Novel compounds as lysyl-tRNA synthetase 1 inhibitors and uses thereof

Abstract

This invention relates to novel compounds as inhibitors of lysyl-tRNA synthetase 1 (KARS1), and uses thereof. More specifically, this invention relates to novel compounds as inhibitors of lysyl-tRNA synthetase 1, and uses thereof for preventing or treating diseases associated with immune cell migration and cancer metastasis.

Description

[Technical Field]

[0001] This application claims priority based on Korean Patent Application No. 10-2023-0009752, filed on January 25, 2023, the entire specification of which is incorporated herein by reference.

[0002] This invention relates to novel compounds as inhibitors of lysyl-tRNA synthetase 1 (KARS1), and uses thereof. More specifically, this invention relates to novel compounds as inhibitors of lysyl-tRNA synthetase 1, and uses thereof for preventing or treating diseases associated with immune cell migration and cancer metastasis. [Background technology]

[0003] In various tissues within the body, cells migrate in different ways depending on their genetic characteristics and environment. Uncontrolled cell migration is associated with various disease states, such as inflammatory diseases and cancer metastasis, but the specific migration signaling and mechanisms underlying each cell remain unclear. In particular, it has been reported that the same factors are involved in different ways in different cells, making it even more difficult to understand the signaling process and mechanisms. For example, AQP1 (water channel aquaporin-1) is known to promote cell migration in epithelial cells, particularly cancer metastasis (Non-Patent Documents 1 and 2). However, in the case of macrophages, despite their expression, AQP1 has been reported to inhibit macrophage migration (Non-Patent Document 3). Because each cell has different migration modes and characteristics, existing drugs designed to prevent the migration of specific cells have very limited and insufficient efficacy. Therefore, there is a need to explore new strategies to control the cell migratory switch and treat migration-related diseases.

[0004] Meanwhile, immune cells are the body's first line of defense, and recent studies have shown that excessive immune cell activation is one of the main mechanisms of disease pathogenesis. When inflammatory immune cells are activated, increased immune cell migration is generally observed, and it has been reported that such immune cell migration and infiltration are closely related to the pathology of the following diseases:

[0005] For example, cardiovascular disease is a condition affecting the heart and major arteries, including atherosclerosis and coronary artery disease. Atherosclerosis is a cholesterol-induced inflammatory disease caused by atheromas, which consist of cholesterol deposited in the arterial lining and immune cells that migrate from the blood into the arteries. Specifically, atheromas form when immune cells such as monocytes migrate to areas of inflammation caused by cholesterol oxidation. When atheromas form, the inner surface of the blood vessels becomes rough and the walls thicken, narrowing the internal diameter through which blood flows and impairing blood circulation. When the fibrous membrane surrounding the atheroma ruptures, a blood clot forms within the blood vessel, causing bleeding into the atheroma, resulting in a sudden narrowing or blockage of the blood vessel's internal diameter, leading to cardiovascular disease. It is known that CCL2 (CC-Chemokine ligand 2, MCP-1), which induces monocyte migration and causes an inflammatory response, plays an important role in the occurrence and development of these existing cardiovascular diseases, and new methods for treating the above-mentioned cardiovascular diseases have been proposed by inhibiting the action of CCL2 and the resulting monocyte migration (Non-Patent Documents 4 to 8). Hypertension is also associated with a pathology in which various immune cells secreting inflammatory cytokines migrate excessively into blood vessels, thickening the vascular walls and causing a loss of vascular elasticity.

[0006] Pulmonary arterial hypertension (PAH) is associated with various pre-existing factors, including genetics, infection, and related diseases, but the immune response associated with endothelial cell injury is known to act as a key pathological factor (Non-Patent Document 9). It is known that a series of processes associated with immune cell infiltration and dysfunction are deeply related to the pathological phenomenon, and the interaction between immune cells and vascular endothelial cells is particularly important in PAH. Furthermore, recent reports have shown that infiltration of monocytes and macrophages also promotes the progression of Alport syndrome.

[0007] On the other hand, in fibrosis-related diseases, persistent (chronic) inflammatory responses activate the wound-healing program, leading to fibrosis. After tissue injury, inflammatory immune cells such as monocytes / macrophages, neutrophils, eosinophils, and mast cells rapidly infiltrate the injury site and become activated, secreting various cytokines. These cytokines then activate surrounding fibroblasts, epithelial cells, and smooth muscle cells to transform into myoblast-like cells. These myoblast-like cells then produce and secrete large amounts of extracellular matrix proteins, ultimately resulting in the massive accumulation of extracellular matrix proteins in the tissue, leaving scars and inducing tissue fibrosis and hypertrophy (Non-Patent Document 10). This pathological mechanism is one of the underlying causes of scar formation in skin tissue following skin injuries such as wounds, burns, and pressure ulcers, as well as sclerotic fibrosis in tissues such as the liver, kidneys, blood vessels, and lungs. Fibrosis is also a major pathological feature in chronic autoimmune diseases such as scleroderma, rheumatoid arthritis, Crohn's disease, ulcerative colitis, myelofibrosis, and systemic lupus erythematosus. Activation of inflammatory immune cells is also known to contribute to the pathology of atopic diseases, asthma, COPD, psoriasis, keloids, and proliferative retinopathy.

[0008] In particular, fibroblasts that are activated into myoblast-like cells during the wound healing program are called myofibroblasts. Because myofibroblasts are at the center of the pathology of all fibrosis-related diseases, eliminating the molecular biological or immunological mechanisms that induce myofibroblast activity is a key element in disease treatment. However, since eliminating the inflammatory response is not easy in practice, understanding the mechanisms of innate and acquired immunity and identifying key mediators are important for delaying fibrosis.

[0009] Monocytes and macrophages contribute to wound healing, but they also secrete reactive oxygen and nitrogen, which can have a detrimental effect on surrounding cells. Therefore, restricting monocytes and macrophages, which are the first to respond in the early stages of disease, is considered a therapeutic strategy for various chronic inflammation- and fibrosis-related diseases.

[0010] When wound healing mechanisms induce fibrosis, platelet-derived growth factor (PDGF), which is involved in platelet aggregation, is known to attract other inflammatory immune cells to the wound site, and transforming growth factor (TGF)-β1 promotes extracellular matrix synthesis from local fibroblasts. However, it has been reported that factors involved in platelet aggregation can induce fibrosis even when they are deficient.

[0011] As mentioned above, in diseases where excessive immune cell activation is a problem, target factors have been proposed to prevent the migration (and infiltration) of existing immune cells, and attempts have been made to devise treatment methods for these diseases using these target factors. However, each method has its own limitations. Therefore, in order to effectively treat diseases, it is still important to identify the key mediators in immune cell migration and the strategies to control them. [Prior art documents] [Non-patent literature]

[0012] [Non-Patent Document 1] Hara-Chikuma M et al., Aquaporin-1 facilitates epithelial cell migration in kidney proximal tubule, J Am Soc Nephrol. 2006 Jan;17(1):39-45

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Non-Patent Document 10

Summary of the Invention

Problems to be Solved by the Invention

[0013] Therefore, the present inventors have been conducting research to find new therapeutic strategies for diseases associated with immune cell migration (infiltration) through existing studies, and have confirmed that an increase in KARS1 levels in the cell membrane region of immune cells (monocytes / macrophages) is an important pathological phenomenon in diseases associated with immune cell migration and infiltration. They have also confirmed that a novel compound represented by the general formula of Chemical Formula 1 inhibits the activity of KARS1, thereby suppressing immune cell migration and infiltration and cancer cell migration, thereby having the effect of treating the associated diseases, and have thus completed the present invention.

[0014] Accordingly, an object of the present invention is to provide a compound of the following Chemical Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof: [ka]

[0015] X is O, NH, S, or CH═N; A is a C5-C10 aryl or a 5-10 atom heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S, which together with B form a bicyclic aromatic ring; R1, R2, R3, and R4 are each independently absent, hydrogen, halogen, ═O, C1-C6 alkyl, or amine; Z is two H or O, R5 is a C5-C10 aryl or pyridinonyl, which is unsubstituted or substituted with C1-C6 alkoxy, —(C═O)NH2, or —OCF3; Q is hydrogen or methylene; D is carboxyl, C5-C10 aryl, benzimidazolyl, benzoxazolyl, isoindolinyl, -C=O-, -C6H4C=O-, or -C6H4NH-; R8 is hydrogen or C1-C6 alkyl; When D is aryl, E is selected from the group consisting of phenyl, C1-C6 alkylene, C2-C8 alkylaminocarbonyl, heterocycloalkyl of 3 to 10 atoms containing one or more heteroatoms selected from the group consisting of N, O, and S, heteroaryl of 5 to 10 atoms containing one or more heteroatoms selected from the group consisting of N, O, and S, C3-C10 cycloalkylamine, C3-C10 cycloalkyl, -B(OH)O-, -CH2CH2(C=O), -C≡C-, -C≡C-( C=O)N-, -cyclobutyl-(C=O)-, -azetinyl-(C=O)-, -CH-(C=O)-, -pyrrolidinyl-(C=O)-, -furanyl-(C=O)-, -piperidinyl-(C=O)-, -pyrazolyl-(C=O)-, or pyrrolyl-(C=O)-, wherein R6 and R7 are each independently absent, hydrogen, a carboxylic acid, a C1-C6 alkyl, a C2-C8 alkylaminocarbonyl, aminocarbonyl, hydroxy, or -Si(CH3)3; E is hydrogen, halogen, -C≡C-, -C≡C-(C=O) when A is pyrrole or pyridone and D is aryl, and R6 and R7 are each independently absent, hydrogen, carboxyl, OH, CH3, CH2CH3, or -Si(CH3)3; When D is -C=O-, benzimidazolyl, benzoxazolyl, isoindolinyl, -C6H4C=O-, or -C6H4NH-, E is absent or -B(OH)2, carboxyl, hydrogen, aminocarbonyl, aminosulfonyl, C1-C6 alkylene, -(C=O)-, -C≡C-, -S(=O)2-, -CH2(C=O)-, -B(OH)O-, -CHR 10 (C=O)-, -NHCHR 10 (C=O)-, cyclobutyl-(C=O)-, furanyl-(C=O)-, or pyrrolidinyl-(C=O)-, wherein R6 and R7 are each independently absent, carboxyl, hydrogen, hydroxy, C1-C6 alkyl, or amine; R9 is hydrogen or C1-C6 alkyl; R 10is hydrogen, C1 to C6 alkyl, or C1 to C6 hydroxyalkyl.

[0016] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating immune cell migration-associated diseases, which comprises the compound, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0017] Another object of the present invention is to provide a pharmaceutical composition for preventing or suppressing cancer metastasis, which comprises the above compound, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0018] Another object of the present invention is to provide use of the compound, its isomer, or a pharmaceutically acceptable salt thereof for producing a composition for treating an immune cell migration-associated disease.

[0019] Another object of the present invention is to provide a method for treating an immune cell migration-associated disease, which comprises administering to an individual in need thereof an effective amount of a composition comprising the compound, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0020] Another object of the present invention is to provide use of the above compound, its isomer, or a pharmaceutically acceptable salt thereof for producing a composition for inhibiting cancer metastasis.

[0021] Another object of the present invention is to provide a method for suppressing cancer, which comprises administering an effective amount of a composition containing the compound, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient to an individual in need thereof. [Means for solving the problem]

[0022] In order to achieve the above-mentioned object of the present invention, the present invention provides a compound of the following Chemical Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof: [ka]

[0023] X is O, NH, S, or CH═N; A is a C5-C10 aryl or a 5-10 atom heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S, which together with B form a bicyclic aromatic ring; R1, R2, R3, and R4 are each independently absent, hydrogen, halogen, ═O, C1-C6 alkyl, or amine; Z is two H or O, R5 is a C5-C10 aryl or pyridinonyl, which is unsubstituted or substituted with C1-C6 alkoxy, —(C═O)NH2, or —OCF3; Q is hydrogen or methylene; D is carboxyl, C5-C10 aryl, benzimidazolyl, benzoxazolyl, isoindolinyl, -C=O-, -C6H4C=O-, or -C6H4NH-; R8 is hydrogen or C1-C6 alkyl; When D is aryl, E is selected from the group consisting of phenyl, C1-C6 alkylene, C2-C8 alkylaminocarbonyl, heterocycloalkyl of 3 to 10 atoms containing one or more heteroatoms selected from the group consisting of N, O, and S, heteroaryl of 5 to 10 atoms containing one or more heteroatoms selected from the group consisting of N, O, and S, C3-C10 cycloalkylamine, C3-C10 cycloalkyl, -B(OH)O-, -CH2CH2(C=O), -C≡C-, -C≡C-( C=O)N-, -cyclobutyl-(C=O)-, -azetinyl-(C=O)-, -CH-(C=O)-, -pyrrolidinyl-(C=O)-, -furanyl-(C=O)-, -piperidinyl-(C=O)-, -pyrazolyl-(C=O)-, or pyrrolyl-(C=O)-, wherein R6 and R7 are each independently absent, hydrogen, a carboxylic acid, a C1-C6 alkyl, a C2-C8 alkylaminocarbonyl, aminocarbonyl, hydroxy, or -Si(CH3)3; E is hydrogen, halogen, -C≡C-, -C≡C-(C=O) when A is pyrrole or pyridone and D is aryl, and R6 and R7 are each independently absent, hydrogen, carboxyl, OH, CH3, CH2CH3, or -Si(CH3)3; When D is -C=O-, benzimidazolyl, benzoxazolyl, isoindolinyl, -C6H4C=O-, or -C6H4NH-, E is absent or -B(OH)2, carboxyl, hydrogen, aminocarbonyl, aminosulfonyl, C1-C6 alkylene, -(C=O)-, -C≡C-, -S(=O)2-, -CH2(C=O)-, -B(OH)O-, -CHR 10 (C=O)-, -NHCHR 10 (C=O)-, cyclobutyl-(C=O)-, furanyl-(C=O)-, or pyrrolidinyl-(C=O)-, wherein R6 and R7 are each independently absent, carboxyl, hydrogen, hydroxy, C1-C6 alkyl, or amine; R9 is hydrogen or C1-C6 alkyl; R 10 is hydrogen, C1 to C6 alkyl, or C1 to C6 hydroxyalkyl.

[0024] To achieve another object of the present invention, the present invention provides a pharmaceutical composition for preventing or treating immune cell migration-associated diseases, comprising the compound, its isomer, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0025] In order to achieve another object of the present invention, the present invention provides a pharmaceutical composition for preventing or suppressing cancer cell metastasis, comprising the above compound, its isomer, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0026] To achieve another object of the present invention, the present invention provides use of the compound, its isomer, or a pharmaceutically acceptable salt thereof for producing a composition for treating an immune cell migration-associated disease.

[0027] In order to achieve another object of the present invention, the present invention provides a method for treating an immune cell migration-associated disease, comprising administering to an individual in need thereof an effective amount of a composition containing the compound, its isomer, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0028] In order to achieve another object of the present invention, the present invention provides use of the above compound, its isomer, or a pharmaceutically acceptable salt thereof for producing a composition for inhibiting cancer metastasis.

[0029] In order to achieve another object of the present invention, the present invention provides a method for suppressing cancer, which comprises administering an effective amount of a composition containing the above-mentioned compound, its isomer, or a pharmaceutically acceptable salt thereof as an active ingredient to an individual in need thereof.

[0030] In this specification, unless otherwise stated, an alkyl, alkenyl, or alkynyl substituent, or alkyl or alkenyl moiety, may be straight-chain or branched (branched, side-chain). Alkyl and alkenyl chains may also contain intervening heteroatoms such as oxygen.

[0031] Cx-Cy alkyl refers to a saturated aliphatic hydrocarbon group having x to y carbon atoms, which may be straight-chain or branched. C1-C6 alkyl contains 1 to 6 carbon atoms. "Branched" refers to the group having one or more carbon branch points. For example, tert-butyl and isopropyl are both branched groups. Examples of C1-C6 alkyl groups include methyl, ethyl, propyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

[0032] A Cx-Cy alkylene residue may be linear or branched and refers to a divalent hydrocarbon group having one less hydrogen atom than a Cx-Cy alkyl as defined above. Non-limiting examples of C1-C6 alkylene groups include methylene, ethylene, n-propylene, n-butylene, methylmethylene, and dimethylmethylene.

[0033] C2-C6 alkenyl refers to a straight or branched hydrocarbon chain radical containing at least two carbon atoms and one or more double bonds. Non-limiting examples of alkenyl groups can include ethenyl, propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-hexenyl, 2-methyl-1-propenyl, 1,2-butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, and 1-hexadienyl.

[0034] C1-C6 alkoxy represents a group or part of a group having an -O-Cx-Cy alkyl group according to the definition of Cx-Cy alkyl above. Non-limiting examples of C1-C6 alkoxy can include methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy, and hexoxy.

[0035] Halogen or halo means a chlorine (Cl), bromine (Br), fluorine (F), or iodine (I) atom.

[0036] Cx-Cy cycloalkyl represents a cyclic non-aromatic hydrocarbon group of x to y carbon atoms. C3-C10 cycloalkyl means a hydrocarbon ring containing 3 to 10 carbon atoms. Non-limiting examples of C3-C10 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylcycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.

[0037] An aryl group refers to any monocyclic or bicyclic hydrocarbon group containing at least one aromatic group, for example having up to 12 carbon atoms in the ring members. Non-limiting examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and biphenyl.

[0038] Heteroaryl groups can be monocyclic or bicyclic. Bicyclic rings can be fused aromatic rings, where the rings are aromatic or one of the rings can be non-aromatic. Heteroaryls contain one, two, or three heteroatoms selected from oxygen (O), sulfur (S), and nitrogen (N). If the heteroatom is nitrogen, it can be oxidized. Non-limiting examples of heteroaryls include pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, indolyl, indolizinyl, isoindolyl, indolinyl, purinyl, prazanyl, imidazolyl, indazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazinanyl, tetrazolyl, thiadiazolyl, benzoyl ... These may include benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, benzimidazolyl, benzothiazolyl, naphthyridinyl, piperidinyl, pyrazinyl, 4H-quinolidinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, imidazopyridinyl, pyrazolopyridinyl, thiazolopyridinyl, indolinyl, isoindolinyl, triazinyl, pyridazinyl, and quinoxalinyl.

[0039] Heterocyclyl groups can also be a single ring or can contain two or more fused rings that are saturated or partially unsaturated and contain one, two, or three heteroatoms selected from oxygen (O), sulfur (S), and nitrogen (N). Non-limiting examples of heterocyclyl include azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, diazepanyl, dihydrofuranyl (i.e., 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), 4,5-dihydro-1H-maleimido, dioxolanyl, morpholinyl, oxazolidinyl, piperazinyl, tetrahydrofuranyl, thiomorpholinyl, dihydropyranyl (i.e., 3,4-dihydropyranyl, 3,6-dihydropyranyl), dioxanyl, hexahydro tetrahydropyrimidinyl, pyrazolinyl, pyrazolidinyl, pyridazinyl, 4H-quinolizinyl, quinuclidinyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetramethylene sulfoxide, thiazolidinyl, hydantoinyl, benzopyranyl, tetrahydrothiazolopyridinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydropyrazolopyrazinyl, and tetrahydrothiazoloazepinyl.

[0040] Pharmaceutically acceptable refers to compositions and molecular entities that are physiologically tolerable and, when administered to humans or animals, generally do not cause allergic or similar adverse reactions, such as gastrointestinal upset, dizziness, etc. For example, the term "pharmaceutically acceptable" means that a molecule, etc., has been approved by a U.S. state or federal regulatory agency or is included in the U.S. Pharmacopoeia or other generally recognized pharmacopoeias for use in animals, more particularly humans.

[0041] General methods for preparing salts are well known to those skilled in the art. Salts are formed by conventional means by reacting the free acid or free base form of the compound with one or more suitable equivalents, optionally in a solvent, or if the salt is insoluble, the solvent or medium is subsequently removed using standard techniques (e.g., vacuum, lyophilization, or filtration). Salts can also be prepared by exchanging the counterion of a compound in salt form with another counterion using aqueous labeled ion exchange resins.

[0042] Pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, formulations, and other substances that are useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0043] The compounds described herein can be prepared and / or formulated as pharmaceutically acceptable salts, or, where appropriate, as free bases. Pharmaceutically acceptable salts are non-toxic salts of the free base form of a compound that retain the desired pharmacological activity of the free base. These salts can be derived from inorganic or organic acids or bases. For example, compounds containing a basic nitrogen can be prepared as pharmaceutically acceptable salts by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6 benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, besylate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharmaceutically acceptable salts is known in the art.

[0044] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein also include salts derived from suitable bases, such as alkali metals (e.g., sodium, potassium), alkaline earth metals (e.g., magnesium), ammonium, and N(C1-C4 alkyl)4+. Also included are base addition salts, such as sodium or potassium salts.

[0045] General methods for preparing salts are well known to those skilled in the art. Salts are formed by conventional means by reacting the free acid or free base form of the compound with one or more suitable equivalents, optionally in a solvent, or if the salt is insoluble, the solvent or medium is subsequently removed using standard techniques (e.g., vacuum, lyophilization, or filtration). Salts can also be prepared by exchanging the counterion of a compound in salt form with another counterion using aqueous labeled ion exchange resins.

[0046] Also provided are compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, in which 1 to n hydrogen atoms attached to a carbon atom can be replaced with deuterium atoms or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, deuterium atoms are non-radioactive isotopes of hydrogen atoms. Such compounds can increase metabolic resistance and therefore can be useful for increasing the half-life of the compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, when administered to a mammal.

[0047] Examples of isotopes that can be incorporated into the disclosed compounds also include, respectively: 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 Includes isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as I. 11 C. 18 F, 15 O, and 13Substitution with positron-emitting isotopes, such as N, can be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by methods similar to those described in the examples provided below, substituting the appropriate isotopically labeled reagent for the previously used non-labeled reagent.

[0048] The compounds of the embodiments disclosed herein, or pharmaceutically acceptable salts thereof, contain one or more asymmetric centers and can therefore form enantiomers, partial stereoisomers, and other stereoisomers that can be defined in terms of absolute stereochemistry as (R)- or (S)-, or, in the case of amino acids, (D)- or (L)-. The present disclosure is meant to encompass all such possible isomers, as well as their racemic and optically pure forms. Optically active (+)- and (−), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for the preparation / separation of individual enantiomers include chiral synthesis from appropriate optically pure precursors, or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). Where compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to include both E and Z geometric isomers. Likewise, all tautomers are intended to be included. Where compounds are represented in their chiral form, it is understood that embodiments include, but are not limited to, the specific partial stereoisomer or enantiomerically enriched form. Where chirality is not specified, it is understood that embodiments relate to the specific partial stereoisomer or enantiomerically enriched form; or to racemic or scalemic mixtures of such compounds. As used herein, a "scalemic mixture" is a mixture of stereoisomers in a ratio other than 1:1.

[0049] Stereoisomers refer to compounds that are not interchangeable as compounds with the same atoms bonded by the same bonds but with different three-dimensional structures. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0050] A tautomer refers to the migration of a proton from one atom of a molecule to another atom of the same molecule. In some embodiments, the present disclosure includes tautomers of the above compounds.

[0051] A solvate refers to the result of the interaction of a solvent and a compound. Solvates of the salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0052] Hydrates refer to compounds of the present disclosure chemically bound to one or more water molecules.

[0053] The present invention will be described in detail below.

[0054] The present invention provides a compound of Formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof: [ka]

[0055] X is O, NH, S, or CH═N; A is a C5-C10 aryl or a 5-10 atom heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S, which together with B form a bicyclic aromatic ring; R1, R2, R3, and R4 are each independently absent, hydrogen, halogen, ═O, C1-C6 alkyl, or amine; Z is two H or O, R5 is a C5-C10 aryl or pyridinonyl, which is unsubstituted or substituted with C1-C6 alkoxy, —(C═O)NH2, or —OCF3; Q is hydrogen or methylene; D is carboxyl, C5-C10 aryl, benzimidazolyl, benzoxazolyl, isoindolinyl, -C=O-, -C6H4C=O-, or -C6H4NH-; R8 is hydrogen or C1-C6 alkyl; When D is aryl, E is selected from the group consisting of phenyl, C1-C6 alkylene, C2-C8 alkylaminocarbonyl, heterocycloalkyl of 3 to 10 atoms containing one or more heteroatoms selected from the group consisting of N, O, and S, heteroaryl of 5 to 10 atoms containing one or more heteroatoms selected from the group consisting of N, O, and S, C3-C10 cycloalkylamine, C3-C10 cycloalkyl, -B(OH)O-, -CH2CH2(C=O), -C≡C-, -C≡C-( C=O)N-, -cyclobutyl-(C=O)-, -azetinyl-(C=O)-, -CH-(C=O)-, -pyrrolidinyl-(C=O)-, -furanyl-(C=O)-, -piperidinyl-(C=O)-, -pyrazolyl-(C=O)-, or pyrrolyl-(C=O)-, wherein R6 and R7 are each independently absent, hydrogen, a carboxylic acid, a C1-C6 alkyl, a C2-C8 alkylaminocarbonyl, aminocarbonyl, hydroxy, or -Si(CH3)3; E is hydrogen, halogen, -C≡C-, -C≡C-(C=O) when A is pyrrole or pyridone and D is aryl, and R6 and R7 are each independently absent, hydrogen, carboxyl, OH, CH3, CH2CH3, or -Si(CH3)3; When D is -C=O-, benzimidazolyl, benzoxazolyl, isoindolinyl, -C6H4C=O-, or -C6H4NH-, E is absent or -B(OH)2, carboxyl, hydrogen, aminocarbonyl, aminosulfonyl, C1-C6 alkylene, -(C=O)-, -C≡C-, -S(=O)2-, -CH2(C=O)-, -B(OH)O-, -CHR 10 (C=O)-, -NHCHR 10(C=O)-, cyclobutyl-(C=O)-, furanyl-(C=O)-, or pyrrolidinyl-(C=O)-, wherein R6 and R7 are each independently absent, carboxyl, hydrogen, hydroxy, C1-C6 alkyl, or amine; R9 is hydrogen or C1-C6 alkyl; R 10 is hydrogen, C1 to C6 alkyl, or C1 to C6 hydroxyalkyl.

[0056] In one embodiment of the present invention, A can be characterized as being benzene, pyridine, pyrimidine, pyridone, or pyrrole which together with B form a bicyclic aromatic ring.

[0057] In one embodiment of the present invention, the bicyclic aromatic ring formed by A and B can be characterized as being selected from the following structures: [ka]

[0058] In one embodiment of the invention, R5 can be characterized as phenyl or pyridinonyl substituted with methoxy, -(C=O)NH2, or -OCF3.

[0059] In one aspect of the invention, D can be characterized as being phenyl, carboxyl, benzimidazolyl, benzoxazolyl, or isoindolinyl.

[0060] In one aspect of the invention, when D is aryl and A is not pyrrole or pyridone, E can be characterized as phenyl, ethylene, -C≡C-, pyrrolidinyl, pyrrolidinylcarbonyl, methylaminocarbonyl, furanyl, cyclobutynylamino, pyrrolyl, cyclobutyl, or azetidinyl, wherein R6, R7 are each independently absent, hydrogen, carboxyl, diethylaminocarbonyl, methylaminocarbonyl, aminocarbonyl, -Si(CH3)3, or isopropyl.

[0061] In one aspect of the invention, when D is aryl and A is pyrrole or pyridone, E can be characterized as halo or -C≡C-, where R6, R7 are each independently absent, hydrogen, Si(CH3)3, or carboxyl.

[0062] In one aspect of the invention, when D is benzimidazolyl, benzoxazolyl, or isoindolinyl, E is hydrogen, -B(OH)2, carboxyl, aminocarbonyl, aminosulfonyl, or methylene, and R6, R7 can each independently be absent or carboxyl.

[0063] In one embodiment of the present invention, the compound of Formula 1 may be selected from the group consisting of the following compounds: N-([1,1'-biphenyl]-4-ylmethyl)-N-(4-methoxyphenethyl)thiazolo[5,4-b]pyridin-2-amine, 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)propanoic acid, N,N-diethyl-3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphen-ethyl)amino)methyl)phenyl)propiolamide, 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)-N-methylpropiolamide, 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)propiolamide, N-(4-methoxyphenethyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine, N-(4-bromobenzyl)-N-(4-methoxyphenethyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 7-fluoro-N-(4-methoxyphenethyl)-N-(3-((trimethylsilyl)ethynyl)-benzyl)benzo[d]thiazol-2-amine, N-(3-ethynylbenzyl)-7-fluoro-N-(4-methoxyphenethyl)benzo[d]thiazol-2-amine, N-(4-methoxyphenethyl)-7-methyl-N-(4-((trimethylsilyl)ethynyl)-benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, N-(4-ethynylbenzyl)-N-(4-methoxyphenethyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 3-(4-(((4-methoxyphenethyl)(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)methyl)phenyl)propiolic acid, 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)pyrrolidine-3-carboxylic acid, (4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)benzoyl)-L-proline, 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)benzoyl)pyrrolidine-3-carboxylic acid, (4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)benzoyl)glycine, 1-(3-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)pyrrolidine-3-carboxylic acid, (4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)benzoyl)-D-valine, (4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)-L-proline, (3-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)-L-proline, (2-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)-1-methyl-1H-benzo[d]imidazol-6-yl)boronic acid, (S)-1-(3-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)pyrrolidine-3-carboxylic acid, (R)-1-(3-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)pyrrolidine-3-carboxylic acid, (R)-1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)-amino)methyl)phenyl)pyrrolidine-3-carboxylic acid, (S)-1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)pyrrolidine-3-carboxylic acid, 5-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)furan-2-carboxylic acid, 2-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)-1-methyl-1H-benzo[d]imidazole-6-carboxylic acid, 2-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)benzo[d]oxazole-5-carboxylic acid, 7-fluoro-N-(isoindolin-5-ylmethyl)-N-(4-methoxyphenethyl)benzo-[d]thiazol-2-amine, 5-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)isoindoline-2-carboxamide, 5-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)isoindoline-2-sulfonamide, 2-(5-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)isoindolin-2-yl)acetic acid, 1-((4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)amino)cyclobutane-1-carboxylic acid, 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)-1H-pyrrole-3-carboxylic acid, N-(7-fluorobenzo[d]thiazol-2-yl)-N-(4-methoxyphenethyl)glycine, 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)cyclobutane-1-carboxylic acid, (R)-1-(4-((benzo[d]oxazol-2-yl(4-methoxyphenethyl)amino)methyl)-phenyl)pyrrolidine-3-carboxylic acid, (S)-1-(4-((benzo[d]oxazol-2-yl(4-methoxyphenethyl)amino)methyl)-phenyl)pyrrolidine-3-carboxylic acid, 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)azetidine-3-carboxylic acid, (R)-1-(3-(((7-fluorobenzo[d]thiazol-2-yl)(4-(trifluoromethoxy)-phenethyl)amino)methyl)phenyl)pyrrolidine-3-carboxylic acid, (3R)-1-(3-(1-((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)-amino)ethyl)phenyl)pyrrolidine-3-carboxylic acid, (3S)-1-(4-(1-((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)-amino)ethyl)phenyl)pyrrolidine-3-carboxylic acid, (S)-1-(4-(((4-methoxyphenethyl)(4,5,7-trifluorobenzo[d]thiazol-2-yl)amino)methyl)phenyl)pyrrolidine-3-carboxylic acid, 3-(4-(((4-methoxyphenethyl)(oxazolo[5,4-b]pyridin-2-yl)amino)-methyl)phenyl)propiolic acid, 3-(4-(((4-methoxyphenethyl)(5-oxo-4,5-dihydrothiazolo[5,4-b]pyridin-2-yl)amino)methyl)phenyl)propiolic acid, 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)piperidine-4-carboxylic acid, 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)-1H-pyrazole-4-carboxylic acid, (S)-1-(4-(((4-carbamoylphenethyl)(7-fluorobenzo[d]thiazol-2-yl)amino)methyl)phenyl)pyrrolidine-3-carboxylic acid,

[0064] (S)-1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(2-(2-oxopyridin-1(2H)-yl)ethyl)amino)methyl)phenyl)pyrrolidine-3-carboxylic acid.

[0065] The present invention also provides a pharmaceutical composition for preventing or treating immune cell migration-associated diseases, comprising the compound, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0066] The term "immune cells" as used herein refers to cells involved in immune responses in the body, and includes, without limitation, any cells known in the art as immune cells, particularly those known to exist in the human body, including monocytes, macrophages, neutrophils, eosinophils, basophils, dendritic cells, natural killer cells, megakaryocytes, T cells, and B cells. Preferably, the term refers to monocytes, macrophages, or neutrophils. The immune cells express KARS1.

[0067] In the present invention, the term "immune cell migration-associated disease" is not particularly limited to a specific type, as long as it is known in the art that excessive immune cell migration (and / or infiltration) is the main pathogenic mechanism, and may be, for example, a disease selected from the group consisting of cardiovascular disease, fibrotic disease, inflammatory disease, and Alport syndrome.

[0068] The specific type of cardiovascular disease is not particularly limited, and may be, for example, selected from the group consisting of hypertension (including inflammatory complications due to hypertension), pulmonary arterial hypertension, atherosclerosis, angina pectoris, myocardial infarction, ischemic cerebrovascular disease, arteriolosclerosis, and medial sclerosis.

[0069] The specific type of fibrotic disease is not particularly limited, but examples thereof include scleroderma, rheumatoid arthritis, Crohn's disease, ulcerative colitis, myelofibrosis, pulmonary fibrosis, hepatic fibrosis, liver cirrhosis, and kidney fibrosis. fibrosis, glomerulosclerosis, myofibrosis, cardiac fibrosis, interstitial fibrosis, pancreatic fibrosis, splenic fibrosis, mediastinal fibrosis, vascular fibrosis, cutaneous fibrosis, ocular fibrosis, macular degeneration, arthritic fibrosis, thyroid fibrosis, endomyocardial fibrosis, peritoneal fibrosis, retroperitoneal fibrosis, progressive mass fibrosis, nephrogenic systemic fibrosis, systemic lupus erythematosus, hereditary fibrosis, infectious fibrosis, irritative fibrosis, fibrosis due to chronic autoimmunity, fibrosis due to antigen incompatibility during organ transplantation, fibrotic complications of surgery, fibrosis due to hyperlipidemia, fibrosis due to obesity, diabetic fibrosis, fibrosis due to hypertension, and fibrotic obstruction during stent insertion.

[0070] In the present invention, the type of inflammatory disease is not particularly limited, but is preferably an autoimmune disease, inflammatory bowel disease, dermatitis (e.g., atopic dermatitis, eczema, psoriasis, etc.), diabetic eye disease (diabetic retinopathy, etc.), peritonitis, osteomyelitis, cellulitis, meningitis, encephalitis, pancreatitis, trauma-induced shock, bronchial asthma, rhinitis, sinusitis, otitis media, pneumonia, gastritis, enteritis, cystic fibrosis, stroke (stroke, etc.), bronchitis, bronchiolitis, hepatitis (cirrhosis, non-alcoholic steatohepatitis, etc.), or a combination thereof. steatohepatitis, etc.), nephritis (diabetic renal failure, etc.), proteinuria, arthritis (psoriatic arthritis, osteoarthritis, etc.), neuritis (diabetic neuropathy, multiple sclerosis, etc.), gout, spondylitis, Reiter's syndrome, polyarteritis nodosa, vasculitis, amyotrophic lateral sclerosis, Wegener's granulomatosis, hypercytokinemia, polymyalgia rheumatica, arthrocellular arteritis, calcium crystal deposition arthropathy, pseudogout, non-rheumatoid arthritis, bursitis, tenosynovitis, epicondylitis (tennis elbow), neuropathic joint disease (Charcot's syndrome) joint, hemarthrosis, Henoch-Schönlein purpura, hypertrophic osteoarthropathy, multicentric reticulohistiocytoma, sarcoidosis, hemochromatosis, sickle cell disease, hyperlipoproteinemia, hypogammaglobulinemia, hyperparathyroidism, acromegaly, familial Mediterranean fever, Behcet's disease, systemic lupus erythematosus, relapsing fever, psoriasis, multiple sclerosis, sepsis, septic shock, acute respiratory distress syndrome, multiple organ failure, chronic obstructive pulmonary disease, acute lung injury, and broncho-pulmonary dysplasia, and also includes chronic inflammatory diseases.

[0071] In the present invention, the autoimmune disease may be selected from the group consisting of rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus, psoriasis, asthma, ulcerative colitis, Behcet's disease, Crohn's disease, multiple sclerosis, dermatomyositis, collagen disease, vasculitis, arthritis, granulomatosis, organ-specific autoimmune lesions, ulcerative colitis, and GvHD (graft-versus-host disease).

[0072] The term "chronic inflammatory disease" refers to the types of inflammatory diseases described above and includes chronic states of these diseases. Preferred examples of these diseases include, but are not limited to, asthma, atopic dermatitis, eczema, psoriasis, osteoarthritis, gout, psoriatic arthritis, cirrhosis, non-alcoholic steatohepatitis, chronic obstructive pulmonary disease, rhinitis, diabetic retinopathy, diabetic renal failure, diabetic neuropathy, and multiple sclerosis.

[0073] The pharmaceutical composition according to the present invention may contain the compound of the present invention alone or may be formulated into an appropriate form together with one or more pharmaceutically acceptable carriers, and may further contain an excipient or diluent. In the above, "pharmaceutically acceptable" means a non-toxic composition that is physiologically acceptable and does not usually cause allergic reactions such as gastrointestinal disorders and dizziness, or similar reactions, when administered to humans.

[0074] In the present invention, the content of the composition is not significantly limited depending on the purpose or mode of use, and may be, for example, 0.01 to 99 wt %, preferably 0.5 to 50 wt %, and more preferably 1 to 30 wt % based on the total weight of the composition. Furthermore, the pharmaceutical composition according to the present invention may further contain additives such as pharmaceutically acceptable carriers, excipients, or diluents in addition to the active ingredient. The pharmaceutical composition of the present invention may contain 0.1 to 99.9 wt % of the compounds represented by Chemical Formulas 1 to 6 prepared by the method of the present invention, and 99.9% to 0.1 wt % of a carrier.

[0075] The pharmaceutically acceptable carrier may further include, for example, a carrier for oral administration or a carrier for parenteral administration. Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. Also, various drug delivery substances used for oral administration of peptide formulations may be included. Carriers for parenteral administration may include water, a suitable oil, saline, aqueous glucose, glycol, etc., and may further include stabilizers and preservatives. Suitable stabilizers include antioxidants such as sodium bisulfite, sodium sulfite, or ascorbic acid. Suitable preservatives include benzalkonium chloride, methyl or propyl paraben, and chlorobutanol.

[0076] In addition to the above ingredients, the pharmaceutical composition of the present invention may further contain lubricants, wetting agents, sweeteners, flavorings, emulsifiers, glossing agents, etc. Other pharmaceutically acceptable carriers and formulations may be selected from those known in the art.

[0077] The compositions of the present invention can be administered to mammals, including humans, by any method. For example, they can be administered orally or parenterally. Specifically, the administration route of the compositions of the present invention can be, but is not limited to, known antibody administration methods, such as injection or infusion via intravenous, intraperitoneal, intracerebral, subcutaneous, intramuscular, intraocular, intraarterial, intracerebrospinal, or intralesional routes, or injection or infusion via a sustained release system described below. For example, the compounds of the present invention can be administered systemically or locally.

[0078] The pharmaceutical composition of the present invention can be formulated as a preparation for oral administration or parenteral administration depending on the administration route as described above.

[0079] In the pharmaceutical composition according to the present invention, the compound can be administered in various oral and parenteral dosage forms during clinical administration. Conventional diluents or excipients, such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants, can be used in the formulation. Solid formulations for oral administration include tablets, pills, powders, granules, capsules, and lozenges. These solid formulations can be prepared by mixing at least one or more excipients, such as starch, calcium carbonate, sucrose, lactose, or gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc can also be used. Liquid formulations for oral administration include suspensions, oral solutions, emulsions, and syrups. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients, such as wetting agents, sweeteners, flavorings, and preservatives, can also be used.

[0080] Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. The therapeutic composition of the present invention can be prepared in the form of a lyophilized cake or aqueous solution for preservation by mixing a compound having a desired purity with any physiologically acceptable carrier, excipient, or stabilizer known in the art. Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed and include buffers such as phosphate, citric acid, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine, or lysine; monosaccharides, disaccharides, glucose, mannose, or other carbohydrates, including dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or nonionic surfactants such as Tween, Pluronics, or polyethylene glycol (PEG).

[0081] In the case of parenteral administration, the formulations can be formulated by methods known in the art in the form of injections, creams, lotions, topical ointments, oils, moisturizers, gels, aerosols, and nasal inhalants. These formulations are known in the art.

[0082] The total effective amount of the compound of the present invention can be administered as a single dose or in a fractionated treatment protocol in which multiple doses are administered over a long period of time. The content of the active ingredient (compound of the present invention) in the pharmaceutical composition of the present invention can be varied depending on the severity and / or purpose of the disease. Typically, the effective dose of the pharmaceutical composition is 0.01 μg to 10,000 mg, preferably 0.1 μg to 1,000 mg, and can be administered several times daily. However, the effective dose of the pharmaceutical composition is determined by taking into account various factors, such as the formulation method, administration route, and number of treatments, as well as the patient's age, weight, health condition, sex, severity of the disease, diet, and excretion rate. Taking these factors into consideration, a person skilled in the art would be able to determine an appropriate effective dose of the composition of the present invention. The pharmaceutical composition of the present invention is not particularly limited in its dosage form, administration route, or administration method, as long as it exhibits the effects of the present invention.

[0083] The present invention also provides a pharmaceutical composition for preventing or suppressing cancer metastasis, which comprises the compound, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0084] The cancer is not particularly limited in type as long as it is known in the art as a malignant tumor, and may be selected from the group consisting of breast cancer, colon cancer, lung cancer, small cell lung cancer, gastric cancer, liver cancer, blood cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, colon cancer, fallopian tube carcinoma, endometrial carcinoma, cervical cancer, vaginal cancer, vulvar carcinoma, Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine gland cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis carcinoma, CNS tumor, primary CNS lymphoma, spinal cord tumor, brainstem glioma, and pituitary adenoma.

[0085] The present invention also provides use of the compound, its isomer, or a pharmaceutically acceptable salt thereof for producing a therapeutic composition for treating an immune cell migration-associated disease.

[0086] The present invention also provides a method for treating an immune cell migration-associated disease, comprising administering to an individual in need thereof an effective amount of a composition comprising the compound, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0087] The present invention also provides use of the compound, an isomer thereof, or a pharmaceutically acceptable salt thereof for producing a composition for inhibiting cancer metastasis.

[0088] The present invention also provides a method for suppressing cancer, which comprises administering an effective amount of a composition containing the compound, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient to an individual in need thereof.

[0089] The term "effective amount" as used herein means an amount that shows an effect of improving, treating, detecting, diagnosing, suppressing, or reducing cancer or the disease when administered to an individual, and the "individual" may be an animal, preferably a mammal, particularly an animal including a human, or may be a cell, tissue, organ, etc. derived from an animal. The individual may be a patient in need of the effect.

[0090] The term "treatment" as used herein refers comprehensively to improving symptoms of cancer or the disease, which may include curing, substantially preventing, or improving the condition of the disease, and includes, but is not limited to, alleviating, curing, or preventing one or most of the symptoms resulting from the disease.

[0091] As used herein, the term "comprising" is used interchangeably with "including" or "characterized by" and does not exclude additional components or method steps not specifically recited in the compositions or methods of the present invention. The term "consisting of" means excluding additional elements, steps, or ingredients not otherwise recited. The term "essentially consisting of" means that the scope of a composition or method may include, in addition to the recited materials or steps, materials or steps that do not substantially affect the basic characteristics of the composition or method. [Effects of the Invention]

[0092] The novel compound of the present invention can regulate the migration of immune cells and cancer cells by inhibiting the activity of KARS1, thereby showing very significant effects in the prevention, amelioration, and treatment of diseases associated with immune cell migration and cancer metastasis. [Brief explanation of the drawings]

[0093] [Figure 1] FIG. 1 shows the results of evaluating the inhibitory ability of compound No. 25 (C0047) and compound No. 43 (C0216) against KARS1-induced migration of Raw264.7 cells. [Figure 2] FIG. 2 shows the results of evaluating the ability to inhibit cancer cell migration after treating cancer cells with compound No. 25 (C0047) and compound No. 43 (C0216) according to the present invention (LN: laminin 421). [Figure 3]FIG. 3 shows the 10 mpk rat po PK (pharmacokinetic) results of Compound No. 25 (C0047), Compound No. 41 (C0189), Compound No. 42 (C0190), and Compound No. 43 (C0216) according to the present invention. [Figure 4] FIG. 4 shows the 30 mpk rat po PK (pharmacokinetics) results of Compound No. 25 (C0047), Compound No. 41 (C0189), and Compound No. 43 (C0216) according to the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0094] The present invention will be described in more detail with reference to the following examples, but the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

[0095] [Example 1] Preparation of Compound In the present invention, the compound of Formula 1 was prepared according to the following synthesis methods 1 to 4: Synthesis method 1 [ka]

[0096] Synthesis method 2 [ka]

[0097] Synthesis method 3 [ka]

[0098] [ka]

[0099] In the above synthesis method, A, B, Q, D, E, Z, and R1 to R10 are as defined above.

[0100] Specific examples, structures, and NMR analysis results of the compounds of Formula 1 prepared by the above method are shown in Tables 1 and 2 below. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13] [Table 14] [Table 15] [Table 16] [Table 17]

[0101] [Example 2] Evaluation of immune cell migration inhibitory activity The 49 compounds synthesized above were evaluated for their immune cell metastasis inhibitory activity.

[0102] Cell migration was performed based on a previous publication (Park, SG et al. Human lysyl-tRNA synthetase is secreted to trigger proinflammatory response. Proceedings of the National Academy of Sciences, 2005, 102.18: 6356-6361.). The specific experimental method is as follows: Transwells (Corning #3421-5 μm pore) were coated with gelatin (0.5 mg / ml), and then Raw 264.7 cells (1 x 10 5 Cells (0.1 μg / well) were seeded into the upper chamber. 500 μl of serum-free DMEM containing LN (Laminin 421 1 μg / ml) was placed in the lower chamber. Each compound was treated at a concentration of 3 μM in the upper chamber. After 24 hours, the cells were fixed with 70% methanol for 30 minutes and then stained with 50% hematoxylin for 30 minutes. Non-migrating cells on the upper side of the membrane were removed with a cotton swab, and the membrane was then mounted on a slide. Migrating cells on the lower side of the membrane were observed under a high-magnification microscope, and the number of cells was counted from the images and expressed as a percentage of inhibition compared to the control group (% inhibition).

[0103] Treatment with 3 μM of the control substance C0001 resulted in an average percentage inhibition of LN-induced cell migration of 41.9%. [ka]

[0104] [Table 18]

[0105] [Example 3] Cell-free ELISA analysis confirming inhibition of binding between KARS1 and 37LR

[0106] Next, cell-free ELISA analysis was performed to select compounds with high inhibitory activity against the protein binding between KARS1 and LR (laminin receptor) based on their mechanism of action.

[0107] In the experiment, KARS1 (1-207aa)-coated plates were treated with LRF (TRX-His-Laminin receptor full length) and compounds at 10 μM, and the reaction was allowed to proceed for 1 hour to confirm whether the compounds inhibited the protein binding between KARS1 and 37LR (Table 4).

[0108] As a control, we used a KARS1 inhibitor (C0001) synthesized in another study by the inventors. When treated with 10 μM of the control substance C0001, the % inhibition of protein binding between KARS1 and 37LR was 64.5.

[0109] [Table 19]

[0110] [Example 4] KARS1-dependent cell migration inhibition C0001 inhibits the binding of KARS1 and 67LR, preventing monocyte / macrophage migration and suppressing inflammation. To this end, we initially screened for drugs that inhibit monocyte / macrophage migration through a transmigration assay using mouse macrophages, Raw264.7.

[0111] KARS1 is known to be secreted extracellularly in an inflammatory environment and to induce migration and M1 polarization of macrophages and peripheral blood mononuclear cells.

[0112] Based on this, direct external treatment with KARS1 protein instead of LN induced cell-to-cell migration of Raw264.7, confirming the inhibitory effect of C0001, a KARS1 inhibitor. We confirmed that C0001, which specifically binds to KARS1, inhibits cell migration by binding to extracellular KARS1, in addition to inhibiting Raw264.7 cell migration through the inhibition of laminin-induced KARS1 cell membrane migration and binding to 67LR. This assay can now be used as a direct assay to evaluate in vitro activity against KARS1.

[0113] An assay for directly inhibiting KARS1-induced cell migration was established, and analysis was performed by treating each of the preliminary candidate substances at a concentration of 1 μM (Table 5).

[0114] As a control, we used a KARS1 inhibitor (C0001) synthesized in another study by the inventors. Treatment with 1 μM of the control substance C0001 resulted in a 68.7% inhibition of KARS1-induced cell migration.

[0115] [Table 20]

[0116] Next, preliminary candidate substances that showed high inhibitory activity at 1 μM were treated at concentrations of 0.1 to 4 μM and analyzed.

[0117] The EC50 values ​​for C0001, compound 25 (C0047), and compound 43 (C0216) were 0.75, 0.57, and 0.64 μM, respectively. These values ​​were similar in activity to the EC50 values ​​of 7.93, 5.96, and 5.09 μM for LN-induced cell migration inhibition, but were approximately 10-fold more sensitive. Compound 47 (C0238) showed the highest activity, with an EC50 of 0.08 μM, approximately 10-fold more potent than C0001 (Figure 1).

[0118] [Example 5] Evaluation of cancer cell migration inhibitory activity The cancer cell metastasis inhibitory activity of three compounds (C0001), 25 (C0047), and 43 (C0216) was evaluated.

[0119] The specific experimental method for cell migration was as follows. The upper chamber of a transwell (Corning #3422-8 μm pore) was turned upside down, and 70 μL of LN (Laminin 421 5 μg / mL) diluted with DPBS was dispensed onto the upper surface and coated at 4°C for 24 hours. Then, A549 cells (5 x 10 4 Cells (0.1 μM / well) were seeded into the membrane, and serum-free medium (700 μL) was placed in the lower chamber. The lower chamber was treated with each compound at a concentration of 3 μM. For the drug control group, DMSO was added at the same concentration as the compound. The cells were cultured in a 5% CO2 cell incubator for 6 hours. The cells were fixed with 70% ethanol for 1 hour and then stained with 0.1% crystal violet for 20 minutes. Non-migrating cells on the upper side of the membrane were removed with a cotton swab and allowed to dry at room temperature for 24 hours. Migrated cells on the lower side of the membrane were observed under a high-power microscope at 100X magnification, and the cell number was determined from the images using the Image-J program (Figure 2).

[0120] [Example 6] Evaluation of metabolic stability To evaluate the metabolic stability (MS) of the selected compounds, in vitro stability measurements were performed in rats and humans using the microsomal stability measurement method. As a result, we discovered that the MS changes with the conversion of parts A, B, and C.

[0121] Table 6 shows a list of six compounds that showed improved effects compared to C0001 in MS, which confirmed the microsomal stability in rats and humans by measuring the remaining percentage after 30 minutes.

[0122] [Table 21]

[0123] Of these, compounds 25 (C0047) and 43 (C0216), which showed improved MS, as well as C0001, were subjected to secondary MS analysis using the S9 method. In this study, the remaining % was measured at 30, 45, and 60 minutes for four S9s: mouse, rat, dog, and human. As a result, compounds 25 and 43 showed improved S9 stability in all four cases compared to C0001, and compound 43 was confirmed to have the most stable metabolic stability (Table 7).

[0124] In particular, MS in humans showed over 70% stability up to 60 minutes, and similar stability was observed in all four species: mouse, rat, dog, and human. This suggests that predictable and stable evaluations will be possible in efficacy and toxicity tests during future drug development.

[0125] [Table 22]

[0126] [Example 8] Pharmacokinetic analysis

[0127] Pharmacokinetic (PK) analysis was performed in rats for five compounds that showed improvement in MS in both rats and humans compared to C0001. To achieve this, formulations that could be administered orally (po) and intravenously (iv) were selected for each compound to ensure stable PK progression.

[0128] The formulations were selected based on the PO dose of 10 or 30 mpk and the condition that a clear solution was maintained for more than 1 hour, and the IV formulation was selected based on the PO dose, but was changed when IV use was not possible (Table 8).

[0129] [Table 23]

[0130] To confirm the oral administration of the selected compounds, a 10 mpk rat PO PK study was performed. The PK profiles and main indices after 10 mpk administration of five compounds, C0001, 25, 41, 42, and 43, are shown in Figure 3 and Table 9.

[0131] Of the five compounds, compound 42 showed the lowest blood exposure with an AUC value of 1,425 ng*h / ml, while compounds C0001, 25, 41, and 43 showed exposures above the reference value with AUC values ​​of 5,000 ng*h / ml or higher, confirming the feasibility of oral administration. Compound 41, with the highest AUC value, showed an AUC value of 11,859 μg*h / ml at 10 mpk po PK, demonstrating a pharmacokinetic profile that was more than two-fold higher than that of compound C0001.

[0132] [Table 24]

[0133] Although none of the substances had an improved half-life compared to C0001, Nos. 25, 41, and 43 showed different Tmax and pharmacokinetic profiles from C0001. In particular, Nos. 25 and 43 showed different blood drug elimination profiles, and considering that the stability of these two substances was improved in previous MS, it was possible to predict in vivo profiles that were differentiated from C0001.

[0134] Based on the results of the previous 10 mpk po rat PK study, a 30 mpk po rat PK study was performed to confirm changes in the blood PK profile of the four compounds C0001, 25, 41, and 43 with increasing dose.

[0135] As a result, all of Nos. 25, 41, and 43 showed higher exposure than C0001. In the case of No. 41, which showed the highest exposure at 10 mpk po PK, the AUC value increased by approximately 2.4-fold at 30 mpk, showing no greater increase in AUC than C0001. On the other hand, Nos. 25 and 43 showed 10.4-fold and 5.7-fold increases, respectively, demonstrating a dose-dependent increase in exposure (Figure 4 and Table 10).

[0136] [Table 25]

[0137] [Example 9] Bioavailability measurement

[0138] Through rat PK at 10 and 30 mpk, compounds 25 and 43 were identified, which showed higher blood exposure and dose-dependent increases compared to C0001. These two compounds were rapidly eliminated from the blood, had shorter half-lives compared to C0001, and were predicted to exhibit differentiated in vivo profiles, including differences in organ distribution. Compound 41 showed high blood exposure at low doses, but no dose-dependent increase in exposure was observed. It also showed similar half-lives and blood elimination rates, suggesting it would not exhibit a differentiated in vivo profile.

[0139] Therefore, three compounds, including Nos. 25 and 43, which had similar target binding inhibitory potency to C0001 but slightly improved in vitro cell migration inhibitory potency and were expected to have differentiated in vivo profiles, were selected as the final preliminary candidate group, and a 2 mpk iv rat PK study was performed on these compounds to calculate their bioavailability (hereinafter referred to as BA) (Table 11).

[0140] [Table 26]

[0141] The preliminary candidates, Nos. 25 and 43, showed higher BA than C0001 and were also dose-dependent. Therefore, Nos. 25 and 43 were predicted to have high pharmacological activity as orally administered drugs.

[0142] [Example 10] Organ Distribution Measurement Although the target binding inhibitory potency was similar to that of C0001, the in vitro cell migration inhibitory potency was slightly improved. In response to this, three types, including No. 25 and No. 43, which are expected to have differentiated in vivo profiles including bioavailability, were selected as the first preliminary candidate group, and their distribution patterns by various organs were analyzed.

[0143] The preliminary candidate compound, compound 25, showed a pattern of increased plasma exposure and a rapid decrease in plasma exposure within a short period of time compared to compound C0001. Compound 43 also showed an increase in plasma exposure within a short period of time, but the decrease was somewhat slower. Furthermore, unlike compound C0001, which showed a liver-specific distribution pattern, the two selected compounds were highly distributed in various organs. Therefore, compounds 25 and 43 not only had high internal exposure and drug activity as orally administered drugs, but also showed distribution in various organs, demonstrating the potential for development as drugs differentiated from compound C0001 (Table 12).

[0144] [Table 27] [Industrial Applicability]

[0145] The novel compound of the present invention can regulate the migration of immune cells and cancer cells by inhibiting the activity of KARS1, thereby showing very significant effects in the prevention, amelioration, and treatment of diseases related to immune cell migration and cancer metastasis, and has very high industrial applicability.

Claims

1. A compound represented by the following chemical formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof: 【Chemistry 10】 wherein X is O, NH, S, or CH═N; A is a C5-C10 aryl or a 5-10 atom heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S, which together with B form a bicyclic aromatic ring; R 1 , R 2 , R 3 , R 4 each independently is absent, hydrogen, halogen, ═O, C1-C6 alkyl, or amine; Z is two H or O, R 5 is C1-C6 alkoxy, -(C=O)NH 2 , or -OCF 3 substituted or unsubstituted C5-C10 aryl or pyridinonyl; Q is hydrogen or methylene; D is carboxyl, C5-C10 aryl, benzimidazolyl, benzoxazolyl, isoindolinyl, -C=O-, -C 6 H 4 C=O- or -C 6 H 4 NH-, R 8 is hydrogen or C1-C6 alkyl, When D is aryl, E is selected from the group consisting of phenyl, C1-C6 alkylene, C2-C8 alkylaminocarbonyl, heterocycloalkyl of 3 to 10 atoms containing one or more heteroatoms selected from the group consisting of N, O, and S, heteroaryl of 5 to 10 atoms containing one or more heteroatoms selected from the group consisting of N, O, and S, C3-C10 cycloalkylamine, C3-C10 cycloalkyl, -B(OH)O-, -CH 2 CH 2 (C=O), -C≡C-, -C≡C-(C=O)N-, -cyclobutyl-(C=O)-, -azetinyl-(C=O)-, -C 6 H 4 -(C=O)-, -pyrrolidinyl-(C=O)-, -furanyl-(C=O)-, -piperidinyl-(C=O)-, -pyrazolyl-(C=O)-, or pyrrolyl-(C=O)-, wherein R 6 , R 7 are each independently absent, hydrogen, a carboxylic acid, a C1-C6 alkyl, a C2-C8 alkylaminocarbonyl, an aminocarbonyl, a hydroxyl, or -Si(CH 3 ) 3 and E is hydrogen, halogen, -C≡C-, -C≡C-(C=O) when A is pyrrole or pyridone and D is aryl, and in this case R 6 , R 7 are each independently absent, hydrogen, carboxyl, OH, CH 3 , C.H. 2 CH 3 , -Si(CH 3 ) 3 It consists of E is -C=O-, benzimidazolyl, benzoxazolyl, isoindolinyl, -C 6 H 4 C=O- or -C 6 H 4 When NH-, it is absent or -B(OH) 2 , carboxyl, hydrogen, aminocarbonyl, aminosulfonyl, C1-C6 alkylene, -(C=O)-, -C≡C-, -S(=O) 2 -, -CH 2 (C=O)-, -B(OH)O-, -CHR 10 (C=O)-, -NHCHR 10 (C=O)-, cyclobutyl-(C=O)-, furanyl-(C=O)-, or pyrrolidinyl-(C=O)-, wherein R 6 , R 7 are each independently absent, carboxyl, hydrogen, hydroxy, C1-C6 alkyl, or amine; R 9 is hydrogen or C1-C6 alkyl, R 10 is hydrogen, C1-C6 alkyl, or C1-C6 hydroxyalkyl.

2. The compound according to claim 1, its isomer, or its pharmaceutically acceptable salt, characterized in that A is benzene, pyridine, pyrimidine, pyridone, or pyrrole, which forms a bicyclic aromatic ring together with B.

3. The compound according to claim 1, its isomer, or a pharmaceutically acceptable salt thereof, wherein the bicyclic aromatic ring formed by A and B is selected from the following structures: 【Chemistry 11】

4. R 5 But methoxy, -(C=O)NH 2 , or -OCF 3 2. The compound of claim 1, its isomer, or a pharmaceutically acceptable salt thereof, characterized in that it is phenyl or pyridinonyl substituted with:

5. 2. The compound according to claim 1, its isomer, or a pharmaceutically acceptable salt thereof, wherein D is phenyl, carboxyl, benzimidazolyl, benzoxazolyl, or isoindolinyl.

6. When D is aryl and A is not pyrrole or pyridone, E is phenyl, ethylene, -C≡C-, pyrrolidinyl, pyrrolidinylcarbonyl, methylaminocarbonyl, furanyl, cyclobutynylamino, pyrrolyl, cyclobutyl, or azetidinyl, wherein R 6 , R 7 are each independently absent, hydrogen, carboxyl, diethylaminocarbonyl, methylaminocarbonyl, aminocarbonyl, -Si(CH 3 ) 3 2. The compound according to claim 1, its isomer, or a pharmaceutically acceptable salt thereof, wherein R is 1 or 2; or R is 2 or 3; or R is 4 or 5;

7. When D is aryl and A is pyrrole or pyridone, E is halogen or -C≡C-, where R 6 , R 7 are each independently absent, hydrogen, Si(CH 3 ) 3 2. The compound according to claim 1, its isomer, or a pharmaceutically acceptable salt thereof, wherein:

8. When D is benzimidazolyl, benzoxazolyl, or isoindolinyl, E is hydrogen, -B(OH) 2 , carboxyl, aminocarbonyl, aminosulfonyl, or methylene, where R 6 , R 7 The compound according to claim 1, its isomer, or a pharmaceutically acceptable salt thereof, wherein each of the groups is independently absent or carboxyl.

9. The compound of claim 1, its isomer, or a pharmaceutically acceptable salt thereof, wherein the compound represented by Chemical Formula 1 is selected from the group consisting of the following compounds: N-([1,1'-biphenyl]-4-ylmethyl)-N-(4-methoxyphenethyl)thiazolo[5,4-b]pyridin-2-amine, 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)propanoic acid, N,N-diethyl-3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphen-ethyl)amino)methyl)phenyl)propiolamide, 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)-N-methylpropiolamide, 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)propiolamide, N-(4-methoxyphenethyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine, N-(4-bromobenzyl)-N-(4-methoxyphenethyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 7-fluoro-N-(4-methoxyphenethyl)-N-(3-((trimethylsilyl)ethynyl)-benzyl)benzo[d]thiazol-2-amine, N-(3-ethynylbenzyl)-7-fluoro-N-(4-methoxyphenethyl)benzo[d]thiazol-2-amine, N-(4-methoxyphenethyl)-7-methyl-N-(4-((trimethylsilyl)ethynyl)-benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, N-(4-ethynylbenzyl)-N-(4-methoxyphenethyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 3-(4-(((4-methoxyphenethyl)(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)methyl)phenyl)propiolic acid, 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)pyrrolidine-3-carboxylic acid, (4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)benzoyl)-L-proline, 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)benzoyl)pyrrolidine-3-carboxylic acid, (4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)benzoyl)glycine, 1-(3-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)pyrrolidine-3-carboxylic acid, (4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)benzoyl)-D-valine, (4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)-L-proline, (3-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)-L-proline, (2-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)-1-methyl-1H-benzo[d]imidazol-6-yl)boronic acid, (S)-1-(3-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)pyrrolidine-3-carboxylic acid, (R)-1-(3-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)pyrrolidine-3-carboxylic acid, (R)-1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)-amino)methyl)phenyl)pyrrolidine-3-carboxylic acid, (S)-1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)pyrrolidine-3-carboxylic acid, 5-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)furan-2-carboxylic acid, 2-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)-1-methyl-1H-benzo[d]imidazole-6-carboxylic acid, 2-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)benzo[d]oxazole-5-carboxylic acid, 7-fluoro-N-(isoindolin-5-ylmethyl)-N-(4-methoxyphenethyl)benzo-[d]thiazol-2-amine, 5-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)isoindoline-2-carboxamide, 5-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)isoindoline-2-sulfonamide, 2-(5-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)isoindolin-2-yl)acetic acid, 1-((4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)amino)cyclobutane-1-carboxylic acid, 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)-1H-pyrrole-3-carboxylic acid, N-(7-fluorobenzo[d]thiazol-2-yl)-N-(4-methoxyphenethyl)glycine, 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)cyclobutane-1-carboxylic acid, (R)-1-(4-((benzo[d]oxazol-2-yl(4-methoxyphenethyl)amino)methyl)-phenyl)pyrrolidine-3-carboxylic acid, (S)-1-(4-((benzo[d]oxazol-2-yl(4-methoxyphenethyl)amino)methyl)-phenyl)pyrrolidine-3-carboxylic acid, 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)azetidine-3-carboxylic acid, (R)-1-(3-(((7-fluorobenzo[d]thiazol-2-yl)(4-(trifluoromethoxy)-phenethyl)amino)methyl)phenyl)pyrrolidine-3-carboxylic acid, (3R)-1-(3-(1-((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)-amino)ethyl)phenyl)pyrrolidine-3-carboxylic acid, (3S)-1-(4-(1-((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)-amino)ethyl)phenyl)pyrrolidine-3-carboxylic acid, (S)-1-(4-(((4-methoxyphenethyl)(4,5,7-trifluorobenzo[d]thiazol-2-yl)amino)methyl)phenyl)pyrrolidine-3-carboxylic acid, 3-(4-(((4-methoxyphenethyl)(oxazolo[5,4-b]pyridin-2-yl)amino)-methyl)phenyl)propiolic acid, 3-(4-(((4-methoxyphenethyl)(5-oxo-4,5-dihydrothiazolo[5,4-b]pyridin-2-yl)amino)methyl)phenyl)propiolic acid, 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)piperidine-4-carboxylic acid, 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)-1H-pyrazole-4-carboxylic acid, (S)-1-(4-(((4-carbamoylphenethyl)(7-fluorobenzo[d]thiazol-2-yl)amino)methyl)phenyl)pyrrolidine-3-carboxylic acid, (S)-1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(2-(2-oxopyridin-1(2H)-yl)ethyl)amino)methyl)phenyl)pyrrolidine-3-carboxylic acid

10. A pharmaceutical composition for preventing or treating a disease associated with immune cell migration, comprising the compound according to any one of claims 1 to 9, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

11. The composition of claim 10, wherein the immune cell migration-associated disease is selected from the group consisting of cardiovascular diseases, fibrotic diseases, inflammatory diseases, and Alport syndrome.

12. 12. The composition of claim 11, wherein the cardiovascular disease is selected from the group consisting of hypertension, pulmonary arterial hypertension, atherosclerosis, angina pectoris, myocardial infarction, ischemic cerebrovascular disease, arteriolosclerosis, and medial sclerosis.

13. The fibrotic disease may be scleroderma, rheumatoid arthritis, Crohn's disease, ulcerative colitis, myelofibrosis, pulmonary fibrosis, hepathic fibrosis, liver cirrhosis, kidney fibrosis, glomerular sclerosis, myofibrosis, cardiac fibrosis, interstitial fibrosis, pancreatic fibrosis, splenic fibrosis, mediastinal fibrosis, vascular fibrosis, cutaneous fibrosis, ocular fibrosis, macular degeneration, arthrofibrosis, thyroid fibrosis, endomyocardial fibrosis, peritoneal fibrosis, retroperitoneal fibrosis, progressive nodular fibrosis, nephrogenic systemic fibrosis, systemic lupus erythematosus, or the like. erythematosus), hereditary fibrosis, infectious fibrosis, irritative fibrosis, fibrosis due to chronic autoimmunity, fibrosis due to antigen incompatibility during organ transplantation, fibrotic complications of surgery, fibrosis due to hyperlipidemia, fibrosis due to obesity, diabetic fibrosis, fibrosis due to hypertension, and fibrotic obstruction during stent insertion.

14. The inflammatory disease may be an autoimmune disease, an inflammatory bowel disease, dermatitis, atopic dermatitis, eczema, psoriasis, diabetic eye disease, diabetic retinopathy, peritonitis, osteomyelitis, cellulitis, meningitis, encephalitis, pancreatitis, trauma-induced shock, bronchial asthma, rhinitis, sinusitis, otitis media, pneumonia, gastritis, enteritis, cystic fibrosis, stroke, bronchitis, bronchiolitis, hepatitis, cirrhosis, non-alcoholic steatohepatitis, or the like. steatohepatitis), nephritis, proteinuria, diabetic renal failure, arthritis, psoriatic arthritis, neuritis, diabetic neuropathy, multiple sclerosis, gout, spondylitis, Reiter's syndrome, polyarteritis nodosa, vasculitis, amyotrophic lateral sclerosis (Lou Gehrig's disease), granulomatosis with polyangiitis (Wegener's granulomatosis), hypercytokinemia, polymyalgia rheumatica, arthrocellular arteritis, calcium crystal deposition arthropathy, pseudogout, non-rheumatoid arthritis, bursitis, tenosynovitis, epicondylitis, neuropathic joint disease (Charcot's syndrome) 12. The composition of claim 11, wherein the inflammatory bowel disease is selected from the group consisting of inflammatory bowel disease (IGD), hematocrit, Henoch-Schönlein purpura, hypertrophic osteoarthropathy, multicentric reticulohistiocytoma, sarcoidosis, hemochromatosis, sickle cell disease, hyperlipoproteinemia, hypogammaglobulinemia, hyperparathyroidism, acromegaly, familial Mediterranean fever, Behcet's disease, systemic lupus erythematosus, relapsing fever, psoriasis, multiple sclerosis, sepsis, septic shock, acute respiratory distress syndrome, multiple organ failure, chronic obstructive pulmonary disease, acute lung injury, and bronchopulmonary dysplasia.

15. 15. The composition of claim 14, wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus, psoriasis, asthma, ulcerative colitis, Behcet's disease, Crohn's disease, multiple sclerosis, dermatomyositis, collagen disease, vasculitis, arthritis, granulomatous disease, organ-specific autoimmune disease, ulcerative colitis, and graft-versus-host disease.

16. A pharmaceutical composition for preventing or suppressing cancer metastasis, comprising the compound according to any one of claims 1 to 9, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

17. Use of the compound according to any one of claims 1 to 9, its isomer, or a pharmaceutically acceptable salt thereof for the manufacture of a composition for treating an immune cell migration-associated disease.

18. A method for treating an immune cell migration-associated disease, comprising administering to an individual in need thereof an effective amount of a composition comprising, as an active ingredient, the compound according to any one of claims 1 to 9, an isomer thereof, or a pharmaceutically acceptable salt thereof.

19. Use of the compound according to any one of claims 1 to 9, its isomer, or its pharmaceutically acceptable salt for the manufacture of a composition for inhibiting cancer metastasis.

20. A method for suppressing cancer, comprising administering an effective amount of a composition containing, as an active ingredient, the compound according to any one of claims 1 to 9, an isomer thereof, or a pharmaceutically acceptable salt thereof to an individual in need thereof.

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