetate) to obtain methyl 2-amino-5-(3-fluorophenoxy)thiazole-4-carboxylate. Synthesis of methyl 5-(3-fluorophenoxy)-2-((phenoxycarbonyl)amino)thiazole-4-carboxylate (methyl 5—(3— f 1 uor ophenoxy) — 2 —((phenoxycarbonyl 1) am i no) th i azo 1 e— 4— carboxylate) 1 equivalent of methyl 2-amino- 5-(3-fluorophenoxy)thiazole-4-carboxylate was dissolved in 10 mL / g of tetrahydrofuran. 1.2 equivalents of phenyl chloroformate and 1.5 equivalents of triethylamine 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, the mixture was extracted with ethyl acetate and water.The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified and separated by column chromatography (hexane:ethyl acetate) to obtain methyl 5-(3-fluorophenoxy)-2-((phenoxycarbonyl)amino)thiazole-4-carboxylate. Synthesis of methyl 5-(3-fluorophenoxy)-2-(3-(3-fluorophenyl)-3-methylureido)thiazole— 4—carboxylate (Example 205) One equivalent of methyl 5-(3-fluorophenoxy)-2-((phenoxycarbonyl)amino)thiazole- 4-carboxylate was added to 1, 4-dioxane 10 mL / g. Dissolved. 1.5 equivalents of 3-fluoro-N-methylaniline and 2 equivalents of N,N-diisopropylethylamine were added as reactant P2, and stirred at 90°C for about 1 hour. After confirming the completion of the reaction, extraction was performed with ethyl acetate and brine. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified and separated by column chromatography (hexane:ethyl acetate) to obtain the title compound, Example 205.

[0223] [Examples 206-210] Compounds of Examples 206-210 were synthesized in substantially the same manner as described in the preparation method of compound of Example 205 (Scheme 26), using reactants P1 and P2 of Table 30 instead of reactants P1 and P2 of the preparation method of compound of Example 205. The structures, reactants Pl, P2, and analytical data of compounds of Examples 205-210 are shown in Table 30.

[0224] [Table 3

[0225] [Example 211]

[0226] Scheme 27 N 5-(3-fluorophenyl)- N 5 -Methylthiazole- 2, 5-diamine(N 5 -(3- f luorophenyl)-

[0227] N 5 — methyl thiazole— 2,5— di amine)As a synthetic reactant QI, 1.3 equivalents of 3-fluoro-N-methylaniline was dissolved in 30 mL / g of acetonitrile, and 2 equivalents of cesium carbonate were added at room temperature. After stirring for 10 minutes, 1 equivalent of 5-bromothiazol-2-amine was added and stirred at 65°C for 12 hours. After completion of the reaction, the mixture was filtered through Celite with acetone, concentrated, and extracted with ethyl acetate and water. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography.

[0228] (Hexane:ethyl acetate) Purification and separation N 5 -(3-fluorophenyl)- N 5 -Methylthiazole-

[0229] 2, 5-diamine was obtained. Synthesis of phenyl (5-((3-fluorophenyl)(methyl)amino)thiazol-2-yl)carbamate (phenyl (5-((3-f luorophenyl)(methyl)amino)thiazol-2-yl)carbamate) N 5 -(3-fluorophenyl)- N 5 -Methylthiazole- 2,5-diamine 1 equivalent was dissolved in 10 mL / g of tetrahydrofuran, 1.5 equivalents of triethylamine were added, and the mixture was stirred at 0°C for 10 minutes. 1.2 equivalents of phenyl chloroformate were slowly added, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the mixture was extracted with methylene chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified and separated by column chromatography (hexane:ethyl acetate) to obtain phenyl (5-((3-fluorophenyl)(methyl)amino)thiazol-2-yl)carbamate.

[0230] Synthesis of 1-(3-fluorophenyl)-3-(5-((3-fluorophenyl)(methyl)amino)thiazol-2-yl)-]-methylurea (1-(3- f luorophenyl)-3-(5-((3- f luorophenyl)(methyl)amino) thiazol-2-yl)-1- methylurea) (Example 211) After dissolving 1 equivalent of phenyl (5-((3-fluorophenyl)(methyl)amino)thiazol-2-yl)carbamate in 10 mL / g of 1,4-dioxane, 1.5 equivalents of 3-fluoro-N-methylaniline and 2 equivalents of N,N-diisopropylethylamine as reactant Q2 were added, and the mixture was stirred at 80°C for 2 hours. After confirming the completion of the reaction, the mixture was extracted with ethyl acetate and water. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified and separated by column chromatography (hexane:ethyl acetate) to obtain the title compound, Example 211.

[0231] [Example 212] Compound Example 212 was synthesized in substantially the same manner as described in the preparation method for compound Example 211 (Scheme 27), using reactants Q1 and Q2 of Table 31 instead of reactants Q1 and Q2 of the preparation method for compound Example 211. The structures, reactants QI, Q2, and analytical data of compounds of Examples 211-212 are shown in Table 31.

[0232] [Table 31] [Example 213]

[0233] Scheme 28 Synthesis of ethyl (5-(4-fluorophenoxy)thiazol-2-yl)carbamate 1 equivalent of 5-(4-fluorophenoxy)thiazol-2-amine was dissolved in 10 mL / g of tetrahydrofuran, 1.5 equivalents of pyridine were added at room temperature, and the mixture was stirred for 10 minutes. 1.2 equivalents of ethyl chloroformate were slowly added, and the mixture was stirred for 1 hour at room temperature. After completion of the reaction, the mixture was concentrated under reduced pressure. The concentrated material was purified by column chromatography (hexane:ethyl acetate) to obtain ethyl (5-(4-fluorophenoxy)thiazol-2-yl)carbamate. Synthesis of 3-(5-(4-fluorophenoxy)thiazol-2-yl)-1-(3-fluorophenyl)-1-methylurea (3—(5—(4—f luorophenoxy)thiazol— 2— yl)—1—(3—f luorophenyl)—1— methylurea) (Example 213) After dissolving 1 equivalent of ethyl (5-(4-fluorophenoxy)thiazol-2-yl)carbamate in 10 mL / g of 1,4-dioxane, 2 equivalents of 3-fluoro-N-methylaniline as reactant R1 were added, and the mixture was stirred in a microwave at 130°C for 30 minutes. After completion of the reaction, it was concentrated under reduced pressure. The concentrated material was purified and separated by column chromatography (hexane:ethyl acetate) to obtain the title compound, Example 213. [Example 214] Compound Example 214 was synthesized in substantially the same manner as described in the method for preparing compound Example 213 (Scheme 28), using reactant R1 of Table 32 instead of reactant R1 of the method for preparing compound Example 213. The structure, reactant R1, and analytical data of compounds of Examples 213-214 are shown in Table 32.

[0234] [Table 32]

[0235] [Example 215]

[0236] Scheme 29 Synthesis of phenyl (5-(4-fluorophenoxy)thiazol-2-yl)carbamate

[0237] 1 equivalent of 5-(4-fluorophenoxy)thiazol-2-amine was dissolved in 10 mL / g of tetrahydrofuran, 1.5 equivalents of pyridine were added at room temperature, and the mixture was stirred for 10 minutes. 1.2 equivalents of phenyl chloroformate were slowly added, and the mixture was stirred for 4 hours at room temperature. After confirming the completion of the reaction, water was added, and the organic layer was extracted using ethyl acetate and tetrahydrofuran. The moisture remaining in the organic layer was removed with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (hexane: ethyl acetate) to obtain phenyl (5-(4-fluorophenoxy)thiazol-2-yl)carbamate.

[0238] 1~(3-cyanophenyl)-3—(5—(4—fluorophenoxy)thiazole-1 2—yl)~!~methylurea °} (1—(3— cyanopheny 1) — 3—(5—(4— f 1 uor ophenoxy) thi azo 1 — 2— y 1) — 1— me t hy 1 ur ea) (Example 215) Synthesis of phenyl (5-(4-fluorophenoxy)thiazol-2-yl)carbamate and 2 equivalents of N, N-diisopropylethylamine were dissolved in 10 mL / g of 1, 4-dioxane, and 1.5 equivalents of 3-(methylamino)benzonitrile as reactant S1 were added, followed by stirring at 80°C for 18 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The above-mentioned concentrated material was purified and separated by column chromatography (hexane:ethyl acetate) to obtain the title compound, Example 215 compound. [Examples 216-219] In substantially the same manner as described in the preparation method of Example 215 compound (Scheme 29), the compounds of Examples 216-219 were synthesized using the reactant S1 of Table 33 instead of the reactant S1 of the preparation method of Example 215 compound. The structures, reactant S1, and analytical data of the compounds of Examples 215-219 are shown in Table 33.

[0239] [Table 33] [Example 220] Scheme 30 Synthesis of phenyl (5-(4-fluorophenoxy)thiazol-2-yl)carbamate

[0240] 5-(4-fluorophenoxy)thiazol-2-amine was dissolved in 10 mL / g of tetrahydrofuran, 1.5 equivalents of triethylamine was added, and the temperature was lowered to 0°C. 1.2 equivalents of phenyl chloroformate was slowly added, the temperature was slowly raised to room temperature, and the mixture was stirred for 4 hours. After completion of the reaction, the mixture was extracted with ethyl acetate and water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified and separated by column chromatography (hexane:ethyl acetate) to obtain phenyl (5-(4-fluorophenoxy)thiazol-2-yl)carbamate.

[0241] Synthesis of 3-(5-(4-fluorophenoxy)thiazol-2-yl)-1-methyl-1-(3-nitrophenyl)urea (3-(5-(4-f 1 uor ophenoxy) thi azo 1-2-y 1)-1-methyl-1-(3-nitrophenyl)urea) (Example 220) One equivalent of phenyl (5-(4-fluorophenoxy)thiazol-2-yl)carbamate was dissolved in 10 mL / g of 1,4-dioxane. 1.5 equivalents of N-methyl-3-nitroaniline and 2 equivalents of N,N-diisopropylethylamine were added as reactant T1 and heated to 80°C. After completion of the reaction, the ethyl acetate layer was extracted with water. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified and separated by column chromatography (hexane:ethyl acetate) to obtain the title compound, Example 220.

[0242] [Examples 221-224] Compounds of Examples 221-224 were synthesized in substantially the same manner as described in the preparation method of compound of Example 220 (Scheme 30), using reactant T1 of Table 34 instead of reactant T1 of the preparation method of compound of Example 220. The structures, reactant T1, and analytical data of compounds of Examples 220-224 are shown in Table 34.

[0243] [Table 34]

[0244] [Example 225] NH2CS2CO3NH2

[0245] QOH + Br 心 “liT 0* 아

[0246] F F

[0247] Scheme 31

[0248] As the synthesis reaction product U1 of 5-(2-fluorophenoxy)thiazol-2-amine (5-(2-fluorophenoxy)thiazol-2-amine), 1.3 equivalents of 2-fluorophenol was dissolved in 10 mL / g of acetonitrile, and then 1.5 equivalents of cesium carbonate was added. After stirring for 10 minutes, 1 equivalent of 5-bromothiazol-2-amine was added and heated at 55 °C for 15 hours. After completion of the reaction, it was filtered through celite with acetonitrile and then extracted with ethyl acetate and water. The ethyl acetate layer was dried over magnesium sulfate and then concentrated under reduced pressure, and purified and separated by column chromatography (hexane:ethyl acetate) to obtain 5-(2-fluorophenoxy)thiazol-2-amine. Synthesis of phenyl (5-(2-fluorophenoxy)thiazol-2-yl)carbamate

[0249] 5-(2-fluorophenoxy)thiazol-2-amine was dissolved in 10 mL / g of tetrahydrofuran, 1.5 equivalents of triethylamine was added, and then the temperature was lowered to 0 °C. 1.2 equivalents of phenyl chloroformate was slowly added, and then slowly warmed to room temperature and stirred for 4 hours. After completion of the reaction, it was extracted with ethyl acetate and water, dried over magnesium sulfate, and then concentrated under reduced pressure. It was purified and separated by column chromatography (hexane:ethyl acetate) to obtain phenyl (5-(2-fluorophenoxy)thiazol-2-yl)carbamate.

[0250] Synthesis of 3-(5-(2-fluorophenoxy)thiazol-2-yl)-1-(3-fluorophenyl)_j-methylurea (3—(5—(2— f luorophenoxy)thiazol— 2— yl)—1—(3— f luorophenyl )—1— methylurea) (Example 225) 1 equivalent of phenyl (5-(2-fluorophenoxy)thiazol-2-yl)carbamate was dissolved in 10 mL / g of 1,4-dioxane. 1.5 equivalents of 3-fluoro-N-methylaniline and 2 equivalents of N,N-diisopropylethylamine were added to reactant U2 and heated to 80°C. After completion of the reaction, the mixture was extracted with ethyl acetate and water. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified and separated by column chromatography (hexane:ethyl acetate) to obtain the title compound, Example 225. [Examples 226-325] In substantially the same manner as described in the preparation method for Example 225 compound (Scheme 31), the compounds of Examples 226-325 were synthesized using the reactants U1 and U2 of Table 35 instead of the reactants U1 and U2 of the preparation method for Example 225 compound. The structures, reactants Ul, U2, and analytical data of the compounds of Examples 225-325 are shown in Table 35.

[0251] [Table 35]

[0252] [Example 326]

[0253] Scheme 32 Synthesis of ethyl (5-(3-chlorophenoxy)thiazol-2-yl)carbamate

[0254] 1 equivalent of 5-(3-chlorophenoxy)thiazol-2-amine was dissolved in 10 mL / g of tetrahydrofuran, 1.5 equivalents of ethyl chloroformate were slowly added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The concentrated material was purified and separated by column chromatography (hexane:ethyl acetate) to obtain ethyl (5-(3-chlorophenoxy)thiazol-2-yl)carbamate.

[0255] Synthesis of 3-(5-(3 -chlorophenoxy)thiazol-2-yl)-1-(3 -fluorophenyl)-1-methylurea(3-(5—(3— chlorophenoxy)thiazol—2— yl)—1—(3— f luorophenyl)—1— methylurea)(Example 326) After dissolving 1 equivalent of ethyl (5-(3 -chlorophenoxy)thiazol-2-yl)carbamate in 10 mL / g of 1,4-dioxane, 2 equivalents of 3-fluoro-N-methylaniline as reactant VI were added, and the mixture was stirred in a microwave at 130°C for 1 hour. After completion of the reaction, it was concentrated under reduced pressure. The concentrated material was purified by column chromatography (hexane:ethyl acetate) to obtain the title compound, Example 326.

[0256] [Examples 327-328] Compounds of Examples 327-328 were synthesized in substantially the same manner as described in the preparation method of compound of Example 326 (Scheme 32), using reactant VI of Table 36 instead of reactant VI of the preparation method of compound of Example 326. The structures, reactant VI, and analytical data of compounds of Examples 326-328 are shown in Table 36.

[0257] [Table 36]

[0258] [Example 329]

[0259] Scheme 33 Synthesis of 5—(3—chlorophenoxy)thiazol— 2—amine As the reactant W1, 1.3 equivalents of 3-chlorophenol were dissolved in 30 mL / g of acetonitrile, and 2 equivalents of cesium carbonate were added. After stirring for 10 minutes, 1 equivalent of 5-bromothiazol- 2-amine was added and heated at 65°C for 12 hours. After completion of the reaction, the mixture was filtered through celite with acetonitrile, concentrated, and extracted with ethyl acetate and water. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography (hexane:ethyl acetate) to obtain 5-(3-chlorophenoxy)thiazol- 2-amine. Synthesis of phenyl (5-(3-chlorophenoxy)thiazol-2-yl)carbamate

[0260] 1 equivalent of 5-(3-chlorophenoxy)thiazol-2-amine was dissolved in 10 mL / g of tetrahydrofuran, 1.5 equivalents of triethylamine were added, and the temperature was lowered to 0°C. 1.2 equivalents of phenyl chloroformate were slowly added, the temperature was slowly raised to room temperature, and the mixture was stirred for 4 hours. After completion of the reaction, the mixture was extracted with methylene chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate) to obtain phenyl (5-(3-chlorophenoxy)thiazol-2-yl)carbamate.

[0261] Synthesis of 3-(3-(5-(3-chlorophenoxy)thiazol-2-yl)-1-methylureido)-N,N-dimethylbenzenesulfonamide (3-(3-(5-(3-chlorophenoxy)thiazol-2-yl)-1-methylureido)-』V,』¥" dimethylbenzenesulfonamide) (Example 329) 1 equivalent of phenyl (5-(3-chlorophenoxy)thiazol-2-yl)carbamate and 2 equivalents of N,N-diisopropylethylamine were dissolved in 10 mL / g of 1,4-dioxane, and then 1.5 equivalents of N,N-dimethyl-3-(methylamino)benzenesulfonamide as reactant W2 was added, and stirred at 80 °C for 18 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The concentrated material was purified by column chromatography. The title compound, Example 329, was obtained by purification and separation using chromatography (hexane:ethyl acetate).

[0262] [Examples 330-342] Compounds of Examples 330-342 were synthesized in substantially the same manner as described in the preparation method of compound of Example 329 (Scheme 33), using reactants W1 and W2 of Table 37 instead of reactants W1 and W2 of the preparation method of compound of Example 329. The structures, reactants W1, W2, and analytical data of compounds of Examples 329-342 are shown in Table 37.

[0263] [Table 37] [Example 343]

[0264] Scheme 34

[0265] Synthesis of 4-((2-(3-(3-fluorophenyl)-3-methyluredo)thiazol-5-yl)oxy)benzoic acid (Example 343) In Example 268, 1 equivalent of ethyl 4-((2-(3-(3-fluorophenyl)-3-methylureido)thiazol-5-yl)oxy)benzoate was dissolved in 50 mL / g of methanol, 10 equivalents of sodium hydroxide were added, and the mixture was stirred at room temperature for 4 hours. After confirming the completion of the reaction, the organic layer was removed using ethyl acetate and water, and the solid obtained by adding hydrochloric acid (1N) in water and filtering it with water was obtained to obtain the title compound, Example 343.

[0266] [Table 38]

[0267] [Example 344]

[0268] Scheme 35 Synthesis of phenyl (3-(4-fluorophenoxy)-1,2,4-thiadiazol-5-yl)carbamate As reactant XI, 1 equivalent of 3-(4-fluorophenoxy)-1,2,4-thiadiazol-5-yl)carbamate was dissolved in 10 mL / g of tetrahydrofuran. 1.2 equivalents of phenyl chloroformate and 1.5 equivalents of triethylamine 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, the mixture was extracted with ethyl acetate and water. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified and separated by column chromatography (hexane:ethyl acetate) to obtain phenyl (3-(4-fluorophenoxy)-1,2,4-thiadiazole-5-yl)carbamate. Synthesis of methylurea (3-(3-(4-f 1 fluorophenoxy)-1,2,4-1 hi ad i azo 1-5-yl)-l-(3-fluorophenyl)-1-methylurea) (Example 344) 1 equivalent of phenyl (3-(4-fluorophenoxy)-1,2,4-thiadiazol-5-yl)carbamate was dissolved in 10 mL / g of 1,4-dioxane. 1.5 equivalents of 3-fluoro-N-methylaniline and 2 equivalents of N,N-diisopropylethylamine as reactant X2 were added, and the mixture was stirred at 90°C for about 1 hour. After confirming the completion of the reaction, the mixture was extracted with ethyl acetate and water. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified and separated by column chromatography (hexane:ethyl acetate) to obtain the title compound, Example 344.

[0269] [Examples 345-350] Compounds of Examples 345-350 were synthesized in substantially the same manner as described in the preparation method of compound of Example 344 (Scheme 35), using reactants XI and X2 of Table 39 instead of reactants XI and X2 of the preparation method of compound of Example 344. The structures, reactants XI, X2 and analytical data of compounds of Examples 344-350 are shown in Table 39.

[0270] [Table 39]

[0271] [Example 351]

[0272] Scheme 36 Synthesis of phenyl (2-(3-fluorophenoxy)thiazol-5-yl)carbamate As reactant Y1, 1 equivalent of 2-(3-fluorophenoxy)thiazol-5-amine was dissolved in 10 mL / g of tetrahydrofuran, 1.5 equivalents of triethylamine were added, and the temperature was lowered to 0°C. 1.2 equivalents of phenyl chloroformate were slowly added, the temperature was slowly raised to room temperature, and the mixture was stirred for 4 hours. After completion of the reaction, the mixture was extracted with ethyl acetate and water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified and separated by column chromatography (hexane:ethyl acetate) to obtain phenyl (2-(3-fluorophenoxy)thiazol-5-yl)carbamate.

[0273] 1-(3-Cyclopropylphenyl)-3-(2-(3-fluorophenoxy)thiazol-5-yl)-1 Methyl urea 0} (1—( 3— eye 1 opr opy 1 pheny 1 ) — 3— ( 2— ( 3— f 1 uor ophenoxy ) thi azo 1 — 5— y 1 )—1— methylurea) (Example 351) Synthesis of phenyl (2- (3 -fluorophenoxy )thiazol- 5 -yl )carbamate was dissolved in 10 mL / g of 1, 4 -dioxane. 1.5 equivalents of 3 -cyclopropyl- N -methylaniline and 2 equivalents of N, N -diisopropylethylamine as reactant Y2 were added and heated to 80°C. After completion of the reaction, the mixture was extracted with ethyl acetate and water. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified and separated by column chromatography (hexane:ethyl acetate) to obtain the title compound, Example 351.

[0274] [Examples 352-362] Compounds of Examples 352-362 were synthesized in substantially the same manner as described in the method for preparing compound of Example 351 (Scheme 36), using reactants Y1 and Y2 of Table 40 instead of reactants Y1 and Y2 of the method for preparing compound of Example 351. The structures, reactants Y1, Y2, and analytical data of compounds of Examples 351-362 are shown in Table 40.

[0275] [Table 4

[0276] [Example 363]

[0277] Scheme 37 Synthesis of 6-aminochroman-4-ol 1 equivalent of 6-nitrochroman-4-one was dissolved in 5 mL / g of ethanol and 5 mL / g of tetrahydrofuran. 10 wt% of palladium / carbon was added, and the reaction was carried out by hydrogen substitution. The reaction mixture was stirred at room temperature for 6 hours. After confirming the completion of the reaction, it was filtered through Celite. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography and concentrated in vacuo to obtain 6-aminochroman-4-ol.

[0278] Synthesis of 6-(methylamino)chroman-4-ol

[0279] 1 equivalent of 6-aminochroman-4-ol was dissolved in 10 mL / g of methanol. 1.5 equivalents of paraformaldehyde and 5 equivalents of sodium methoxide were added, and the mixture was refluxed and stirred for about 1 hour. 1 equivalent of sodium borohydride was added at 0°C, and the mixture was stirred for about 30 minutes. After adding water, the organic layer was extracted using ethyl acetate and brine. The moisture remaining in the organic layer was completely removed with magnesium sulfate, and then filtered. The moisture remaining in the organic layer was completely removed with magnesium sulfate, 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 6-(methylamino)chroman-4-ol.

[0280] 3-(5-(3-fluorophenoxy)thiazole-2-yl)-1-(4-hydroxychroman-6-yl)-1-methylurea 0}( 3—( 5—( 3— f 1 uor ophenoxy)thiazol— 2— yl)— 1—( 4— hydr oxychr oman— 6— y 1)— 1— methylurea) (Example 363) Synthesis of phenyl (5-(3 -fluorophenoxy)thiazol- 2 -yl)carbamate was dissolved in 10 mL / g of 1, 4 -dioxane. 1.5 equivalents of 6-(methylamino)chroman- 4 -ol and 2 equivalents of N,N-diisopropylethylamine were added, and the mixture was stirred at 90°C for about 1 hour. After confirming the completion of the reaction, water was added, and the organic layer was extracted using ethyl acetate and brine. The moisture remaining in the organic layer was completely removed with magnesium sulfate, 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, Example 363.

[0281] [Table 41]

[0282] [Example 364]

[0283] Scheme 38

[0284] Synthesis of N-(2, 2 ■difluoroethyl)-3 ■nitrobenzenesulfonamide (N-(2, 2 - dif luoroethy! )—3— nitrobenzenesulfonamide)

[0285] 3-Nitrobenzenesulfonyl chloride 1 equivalent was dissolved in 10 mL / g of methylene chloride. 1.2 equivalents of 2,2-difluoroethane-1-amine and 3 equivalents of triethylamine were added at 0°C and stirred. After confirming the completion of the reaction, water was added and the organic layer was extracted using methylene chloride and brine. The remaining moisture in the organic layer was completely removed with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude product obtained was purified by column chromatography and concentrated in vacuo to obtain N-(2,2-difluoroethyl)-3-nitrobenzenesulfonamide. Synthesis of 3-amino-N-(2,2-difluoroethyl)benzenesulfonamide

[0286] 1 equivalent of N-(2,2-difluoroethyl)-3-nitrobenzenesulfonamide was dissolved in 5 mL / g of ethanol and 5 mL / g of tetrahydrofuran. 10 wt% of palladium / carbon was added, and the reaction was carried out by hydrogen substitution. The reaction mixture was stirred at room temperature for 8 hours. After confirming the completion of the reaction, it was filtered through Celite. The filtrate was concentrated under reduced pressure, and the crude product obtained was purified by column chromatography and concentrated in vacuo to obtain 3-amino-N-(2,2-difluoroethyl)benzenesulfonamide.

[0287] Synthesis of N-(2, 2-difluoroethyl)-3-(methylamino)benzenesulfonamide

[0288] 1 equivalent of 3-amino-N-(2,2-difluoroethyl)benzenesulfonamide was dissolved in 10 mL / g of methanol. 1.5 equivalents of paraformaldehyde and 5 equivalents of sodium methoxide were added, and the mixture was refluxed and stirred for about 1 hour. 1 equivalent of sodium borohydride was added at 0°C, and the mixture was stirred for about 30 minutes. After adding water, the organic layer was extracted using ethyl acetate and brine. The moisture remaining in the organic layer was completely removed with magnesium sulfate, and then filtered. The moisture remaining in the organic layer was completely removed with magnesium sulfate, 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 N-(2,2-difluoroethyl)-3-(methylamino)benzenesulfonamide.

[0289] Synthesis of N~(2,2-difluoroethyl)-3-(3-(5-(3-fluorophenoxy)thiazol- 2-yl)-1-methyl ureido)benzenesulfonamide (N-(2,2-di f luoroethyl)-3-(3-(5-(3- f 1 fluorophenoxy)thiazol— 2— yl)— l~me t hy 1 ur ei do) benzene su 1 f onam i de) (Example 364) One equivalent of phenyl (5-(3-fluorophenoxy)thiazol- 2 -yl)carbamate was dissolved in 10 mL / g of 1,4-dioxane. 1.5 equivalents of N-(2,2-difluoroethyl)-3-(methylamino)benzenesulfonamide and 2 equivalents of N,N-diisopropylethylamine were added and stirred at 90°C for about 1 hour. After confirming the completion of the reaction, water was added and the organic layer was extracted using ethyl acetate and brine. The moisture remaining in the organic layer was completely removed with magnesium sulfate 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 Example 364.

[0290] [Table 42]

[0291] <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 (DMSO) was serially diluted in a 1:3 ratio and diluted in the assay buffer included in the IP-one Gq kit (IP-one Gq kit (Cisbio; 62IPAPEB)) to prepare a total of 10 dilutions (from 1 nM to 30 μM). The final DMSO concentration of each dilution was 0.3%, and an equal amount of DMSO 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 37 °C, 5% CO2 cell culture incubator.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 IC5o value was calculated using GraphPad Prism 10. The results of Experimental Example 1 are shown in Table 43 below, and in Table 43, A, B, and C each represent the following.

[0292] A: IC5o < 500 nM, B: 500 nM < IC5o < 1 uM, C: 1 uM < IC5o < 3 uM,

[0293] [Table 43] 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 DMSO 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 uM. 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 44 below, and in Table 44, A, B, and C each represent the following.

[0294] A: IC5o < 500 nM, B: 500 nM < IC5o < luM, C: 1 uM < IC5o < 3 uM

[0295] [Table 44] The superior efficacy of the present compound was confirmed through the IP-one assay and the Calcium mobi 1 izat ion assay of the above Experimental Examples 1 and 2. In addition, the present compound was confirmed to have superior physical properties and low toxicity in ADMET (metabolic stability, PK, CYP, hERG).

Claims

【Scope of Claims】 【 Claim 11 A compound represented by the following formula I or formula II, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: <화학식 1> In formula I, Ra \느、 Rc k 人 z A is Rb' ? (Ra, Rb and Rc are each independently H, halogen, CN, -N02, C1-C6 alkyl, C1-C6 haloalkyl, -O-(C1-C6 alkyl), -C(=O)-OH, -C(=O)-(C1-C6 alkyl), -C(=0)-0-(Cl-C6 alkyl), -N(C1-C6 alkyl)(Cl- C6 alkyl) or C3-C12 cycloalkyl), and Re are each independently H or halogen), R2 is H or halogen; in each of formula I and formula II, Li is -(CH2)X- (x is an integer from 1 to 3), -O-, -N(Rg)- (Rg is H or C1- C6 alkyl) or -O-(CH2)y- (y is an integer from 1 to 3), Rs and R4 are each a functional group defined below, or are connected to each other to form a ring group containing at least 1 ring, R3 is H, C1-C6 alkyl or 3- to 12-membered heterocycloalkyl containing one or more heteroatoms selected from N, 0 and S, wherein one or more of the C1-C6 alkyl groups may be independently substituted with OH, CN, -0-CC1-C6 alkyl) or C3-C12 cycloalkyl, Y3 each independently represents CH2, 0, S or NH), Y6 is each independently CH2, O, S, C(=O) or A 5- to 12-membered heteroaryl group containing a terephthalic acid atom, wherein one or more of R4's groups are each independently halogen, -CN, - NO2, -OH, C1-C6 alkyl (wherein one or more of C1-C6 alkyl's groups can be each independently substituted with - O- (Cl- C6 alkyl)), C1-C6 haloalkyl, C2-C6 alkynyl, C3-C6 cycloalkyl, - O- (Cl- C6 alkyl), - O-CC1-C6 haloalkyl), -S-CC1-C6 haloalkyl), - NH2, - N (C1- C6 alkyl) (Cl- C6 alkyl), -C (=O)-Rg (Rg is C1-C6 alkyl, - NH2, - O- (Cl- C6 alkyl), -OH, , Magic - R K 91 (where Rgi is H or C1 - C6 alkyl), or O, (wherein), - [(C1 - C6 alkylene)] z - NH - S(=O) 『R h (where Rh is C1 - C6 alkyl, C3 - C6 cycloalkyl, - N(C1 - C6 alkyl)(C1 - C6 alkyl) and z is 0 or 1), - O - S(=O) 『R, (where R, is C1 - C6 alkyl or C6 - C12 aryl, and at least one H of C6 - C12 aryl is independently substituted by C1 - C6 alkyl each) 'S? can be used), -S(=O)2-Rj (Rj is C1-C6 alkyl or, and Y8 is CH2, O or, is 0 or 1, y is 0 or 1, wherein one or more of the substituents of Rj can each be independently substituted with halogen, C1-C6 alkyl or C1-C6 haloalkyl), or - S(=0)『 N(R m )R n (Rm and Rn are each independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, a 3- to 12-member heterocycloalkyl containing one or more heteroatoms selected from N, O and S, or C6-C12 aryl, and one or more of the substituents of each of Rm and Rn can each be independently substituted with OH or -O-(C1-C6 alkyl)); can be substituted; The ring formed by R3 and R4 connecting to each other and each independently represents an integer from 0 to 3), W2 independently represents CH2, NH or 0, and Wi and W2 simultaneously represent CH2. One or more of the above ring groups are independently selected from the group consisting of halogen, CN, OH, N02, C1-C6 alkyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, (Rp is H or C1-C6 alkyl) or can be substituted with -S(=O)2-N(C1-C6 alkyl)(C1-C6 alkyl). 【 Claim 2 According to claim 1, 180 One or more of the substituents of R4 are each independently halogen, -CN, -NO2, -OH, C1-C6 alkyl (wherein one or more of the substituents of C1-C6 alkyl can each be independently substituted with -O-(C1-C6 alkyl)), C1-C6 haloalkyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -O-(C1-C6 alkyl), -0-CC1-C6 haloalkyl), -S-CC1-C6 haloalkyl), -NH2, -N(C1-C6 alkyl)(Cl- C6 alkyl), Kill Len)] z-NH-S(=0)『Rh (Rh is C1-C6 alkyl, C3-C6 cycloalkyl, -N(C1-C6 alkyl)(C1-C6 alkyl), and z is 0 or 1), -O-S(=0)『R, (R, is C1-C6 alkyl or C6-C12 aryl , wherein one or more of the C6-C12 aryl groups may be independently substituted with C1-C6 alkyl), -S(=0)2-RJ (RJ is C1-C6 alkyl and Y8 is CH2, 0 or NH, and is 0 or 1, and y is 0 or 1, and in this case, one or more substituents of Rj can each be independently substituted with halogen, C1-C6 alkyl or C1-C6 haloalkyl), or - S(=0)『 N(R m )R n (Rm and Rn are each independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, or C6-C12 aryl, and each of Rm and Rn may be independently substituted with 0H or - 0- (Cl- C6 alkyl); one or more substituents can each be independently halogen, CN, OH, NO2, C1- C6 alkyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, alkyl), or -S(=O)2-N(C1-C6 alkyl)(C1-C6 alkyl), a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 182 【

3. A compound according to claim 1, comprising a compound represented by the following chemical formula la, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: Rs and R4 are each a functional group defined below, or are connected to each other to form a ring group containing at least one ring, R3 is H or C1-C6 alkyl, and in this case, one or more substituents of C1-C6 alkyl can each be independently It can be replaced with CN, Independently represents H, C1-C6 haloalkyl or - CF3), independently H, halogen, -CN, -NO2, -OH, C1-C6 alkyl (where one or more substituents of C1-C6 alkyl can each be independently substituted with -O-(C1-C6 alkyl)), -CHs, CH(CH3)(CH3), -CH(CH3)-0-CH3, C1-C6 haloalkyl, -CF3, - OC- CH3, C3-C6 cycloalkyl, - 0- (Cl- C6 alkyl), -O-CHs, -0-CC1-C6 haloalkyl), -0-CF3, C6 haloalkyl), -S-CFs, - NH2, - MCH3XCH3), or -C(=O)-Rg (Rg is C1-C6 alkyl, - and ※ <7 any one of the selected heteroaryl, and in this case, one or more substituents of heteroaryl can be substituted with C1-C6 alkyl, C1-C6 haloalkyl or -CF3; The ring formed by R3 and R4 connecting to each other and each independently represents an integer of any one of 0 to 3, and R7 is H, halogen, OH, N02, C1-C6 alkyl, C1-C6 haloalkyl, -CF3, or -S(=O)2-N(C1-C6 alkyl)(Cl- C6 alkyl) (W1 and W2 each independently represent CH2, NH, N (C1-C6 alkyl) or 0, and W1 and W2 are not CH2 at the same time, and R8 is H, halogen, CN, OH, N02, C1-C6 alkyl, C1-C6 haloalkyl or - CF3), (where R9 is H, C1-C6 alkyl or C3-C12 cycloalkyl), (Rio and Rii are each independently H, C1-C6 alkyl, C1-C6 haloalkyl, Rp is H or C1-C6 【 According to claim 4, a compound represented by the following formula lb, formula Ic or formula Id, a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: <Chemical Formula Ib> In chemical formula lb, chemical formula Ic and chemical formula Id respectively, (Ra, Rb and so are each independently H, halogen, CN, NO2, C1-C6 alkyl, C1-C6 haloalkyl, -CF3, -O-C(C1-C6 alkyl), -C(=0)-(C1-C6 alkyl) or -C(=0)-0-(Cl-C6 alkyl) and Re are each independently H or halogen), or (where Rf is H or C1-C6 alkyl); R3 is H or C1-C6 alkyl; L2 is -NH- or - 0-, and e and f are each independently 0 or 1; R12 is H, halogen, C1-C6 alkyl or -0-(Cl- C6 alkyl); R13 is C1-C6 alkyl, C3-C6 cycloalkyl, C6-C12 aryl (wherein C6-C12 aryl 1 or more of which may each be independently substituted with C1-C6 alkyl), (Y8 is CH2 or 0, b is 0 or 1, y is 0 or 1, wherein at least one of these complements may be independently substituted with halogen, C1-C6 alkyl, C1-C6 haloalkyl or - CH2F) or - N(R m )R n (wherein, Rm and Rn are each independently H, C1-C6 alkyl (wherein, one or more of H of C1-C6 alkyl may be independently substituted with -0-(Cl-C6 alkyl) or 0H), -CHs, -CH2CH3, -CH(CH3)(CH3), -CH2CH2-O-CH3, -CH2-C(CH3)2(0H), C1-C6 haloalkyl, - CH2CH2F, -CH2-CF2H, C3-C12 cycloalkyl, or C6- C12 aryl).

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

6. 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, and rosacea; inflammatory bowel disease; arthritis; and migraine, comprising a compound according to any one of claims 1 to 5, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. 【

7. 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 5, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

8. Use of a compound according to any one of claims 1 to 5, 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.

9. Use of a compound according to any one of claims 1 to 5, 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. 222

Images