Composition for preventing or treating diseases caused by immune cell migration, comprising lysyl-trna synthetase 1 inhibitor

Abstract

The present invention relates to a composition for preventing or treating diseases caused by immune cell migration, the composition comprising a lysyl-tRNA synthetase 1 (KARS1) inhibitor.

Description

Composition for preventing or treating diseases caused by immune cell migration comprising a lysyl-tRNA synthetase 1 inhibitor

[0001] This application claims the benefit of Republic of Korea Patent Application No. 10-2024-0098180, filed on July 24, 2024, the entire disclosure of which is incorporated herein by reference.

[0002] The present invention relates to a composition for preventing or treating a disease by immune cell migration, comprising a lysyl-tRNA synthetase 1 (KARS1) inhibitor.

[0003]

[0004] In various tissues within the body, each cell migrates in different ways depending on its genetic characteristics and environment. It has been reported that even the same factor interacts differently with each cell, making it more difficult to elucidate signaling processes and mechanisms. For example, AQP1 (water channel aquaporin-1) is known to promote cell migration in epithelial cells and is particularly known to promote cancer metastasis. However, despite expressing AQP1 in macrophages, it is known in the art to inhibit their migration. Because each cell has various methods and characteristics for migration, existing drugs designed to inhibit specific cell migration have shown considerable limitations and insufficient efficacy. Therefore, there is a pressing need to explore new strategies to control the cell migratory switch and treat migration-related diseases.

[0005]

[0006] Meanwhile, when inflammatory immune cells are activated, increased immune cell mobility is generally observed, and specifically, in the following diseases, such immune cell migration and infiltration are reported to be closely related to the pathology of the disease.

[0007]

[0008] For example, cardiovascular disease (CVD) refers to diseases that occur in the heart and major arteries, and includes atherosclerosis and coronary artery disease. Atherosclerosis is an inflammatory disease caused by cholesterol, and is caused by atheroma, which is composed of cholesterol deposited in the inner lining of the artery and immune cells that migrate from the blood into the artery. Previously, it was known that CCL2 (CC-Chemokine ligand 2, MCP-1), which induces monocyte migration and thus triggers an inflammatory response, plays a key role in the occurrence and development of such cardiovascular diseases. Therefore, a new method for treating such cardiovascular diseases by inhibiting the action of CCL2 and the resulting monocyte migration has been proposed. Furthermore, hypertension is also related to the pathology in which various immune cells that secrete inflammatory cytokines excessively migrate into the blood vessels, thickening the blood vessel walls and causing a loss of vascular elasticity.

[0009]

[0010] Meanwhile, in diseases associated with fibrosis, a persistent (chronic) inflammatory response activates a wound-healing program, which leads to fibrosis. Following tissue damage, inflammatory immune cells, such as monocytes / macrophages, neutrophils, eosinophils, and mast cells, rapidly infiltrate the damaged area and become activated. They secrete various cytokines, which in turn activate surrounding fibroblasts, epithelial cells, and smooth muscle cells into myoblasts. These myoblasts produce and secrete large amounts of extracellular matrix proteins, ultimately leading to the accumulation of these proteins in tissues, leaving scars and inducing fibrosis or hypertrophy. This pathological mechanism is one of the fundamental causes of scarring in skin tissues caused by wounds, burns, and pressure ulcers, as well as sclerosing 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. Furthermore, the activation of inflammatory immune cells is known to contribute to the pathological phenomena of atopic diseases, asthma, COPD, psoriasis, keloids, and proliferative retinopathy.

[0011]

[0012] While monocytes and macrophages contribute to wound healing, they also secrete reactive oxygen and nitrogen, which can have detrimental effects on surrounding cells. Consequently, failure to rapidly remove monocytes and macrophages can lead to further tissue damage and fibrosis. Therefore, limiting monocytes and macrophages, which are the first to respond in the early stages of disease, is considered a therapeutic strategy for various chronic inflammatory and fibrotic diseases.

[0013]

[0014] When the above wound healing mechanism triggers a fibrotic response, platelet-derived growth factor (PDGF), involved in hemagglutination, is known to recruit other inflammatory immune cells to the wound site, and transforming growth factor-β1 (TGF-β1) promotes extracellular matrix synthesis from local fibroblasts. However, it has been reported that factors involved in hemagglutination can induce fibrosis even when they are deficient.

[0015]

[0016] As mentioned above, in diseases where excessive immune cell activation is a problem, target factors to block the movement (and infiltration) of immune cells have been proposed, and attempts are being made to devise therapeutic methods targeting these factors. However, each of these has its own limitations, and accordingly, it is still an important task to find out what the key mediator is in the movement of immune cells and what strategies to control it are for effective disease treatment.

[0017]

[0018] Accordingly, the present inventors, while researching to find a new therapeutic strategy for diseases related to immune cell migration (infiltration) through existing research, confirmed that the phenomenon of increased KARS1 levels in the cell membrane region of immune cells (monocytes / macrophages) is an important pathological phenomenon for diseases related to immune cell migration and infiltration, and confirmed that novel compounds represented by the general formula of Chemical Formula 1 have the effect of inhibiting immune cell migration and infiltration by inhibiting the activity of KARS1 and inhibiting the migration of cancer cells, thereby treating related diseases, and completed the present invention.

[0019]

[0020] Accordingly, the purpose of the present invention is to provide a pharmaceutical composition for preventing or treating a disease related to immune cell movement, comprising a compound of the following chemical formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient:

[0021] [Chemical Formula 1]

[0022]

[0023] In the above formula,

[0024] X is one of O, NH, S or CH=N,

[0025] A is a C5~C10 aryl forming a bicyclic aromatic ring together with B or a 5~10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S,

[0026] R1, R2, R3, R4 are each independently absent or hydrogen, halogen (F, Cl, Br), =O, C1~C6 alkyl, amine, C1~C6 substituted amine, C1~C6 alkoxy, C1~C6 amino alkyl, -CF3, -CN, -NO 2, or aminocarbonyl substituted or unsubstituted with one or more C1~C6 alkyl,

[0027] Q is absent, H, a C1~C3 alkyl group, or -(C=O)-,

[0028] R5 is hydrogen or C1~C6 alkyl,

[0029] D is absent, carboxyl, -CN, -CH2-, -C≡C-, C1~C6 alkylene, C6~C10 aryl, 5~10 membered heteroaryl, C5~C6 cycloalkyl, 5~7 membered heterocycloalkyl, isoindoline, -(C=O)-, -C6H4(C=O)- or -C6H4NH-,

[0030] R6 is one or more substituents, each independently hydrogen, C1~C6 alkyl, F, Cl, OH, NH2 or C1~C6 alkoxy,

[0031] E is -C≡C-, sulfonic acid, -CN, 5-10 membered heteroaryl when D is not present,

[0032] E is when D is -C≡C-, phenyl, heteroaryl of 5 to 10 atoms, cycloalkyl of C3 to C6, heterocycloalkyl of 5 to 7 atoms, alkylaminocarbonyl of C2 to C8, -(C=O)-, -C6H4(C=O)-, or -C6H4NH-, alkyl of C1 to C4, -C=C-, -C≡C-, Br, -C≡C(C=O)-, -NHCH-, -B(OH)O-, -CH2CH2(C=O)-, -cyclobutyl-(C=O)-, -azetinyl-(C=O)-, -pyrrolidinyl-(C=O)-, -furanyl-(C=O)-, -piperidinyl-(C=O)-, -pyrazolyl-(C=O)-, -pyrrolyl-(C=O)-, phenyl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, C3-C10 cycloalkylamine, C5-C7 cycloalkenyl, 3-7 membered heterocycloalkyl, isoindoline, or azabicycloheptane,

[0033] R7 and R8 are each independently absent, hydrogen, halogen, hydroxy, amine, trimethylsilyl, amine substituted with one or more C1~C3 alkyl groups, carboxylic acid, boronic acid, ester containing C1~C3 alkyl groups, sulfonic acid, -S(=O)2NH2, oxygen of double bond (=O), -(C=O)NH2, -(C=O)NHCH3, -(C=O)NHC2H5, -(C=O)N(CH3)2, -(C=O)N(C2H5)2, -CH2(C=O)OH, C1~C3 alkyl, C1~C3 alkoxy, C2~C7 alkoxycarbonyl, or However, if D does not exist and E is phenyl and Q is -CH2- or -CH-, then at least one of R7 and R8 is not H and is independently H, Br, C1~C2 alkoxy, amine, or amine substituted with at least one C1~C2 alkyl,

[0034] Z is two H, or O,

[0035] R9 is hydroxy, C3~C10 cycloalkyl, C1~C6 alkoxy, pyridine, 3~10 membered heterocycloalkyl, phenyl, 5~10 membered heteroaryl, or and,

[0036] R10 is one or more substituents, such as heterocycloalkyl having 3 to 10 atoms, H, F, Cl, Br, amine, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 alkylsulfonyl, -CF3, amine, amine substituted with one or more C1 to C6 alkyl substituents, C1 to C6 amino alkyl, amino carbonyl substituted or unsubstituted with C1 to C6 alkyl, -CN, -(C=O)NH2, -S(=O)2CH3, These or when adjacent to each other can combine to form a ring.

[0037]

[0038] Another object of the present invention is to provide a pharmaceutical composition for preventing or inhibiting cancer metastasis, comprising the compound of the above chemical formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0039]

[0040] Another object of the present invention is to provide a use of the compound of formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition for treating a disease related to immune cell movement.

[0041]

[0042] Another object of the present invention is to provide a method for treating a disease related to immune cell movement, which comprises administering an effective amount of a composition containing the compound of the above chemical formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient to a subject in need thereof.

[0043]

[0044] Another object of the present invention is to provide a use of the compound of formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof for providing a pharmaceutical composition for preventing or inhibiting cancer metastasis.

[0045]

[0046] Another object of the present invention is to provide a method for preventing or inhibiting cancer metastasis, characterized in that an effective amount of a composition containing the compound of the above chemical formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient is administered to a subject in need thereof.

[0047]

[0048] In order to achieve the above-mentioned object of the present invention, the present invention provides a pharmaceutical composition for preventing or treating a disease related to immune cell movement, comprising a compound of the following chemical formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient:

[0049] [Chemical Formula 1]

[0050]

[0051] In the above formula,

[0052] X is one of O, NH, S or CH=N,

[0053] A is a C5~C10 aryl forming a bicyclic aromatic ring together with B or a 5~10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S,

[0054] R1, R2, R3, R4 are each independently absent or hydrogen, halogen (F, Cl, Br), =O, C1~C6 alkyl, amine, C1~C6 substituted amine, C1~C6 alkoxy, C1~C6 amino alkyl, -CF3, -CN, -NO 2, or aminocarbonyl substituted or unsubstituted with one or more C1~C6 alkyl,

[0055] Q is absent, H, a C1~C3 alkyl group, or -(C=O)-,

[0056] R5 is hydrogen or C1~C6 alkyl,

[0057] D is absent, carboxyl, -CN, -CH2-, -C≡C-, C1~C6 alkylene, C6~C10 aryl, 5~10 membered heteroaryl, C5~C6 cycloalkyl, 5~7 membered heterocycloalkyl, isoindoline, -(C=O)-, -C6H4(C=O)- or -C6H4NH-,

[0058] R6 is one or more substituents, each independently hydrogen, C1~C6 alkyl, F, Cl, OH, NH2 or C1~C6 alkoxy,

[0059] E is -C≡C-, sulfonic acid, -CN, 5-10 membered heteroaryl when D is not present,

[0060] E is when D is -C≡C-, phenyl, heteroaryl of 5 to 10 atoms, cycloalkyl of C3 to C6, heterocycloalkyl of 5 to 7 atoms, alkylaminocarbonyl of C2 to C8, -(C=O)-, -C6H4(C=O)-, or -C6H4NH-, alkyl of C1 to C4, -C=C-, -C≡C-, Br, -C≡C(C=O)-, -NHCH-, -B(OH)O-, -CH2CH2(C=O)-, -cyclobutyl-(C=O)-, -azetinyl-(C=O)-, -pyrrolidinyl-(C=O)-, -furanyl-(C=O)-, -piperidinyl-(C=O)-, -pyrazolyl-(C=O)-, -pyrrolyl-(C=O)-, phenyl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, C3-C10 cycloalkylamine, C5-C7 cycloalkenyl, 3-7 membered heterocycloalkyl, isoindoline, or azabicycloheptane,

[0061] R7 and R8 are each independently absent, hydrogen, halogen, hydroxy, amine, trimethylsilyl, amine substituted with one or more C1~C3 alkyl groups, carboxylic acid, boronic acid, ester containing C1~C3 alkyl groups, sulfonic acid, -S(=O)2NH2, oxygen of double bond (=O), -(C=O)NH2, -(C=O)NHCH3, -(C=O)NHC2H5, -(C=O)N(CH3)2, -(C=O)N(C2H5)2, -CH2(C=O)OH, C1~C3 alkyl, C1~C3 alkoxy, C2~C7 alkoxycarbonyl,

[0062] or However, if D does not exist and E is phenyl and Q is -CH2- or -CH-, then at least one of R7 and R8 is not H and is independently H, Br, C1~C2 alkoxy, amine, or amine substituted with at least one C1~C2 alkyl,

[0063] Z is two H, or O,

[0064] R9 is hydroxy, C3~C10 cycloalkyl, C1~C6 alkoxy, pyridine, 3~10 membered heterocycloalkyl, phenyl, 5~10 membered heteroaryl, or and,

[0065] R10 is one or more substituents, such as heterocycloalkyl having 3 to 10 atoms, H, F, Cl, Br, amine, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 alkylsulfonyl, -CF3, amine, amine substituted with one or more C1 to C6 alkyl substituents, C1 to C6 amino alkyl, amino carbonyl substituted or unsubstituted with C1 to C6 alkyl, -CN, -(C=O)NH2, -S(=O)2CH3, These or when adjacent to each other can combine to form a ring.

[0066]

[0067] In order to achieve another object of the present invention, the present invention provides a pharmaceutical composition for treating a disease related to immune cell movement, comprising a compound of the above chemical formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof.

[0068]

[0069] In order to achieve another object of the present invention, the present invention provides a pharmaceutical composition for treating a disease related to immune cell movement, which essentially consists of a compound of the above chemical formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof.

[0070]

[0071] In order to achieve another object of the present invention, the present invention provides a pharmaceutical composition for preventing or inhibiting cancer metastasis, comprising a compound of the above chemical formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0072]

[0073] In order to achieve another object of the present invention, the present invention provides a use of the compound of formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition for treating a disease related to immune cell movement.

[0074]

[0075] In order to achieve another object of the present invention, the present invention provides a method for treating a disease related to immune cell movement, which comprises administering an effective amount of a composition comprising a compound of the above chemical formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient to a subject in need thereof.

[0076]

[0077] In order to achieve another object of the present invention, the present invention provides a use of the compound of formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof for providing a pharmaceutical composition for preventing or inhibiting cancer metastasis.

[0078]

[0079] In order to achieve another object of the present invention, the present invention provides a method for preventing or inhibiting cancer metastasis, characterized in that an effective amount of a composition comprising a compound of the above chemical formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient is administered to a subject in need thereof.

[0080]

[0081] In this specification, the term "comprising" is used with the same meaning as "including" or "characterized by", and does not exclude additional components or method steps, etc. that are not specifically mentioned in the composition or method according to the present invention. In addition, the term "consisting of" means excluding additional elements, steps, or components, etc. that are not separately described. The term "essentially consisting of" means that, in the scope of the composition or method, it can include materials or steps, etc. that do not substantially affect the basic characteristics thereof, in addition to the materials or steps described.

[0082]

[0083] The 'treatment' of the present invention comprehensively refers to improving a disease related to immune cell movement or a symptom caused by 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.

[0084]

[0085] In this specification, unless otherwise stated, the alkyl, alkenyl, or alkynyl substituents or alkyne alkenyl moieties of a substituent may be linear or branched (branched chain, side chain). The alkyl and alkenyl chains may also include intervening heteroatoms such as oxygen.

[0086]

[0087] Cx-Cy alkyl refers to a saturated aliphatic hydrocarbon group having xy carbon atoms, which may be linear or branched. C1-C6 alkyl contains 1 to 6 carbon atoms. "Branched" means that the group has 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.

[0088]

[0089] A Cx-Cy alkylene moiety may be linear or branched and refers to a divalent hydrocarbon group having one less hydrogen atom from 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.

[0090]

[0091] C2-C6 alkenyl refers to a linear or branched hydrocarbon chain radical containing at least two carbon atoms and one or more double bonds. Non-limiting examples of alkenyl groups 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.

[0092]

[0093] C1-C6 alkoxy refers to a group or a part of a group having an -O-Cx-Cy alkyl group, as defined above for Cx-Cy alkyl. Non-limiting examples of C1-C6 alkoxy may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy, and hexoxy.

[0094]

[0095] Halogen or halo refers to chlorine (Cl), bromine (Br), fluorine (F), or iodine (I) atoms.

[0096]

[0097] Cx-Cy cycloalkyl refers to a cyclic non-aromatic hydrocarbon group of xy carbon atoms. C3-C10 cycloalkyl refers to a hydrocarbon ring containing 3-10 carbon atoms. Non-limiting examples of C3-C10 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclohexyl cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.

[0098]

[0099] For example, an aryl group refers to any monocyclic or bicyclic hydrocarbon group containing at least one aromatic group, with ring members having 12 or fewer carbon atoms. Non-limiting examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and biphenyl.

[0100]

[0101] A heteroaryl group may be monocyclic or bicyclic. A bicyclic ring may be a fused aromatic ring, wherein the rings are aromatic or fused to one another, wherein one of the rings is non-aromatic. A heteroaryl group contains one, two, or three heteroatoms selected from oxygen (O), sulfur (S), and nitrogen (N). If the heteroatom is nitrogen, it may be oxidized. Non-limiting examples of heteroaryl include pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, indolyl, indolizinyl, isoindolyl, indolinyl, purinyl, furazanyl, imidazolyl, indazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazinanyl, tetrazolyl, thiadiazolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, benzimidazolyl, benzothiazolyl, naphthyridinyl, piperidinyl, pyrazinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, It may include quinazolinyl, imidazopyridinyl, pyrazolopyridinyl, thiazolopyridinyl, indolinyl, isoindolinyl, triazinyl, pyridazinyl, and quinoxalinyl.

[0102]

[0103] A heterocyclyl group may also be a single ring or may comprise two or more fused rings which may be saturated or partially unsaturated and which 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, hexahydropyrimidinyl, pyrazolinyl, pyrazolidinyl, pyridazinyl, 4H-quinolizinyl, quinuclinyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, It may include tetrahydrothiophenyl, tetramethylene sulfoxide, thiazolidinyl, hydantoinyl, benzopyranyl, tetrahydrothiazolopyridinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydropyrazolopyrazinyl, and tetrahydrothiazoloazepinyl.

[0104]

[0105] Pharmaceutically acceptable refers to compositions and molecular entities that are physiologically tolerable and do not generally cause allergic or similar adverse reactions, such as gastrointestinal upset, dizziness, etc., when administered to humans or animals. For example, the term "pharmaceutically acceptable" means that the molecule or the like has been approved by a regulatory agency of a state or federal government of the United States, or is included in the United States Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly, in humans.

[0106]

[0107] General methods for preparing salts are well known to those skilled in the art. The salts may be formed by conventional means, such as by reacting the free acid or free base form of the compound with one or more equivalents of a suitable solvent, or, if the salt is insoluble, by removing the solvent or medium using standard techniques (e.g., vacuum, freeze-drying, or filtration). Salts may also be prepared by exchanging the counter ion of the compound with another counter ion in the form of a salt using an aqueous labeled ion exchange resin.

[0108]

[0109] 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 materials useful for preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0110]

[0111] 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 the 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 sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, 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-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, Propylsulfonate, besylate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharmaceutically acceptable salts can be found in the literature.

[0112]

[0113] 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, calcium), ammonium, and N(C1-C4 alkyl)4+. Also included are base addition salts such as sodium or potassium salts.

[0114]

[0115] General methods for preparing salts are well known to those skilled in the art. The salts may be formed by conventional means, such as by reacting the free acid or free base form of the compound with one or more equivalents of a suitable solvent, or, if the salt is insoluble, by removing the solvent or medium using standard techniques (e.g., vacuum, freeze-drying, or filtration). Salts may also be prepared by exchanging the counter ion of the compound with another counter ion in the form of a salt using an aqueous labeled ion exchange resin.

[0116]

[0117] Also provided are compounds described herein, or pharmaceutically acceptable salts, isomers or mixtures thereof, wherein 1 to n hydrogen atoms attached to a carbon atom may be replaced with deuterium atoms or D, wherein 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 may 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, since such compounds may increase metabolic resistance. See, for example, literature known in the art. Such compounds are synthesized by means well known in the art, for example, using starting materials in which one or more hydrogen atoms are replaced with deuterium. In some embodiments, the compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) comprises one or more deuterium atoms.

[0118]

[0119] Examples of isotopes that can be incorporated into the disclosed compounds are also, respectively, 2 H, 3 H, 11 C, 　13 C, 14C, 13 N, 　15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I and 125 I include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine. Substitution with positron-emitting isotopes such as 11C, 18F, 15O and 13N may be useful in positron emission topography (PET) studies to investigate 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 presented below using appropriate isotopically labeled reagents in place of previously used unlabeled reagents.

[0120]

[0121] The compounds of the embodiments disclosed herein, or pharmaceutically acceptable salts thereof, contain one or more asymmetric centers and therefore can form enantiomers, diastereomers and other stereoisomers which can be defined in terms of absolute stereochemistry as (R)- or (S)-, or in the case of amino acids as (D)- or (L)-. The present disclosure is meant to include all such possible isomers as well as their racemates and optically pure forms. The 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 racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). When a compound described herein contains an olefinic double bond or other center of geometric asymmetry, and unless otherwise specified, the compound is intended to include both E and Z geometric isomers. Likewise, all tautomers are intended to be included. When a compound is represented by its chiral form, it is understood that embodiments include, but are not limited to, the particular diastereomeric or enantiomerically enriched form. When chirality is not specified but is present, embodiments are understood to relate to the particular diastereomeric or enantiomerically enriched form; or a racemic or scalemic mixture of such compound(s). As used herein, a "scalemic mixture" is a mixture of stereoisomers in a ratio other than 1:1.

[0122]

[0123] Stereoisomers are compounds that are non-interchangeable, having identical atoms bonded by identical bonds but different three-dimensional structures. The present disclosure contemplates various stereoisomers and mixtures thereof, including "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other.

[0124]

[0125] Tautomerism refers to the transfer of a proton from one atom of a molecule to another atom of the same molecule. In some embodiments, the present disclosure encompasses tautomers of the compounds.

[0126]

[0127] Solvates refer to the result of the interaction between a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0128]

[0129] Hydrate refers to a compound of the present disclosure chemically bound to one or more water molecules.

[0130]

[0131] Hereinafter, the present invention will be described in detail.

[0132]

[0133] The present invention provides a pharmaceutical composition for preventing or treating a disease related to immune cell movement, comprising a compound of the following chemical formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient:

[0134] [Chemical Formula 1]

[0135]

[0136] In the above formula,

[0137] X is one of O, NH, S or CH=N,

[0138] A is a C5~C10 aryl forming a bicyclic aromatic ring together with B or a 5~10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S,

[0139] R1, R2, R3, R4 are each independently absent or hydrogen, halogen (F, Cl, Br), =O, C1~C6 alkyl, amine, C1~C6 substituted amine, C1~C6 alkoxy, C1~C6 amino alkyl, -CF3, -CN, -NO 2, or aminocarbonyl substituted or unsubstituted with one or more C1~C6 alkyl,

[0140] Q is absent, H, a C1~C3 alkyl group, or -(C=O)-,

[0141] R5 is hydrogen or C1~C6 alkyl,

[0142] D is absent, carboxyl, -CN, -CH2-, -C≡C-, C1~C6 alkylene, C6~C10 aryl, 5~10 membered heteroaryl, C5~C6 cycloalkyl, 5~7 membered heterocycloalkyl, isoindoline, -(C=O)-, -C6H4(C=O)- or -C6H4NH-,

[0143] R6 is one or more substituents, each independently hydrogen, C1~C6 alkyl, F, Cl, OH, NH2 or C1~C6 alkoxy,

[0144] E is -C≡C-, sulfonic acid, -CN, 5-10 membered heteroaryl when D is not present,

[0145] E is when D is -C≡C-, phenyl, heteroaryl of 5 to 10 atoms, cycloalkyl of C3 to C6, heterocycloalkyl of 5 to 7 atoms, alkylaminocarbonyl of C2 to C8, -(C=O)-, -C6H4(C=O)-, or -C6H4NH-, alkyl of C1 to C4, -C=C-, -C≡C-, Br, -C≡C(C=O)-, -NHCH-, -B(OH)O-, -CH2CH2(C=O)-, -cyclobutyl-(C=O)-, -azetinyl-(C=O)-, -pyrrolidinyl-(C=O)-, -furanyl-(C=O)-, -piperidinyl-(C=O)-, -pyrazolyl-(C=O)-, -pyrrolyl-(C=O)-, phenyl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, C3-C10 cycloalkylamine, C5-C7 cycloalkenyl, 3-7 membered heterocycloalkyl, isoindoline, or azabicycloheptane,

[0146] R7 and R8 are each independently absent, hydrogen, halogen, hydroxy, amine, trimethylsilyl, amine substituted with one or more C1~C3 alkyl groups, carboxylic acid, boronic acid, ester containing C1~C3 alkyl groups, sulfonic acid, -S(=O)2NH2, oxygen of double bond (=O), -(C=O)NH2, -(C=O)NHCH3, -(C=O)NHC2H5, -(C=O)N(CH3)2, -(C=O)N(C2H5)2, -CH2(C=O)OH, C1~C3 alkyl, C1~C3 alkoxy, C2~C7 alkoxycarbonyl, or However, if D does not exist and E is phenyl and Q is -CH2- or -CH-, then at least one of R7 and R8 is not H and is independently H, Br, C1~C2 alkoxy, amine, or amine substituted with at least one C1~C2 alkyl,

[0147] Z is two H, or O,

[0148] R9 is hydroxy, C3~C10 cycloalkyl, C1~C6 alkoxy, pyridine, 3~10 membered heterocycloalkyl, phenyl, 5~10 membered heteroaryl, or and,

[0149] R10 is one or more substituents, such as heterocycloalkyl having 3 to 10 atoms, H, F, Cl, Br, amine, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 alkylsulfonyl, -CF3, amine, amine substituted with one or more C1 to C6 alkyl substituents, C1 to C6 amino alkyl, amino carbonyl substituted or unsubstituted with C1 to C6 alkyl, -CN, -(C=O)NH2, -S(=O)2CH3, These or when adjacent to each other can combine to form a ring.

[0150]

[0151] In one aspect of the present invention, the compound may be characterized as being a compound of the following chemical formula 2:

[0152] [Chemical Formula 2]

[0153]

[0154] In the above formula,

[0155] X is each independently N, CH or CR1,

[0156] R1 is each independently hydrogen, halogen, C1~C6 alkyl, amine unsubstituted or substituted with C1~C6 alkyl, C1~C6 alkoxy, C1~C6 aminoalkyl, -CF3, -CN, -NO2 or aminocarbonyl unsubstituted or substituted with C1~C6 alkyl,

[0157] A is a 3 to 10-membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of C3 to C10 cycloalkyl, N, O and S, C5 to C10 aryl or 5 to 10-membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S,

[0158] R2, R3 are each independently hydrogen, halogen, C1~C6 alkyl, C1~C6 alkoxy, C1~C6 alkylsulfonyl, -CF3, N, O and S containing one or more heteroatoms selected from the group consisting of 3 to 10 membered heterocycloalkyl, amine substituted or unsubstituted with C1~C6 alkyl, C1~C6 aminoalkyl, aminocarbonyl substituted or unsubstituted with C1~C6 alkyl, -CN or or when adjacent to each other, they can combine to form a ring,

[0159] B is C1~C6 alkylene, -C≡C-, -CN or C5~C10 aryl, or is absent,

[0160] C' is -C≡C- when B is C1~C6 alkylene, hydrogen, carboxyl or C5~C10 aryl when B is -C≡C-, does not exist when B is CN, and when B is aryl, is C1~C6 alkylene, C2~C6 alkenylene, -C≡C-, C3~C10 cycloalkyl or C4~C7 cycloalkenyl, or when B is not present, C' is carboxyl,

[0161] R4, R5 are each independently hydrogen, halogen, C1~C6 alkyl substituted or unsubstituted amine, C1~C6 aminoalkyl, -B(OH)2, carboxyl, C2~C7 alkoxycarbonyl, or and, and

[0162] R6 is hydrogen or C1~C6 alkyl.

[0163]

[0164] In the chemical formula 2 of the present invention, R1 may be characterized as being hydrogen, halogen, methyl, methoxy, ethoxy, amine, -CF3, -CN or -NO2.

[0165]

[0166] In the chemical formula 2 of the present invention, A may be characterized as being phenyl, morpholinyl, piperazinyl, pyridinyl or pyrrolidinyl.

[0167]

[0168] In the chemical formula 2 of the present invention, R2 and R3 are each independently hydrogen, halogen, methoxy, methyl, methylsulfonyl, -CF3, morpholinyl, amine, dimethylamine, aminomethyl, aminocarbonyl, -CN or or with the above A It can be characterized by forming a structure.

[0169]

[0170] In the chemical formula 2 of the present invention, B may be characterized as being phenyl, -C≡C-, methylene, -CN, or absent.

[0171]

[0172] In the above chemical formula 2 of the present invention, C' may be characterized in that when B is alkylene of C1 to C6, it is -C≡C-, when B is -C≡C-, it is hydrogen, carboxyl or phenyl, when B is -CN, it does not exist, when B is aryl, it is ethenylene, methylethenylene, -C≡C-, cyclopropyl or cyclohexenyl, or when B does not exist, it is carboxyl.

[0173]

[0174] In the chemical formula 2 of the present invention, R4 and R5 are each independently hydrogen, halogen, -B(OH)2, carboxyl, ethoxycarbonyl, or It can be characterized by being.

[0175]

[0176] In the chemical formula 2 of the present invention, R6 may be characterized as being hydrogen or methyl.

[0177]

[0178] In another aspect of the present invention, the compound may be characterized as being a compound of the following chemical formula 3:

[0179] [Chemical Formula 3]

[0180]

[0181] X is O, NH, S or CH=N,

[0182] A is a C5-C10 aryl forming a bicyclic aromatic ring together with B or a 5 to 10-membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S,

[0183] R1, R2, R3, R4 are each independently absent, hydrogen, halogen, =O, C1~C6 alkyl or amine,

[0184] Z is two H, or O,

[0185] R5 is C1~C6 alkoxy, -(C=O)NH2 or -OCF3 substituted or unsubstituted C5~C10 aryl or pyridinonyl,

[0186] Q is hydrogen or methylene,

[0187] D is carboxyl, C5~C10 aryl, benzoimidazolyl, benzoxazolyl, isoindolinyl, -C=O-, -C6H4C=O- or -C6H4NH-,

[0188] R8 is hydrogen or C1~C6 alkyl,

[0189] E is a 3 to 10-membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of phenyl, C1 to C6 alkylene, C2 to C8 alkylaminocarbonyl, N, O and S, when D is aryl. A 5 to 10-membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S, a C3 to C10 cycloalkylamine, a C3 to C10 cycloalkyl, -B(OH)O-, -CH2CH2(C=O), -C≡C-, -C≡C-(C=O)N-, -cyclobutyl-(C=O)-, -azetinyl-(C=O)-, -C6H4-(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 or hydrogen, carboxyl, C1 to C6 alkyl, C2 to C8 alkylaminocarbonyl, Aminocarbonyl, hydroxy or -Si(CH3)3,

[0190] E is hydrogen, halogen, -C≡C-, -C≡C-(C=O) when A is pyrrole or pyridone and D is aryl, and in this case, R6 and R7 are independently absent or composed of hydrogen, carboxyl, OH, CH3, CH2CH3, -Si(CH3)3.

[0191] E is absent when D is -C=O-, benzoimidazolyl, benzoxazolyl, isoindolinyl, -C6H4C=O- or -C6H4NH-, -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,

[0192] R9 is hydrogen or C1~C6 alkyl,

[0193] R 10 is hydrogen, C1~C6 alkyl or C1~C6 hydroxyalkyl.

[0194]

[0195] In the chemical formula 3 of the present invention, A may be characterized as being benzene, pyridine, pyrimidine, pyridone or pyrrole forming a bicyclic aromatic ring together with B.

[0196]

[0197] In the chemical formula 3 of the present invention, the bicyclic aromatic ring formed by A and B may be characterized by being selected from the structures below:

[0198] , , , , and

[0199]

[0200] In the chemical formula 3 of the present invention, R5 may be characterized as being phenyl substituted with methoxy, -(C=O)NH2 or -OCF3, or pyridinonyl.

[0201]

[0202] In the chemical formula 3 of the present invention, D may be characterized as being phenyl, carboxyl, benzoimidazolyl, benzoxazolyl or isoindolinyl.

[0203]

[0204] In the above chemical formula 3 of the present invention, when D is aryl and A is not pyrrole or pyridone, E is carboxyalkyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, piperazinyl, cyanazolyl, azabicyclo[2,2,1]heptanyl, azetidinyl, pyrrolidinyl, tetrazolyl, piperidinyl, oxazolyl, cyclobutanyl, phenyl, ethylene, -C≡C-, pyrrolidinyl, pyrrolidinylcarbonyl, methylaminocarbonyl, furanyl, cyclobutynylamino, pyrrolyl, cyclobutyl or azetidinyl, and at this time, R6 and R7 may be each independently absent, hydrogen, carboxyl, diethylaminocarbonyl, methylaminocarbonyl, aminocarbonyl, -Si(CH3)3 or isopropyl.

[0205]

[0206] In the chemical formula 3 of the present invention, when D is aryl and A is pyrrole or pyridone, E is pyrazolyl, halo or -C≡C-, and in this case, R6 and R7 may be each independently absent, hydrogen, Si(CH3)3 or carboxyl.

[0207]

[0208] In the chemical formula 3 of the present invention, when D is benzoimidazolyl, benzoxazolyl or isoindolinyl, E is hydrogen, -B(OH)2, carboxyl, aminocarbonyl, aminosulfonyl or methylene, and in this case, R6 and R7 may be characterized in that they are each independently absent or carboxyl.

[0209]

[0210] In one aspect of the present invention, the compound of Chemical Formula 1 may be selected from the group consisting of the following compounds:

[0211] N-(4-(2H-tetrazol-5-yl)benzyl)-5,6-difluoro-N-(4-methoxyphenethyl)-benzo[d]thiazol-2-amine,

[0212] Ethyl 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)-amino)methyl)phenyl)propiolate,

[0213] 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)phenyl)propiolic acid,

[0214] N-(4-(2H-tetrazol-5-yl)benzyl)-5,6-difluoro-N-(4-methoxyphenethyl)- benzo[d]thiazol-2-amine,

[0215] N-(4-ethynylbenzyl)-5,6-difluoro-N-(4-methoxyphenethyl)benzo[d]-thiazol-2-amine,

[0216] N-(4-ethynylbenzyl)-N-(4-methoxyphenethyl)thiazolo[5,4-b]pyridin-2-amine,

[0217] N-(4-ethynylbenzyl)-7-fluoro-N-(4-methoxyphenethyl)benzo[d]thiazol-2-amine,

[0218] ((4-(((5,6-difluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)phenyl)ethynyl)boronic acid,

[0219] 3-(4-(((5,6-difluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)phenyl)propiolic acid,

[0220] 3-(4-(((4-methoxyphenethyl)(thiazolo[4,5-b]pyrazin-2-yl)amino)-methyl)phenyl)propiolic acid,

[0221] 3-(4-(((5,7-difluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)phenyl)propiolic acid,

[0222] 3-(4-(((4,6-difluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)phenyl)propiolic acid,

[0223] 3-(4-(((5-fluorothiazolo[5,4-b]pyridin-2-yl)(4-methoxyphenethyl)- amino)methyl)phenyl)propiolic acid,

[0224] 3-(4-(((4-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)phenyl)propiolic acid,

[0225] 3-(4-(((4-methoxyphenethyl)(5,6,7-trifluorobenzo[d]thiazol-2-yl)amino)methyl)phenyl)propiolic acid,

[0226] 3-(4-(((5-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)phenyl)propiolic acid,

[0227] 3-(4-(((6-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)phenyl)propiolic acid,

[0228] 3-(4-(((4-methoxyphenethyl)(thiazolo[5,4-b]pyridin-2-yl)amino)-methyl)phenyl)propiolic acid,

[0229] 3-(4-(((4-methoxyphenethyl)(4,5,6-trifluorobenzo[d]thiazol-2-yl)- amino)methyl)phenyl)propiolic acid,

[0230] 3-(4-(((4-methoxyphenethyl)(4,5,7-trifluorobenzo[d]thiazol-2-yl)- amino)methyl)phenyl)propiolic acid,

[0231] 3-(4-(((4-methoxyphenethyl)(perfluorobenzo[d]thiazol-2-yl)- amino)methyl)phenyl)propiolic acid,

[0232] 3-(4-(((4-methoxyphenethyl)(5-methylthiazolo[5,4-b]pyridin-2-yl)- amino)methyl)phenyl)propiolic acid,

[0233] 3-(4-(((4-methoxyphenethyl)(5-methoxythiazolo[5,4-b]pyridin-2-yl)- amino)methyl)phenyl)propiolic acid,

[0234] 3-(4-(((6-ethoxybenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)phenyl)propiolic acid,

[0235] 3-(4-(((5-methoxybenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)phenyl)propiolic acid,

[0236] 3-(4-(((5-aminobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)propiolic acid,

[0237] (4-(2-((4-(carboxyethynyl)benzyl)(7-fluorobenzo[d]thiazol-2-yl)-amino)ethyl)phenyl)methanaminium chloride,

[0238] 3-(4-(((4-carbamoylphenethyl)(7-fluorobenzo[d]thiazol-2-yl)amino)- methyl)phenyl)propiolic acid,

[0239] 3-(4-(((4-cyanophenethyl)(7-fluorobenzo[d]thiazol-2-yl)amino)- methyl)phenyl)propiolic acid,

[0240] 3-(4-(((4-methoxyphenethyl)(thiazolo[4,5-b]pyridin-2-yl)amino)-methyl)phenyl)propiolic acid,

[0241] 3-(4-(((4-methoxyphenethyl)(6-(trifluoromethyl)benzo[d]thiazol-2-yl)amino)methyl)phenyl)propiolic acid,

[0242] 3-(4-(((4-methoxyphenethyl)(7-(trifluoromethyl)benzo[d]thiazol-2- yl)amino)methyl)phenyl)propiolic acid,

[0243] 3-(4-(((4-methoxyphenethyl)(7-nitrobenzo[d]thiazol-2-yl)amino)-methyl)phenyl)propiolic acid,

[0244] 3-(4-(((7-chlorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)phenyl)propiolic acid,

[0245] 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)phenyl)-N-(4-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)butyl)propiolamide,

[0246] N-(15-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)phenyl)-13-oxo-3,6,9-trioxa-12-azapentadec-14-yn-1-yl)-5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide,

[0247] 3-(4-(((4-methoxyphenethyl)(5-(trifluoromethyl)benzo[d]thiazol-2- yl)amino)methyl)phenyl)propiolic acid,

[0248] 3-(4-(((5-bromobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)phenyl)propiolic acid,

[0249] 3-(4-(((4-methoxyphenethyl)(5-methylbenzo[d]thiazol-2-yl)amino)- methyl)phenyl)propiolic acid,

[0250] 3-(4-(((4-methoxyphenethyl)(5-nitrobenzo[d]thiazol-2-yl)amino)-methyl)phenyl)propiolic acid,

[0251] 3-(4-(((4-methoxyphenethyl)(6-nitrobenzo[d]thiazol-2-yl)amino)-methyl)phenyl)propiolic acid,

[0252] 3-(4-(((4-methoxyphenethyl)(thiazolo[4,5-c]pyridin-2-yl)amino)-methyl)phenyl)propiolic acid,

[0253] 3-(4-(((5-chlorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)phenyl)propiolic acid,

[0254] 3-(4-(((2-fluoro-4-methoxyphenethyl)(7-(trifluoromethyl)benzo- [d]thiazol-2-yl)amino)methyl)phenyl)propiolic acid,

[0255] 3-(4-(((2-fluoro-4-methoxyphenethyl)(7-nitrobenzo[d]thiazol-2-yl)amino)methyl)phenyl)propiolic acid,

[0256] 3-(4-(((7-chlorobenzo[d]thiazol-2-yl)(2-fluoro-4-methoxyphenethyl)- amino)methyl)phenyl)propiolic acid,

[0257] 3-(4-(((2-fluoro-4-methoxyphenethyl)(thiazolo[5,4-b]pyridin-2-yl)amino)methyl)phenyl)propiolic acid,

[0258] 3-(4-(((2-fluoro-4-methoxyphenethyl)(5-fluorobenzo[d]thiazol-2-yl)amino)methyl)phenyl)propiolic acid,

[0259] 3-(4-(((5-bromobenzo[d]thiazol-2-yl)(2-fluoro-4-methoxyphenethyl)- amino)methyl)phenyl)propiolic acid,

[0260] 3-(3-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)phenyl)propiolic acid,

[0261] 3-(4-(((2-fluoro-4-methoxyphenethyl)(5-(trifluoromethyl)benzo[d]- thiazol-2-yl)amino)methyl)phenyl)propiolic acid,

[0262] 3-(4-(((5-chlorobenzo[d]thiazol-2-yl)(2-fluoro-4-methoxyphenethyl)- amino)methyl)phenyl)propiolic acid,

[0263] 3-(4-(((2-fluoro-4-methoxyphenethyl)(7-fluorobenzo[d]thiazol-2-yl)- amino)methyl)phenyl)propiolic acid,

[0264] 3-(4-(((5,7-difluorobenzo[d]thiazol-2-yl)(2-fluoro-4-methoxy-phenethyl)amino)methyl)phenyl)propiolic acid,

[0265] 3-(4-(((5,6-difluorobenzo[d]thiazol-2-yl)(2-fluoro-4-methoxy-phenethyl)amino)methyl)phenyl)propiolic acid,

[0266] 3-(4-(((2-fluoro-4-methoxyphenethyl)(5-nitrobenzo[d]thiazol-2-yl)- amino)methyl)phenyl)propiolic acid,

[0267] 3-(4-(((2-fluoro-4-methoxyphenethyl)(5,6,7-trifluorobenzo[d]thiazol-2-yl)amino)methyl)phenyl)propiolic acid,

[0268] 3-(4-(((3-fluoro-4-methoxyphenethyl)(5-fluorobenzo[d]thiazol-2-yl)- amino)methyl)phenyl)propiolic acid,

[0269] 3-(4-(((5,6-difluorobenzo[d]thiazol-2-yl)(3-fluoro-4-methoxy-phenethyl)amino)methyl)phenyl)propiolic acid,

[0270] 3-(4-(((3-fluoro-4-methoxyphenethyl)(7-(trifluoromethyl)benzo[d]- thiazol-2-yl)amino)methyl)phenyl)propiolic acid,

[0271] 3-(4-(((3-fluoro-4-methoxyphenethyl)(7-nitrobenzo[d]thiazol-2-yl)- amino)methyl)phenyl)propiolic acid,

[0272] 3-(4-(((5,7-difluorobenzo[d]thiazol-2-yl)(3-fluoro-4-methoxy-phenethyl)amino)methyl)phenyl)propiolic acid,

[0273] 3-(4-(((3-fluoro-4-methoxyphenethyl)(4,5,7-trifluorobenzo[d]thiazol-2-yl)amino)methyl)phenyl)propiolic acid,

[0274] 3-(4-(((3-fluoro-4-methoxyphenethyl)(4-fluorobenzo[d]thiazol-2-yl)- amino)methyl)phenyl)propiolic acid,

[0275] 3-(4-(((3-fluoro-4-methoxyphenethyl)(5-methoxythiazolo[5,4b]- pyridin-2-yl)amino)methyl)phenyl)propiolic acid,

[0276] 3-(4-(((3-fluoro-4-methoxyphenethyl)(5-fluorothiazolo[5,4-b]pyridin-2-yl)amino)methyl)phenyl)propiolic acid,

[0277] 3-(4-(((2-fluoro-4-methoxyphenethyl)(5-methoxythiazolo[5,4b]- pyridin-2-yl)amino)methyl)phenyl)propiolic acid,

[0278] 3-(4-(((2-fluoro-4-methoxyphenethyl)(4,5,7-trifluorobenzo[d]thiazol-2-yl)amino)methyl)phenyl)propiolic acid,

[0279] (E)-3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)phenyl)acrylic acid,

[0280] 2-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)cyclopropanecarboxylic acid,

[0281] 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(2-(4-methylpiperazin-1-yl)-ethyl)amino)methyl)phenyl)propiolic acid,

[0282] 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(2-morpholinoethyl)amino)-methyl)phenyl)propiolic acid,

[0283] 4'-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carboxylic acid,

[0284] 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-fluorophenethyl)amino)-methyl)phenyl)propiolic acid,

[0285] 4-(3-((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)prop-1-yn-1-yl)benzoic acid,

[0286] (3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(phenethyl)amino)methyl)-phenyl)propiolic acid,

[0287] 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(3-fluorophenethyl)amino)-methyl)phenyl)propiolic acid,

[0288] 3-(4-(((3-chlorophenethyl)(7-fluorobenzo[d]thiazol-2-yl)amino)-methyl)phenyl)propiolic acid,

[0289] 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(2-(pyridin-4-yl)ethyl)amino)-methyl)phenyl) propiolic acid,

[0290] 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(2-(pyrrolidin-1-yl)ethyl)-amino)methyl)phenyl) propiolic acid,

[0291] 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(2-(2-methylpyrrolidin-1-yl)-ethyl)amino)methyl) phenyl)propiolic acid,

[0292] 3-(4-(((3,4-dimethoxyphenethyl)(7-fluorobenzo[d]thiazol-2-yl)amino)-methyl)phenyl)propiolic acid,

[0293] 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-(methylsulfonyl)phenethyl)-amino)methyl)phenyl)propiolic acid,

[0294] 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(2-fluorophenethyl)amino)-methyl)phenyl)propiolic acid,

[0295] 3-(4-(((4-chlorophenethyl)(7-fluorobenzo[d]thiazol-2-yl)amino)-methyl)phenyl)propiolic acid,

[0296] 3-(4-(((2-(2,2-dimethylpyrrolidin-1-yl)ethyl)(7-fluorobenzo[d]-thiazol-2-yl)amino)methyl) phenyl)propiolic acid,

[0297] 3-(4-(((3,4-dichlorophenethyl)(7-fluorobenzo[d]thiazol-2-yl)amino)- methyl)phenyl) propiolic acid,

[0298] 3-(4-(((3-bromophenethyl)(7-fluorobenzo[d]thiazol-2-yl)amino)-methyl)phenyl)propiolic acid,

[0299] 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-(trifluoromethyl)phenethyl)-amino)methyl)phenyl) propiolic acid,

[0300] 3-(4-(((2,4-dichlorophenethyl)(7-fluorobenzo[d]thiazol-2-yl)amino)-methyl)phenyl) propiolic acid,

[0301] 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(3-methoxyphenethyl)amino)-methyl)phenyl)propiolic acid,

[0302] 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(3-(trifluoromethyl)phenethyl)-amino)methyl)phenyl)propiolic acid,

[0303] 3-(4-(((2-(benzo[d][1,3]dioxol-5-yl)ethyl)(7-fluorobenzo[d]thiazol-2-yl)amino)methyl)phenyl)propiolic acid,

[0304] 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-morpholinophenethyl)amino)-methyl)phenyl)propiolic acid,

[0305] 3-(4-(((2-bromophenethyl)(7-fluorobenzo[d]thiazol-2-yl)amino)-methyl)phenyl)propiolic acid,

[0306] 7-fluoro-N-(4-methoxyphenethyl)-N-(prop-2-yn-1-yl)benzo[d]thiazol-2-amine,

[0307] 3-(4-(((4-aminophenethyl)(7-fluorobenzo[d]thiazol-2-yl)amino)-methyl)phenyl)propiolic acid,

[0308] 3-(4-(((4-(dimethylamino)phenethyl)(7-fluorobenzo[d]thiazol-2-yl)-amino)methyl)phenyl) propiolic acid,

[0309] 4'-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)-3,4,5,6-tetrahydro-[1,1'-biphenyl]-3-carboxylic acid,

[0310] 4,5,7-trifluoro-N-(4-methoxyphenethyl)-N-(prop-2-yn-1-yl)benzo[d]-thiazol-2-amine,

[0311] 4-fluoro-N-(4-methoxyphenethyl)-N-(prop-2-yn-1-yl)benzo[d]thiazol-2-amine,

[0312] 5,7-difluoro-N-(4-methoxyphenethyl)-N-(prop-2-yn-1-yl)benzo[d]-thiazol-2-amine,

[0313] 5-fluoro-N-(4-fluorophenethyl)-N-(prop-2-yn-1-yl)benzo[d]thiazol-2-amine,

[0314] 7-fluoro-N-(4-fluorophenethyl)-N-(prop-2-yn-1-yl)benzo[d]thiazol-2-amine,

[0315] 4,5,7-trifluoro-N-(4-fluorophenethyl)-N-(prop-2-yn-1-yl)benzo[d]-thiazol-2-amine,

[0316] 5,6-difluoro-N-(4-methoxyphenethyl)-N-(prop-2-yn-1-yl)benzo[d]-thiazol-2-amine,

[0317] 5,7-difluoro-N-(4-fluorophenethyl)-N-(prop-2-yn-1-yl)benzo[d]-thiazol-2-amine,

[0318] 3-(4-(((7-aminobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)propiolic acid

[0319] 5,6-difluoro-N-(4-fluorophenethyl)-N-(prop-2-yn-1-yl)benzo[d]-thiazol-2-amine,

[0320] 5-fluoro-N-(3-fluoro-4-methoxyphenethyl)-N-(prop-2-yn-1-yl)benzo[d]-thiazol-2-amine,

[0321] 5,7-difluoro-N-(3-fluoro-4-methoxyphenethyl)-N-(prop-2-yn-1-yl)-benzo[d]thiazol-2-amine,

[0322] 5,6-difluoro-N-(3-fluoro-4-methoxyphenethyl)-N-(prop-2-yn-1-yl)-benzo[d]thiazol-2-amine,

[0323] 7-fluoro-N-(2-fluoro-4-methoxyphenethyl)-N-(prop-2-yn-1-yl)benzo[d]-thiazol-2-amine,

[0324] 4,5,7-trifluoro-N-(2-fluoro-4-methoxyphenethyl)-N-(prop-2-yn-1-yl)-benzo[d]thiazol-2-amine,

[0325] N-(2-bromophenethyl)-5-fluoro-N-(prop-2-yn-1-yl)benzo[d]thiazol-2-amine,

[0326] N-(2-bromophenethyl)-4,5,7-trifluoro-N-(prop-2-yn-1-yl)benzo[d]-thiazol-2-amine,

[0327] 5,6-difluoro-N-(2-fluoro-4-methoxyphenethyl)-N-(prop-2-yn-1-yl)benzo[d]thiazol-2-amine,

[0328] 5-fluoro-N-phenethyl-N-(prop-2-yn-1-yl)benzo[d]thiazol-2-amine,

[0329] 4,5,7-trifluoro-N-(3-fluoro-4-methoxyphenethyl)-N-(prop-2-yn-1-yl)benzo[d]thiazol-2-amine,

[0330] 4-fluoro-N-(2-fluoro-4-methoxyphenethyl)-N-(prop-2-yn-1-yl)benzo[d]thiazol-2-amine,

[0331] 4-fluoro-N-(2-fluoro-4-methoxyphenethyl)-N-(prop-2-yn-1-yl)benzo[d]thiazol-2-amine,

[0332] 3-(4-((4-(2-((4-(carboxyethynyl)benzyl)(7-fluorobenzo[d]thiazol-2-yl)amino)ethyl)phenoxy)methyl)phenyl)propiolic acid,

[0333] N-(7-fluorobenzo[d]thiazol-2-yl)-N-(4-methoxyphenethyl)alanine,

[0334] N-(but-3-yn-1-yl)-7-fluoro-N-(4-methoxyphenethyl)benzo[d]thiazol-2-amine,

[0335] 2-((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-acetonitrile,

[0336] (E)-3-(4-(((4-methoxyphenethyl)(4,5,7-trifluorobenzo[d]thiazol-2-yl)amino)methyl)phenyl)acrylic acid,

[0337] (E)-3-(4-(((3-fluoro-4-methoxyphenethyl)(4,5,7-trifluorobenzo[d]-thiazol-2-yl)amino)methyl)phenyl)acrylic acid,

[0338] (E)-3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-fluorophenethyl)amino)-methyl)phenyl)acrylic acid,

[0339] 4-(3-((7-fluorobenzo[d]thiazol-2-yl)(4-fluorophenethyl)amino)prop-1-yn-1-yl)benzoic acid,

[0340] 3-(3-(((7-fluorobenzo[d]thiazol-2-yl)(4-fluorophenethyl)amino)-methyl)phenyl)propiolic acid,

[0341] (E)-3-(3-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)acrylic acid,

[0342] (E)-3-(3-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)but-2-enoic acid,

[0343] N-([1,1'-biphenyl]-4-ylmethyl)-N-(4-methoxyphenethyl)thiazolo[5,4-b]pyridin-2-amine,

[0344] 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)propanoic acid,

[0345] N,N-diethyl-3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphen-ethyl)amino)methyl)phenyl)propiolamide,

[0346] 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)-N-methylpropiolamide,

[0347] 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)propiolamide,

[0348] N-(4-methoxyphenethyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine,

[0349] N-(4-bromobenzyl)-N-(4-methoxyphenethyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine,

[0350] 7-fluoro-N-(4-methoxyphenethyl)-N-(3-((trimethylsilyl)ethynyl)-benzyl)benzo[d]thiazol-2-amine,

[0351] N-(3-ethynylbenzyl)-7-fluoro-N-(4-methoxyphenethyl)benzo[d]thiazol-2-amine,

[0352] N-(4-methoxyphenethyl)-7-methyl-N-(4-((trimethylsilyl)ethynyl)-benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine,

[0353] N-(4-ethynylbenzyl)-N-(4-methoxyphenethyl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine,

[0354] 3-(4-(((4-methoxyphenethyl)(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)methyl)phenyl)propiolic acid,

[0355] 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)pyrrolidine-3-carboxylic acid,

[0356] (4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)benzoyl)-L-proline,

[0357] 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)benzoyl)pyrrolidine-3-carboxylic acid,

[0358] (4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)benzoyl)glycine,

[0359] 1-(3-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)pyrrolidine-3-carboxylic acid,

[0360] (4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)benzoyl)-D-valine,

[0361] (4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)-L-proline,

[0362] (3-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)-L-proline,

[0363] (2-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)-1-methyl-1H-benzo[d]imidazol-6-yl)boronic acid,

[0364] (S)-1-(3-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)pyrrolidine-3-carboxylic acid,

[0365] (R)-1-(3-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)pyrrolidine-3-carboxylic acid,

[0366] (R)-1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)-amino)methyl)phenyl)pyrrolidine-3-carboxylic acid,

[0367] (S)-1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)pyrrolidine-3-carboxylic acid,

[0368] 5-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)furan-2-carboxylic acid,

[0369] 2-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)-1-methyl-1H-benzo[d]imidazole-6-carboxylic acid,

[0370] 2-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)benzo[d]oxazole-5-carboxylic acid,

[0371] 7-fluoro-N-(isoindolin-5-ylmethyl)-N-(4-methoxyphenethyl)benzo-[d]thiazol-2-amine,

[0372] 5-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)isoindoline-2-carboxamide,

[0373] 5-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)isoindoline-2-sulfonamide,

[0374] 2-(5-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)isoindolin-2-yl)acetic acid,

[0375] 1-((4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)amino)cyclobutane-1-carboxylic acid,

[0376] 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)-1H-pyrrole-3-carboxylic acid,

[0377] N-(7-fluorobenzo[d]thiazol-2-yl)-N-(4-methoxyphenethyl)glycine,

[0378] 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)cyclobutane-1-carboxylic acid,

[0379] (R)-1-(4-((benzo[d]oxazol-2-yl(4-methoxyphenethyl)amino)methyl)-phenyl)pyrrolidine-3-carboxylic acid,

[0380] (S)-1-(4-((benzo[d]oxazol-2-yl(4-methoxyphenethyl)amino)methyl)-phenyl)pyrrolidine-3-carboxylic acid,

[0381] 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)azetidine-3-carboxylic acid,

[0382] (R)-1-(3-(((7-fluorobenzo[d]thiazol-2-yl)(4-(trifluoromethoxy)-phenethyl)amino)methyl)phenyl)pyrrolidine-3-carboxylic acid,

[0383] (3R)-1-(3-(1-((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)-amino)ethyl)phenyl)pyrrolidine-3-carboxylic acid,

[0384] (3S)-1-(4-(1-((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)-amino)ethyl)phenyl)pyrrolidine-3-carboxylic acid,

[0385] (S)-1-(4-(((4-methoxyphenethyl)(4,5,7-trifluorobenzo[d]thiazol-2-yl)amino)methyl)phenyl)pyrrolidine-3-carboxylic acid,

[0386] 3-(4-(((4-methoxyphenethyl)(oxazolo[5,4-b]pyridin-2-yl)amino)-methyl)phenyl)propiolic acid,

[0387] 3-(4-(((4-methoxyphenethyl)(5-oxo-4,5-dihydrothiazolo[5,4-b]pyridin-2-yl)amino)methyl)phenyl)propiolic acid,

[0388] 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)piperidine-4-carboxylic acid,

[0389] 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)-1H-pyrazole-4-carboxylic acid,

[0390] (S)-1-(4-(((4-carbamoylphenethyl)(7-fluorobenzo[d]thiazol-2-yl)amino)methyl)phenyl)pyrrolidine-3-carboxylic acid,

[0391] (S)-1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(2-(2-oxopyridin-1(2H)-yl)ethyl)amino)methyl)phenyl)pyrrolidine-3-carboxylic acid,

[0392] 2-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)acetic acid,

[0393] 3-(3-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)propanoic acid,

[0394] (S)-1-(4-(((4-methoxyphenethyl)(thiazolo[5,4-b]pyridin-2-yl)amino)methyl)phenyl)pyrrolidine-3-carboxylic acid,

[0395] 4'-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)-[1,1'-biphenyl]-4-carboxylic acid,

[0396] 5-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)picolinic acid,

[0397] 4'-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)-[1,1'-biphenyl]-3-carboxylic acid,

[0398] 6-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)picolinic acid,

[0399] 1-(4-(((4-methoxyphenethyl)(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)methyl)phenyl)-1H-pyrazole-4-carboxylic acid,

[0400] 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)-1H-pyrazole-4-carboxamide,

[0401] 5-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)-1H-pyrrole-3-carboxylic acid,

[0402] 5-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)furan-3-carboxylic acid,

[0403] 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)-1H-imidazole-4-carboxylic acid,

[0404] 2-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)-2H-1,2,3-triazole-4-carboxylic acid,

[0405] 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)-1H-1,2,4-triazole-3-carboxylic acid,

[0406] 4-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)piperazine-1-carboxamide,

[0407] 4'-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)-5-hydroxy-[1,1'-biphenyl]-3-carboxylic acid,

[0408] 2-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)thiazole-5-carboxylic acid,

[0409] 2-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)-2-azabicyclo[2.2.1]heptane-5-carboxylic acid,

[0410] 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid,

[0411] 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)-3-methyl-1H-pyrazole-4-carboxylic acid,

[0412] 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid,

[0413] 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)-2-methylazetidine-3-carboxylic acid,

[0414] (S)-1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)-3-methylpyrrolidine-3-carboxylic acid,

[0415] 2-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)-2H-tetrazole-5-carboxylic acid,

[0416] 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)-4-methylpiperidine-4-carboxylic acid,

[0417] 2-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)oxazole-5-carboxylic acid,

[0418] 1-(4-(1-((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)ethyl)phenyl)cyclobutane-1-carboxylic acid,

[0419] 1-(3-fluoro-4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)azetidine-3-carboxylic acid,

[0420] 1-(3-chloro-4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)azetidine-3-carboxylic acid,

[0421] 1-(2-fluoro-4-(((3-fluoro-4-methoxyphenethyl)(7-fluorobenzo[d]thiazol-2-yl)amino)methyl)phenyl)azetidine-3-carboxylic acid, and

[0422] 1-(2-fluoro-4-(((2-fluoro-4-methoxyphenethyl)(7-fluorobenzo[d]thiazol-2-yl)amino)methyl)phenyl)azetidine-3-carboxylic acid.

[0423]

[0424] In the present invention, the term 'immune cell' refers to a cell involved in an immune response in the body, and is not particularly limited in type as long as it is known in the art as an immune cell, and in particular, is known as an immune cell existing in the human body, but includes monocytes, macrophages, neutrophils, eosinophils, basophils, dendritic cells, natural killer cells, megakaryocytes, T cells, and B cells. Preferably, it may refer to monocytes, macrophages, or neutrophils. Immune cells express KARS1.

[0425]

[0426] In the present invention, the term 'disease related to immune cell movement' is not particularly limited in its specific type as long as it is known in the art that excessive immune cell movement (or / and infiltration) is a major pathogenic mechanism, but may be selected from the group consisting of, for example, cardiovascular disease, fibrotic disease, inflammatory disease, and Alport syndrome.

[0427]

[0428] The above cardiovascular disease is not particularly limited in its specific type, but may be selected from the group consisting of, for example, hypertension (including inflammatory complications due to hypertension), pulmonary hypertension, atherosclerosis, angina pectoris, myocardial infarction, ischemic cerebrovascular disease, arteriosclerosis, and media sclerosis.

[0429]

[0430] The above fibrotic diseases are not particularly limited in their specific types, but include, for example, scleroderma, rheumatoid arthritis, neural fibrosis, Crohn's disease, ulcerative colitis, myelofibrosis, pulmonary fibrosis, hepatic fibrosis, liver cirrhosis, kidney fibrosis, glomerulosclerosis, myofibrosis, cardiac fibrosis, interstitial fibrosis, pancreatic fibrosis, splenic fibrosis, mediastinal fibrosis, vascular fibrosis, skin fibrosis, ocular fibrosis, macular degeneration, arthrofibrosis, thyroid fibrosis, endomyocardial fibrosis, peritoneal fibrosis, retroperitoneal fibrosis, progressive mass fibrosis, nephrogenic systemic fibrosis, and systemic erythematosus. It can be characterized by being selected from the group consisting of systemic lupus erythematosus, hereditary fibrosis, infectious fibrosis, irritant fibrosis, chronic autoimmune fibrosis, fibrosis due to antigen incompatibility in organ transplantation, fibrotic complications of surgery, fibrosis due to hyperlipidemia, fibrosis due to obesity, diabetic fibrosis, fibrosis due to hypertension, and occlusion due to fibrosis during stent insertion.

[0431]

[0432] In the present invention, the inflammatory disease is not particularly limited in type, but is preferably an autoimmune disease, 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, metabolic dysfunction-associated steatohepatitis, chronic kidney disease, nephritis, proteinuria, diabetic renal failure, arthritis, psoriatic arthritis, neuritis, diabetic neuropathy, multiple sclerosis, gout, spondylitis, Reiter's syndrome, polyarteritis nodosa, vasculitis, Lou Gehrig's disease, Wegener's granulomatosis, hypercytokinemia, Polymyalgia rheumatica, articular cell arteritis, calcium crystal deposition arthropathy, pseudogout, non-articular rheumatism, bursitis, tenosynovitis, epicondylitis, Charcot's joint, hemarthrosis, Henoch-Schonlein purpura, hypertrophic osteoarthropathy, multicentric reticulohistiocytoma, surcoilosis, hemochromatosis, sickle cell disease, hyperlipoproteinemia, hypogammaglobulinemia, hyperparathyroidism, acromegaly, familial Mediterranean fever, Behçet'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 It may be characterized by being selected from the group consisting of broncho-pulmonary dysplasia.

[0433]

[0434] In the present invention, the autoimmune disease may be characterized as being selected from the group consisting of rheumatoid arthritis, systemic scleroderma, 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 graft-versus-host disease.

[0435]

[0436] The above chronic inflammatory disease refers to a state in which the above-mentioned types of inflammatory diseases have become chronic, and preferred examples thereof 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 nephropathy, chronic renal failure, diabetic neuropathy, and multiple sclerosis.

[0437]

[0438] The pharmaceutical composition according to the present invention may be formulated in a suitable form, containing the compound of the present invention alone or together with one or more pharmaceutically acceptable carriers, and may additionally contain excipients or diluents. As used herein, "pharmaceutically acceptable" refers to a non-toxic composition that is physiologically acceptable and does not typically cause allergic reactions or similar reactions, such as gastrointestinal upset or dizziness, when administered to humans.

[0439]

[0440] In the present invention, the content of the composition is not particularly limited depending on the purpose or aspect 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. The pharmaceutical composition of the present invention may contain 0.1 to 99.9 wt% of the compounds represented by chemical formulae 1 to 3 prepared by the method of the present invention, and 99.9 to 0.1 wt% of the carrier.

[0441]

[0442] Pharmaceutically acceptable carriers may further include, for example, carriers for oral administration or carriers for parenteral administration. Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. In addition, various drug delivery substances used for oral administration of peptide formulations may be included. In addition, carriers for parenteral administration may include water, suitable oils, saline solution, aqueous glucose, and glycols, 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.

[0443]

[0444] The pharmaceutical composition of the present invention may further include, in addition to the above ingredients, lubricants, humectants, sweeteners, flavoring agents, emulsifiers, suspending agents, etc. Other pharmaceutically acceptable carriers and formulations may be referred to as described in the following literature.

[0445]

[0446] The composition of the present invention can be administered to mammals, including humans, by any method. For example, it can be administered orally or parenterally. Specifically, the route of administration of the composition of the present invention can be, but is not limited to, injection or infusion via known routes, such as intravenous, intraperitoneal, intracerebral, subcutaneous, intramuscular, intraocular, intraarterial, intracerebrospinal, or intralesional routes, or injection or infusion using a sustained-release system as described below. For example, the compound of the present invention can be administered systemically or locally.

[0447]

[0448] The pharmaceutical composition of the present invention can be formulated as a preparation for oral administration or parenteral administration according to the administration route described above.

[0449]

[0450] In the pharmaceutical composition according to the present invention, the compound can be administered in various oral and parenteral dosage forms during clinical administration. When formulating, it can be prepared using diluents or excipients such as commonly used fillers, bulking agents, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include tablets, tablets, powders, granules, capsules, troches, etc., and these solid preparations can be prepared by mixing at least one excipient, 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 preparations for oral administration include suspensions, solutions, emulsions, and syrups, and in addition to commonly used simple diluents such as water and liquid paraffin, they may contain various excipients such as wetting agents, sweeteners, flavoring agents, and preservatives.

[0451]

[0452] Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. The therapeutic compositions of the present invention can be prepared in the form of lyophilized cakes or aqueous solutions for storage by mixing the compound having the desired purity with any physiologically acceptable carrier, excipient, or stabilizer. Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphoric acid, 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, and other carbohydrates including glucose, mannose, or 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).

[0453]

[0454] For parenteral administration, preparations can be formulated into injections, creams, lotions, topical ointments, oils, moisturizers, gels, aerosols, and nasal inhalers using methods known in the art. These formulations can be found in the literature, which is a commonly known prescription manual for all pharmaceutical chemistry disciplines.

[0455]

[0456] The total effective amount of the compound of the present invention can be administered as a single dose, or can be administered by a fractionated treatment protocol in which multiple doses are administered over a long period of time. The pharmaceutical composition of the present invention may vary the content of the active ingredient depending on the degree and / or purpose of the disease, but can typically be administered several times a day at an effective dose of 0.01 ㎍ to 10,000 mg, preferably 0.1 ㎍ to 1,000 mg, at a single administration. However, since the dosage of the pharmaceutical composition is determined by taking into consideration various factors such as the formulation method, administration route, and number of treatments, as well as the patient's age, weight, health status, sex, severity of the disease, diet, and excretion rate, a person having ordinary skill in the art will be able to determine an appropriate effective dosage of the composition of the present invention, taking these points into consideration. The pharmaceutical composition according to the present invention is not particularly limited in its formulation, administration route, and administration method as long as it exhibits the effects of the present invention.

[0457]

[0458] The present invention also provides a pharmaceutical composition for preventing or inhibiting cancer metastasis, comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0459]

[0460] The cancer is not particularly limited in type as long as it is known in the art as a malignant tumor, but may be selected from the group consisting of breast cancer, colon cancer, lung cancer, small cell lung cancer, stomach cancer, liver cancer, blood cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous 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 disease, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal 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 pelvic carcinoma, CNS tumor, primary CNS lymphoma, spinal cord tumor, brainstem glioma, and pituitary adenoma.

[0461]

[0462] In order to achieve another object of the present invention, the present invention provides a use of the compound of formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition for treating a disease related to immune cell movement.

[0463]

[0464] In order to achieve another object of the present invention, the present invention provides a method for treating a disease related to immune cell movement, which comprises administering an effective amount of a composition comprising a compound of the above chemical formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient to a subject in need thereof.

[0465]

[0466] In order to achieve another object of the present invention, the present invention provides a use of the compound of formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof for providing a pharmaceutical composition for preventing or inhibiting cancer metastasis.

[0467]

[0468] In order to achieve another object of the present invention, the present invention provides a method for preventing or inhibiting cancer metastasis, characterized in that an effective amount of a composition comprising a compound of the above chemical formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient is administered to a subject in need thereof.

[0469]

[0470] The compound of the present invention can regulate the movement of immune cells and cancer cells by inhibiting the activity of KARS1, and thus exhibits a very remarkable effect in the prevention, improvement, and treatment of diseases related to immune cell movement and cancer metastasis.

[0471]

[0472] Figures 1a and 1b illustrate the experimental design to evaluate the effect of drugs in the MASH model induced by a methionine and choline deficient diet (MCD).

[0473]

[0474] Figures 2a to 2c show the results of measuring changes in body weight and liver weight due to treatment with three types of drugs in a 3-week MCD preventive model.

[0475]

[0476] Figures 3a to 3c show the results of measuring changes in AST, ALT, and TG by treatment with three drugs in the MCD 3-week preventive model.

[0477]

[0478] Figures 4a and 4b show the results of measuring the Sirius Red staining area indicating the degree of fibrosis by treatment with three types of drugs in a 3-week MCD preventive model, and the F4 / 80 staining foci indicating the degree of inflammation.

[0479]

[0480] Figures 5a and 5b illustrate the experimental design to evaluate the effects of compounds 3, 157, and 175 in the MASH model induced by a CDAHFD (Choline-deficient, L-amino acid-defined, high-fat diet) diet.

[0481]

[0482] Figures 6a and 6b show the results of measuring changes in body weight and liver weight due to treatment with four types of drugs in the CDAHFD 8-week preventive model.

[0483]

[0484] Figures 7a to 7c show the results of measuring changes in AST, ALT, and TG by treatment with four drugs in the CDAHFD 8-week preventive model.

[0485]

[0486] Figure 8 shows the results of mRNA analysis in the CDAHFD 8-week prevention model, confirming that fibrosis and inflammation indicators were alleviated by drug treatment.

[0487]

[0488] Figures 9a to 9e show the results of measuring fibrosis-related indicators in the CDAHFD 8-week preventive model.

[0489]

[0490] Figures 10a to 10e show the results of measuring inflammatory indicators in the CDAHFD 8-week preventive model.

[0491]

[0492] Figure 11 is a schematic diagram showing the process of creating a chronic kidney disease (CDK) animal model.

[0493]

[0494] Figure 12 shows the results confirming that the expression of KARS1 in renal tissue was increased in three CKD animal models (folic acid administration, adenine diet, and ureteral ligation model).

[0495]

[0496] Figures 13a and 13b show the results of confirming that the areas of high expression of KARS1 in renal tissue in the CKD model tend to coincide with markers indicating influxed inflammatory macrophages and damaged proximal tubules.

[0497]

[0498] Figures 14a and 14b are schematic diagrams showing the experimental design for evaluating the activity of a test substance in an animal model of CKD induced by an adenine diet.

[0499]

[0500] Figures 15a to 15e and Figures 16a to 16i are results confirming the effect of significantly improving renal fibrosis, tubular damage, and inflammation indicators by administering an experimental substance in an animal model of CKD induced by an adenine diet.

[0501]

[0502] Figures 17a and 17b show the results of confirming changes in renal function indicators (BUN, Cystatin C) due to administration of experimental substances in an animal model of CKD induced by an adenine diet.

[0503]

[0504] Figures 18a to 18g show the results of urine analysis by administration of experimental substances in an animal model of CKD induced by an adenine diet.

[0505]

[0506] Figures 19a and 19b show the results of confirming changes in kidney shape and reduction of fibrosis area by administration of an experimental substance in an animal model of CKD induced by an adenine diet.

[0507]

[0508] Figures 20a and 20b show the results confirming the reduction in tubular dilatation by administration of an experimental substance in an animal model of CKD induced by an adenine diet.

[0509]

[0510] Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are intended only to illustrate the present invention and the present invention is not limited thereto.

[0511]

[0512] Example 1: Preparation of compounds

[0513] In the present invention, the compound of chemical formula 2 was prepared according to the following synthetic method:

[0514] Synthesis method 1.

[0515]

[0516]

[0517] Synthesis method 2.

[0518]

[0519]

[0520] Synthesis method 3.

[0521]

[0522]

[0523] Synthesis method 4.

[0524]

[0525] In the above synthesis method, X and R1 to R6 are as defined in the above chemical formula 2.

[0526]

[0527] In the present invention, the compound of chemical formula 3 was prepared according to the following synthetic method:

[0528] Synthesis method 1.

[0529]

[0530]

[0531] Synthesis method 2.

[0532]

[0533]

[0534] Synthesis method 3.

[0535]

[0536]

[0537] Synthesis method 4.

[0538]

[0539]

[0540] In the above synthetic method, A, B, Q, D, E, Z and R1 to R10 are as defined in the above chemical formula 3.

[0541] Specific examples, structures, and NMR analysis results of the compounds of the above chemical formula 1 manufactured according to the above method are specifically shown in Tables 1 and 2 below.

[0542]

[0543] [Table 1]

[0544]

[0545]

[0546] [Table 2]

[0547]

[0548] Example 3: Cell-free ELISA assay to confirm inhibition of KARS1 and 37LR binding.

[0549] Next, a cell-free ELISA analysis was conducted to select compounds with high protein binding inhibition ability between KARS1 and LR (laminin receptor) based on the mechanism of action.

[0550] The experiment was conducted by treating a plate coated with KARS1 (1-207aa) with LRF (TRX-His-Laminin receptor full length) and the compound at 10 μM and allowing the reaction to proceed for 1 hour to confirm whether the compound inhibits the protein binding between KARS1 and 37LR (Table 3).

[0551]

[0552] [Table 3]

[0553]

[0554] [Table 4]

[0555]

[0556] It is known that KARS1 is secreted extracellularly in an inflammatory environment and induces the migration and M1 polarization of macrophages and peripheral blood mononuclear cells. Based on this, we confirmed that trans-cellular migration of Raw264.7 was induced when KARS1 protein was directly treated externally and that the cell migration inhibition effect of KARS1 inhibitory compound was confirmed. Raw 264.7 cells (1 x 10) were seeded in the upper chamber of a transwell (Corning#3421-5 μm pore). 5 (cells / well) were seeded. The lower chamber was filled with serum-free medium (Serum Free DMEM, 600 μL) containing 100 nM KARS1 protein and 1 μM compound. For the drug control group, DMSO was treated at the same ratio as the compound. The cells were cultured in a 5% CO2 cell incubator for 6 hours. After fixing the cells with 70% ethanol for 30 minutes, they were 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 dried at room temperature for 24 hours. Migrating cells on the lower side of the membrane were observed at 100X magnification under a high-power microscope, and the number of cells was measured using the Image-J program in the obtained images, which was expressed as the inhibition ratio (% inhibition) compared to the control group.

[0557]

[0558] Based on the above experimental results, compounds 3 (hereinafter referred to as ZMC0001, C0001, 0001 or C001), 157 (hereinafter referred to as ZMC0047, C0047, 0047 or C047) and 175 (hereinafter referred to as ZMC0216, C0216, 0216 or C216) were selected and subjected to in vivo experiments.

[0559]

[0560] Example 4: In vivo experiment of the MCD diet MASH model

[0561] To evaluate the effects of compounds 3, 157, and 175 in the MASH model induced by the MCD (methionine and choline deficient diet), experiments were conducted according to the experimental schedule shown in Fig. 1a and Fig. 1b.

[0562]

[0563] As a result, it was confirmed that there was no effect on body weight or liver weight by the three drug treatments in the MCD 3-week prevention model (Fig. 2a to Fig. 2c).

[0564]

[0565] Liver function indicators AST, ALT, and liver fat indicator TG increased in the MCD model and were significantly reduced by the three drug treatments, with C0047 being the most effective (Figs. 3a to 3c).

[0566]

[0567] The Sirius Red staining area, which indicates the degree of fibrosis, and the number of F4 / 80 staining foci, which indicates the degree of inflammation, were reduced by treatment with the experimental substance, and C0001 and C0047 showed similar results (Fig. 4a and Fig. 4b).

[0568]

[0569] Example 5: CDAHFD-induced MASH in vivo experiment

[0570] To evaluate the effects of compounds 3, 157, and 175 in the MASH model induced by a CDAHFD (Choline-deficient, L-amino acid-defined, high-fat diet) diet, experiments were conducted according to the experimental schedule shown in Figs. 5a and 5b. Resmetirom was treated as a positive control.

[0571]

[0572] As a result of the experiment, in the CDAHFD 8-week preventive model, it was confirmed that body weight significantly decreased when treated with four drugs, and liver weight significantly decreased when treated with resmetirom and C0047 (Fig. 6a and Fig. 6b).

[0573]

[0574] Liver function indicators AST, ALT, and liver fat indicator TG increased in the CDAHFD model and significantly decreased in resmetirom, and the greatest decrease in ALT was confirmed when C0047 was treated (Figs. 7a to 7c).

[0575]

[0576] The Sirius Red staining area, which indicates the degree of fibrosis by drug treatment, was confirmed to be significantly reduced in all four drug treatments (Fig. 8).

[0577]

[0578] In the CDAHFD 8-week prevention model, mRNA analysis confirmed that fibrosis and inflammation markers were alleviated by drug treatment.

[0579] In particular, C0047 treatment showed a strong and significant improvement in all fibrosis-related indicators and showed a better effect than resmetirom (Figs. 9a to 9e).

[0580]

[0581] C0047 treatment also showed a strong and significant improvement in inflammation indices, and showed better effects than resmetirom in some indices (Figs. 10a to 10e).

[0582]

[0583] Example 6: In vivo experiment on a chronic kidney disease model

[0584] A chronic kidney disease (CKD) animal model was created according to the experimental design shown in Fig. 11.

[0585]

[0586] In three CKD animal models (folic acid administration, adenine diet, and ureteral ligation model), increased expression of KARS1 in renal tissue was confirmed, and in the CKD models, the areas of high expression of KARS1 in renal tissue tended to coincide with markers indicating infiltrated inflammatory macrophages and damaged proximal tubules (Fig. 12, and Figs. 13a and 13b).

[0587]

[0588] Among the three CKD models manufactured above, the pharmacological activity of the experimental substance was evaluated in the model induced by the adenine diet (AD model) according to the experimental design of Figs. 14a and 14b.

[0589]

[0590] In the AD 2-week preventive model, mRNA analysis confirmed that C0047 treatment significantly improved renal fibrosis, tubular damage, and inflammation indicators (Figs. 15a to 15e and Figs. 16a to 16i).

[0591]

[0592] BUN and Cystatin C, which are kidney function indicators, increased in the AD model and were significantly reduced when treated with C0047 (Figs. 17a and 17b), and urine analysis showed an overall improvement in urine volume and urine protein due to kidney failure (Figs. 18a to 18g).

[0593]

[0594] Additionally, in the AD 2-week preventive model, it was confirmed that the renal morphology was alleviated by C0047 treatment, and the fibrotic area in the renal tissue was reduced to near normal levels (Fig. 19a and Fig. 19b).

[0595]

[0596] The AD diet increased tubular dilatation, an indicator of renal damage, and C0047 administration tended to reduce this tubular dilatation (Figs. 20a and 20b).

[0597]

[0598] The compound of the present invention can regulate the movement of immune cells and cancer cells by inhibiting the activity of KARS1, and thus exhibits a very remarkable effect in the prevention, improvement, and treatment of diseases related to immune cell movement and cancer metastasis, and thus has a very high potential for industrial use.

Claims

1. A pharmaceutical composition for preventing or treating a disease related to immune cell movement, comprising a compound of the following chemical formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient: [Chemical Formula 1] In the above formula, X is one of O, NH, S or CH=N, A is a C5~C10 aryl forming a bicyclic aromatic ring together with B or a 5~10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S, R1, R2, R3, R4 are each independently absent or hydrogen, halogen (F, Cl, Br), =O, C1~C6 alkyl, amine, C1~C6 substituted amine, C1~C6 alkoxy, C1~C6 amino alkyl, -CF3, -CN, -NO 2, or aminocarbonyl substituted or unsubstituted with one or more C1~C6 alkyl, Q is absent, H, a C1~C3 alkyl group, or -(C=O)-, R5 is hydrogen or C1~C6 alkyl, D is absent, carboxyl, -CN, -CH2-, -C≡C-, C1~C6 alkylene, C6~C10 aryl, 5~10 membered heteroaryl, C5~C6 cycloalkyl, 5~7 membered heterocycloalkyl, isoindoline, -(C=O)-, -C6H4(C=O)- or -C6H4NH-, R6 is one or more substituents, each independently hydrogen, C1~C6 alkyl, F, Cl, OH, NH2 or C1~C6 alkoxy, E is -C≡C-, sulfonic acid, -CN, 5-10 membered heteroaryl when D is not present, E is when D is -C≡C-, phenyl, heteroaryl of 5 to 10 atoms, cycloalkyl of C3 to C6, heterocycloalkyl of 5 to 7 atoms, alkylaminocarbonyl of C2 to C8, -(C=O)-, -C6H4(C=O)-, or -C6H4NH-, alkyl of C1 to C4, -C=C-, -C≡C-, Br, -C≡C(C=O)-, -NHCH-, -B(OH)O-, -CH2CH2(C=O)-, -cyclobutyl-(C=O)-, -azetinyl-(C=O)-, -pyrrolidinyl-(C=O)-, -furanyl-(C=O)-, -piperidinyl-(C=O)-, -pyrazolyl-(C=O)-, -pyrrolyl-(C=O)-, phenyl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, C3-C10 cycloalkylamine, C5-C7 cycloalkenyl, 3-7 membered heterocycloalkyl, isoindoline, or azabicycloheptane, R7 and R8 are each independently absent, hydrogen, halogen, hydroxy, amine, trimethylsilyl, amine substituted with one or more C1~C3 alkyl groups, carboxylic acid, boronic acid, ester containing C1~C3 alkyl groups, sulfonic acid, -S(=O)2NH2, oxygen of double bond (=O), -(C=O)NH2, -(C=O)NHCH3, -(C=O)NHC2H5, -(C=O)N(CH3)2, -(C=O)N(C2H5)2, -CH2(C=O)OH, C1~C3 alkyl, C1~C3 alkoxy, C2~C7 alkoxycarbonyl, or However, if D does not exist and E is phenyl and Q is -CH2- or -CH-, then at least one of R7 and R8 is not H and is independently H, Br, C1~C2 alkoxy, amine, or amine substituted with at least one C1~C2 alkyl, Z is two H, or O, R9 is hydroxy, C3~C10 cycloalkyl, C1~C6 alkoxy, pyridine, 3~10 membered heterocycloalkyl, phenyl, 5~10 membered heteroaryl, or and, R10 is one or more substituents, such as heterocycloalkyl having 3 to 10 atoms, H, F, Cl, Br, amine, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 alkylsulfonyl, -CF3, amine, amine substituted with one or more C1 to C6 alkyl substituents, C1 to C6 amino alkyl, amino carbonyl substituted or unsubstituted with C1 to C6 alkyl, -CN, -(C=O)NH2, -S(=O)2CH3, These or when adjacent to each other can combine to form a ring.

2. A pharmaceutical composition according to claim 1, wherein the compound is a compound of the following chemical formula 2: [Chemical Formula 2] In the above formula, X is each independently N, CH or CR1, R1 is each independently hydrogen, halogen, C1~C6 alkyl, amine unsubstituted or substituted with C1~C6 alkyl, C1~C6 alkoxy, C1~C6 aminoalkyl, -CF3, -CN, -NO2 or aminocarbonyl unsubstituted or substituted with C1~C6 alkyl, A is a 3 to 10-membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of C3 to C10 cycloalkyl, N, O and S, C5 to C10 aryl or 5 to 10-membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S, R2, R3 are each independently hydrogen, halogen, C1~C6 alkyl, C1~C6 alkoxy, C1~C6 alkylsulfonyl, -CF3, N, O and S containing one or more heteroatoms selected from the group consisting of 3 to 10 membered heterocycloalkyl, amine substituted or unsubstituted with C1~C6 alkyl, C1~C6 aminoalkyl, aminocarbonyl substituted or unsubstituted with C1~C6 alkyl, -CN or or when adjacent to each other, they can combine to form a ring, B is C1~C6 alkylene, -C≡C-, -CN or C5~C10 aryl, or is absent, C' is -C≡C- when B is C1~C6 alkylene, hydrogen, carboxyl or C5~C10 aryl when B is -C≡C-, does not exist when B is CN, and when B is aryl, is C1~C6 alkylene, C2~C6 alkenylene, -C≡C-, C3~C10 cycloalkyl or C4~C7 cycloalkenyl, or when B is not present, C' is carboxyl, R4, R5 are each independently hydrogen, halogen, C1~C6 alkyl substituted or unsubstituted amine, C1~C6 aminoalkyl, -B(OH)2, carboxyl, C2~C7 alkoxycarbonyl, or and, R6 is hydrogen or C1~C6 alkyl.

3. A pharmaceutical composition according to claim 2, wherein R1 is hydrogen, halogen, methyl, methoxy, ethoxy, amine, -CF3, -CN or -NO2.

4. A pharmaceutical composition according to claim 2, characterized in that A is phenyl, morpholinyl, piperazinyl, pyridinyl or pyrrolidinyl.

5. In the second paragraph, R2 and R3 are each independently hydrogen, halogen, methoxy, methyl, methylsulfonyl, -CF3, morpholinyl, amine, dimethylamine, aminomethyl, aminocarbonyl, -CN or or with the above A A pharmaceutical composition characterized by forming a structure.

6. A pharmaceutical composition according to claim 2, wherein B is phenyl, -C≡C-, methylene, -CN, or absent.

7. A pharmaceutical composition characterized in that in the second paragraph, C' is -C≡C- when B is C1~C6 alkylene, hydrogen, carboxyl or phenyl when B is -C≡C-, absent when B is -CN, ethenylene, methylethenylene, -C≡C-, cyclopropyl or cyclohexenyl when B is aryl, or carboxyl when B is absent.

8. In the second paragraph, R4 and R5 are each independently hydrogen, halogen, -B(OH)2, carboxyl, ethoxycarbonyl, or A pharmaceutical composition characterized by:

9. A pharmaceutical composition according to claim 2, wherein R6 is hydrogen or methyl.

10. A pharmaceutical composition according to claim 1, wherein the chemical formula is a compound represented by the following chemical formula 3: [Chemical Formula 3] X is O, NH, S or CH=N, A is a C5-C10 aryl forming a bicyclic aromatic ring together with B or a 5 to 10-membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S, R1, R2, R3, R4 are each independently absent, hydrogen, halogen, =O, C1~C6 alkyl or amine, Z is two H, or O, R5 is C1~C6 alkoxy, -(C=O)NH2 or -OCF3 substituted or unsubstituted C5~C10 aryl or pyridinonyl, Q is hydrogen or methylene, D is carboxyl, C5~C10 aryl, benzoimidazolyl, benzoxazolyl, isoindolinyl, -C=O-, -C6H4C=O- or -C6H4NH-, R8 is hydrogen or C1~C6 alkyl, E is a 3 to 10-membered heterocycloalkyl containing one or more heteroatoms selected from the group consisting of phenyl, C1 to C6 alkylene, C2 to C8 alkylaminocarbonyl, N, O and S, when D is aryl. A 5 to 10-membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S, a C3 to C10 cycloalkylamine, a C3 to C10 cycloalkyl, -B(OH)O-, -CH2CH2(C=O), -C≡C-, -C≡C-(C=O)N-, -cyclobutyl-(C=O)-, -azetinyl-(C=O)-, -C6H4-(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 or hydrogen, carboxyl, C1 to C6 alkyl, C2 to 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 in this case, R6 and R7 are independently absent or composed of hydrogen, carboxyl, OH, CH3, CH2CH3, -Si(CH3)3. E is absent when D is -C=O-, benzoimidazolyl, benzoxazolyl, isoindolinyl, -C6H4C=O- or -C6H4NH-, -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~C6 alkyl or C1~C6 hydroxyalkyl.

11. A pharmaceutical composition according to claim 10, wherein A is benzene, pyridine, pyrimidine, pyridone or pyrrole forming a bicyclic aromatic ring together with B.

12. A pharmaceutical composition according to claim 10, wherein the bicyclic aromatic ring formed by A and B is selected from the following structures: , , , , and .

13. A pharmaceutical composition according to claim 10, wherein R5 is phenyl substituted with methoxy, -(C=O)NH2 or -OCF3, or pyridinonyl.

14. A pharmaceutical composition according to claim 10, wherein D is phenyl, carboxyl, benzoimidazolyl, benzoxazolyl, or isoindolinyl.

15. A pharmaceutical composition according to claim 10, wherein when D is aryl and A is not pyrrole or pyridone, E is carboxyalkyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, piperazinyl, cyanazolyl, azabicyclo[2,2,1]heptanyl, azetidinyl, pyrrolidinyl, tetrazolyl, piperidinyl, oxazolyl, cyclobutanyl, phenyl, ethylene, -C≡C-, pyrrolidinyl, pyrrolidinylcarbonyl, methylaminocarbonyl, furanyl, cyclobutynylamino, pyrrolyl, cyclobutyl or azetidinyl, wherein R6 and R7 are each independently absent, hydrogen, carboxyl, diethylaminocarbonyl, methylaminocarbonyl, aminocarbonyl, -Si(CH3)3 or isopropyl.

16. A pharmaceutical composition characterized in that in paragraph 10, when D is aryl and A is pyrrole or pyridone, E is pyrazolyl, halo or -C≡C-, and wherein R6 and R7 are each independently absent, hydrogen, Si(CH3)3 or carboxyl.

17. A pharmaceutical composition according to claim 10, wherein when D is benzoimidazolyl, benzoxazolyl or isoindolinyl, E is hydrogen, -B(OH)2, carboxyl, aminocarbonyl, aminosulfonyl or methylene, and wherein R6 and R7 are each independently absent or carboxyl.

18. A pharmaceutical composition according to claim 1, wherein the compound of formula 1 is selected from the group consisting of the following compounds: N-(4-(2H-tetrazol-5-yl)benzyl)-5,6-difluoro-N-(4-methoxyphenethyl)-benzo[d]thiazol-2-amine, Ethyl 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)-amino)methyl)phenyl)propiolate, 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)propiolic acid, N-(4-(2H-tetrazol-5-yl)benzyl)-5,6-difluoro-N-(4-methoxyphenethyl)-benzo[d]thiazol-2-amine, N-(4-ethynylbenzyl)-5,6-difluoro-N-(4-methoxyphenethyl)benzo[d]-thiazol-2-amine, N-(4-ethynylbenzyl)-N-(4-methoxyphenethyl)thiazolo[5,4-b]pyridin-2-amine, N-(4-ethynylbenzyl)-7-fluoro-N-(4-methoxyphenethyl)benzo[d]thiazol-2-amine, ((4-(((5,6-difluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)phenyl)ethynyl)boronic acid, 3-(4-(((5,6-difluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)phenyl)propiolic acid, 3-(4-(((4-methoxyphenethyl)(thiazolo[4,5-b]pyrazin-2-yl)amino)-methyl)phenyl)propiolic acid, 3-(4-(((5,7-difluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)phenyl)propiolic acid, 3-(4-(((4,6-difluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)phenyl)propiolic acid, 3-(4-(((5-fluorothiazolo[5,4-b]pyridin-2-yl)(4-methoxyphenethyl)- amino)methyl)phenyl)propiolic acid, 3-(4-(((4-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)phenyl)propiolic acid, 3-(4-(((4-methoxyphenethyl)(5,6,7-trifluorobenzo[d]thiazol-2-yl)amino)methyl)phenyl)propiolic acid, 3-(4-(((5-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)phenyl)propiolic acid, 3-(4-(((6-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)phenyl)propiolic acid, 3-(4-(((4-methoxyphenethyl)(thiazolo[5,4-b]pyridin-2-yl)amino)-methyl)phenyl)propiolic acid, 3-(4-(((4-methoxyphenethyl)(4,5,6-trifluorobenzo[d]thiazol-2-yl)- amino)methyl)phenyl)propiolic acid, 3-(4-(((4-methoxyphenethyl)(4,5,7-trifluorobenzo[d]thiazol-2-yl)- amino)methyl)phenyl)propiolic acid, 3-(4-(((4-methoxyphenethyl)(perfluorobenzo[d]thiazol-2-yl)- amino)methyl)phenyl)propiolic acid, 3-(4-(((4-methoxyphenethyl)(5-methylthiazolo[5,4-b]pyridin-2-yl)- amino)methyl)phenyl)propiolic acid, 3-(4-(((4-methoxyphenethyl)(5-methoxythiazolo[5,4-b]pyridin-2-yl)- amino)methyl)phenyl)propiolic acid, 3-(4-(((6-ethoxybenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)phenyl)propiolic acid, 3-(4-(((5-methoxybenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)phenyl)propiolic acid, 3-(4-(((5-aminobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)propiolic acid, (4-(2-((4-(carboxyethynyl)benzyl)(7-fluorobenzo[d]thiazol-2-yl)-amino)ethyl)phenyl)methanaminium chloride, 3-(4-(((4-carbamoylphenethyl)(7-fluorobenzo[d]thiazol-2-yl)amino)- methyl)phenyl)propiolic acid, 3-(4-(((4-cyanophenethyl)(7-fluorobenzo[d]thiazol-2-yl)amino)- methyl)phenyl)propiolic acid, 3-(4-(((4-methoxyphenethyl)(thiazolo[4,5-b]pyridin-2-yl)amino)-methyl)phenyl)propiolic acid, 3-(4-(((4-methoxyphenethyl)(6-(trifluoromethyl)benzo[d]thiazol-2-yl)amino)methyl)phenyl)propiolic acid, 3-(4-(((4-methoxyphenethyl)(7-(trifluoromethyl)benzo[d]thiazol-2- yl)amino)methyl)phenyl)propiolic acid, 3-(4-(((4-methoxyphenethyl)(7-nitrobenzo[d]thiazol-2-yl)amino)-methyl)phenyl)propiolic acid, 3-(4-(((7-chlorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)phenyl)propiolic acid, 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)phenyl)-N-(4-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)butyl)propiolamide, N-(15-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)phenyl)-13-oxo-3,6,9-trioxa-12-azapentadec-14-yn-1-yl)-5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide, 3-(4-(((4-methoxyphenethyl)(5-(trifluoromethyl)benzo[d]thiazol-2- yl)amino)methyl)phenyl)propiolic acid, 3-(4-(((5-bromobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)phenyl)propiolic acid, 3-(4-(((4-methoxyphenethyl)(5-methylbenzo[d]thiazol-2-yl)amino)- methyl)phenyl)propiolic acid, 3-(4-(((4-methoxyphenethyl)(5-nitrobenzo[d]thiazol-2-yl)amino)-methyl)phenyl)propiolic acid, 3-(4-(((4-methoxyphenethyl)(6-nitrobenzo[d]thiazol-2-yl)amino)-methyl)phenyl)propiolic acid, 3-(4-(((4-methoxyphenethyl)(thiazolo[4,5-c]pyridin-2-yl)amino)-methyl)phenyl)propiolic acid, 3-(4-(((5-chlorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)phenyl)propiolic acid, 3-(4-(((2-fluoro-4-methoxyphenethyl)(7-(trifluoromethyl)benzo- [d]thiazol-2-yl)amino)methyl)phenyl)propiolic acid, 3-(4-(((2-fluoro-4-methoxyphenethyl)(7-nitrobenzo[d]thiazol-2-yl)amino)methyl)phenyl)propiolic acid, 3-(4-(((7-chlorobenzo[d]thiazol-2-yl)(2-fluoro-4-methoxyphenethyl)- amino)methyl)phenyl)propiolic acid, 3-(4-(((2-fluoro-4-methoxyphenethyl)(thiazolo[5,4-b]pyridin-2-yl)amino)methyl)phenyl)propiolic acid, 3-(4-(((2-fluoro-4-methoxyphenethyl)(5-fluorobenzo[d]thiazol-2-yl)amino)methyl)phenyl)propiolic acid, 3-(4-(((5-bromobenzo[d]thiazol-2-yl)(2-fluoro-4-methoxyphenethyl)- amino)methyl)phenyl)propiolic acid, 3-(3-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)phenyl)propiolic acid, 3-(4-(((2-fluoro-4-methoxyphenethyl)(5-(trifluoromethyl)benzo[d]- thiazol-2-yl)amino)methyl)phenyl)propiolic acid, 3-(4-(((5-chlorobenzo[d]thiazol-2-yl)(2-fluoro-4-methoxyphenethyl)- amino)methyl)phenyl)propiolic acid, 3-(4-(((2-fluoro-4-methoxyphenethyl)(7-fluorobenzo[d]thiazol-2-yl)- amino)methyl)phenyl)propiolic acid, 3-(4-(((5,7-difluorobenzo[d]thiazol-2-yl)(2-fluoro-4-methoxy-phenethyl)amino)methyl)phenyl)propiolic acid, 3-(4-(((5,6-difluorobenzo[d]thiazol-2-yl)(2-fluoro-4-methoxy-phenethyl)amino)methyl)phenyl)propiolic acid, 3-(4-(((2-fluoro-4-methoxyphenethyl)(5-nitrobenzo[d]thiazol-2-yl)- amino)methyl)phenyl)propiolic acid, 3-(4-(((2-fluoro-4-methoxyphenethyl)(5,6,7-trifluorobenzo[d]thiazol-2-yl)amino)methyl)phenyl)propiolic acid, 3-(4-(((3-fluoro-4-methoxyphenethyl)(5-fluorobenzo[d]thiazol-2-yl)- amino)methyl)phenyl)propiolic acid, 3-(4-(((5,6-difluorobenzo[d]thiazol-2-yl)(3-fluoro-4-methoxy-phenethyl)amino)methyl)phenyl)propiolic acid, 3-(4-(((3-fluoro-4-methoxyphenethyl)(7-(trifluoromethyl)benzo[d]- thiazol-2-yl)amino)methyl)phenyl)propiolic acid, 3-(4-(((3-fluoro-4-methoxyphenethyl)(7-nitrobenzo[d]thiazol-2-yl)- amino)methyl)phenyl)propiolic acid, 3-(4-(((5,7-difluorobenzo[d]thiazol-2-yl)(3-fluoro-4-methoxy-phenethyl)amino)methyl)phenyl)propiolic acid, 3-(4-(((3-fluoro-4-methoxyphenethyl)(4,5,7-trifluorobenzo[d]thiazol-2-yl)amino)methyl)phenyl)propiolic acid, 3-(4-(((3-fluoro-4-methoxyphenethyl)(4-fluorobenzo[d]thiazol-2-yl)- amino)methyl)phenyl)propiolic acid, 3-(4-(((3-fluoro-4-methoxyphenethyl)(5-methoxythiazolo[5,4b]- pyridin-2-yl)amino)methyl)phenyl)propiolic acid, 3-(4-(((3-fluoro-4-methoxyphenethyl)(5-fluorothiazolo[5,4-b]pyridin-2-yl)amino)methyl)phenyl)propiolic acid, 3-(4-(((2-fluoro-4-methoxyphenethyl)(5-methoxythiazolo[5,4b]- pyridin-2-yl)amino)methyl)phenyl)propiolic acid, 3-(4-(((2-fluoro-4-methoxyphenethyl)(4,5,7-trifluorobenzo[d]thiazol-2-yl)amino)methyl)phenyl)propiolic acid, (E)-3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)- methyl)phenyl)acrylic acid, 2-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)cyclopropanecarboxylic acid, 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(2-(4-methylpiperazin-1-yl)-ethyl)amino)methyl)phenyl)propiolic acid, 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(2-morpholinoethyl)amino)-methyl)phenyl)propiolic acid, 4'-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-carboxylic acid, 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-fluorophenethyl)amino)-methyl)phenyl)propiolic acid, 4-(3-((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)prop-1-yn-1-yl)benzoic acid, (3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(phenethyl)amino)methyl)-phenyl)propiolic acid, 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(3-fluorophenethyl)amino)-methyl)phenyl)propiolic acid, 3-(4-(((3-chlorophenethyl)(7-fluorobenzo[d]thiazol-2-yl)amino)-methyl)phenyl)propiolic acid, 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(2-(pyridin-4-yl)ethyl)amino)-methyl)phenyl) propiolic acid, 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(2-(pyrrolidin-1-yl)ethyl)-amino)methyl)phenyl) propiolic acid, 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(2-(2-methylpyrrolidin-1-yl)-ethyl)amino)methyl) phenyl)propiolic acid, 3-(4-(((3,4-dimethoxyphenethyl)(7-fluorobenzo[d]thiazol-2-yl)amino)-methyl)phenyl)propiolic acid, 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-(methylsulfonyl)phenethyl)-amino)methyl)phenyl)propiolic acid, 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(2-fluorophenethyl)amino)-methyl)phenyl)propiolic acid, 3-(4-(((4-chlorophenethyl)(7-fluorobenzo[d]thiazol-2-yl)amino)-methyl)phenyl)propiolic acid, 3-(4-(((2-(2,2-dimethylpyrrolidin-1-yl)ethyl)(7-fluorobenzo[d]-thiazol-2-yl)amino)methyl) phenyl)propiolic acid, 3-(4-(((3,4-dichlorophenethyl)(7-fluorobenzo[d]thiazol-2-yl)amino)- methyl)phenyl) propiolic acid, 3-(4-(((3-bromophenethyl)(7-fluorobenzo[d]thiazol-2-yl)amino)-methyl)phenyl)propiolic acid, 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-(trifluoromethyl)phenethyl)-amino)methyl)phenyl) propiolic acid, 3-(4-(((2,4-dichlorophenethyl)(7-fluorobenzo[d]thiazol-2-yl)amino)-methyl)phenyl) propiolic acid, 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(3-methoxyphenethyl)amino)-methyl)phenyl)propiolic acid, 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(3-(trifluoromethyl)phenethyl)-amino)methyl)phenyl)propiolic acid, 3-(4-(((2-(benzo[d][1,3]dioxol-5-yl)ethyl)(7-fluorobenzo[d]thiazol-2-yl)amino)methyl)phenyl)propiolic acid, 3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-morpholinophenethyl)amino)-methyl)phenyl)propiolic acid, 3-(4-(((2-bromophenethyl)(7-fluorobenzo[d]thiazol-2-yl)amino)-methyl)phenyl)propiolic acid, 7-fluoro-N-(4-methoxyphenethyl)-N-(prop-2-yn-1-yl)benzo[d]thiazol-2-amine, 3-(4-(((4-aminophenethyl)(7-fluorobenzo[d]thiazol-2-yl)amino)-methyl)phenyl)propiolic acid, 3-(4-(((4-(dimethylamino)phenethyl)(7-fluorobenzo[d]thiazol-2-yl)-amino)methyl)phenyl) propiolic acid, 4'-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)-3,4,5,6-tetrahydro-[1,1'-biphenyl]-3-carboxylic acid, 4,5,7-trifluoro-N-(4-methoxyphenethyl)-N-(prop-2-yn-1-yl)benzo[d]-thiazol-2-amine, 4-fluoro-N-(4-methoxyphenethyl)-N-(prop-2-yn-1-yl)benzo[d]thiazol-2-amine, 5,7-difluoro-N-(4-methoxyphenethyl)-N-(prop-2-yn-1-yl)benzo[d]-thiazol-2-amine, 5-fluoro-N-(4-fluorophenethyl)-N-(prop-2-yn-1-yl)benzo[d]thiazol-2-amine, 7-fluoro-N-(4-fluorophenethyl)-N-(prop-2-yn-1-yl)benzo[d]thiazol-2-amine, 4,5,7-trifluoro-N-(4-fluorophenethyl)-N-(prop-2-yn-1-yl)benzo[d]-thiazol-2-amine, 5,6-difluoro-N-(4-methoxyphenethyl)-N-(prop-2-yn-1-yl)benzo[d]-thiazol-2-amine, 5,7-difluoro-N-(4-fluorophenethyl)-N-(prop-2-yn-1-yl)benzo[d]-thiazol-2-amine, 3-(4-(((7-aminobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)propiolic acid 5,6-difluoro-N-(4-fluorophenethyl)-N-(prop-2-yn-1-yl)benzo[d]-thiazol-2-amine, 5-fluoro-N-(3-fluoro-4-methoxyphenethyl)-N-(prop-2-yn-1-yl)benzo[d]-thiazol-2-amine, 5,7-difluoro-N-(3-fluoro-4-methoxyphenethyl)-N-(prop-2-yn-1-yl)-benzo[d]thiazol-2-amine, 5,6-difluoro-N-(3-fluoro-4-methoxyphenethyl)-N-(prop-2-yn-1-yl)-benzo[d]thiazol-2-amine, 7-fluoro-N-(2-fluoro-4-methoxyphenethyl)-N-(prop-2-yn-1-yl)benzo[d]-thiazol-2-amine, 4,5,7-trifluoro-N-(2-fluoro-4-methoxyphenethyl)-N-(prop-2-yn-1-yl)-benzo[d]thiazol-2-amine, N-(2-bromophenethyl)-5-fluoro-N-(prop-2-yn-1-yl)benzo[d]thiazol-2-amine, N-(2-bromophenethyl)-4,5,7-trifluoro-N-(prop-2-yn-1-yl)benzo[d]-thiazol-2-amine, 5,6-difluoro-N-(2-fluoro-4-methoxyphenethyl)-N-(prop-2-yn-1-yl)benzo[d]thiazol-2-amine, 5-fluoro-N-phenethyl-N-(prop-2-yn-1-yl)benzo[d]thiazol-2-amine, 4,5,7-trifluoro-N-(3-fluoro-4-methoxyphenethyl)-N-(prop-2-yn-1-yl)benzo[d]thiazol-2-amine, 4-fluoro-N-(2-fluoro-4-methoxyphenethyl)-N-(prop-2-yn-1-yl)benzo[d]thiazol-2-amine, 4-fluoro-N-(2-fluoro-4-methoxyphenethyl)-N-(prop-2-yn-1-yl)benzo[d]thiazol-2-amine, 3-(4-((4-(2-((4-(carboxyethynyl)benzyl)(7-fluorobenzo[d]thiazol-2-yl)amino)ethyl)phenoxy)methyl)phenyl)propiolic acid, N-(7-fluorobenzo[d]thiazol-2-yl)-N-(4-methoxyphenethyl)alanine, N-(but-3-yn-1-yl)-7-fluoro-N-(4-methoxyphenethyl)benzo[d]thiazol-2-amine, 2-((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-acetonitrile, (E)-3-(4-(((4-methoxyphenethyl)(4,5,7-trifluorobenzo[d]thiazol-2-yl)amino)methyl)phenyl)acrylic acid, (E)-3-(4-(((3-fluoro-4-methoxyphenethyl)(4,5,7-trifluorobenzo[d]-thiazol-2-yl)amino)methyl)phenyl)acrylic acid, (E)-3-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-fluorophenethyl)amino)-methyl)phenyl)acrylic acid, 4-(3-((7-fluorobenzo[d]thiazol-2-yl)(4-fluorophenethyl)amino)prop-1-yn-1-yl)benzoic acid, 3-(3-(((7-fluorobenzo[d]thiazol-2-yl)(4-fluorophenethyl)amino)-methyl)phenyl)propiolic acid, (E)-3-(3-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)acrylic acid, (E)-3-(3-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)-methyl)phenyl)but-2-enoic acid, 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, 2-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)acetic acid, 3-(3-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)propanoic acid, (S)-1-(4-(((4-methoxyphenethyl)(thiazolo[5,4-b]pyridin-2-yl)amino)methyl)phenyl)pyrrolidine-3-carboxylic acid, 4'-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)-[1,1'-biphenyl]-4-carboxylic acid, 5-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)picolinic acid, 4'-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)-[1,1'-biphenyl]-3-carboxylic acid, 6-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)picolinic acid, 1-(4-(((4-methoxyphenethyl)(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)methyl)phenyl)-1H-pyrazole-4-carboxylic acid, 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)-1H-pyrazole-4-carboxamide, 5-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)-1H-pyrrole-3-carboxylic acid, 5-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)furan-3-carboxylic acid, 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)-1H-imidazole-4-carboxylic acid, 2-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)-2H-1,2,3-triazole-4-carboxylic acid, 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)-1H-1,2,4-triazole-3-carboxylic acid, 4-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)piperazine-1-carboxamide, 4'-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)-5-hydroxy-[1,1'-biphenyl]-3-carboxylic acid, 2-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)thiazole-5-carboxylic acid, 2-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)-2-azabicyclo[2.2.1]heptane-5-carboxylic acid, 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid, 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)-3-methyl-1H-pyrazole-4-carboxylic acid, 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid, 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)-2-methylazetidine-3-carboxylic acid, (S)-1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)-3-methylpyrrolidine-3-carboxylic acid, 2-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)-2H-tetrazole-5-carboxylic acid, 1-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)-4-methylpiperidine-4-carboxylic acid, 2-(4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)oxazole-5-carboxylic acid, 1-(4-(1-((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)ethyl)phenyl)cyclobutane-1-carboxylic acid, 1-(3-fluoro-4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)azetidine-3-carboxylic acid, 1-(3-chloro-4-(((7-fluorobenzo[d]thiazol-2-yl)(4-methoxyphenethyl)amino)methyl)phenyl)azetidine-3-carboxylic acid, 1-(2-fluoro-4-(((3-fluoro-4-methoxyphenethyl)(7-fluorobenzo[d]thiazol-2-yl)amino)methyl)phenyl)azetidine-3-carboxylic acid, and 1-(2-fluoro-4-(((2-fluoro-4-methoxyphenethyl)(7-fluorobenzo[d]thiazol-2-yl)amino)methyl)phenyl)azetidine-3-carboxylic acid.

19. A composition according to claim 1, wherein the disease related to immune cell movement is selected from the group consisting of cardiovascular disease, fibrotic disease, inflammatory disease, and Alport syndrome.

20. A composition according to claim 1, characterized in that the cardiovascular disease is selected from the group consisting of hypertension, pulmonary hypertension, atherosclerosis, angina pectoris, myocardial infarction, ischemic cerebrovascular disease, arteriosclerosis, and media sclerosis.

21. In the first paragraph, the fibrotic disease is scleroderma, rheumatoid arthritis, neural fibrosis, Crohn's disease, ulcerative colitis, myelofibrosis, pulmonary fibrosis, hepatic fibrosis, liver cirrhosis, kidney fibrosis, glomerulosclerosis, myofibrosis, cardiac fibrosis, interstitial fibrosis, pancreatic fibrosis, splenic fibrosis, mediastinal fibrosis, vascular fibrosis, skin fibrosis, ocular fibrosis, macular degeneration, arthrofibrosis, thyroid fibrosis, endomyocardial fibrosis, peritoneal fibrosis, retroperitoneal fibrosis, progressive mass fibrosis, nephrogenic systemic fibrosis, systemic erythematosus A composition characterized in that it is selected from the group consisting of lupus (systemic lupus erythematosus), hereditary fibrosis, infectious fibrosis, irritant fibrosis, chronic autoimmune fibrosis, fibrosis due to antigen incompatibility during organ transplantation, fibrotic complications of surgical operations, fibrosis due to hyperlipidemia, fibrosis due to obesity, diabetic fibrosis, fibrosis due to hypertension, and occlusion due to fibrosis during stent insertion.

22. In paragraph 1, the inflammatory disease is an autoimmune disease, 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, metabolic dysfunction-associated steatohepatitis, chronic kidney disease, nephritis, proteinuria, diabetic renal failure, arthritis, psoriatic arthritis, neuritis, diabetic neuropathy, multiple sclerosis, gout, spondylitis, Reiter's syndrome, polyarteritis nodosa, vasculitis, Lou Gehrig's disease, Wegener's granulomatosis, hypercytokinemia, Polymyalgia rheumatica, articular cell arteritis, calcium crystal deposition arthropathy, pseudogout, non-articular rheumatism, bursitis, tenosynovitis, epicondylitis, Charcot's joint, hemarthrosis, Henoch-Schonlein purpura, hypertrophic osteoarthropathy, multicentric reticulohistiocytoma, surcoilosis, hemochromatosis, sickle cell disease, hyperlipoproteinemia, hypogammaglobulinemia, hyperparathyroidism, acromegaly, familial Mediterranean fever, Behçet'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 A composition characterized by being selected from the group consisting of broncho-pulmonary dysplasia.

23. A composition according to claim 1, wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, systemic scleroderma, 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 graft-versus-host disease.

24. A pharmaceutical composition for preventing or inhibiting cancer metastasis, comprising the compound of the above chemical formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

25. Use of the compound of formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition for treating a disease related to immune cell movement.

26. A method for treating a disease related to immune cell movement, comprising administering an effective amount of a composition containing the compound of the above chemical formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient to a subject in need thereof.

27. Use of the compound of formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof for preparing a composition for preventing or inhibiting cancer metastasis.

28. A method for preventing or inhibiting cancer metastasis, comprising administering an effective amount of a composition containing the compound of the above chemical formula 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient to a subject in need thereof.

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