WO2019147104A1 - Pharmaceutical composition for preventing or treating immunocyte migration-related diseases comprising benzo[d]thiazole derivative or salt thereof as active ingredient - Google Patents

Abstract

The present invention relates to a use of a benzo[d]thiazole derivative, having the structure of chemical formula 1, for preventing or treating immunocyte migration-related diseases. A compound of chemical formula 1 can regulate the migration of immunocytes and thereby exhibits a very remarkable effect in the prevention, amelioration, and treatment of diseases related to the immunocyte migration.

Description

A pharmaceutical composition for the prevention or treatment of diseases related to immune cell migration comprising the benzo [d] thiazole derivative or a salt thereof as an active ingredient

This application claims priority to Korean Patent Application No. 10-2018-0010398 filed on January 29, 2018, the entire contents of which are incorporated herein by reference.

The present invention relates to novel uses of benzo [d] thiazole derivatives having the unique structure disclosed in the present invention, and more particularly to the use of benzo [d] thiazole derivatives having the structure of formula And to the use for the prophylaxis or treatment of a related disease.

In various tissues of the body, each cell migrates differently depending on their genetic characteristics and environment. Uncontrolled cell migration is related to various disease states such as inflammatory diseases and cancer metastasis, but the characteristics of the migration signaling and mechanism of each cell are not fully understood. For example, AQP1 (water channel aquaporin-1) promotes cell migration in epithelial cells and the like. In addition, AQP1 (water channel aquaporin-1) (Hara-Chikuma M et al., 2002), which has been known to promote cancer metastasis (JS Soc Nephrol 2006 Jan; 17 (1): 39-45 ; Jiang Y, Aquaporin-1 activity of plasma membrane affects HT20 colon cancer cell migration, IUBMB Life 2009 Oct; 61 (10): 1001-9). In the case of macrophages, although they express the AQP1, (Tyteca D et al., Regulation of Macrophage Motility by the Water Channel Aquaporin-1: Crucial Role of M0 / M2 Phenotype Switch, PLoS One. As such, each of the cells has a variety of ways and characteristics in their migration, and drugs designed to prevent the migration of specific cells have been shown to have limited and ineffective efficacy. Therefore, there is a need to find a new strategy for controlling migratory switch of cells and treating immune related diseases.

On the other hand, although immune cells are the primary defense networks in the body, it has recently been reported that excessive activation of immune cells is one of the major pathogenic mechanisms. In general, immune cell mobility is increased upon activation of inflammatory immune cells. Specifically, it has been reported that immune cell migration and invasion are closely related to disease pathologies in the following diseases.

For example, cardiovascular disease is a disease that occurs in the heart and major arteries, including atherosclerosis and coronary artery disease. Atherosclerosis is an inflammatory disease caused by cholesterol, and is caused by atheroma composed of cholesterol deposited in the inner membrane of the artery and immune cells moving inward from the blood into the artery. In other words, cholesterol oxide is a site where inflammation occurs, and the immune cells such as mononuclear cells migrate, forming atheroma. When atheroma is formed, the inner surface of the blood vessel becomes rough and the wall becomes thick, and the diameter of the blood flowing inside becomes narrow, thereby obstructing blood circulation. When the fibrous membrane surrounding the bacillus arose, thrombosis occurs in the blood vessel, bleeding into the atheroma occurs, and the diameter of the blood vessel becomes suddenly narrowed or clogged. It occurs mainly in blood vessels supplying blood to the heart, blood vessels supplying blood to the brain, blood vessels supplying blood to the kidneys, and peripheral blood vessels causing ischemic heart disease, ischemic cerebrovascular disease (stroke), kidney failure, and limb ischemic arterial disease . It is known that CCL2 (CCChemokine ligand 2, MCP-1) plays an important role in the development and development of these cardiovascular diseases by inducing the migration of mononuclear cells. Thus, the action of CCL2 and the migration of mononuclear cells A new method of treating the above-mentioned cardiovascular diseases has been newly proposed. Also, even in hypertension, various immune cells that secrete inflammatory cytokines migrate excessively into the blood vessels, resulting in thickening of the blood vessel walls and loss of elasticity of blood vessels.

Pulmonary arterial hypertension (PAH) is classified as Group 1 of the World Health Organization (WHO) clinical classification system (ESC Guidelines, European Heart Journal 2015). Pulmonary arterial hypertension (PAH) is classified as respiratory distress, mean pulmonary artery pressure ) (MPAP> 25 mmHg) and right ventricular dysfunction as the common clinical features. Although pulmonary arterial hypertension is associated with various pre-existing factors such as genetic, infectious and related diseases, it is known that immune response following endothelial cell injury acts as a key pathological factor. This phenomenon is known to be closely related to the pathology of immune cell infiltration and dysfunction. In particular, immune cell and vascular endothelial cell interaction is important in PAH. In addition, there has been a recent report that invasion of monocytes and macrophages also promotes the progression of the disease in Alport syndrome.

On the other hand, in fibrosis-related diseases, a sustained (chronic) inflammatory response activates a wound-healing program, which leads to fibrosis. Inflammatory immune cells such as monocytes / macrophages, neutrophils, eosinophils, and mast cells rapidly become active after penetrating into damaged areas and secrete several cytokines. These cells are released into surrounding fibroblasts, epithelial cells, Activating cells to activate them into myoblast-like cells. Myoblast-like cells produce and secrete a large amount of extracellular matrix proteins, which ultimately leads to a large accumulation of extracellular matrix proteins in the tissue, And also leads to fibrosis and hypertrophy of the tissue. This pathological mechanism is one of the fundamental causes of the sclerotic fibrosis of tissues such as wound, skin, kidney, blood vessels, and lungs caused by skin wounds caused by wound, burns, and pressure ulcers. It has also been shown that fibrosis in chronic autoimmune diseases such as scleroderma, rheumatoid arthritis, Crohn's disease, ulcerative colitis, myelofibrosis and systemic lupus erythematosus, Is a major pathological feature. In addition, activation of inflammatory immune cells in atopic diseases, asthma diseases, COPD, psoriasis, keloids, proliferative retinopathy, etc. is known to contribute to the pathology.

 Particularly, fibroblasts activated by MyoBrast-type cells in the wound-healing program are called myofibroblasts (myofibroblasts). Because myofibroblast is at the heart of all fibrosis-related disease pathologies, elimination of the molecular or immunological mechanisms leading to myofibroblast activity is a key factor in the treatment of disease. It is well known that many innate immunity or adaptive immunity immunity is important for the activation and differentiation of fibroblasts. Removal of the inflammatory response at the wound site thus stops tissue remodeling to fibrosis, It is a key factor to maintain. However, since the removal of the inflammatory reaction is not practically practicable, understanding the mechanism of innate acquired immunity and finding a mediator is important for delaying fibrosis.

Monocytes, macrophages, etc. contribute to wound healing, but secrete reactive oxygen, nitrogen, and other harmful effects on surrounding cells. Therefore, if there is no rapid removal of monocytes or macrophages, it causes more tissue damage and fibrosis. Restricting the monocyte, macrophage, which is the earliest reacting early in the disease is therefore considered a therapeutic strategy in various chronic inflammation and fibrosis related diseases.

When the wound-healing mechanism triggers the fibrotic reaction, platelet-derived growth factor (PDGF) associated with hemagglutination invokes other inflammatory immune cells to the wound site and TGF-β1 promotes extracellular matrix synthesis from local fibroblasts . However, factors related to the hemagglutination reaction have been reported to induce fibrosis even when they are deficient.

As described above, target factors for preventing migration (and invasion) of immune cells have been proposed in diseases where excessive immune cell activation is a problem, and an attempt to devise a therapeutic method for diseases In order to treat effective diseases, it is still important to find out what kind of mediator is to control immune cell migration and how to control it. In fact.

Accordingly, the present inventors have sought to find a new therapeutic strategy for immune cell migration (infiltration) -related diseases, and the KRS level increase in the cell membrane region of immune cells (monocytes / macrophages) Which has a special relationship with laminin (in particular, the laminin subtype, alpha 4 beta 2 gamma 1). It has been found that certain compounds having the structure of formula (I) inhibit the migration of KRS into the cell membrane, And actually inhibits immune cell migration and infiltration to thereby treat the related diseases. Thus, the present invention has been completed.

Accordingly, an object of the present invention is to provide a pharmaceutical composition for preventing or treating immune cell migration-related diseases, which comprises a compound of the following formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

Further, it is intended to provide a pharmaceutical composition for preventing or treating immune cell migration-related diseases comprising the active ingredient of the compound of formula (1) or a pharmaceutically acceptable salt thereof.

The present invention also provides a pharmaceutical composition for preventing or treating immune cell migration-related diseases consisting essentially of a compound of the following formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:

≪ Formula 1 >

In this formula,

R1, R2, and R3 are, independently of each other, hydrogen; A halogen group; A nitro group; An amino group; A C1-C6 alkyl group optionally substituted by halogen; Or a hydroxycarbonyl group (provided that R1, R2, and R3 can not be hydrogen at the same time)

R4, R5, and R6 are, independently of each other, hydrogen; A halogen group; A C1 to C6 alkyl group; A C1 to C6 alkoxy group optionally substituted with C3 to C6 cycloalkyl; A C1-C6 alkylsulfanyl group; Or a mono- or di-C 1 -C 6 alkylamino group,

R7 and R8 are, independently of each other, hydrogen; A hydroxyl group; A halogen group; Or a hydroxycarbonyl group (provided that R7 and R8 can not be simultaneously hydrogen),

R9 is hydrogen or a C1 to C6 alkyl group.

It is still another object of the present invention to provide the use of the compound of the formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the prevention or treatment of immune cell migration-related diseases.

Another object of the present invention is to provide a method for treating immune cell migration-related diseases, which comprises administering an effective amount of a composition comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient to a subject in need thereof .

In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating immune cell migration-related diseases, which comprises a compound of the following formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a pharmaceutical composition for preventing or treating immune cell migration-related diseases comprising the active ingredient of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

The present invention also provides a pharmaceutical composition for preventing or treating immune cell migration-related diseases consisting essentially of a compound of the following formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:

≪ Formula 1 >

In this formula,

R1, R2, and R3 are, independently of each other, hydrogen; A halogen group; A nitro group; An amino group; A C1-C6 alkyl group optionally substituted by halogen; Or a hydroxycarbonyl group (provided that R1, R2, and R3 can not be hydrogen at the same time)

R4, R5, and R6 are, independently of each other, hydrogen; A halogen group; A C1 to C6 alkyl group; A C1 to C6 alkoxy group optionally substituted with C3 to C6 cycloalkyl; A C1-C6 alkylsulfanyl group; Or a mono- or di-C 1 -C 6 alkylamino group,

R7 and R8 are, independently of each other, hydrogen; A hydroxyl group; A halogen group; Or a hydroxycarbonyl group (provided that R7 and R8 can not be simultaneously hydrogen),

R9 is hydrogen or a C1 to C6 alkyl group.

In order to accomplish still another object of the present invention, the present invention provides the use of the compound of the formula (I) or a pharmaceutically acceptable salt thereof for producing an agent for the prevention or treatment of diseases related to immune cell migration.

In order to accomplish still another object of the present invention, the present invention provides an immunoassay comprising administering an effective amount of a composition comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient to a subject in need thereof And a method for treating cell migration-related diseases.

Justice

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The following definitions are also provided to assist the reader in the practice of the present invention.

The term " alkyl " as used herein refers to an aliphatic hydrocarbon radical, including both linear and branched hydrocarbon radicals. For example, C1-C6 alkyl is an aliphatic hydrocarbon having from 1 to 6 carbon atoms and is selected from the group consisting of methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec- , Neopentyl, isopentyl, and the like.

The term " alkoxy " means a radical in which a hydrogen atom of a hydroxy group is substituted with an alkyl, unless otherwise defined, for example C1-C6 alkoxy is methoxy, ethoxy, propoxy, n- Pentyloxy, isopropoxy, sec-butoxy, tert-butoxy, neopentyloxy, isopentyloxy and the like.

In the present invention, "KRS protein" means a polypeptide known as lysyl tRNA synthetase. KRS is an enzyme that mediates the aminoacylation reaction of amino acid lysine and tRNA. In the present invention, KRS is not particularly limited as long as it is known in the art as a lysyltriene synthetase. For example, the KRS of the present invention is derived from human ( homo sapiens ). NP_005539.1, and the like.

Hereinafter, the present invention will be described in detail.

The present inventors have found that, in relation to the pathological migration phenomenon of cells, it is important that the level of KRS specifically increases in the cytoplasmic cell membrane of immune cells (particularly, monocytes / macrophages) in relation to the immune cell migration and invasion state And specifically confirmed the specific regulatory function of KRS in the migration of immune cells (monocytes / macrophages) with a particular relationship with LN421 (laminin subtype α4β2γ1). Accordingly, the compound of formula (I) specifically inhibits the migration of KRS from the cytoplasm to the cell membrane, thereby remarkably reducing the KRS level of the cell membrane. Thus, in fact, the pathological phenomenon of immune cell migration and invasion such as pulmonary arterial hypertension And exhibit a remarkable therapeutic effect in associated diseases.

Accordingly, the present invention provides a pharmaceutical composition for preventing or treating immune cell migration-related diseases, which comprises the compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a pharmaceutical composition for preventing or treating immune cell migration-related diseases comprising the above-mentioned compound of formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a pharmaceutical composition for preventing or treating immune cell migration-related diseases, which is essentially composed of the compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

In a compound according to the present invention or a pharmaceutically acceptable salt thereof, preferably R1, R2, and R3 are, independently of each other, hydrogen; Or a halogen group (provided that R1, R2, and R3 can not be hydrogen at the same time)

R4, R5, and R6 are, independently of each other, hydrogen; A halogen group; Or a C1 to C6 alkoxy group (provided that R4, R5, and R6 can not be simultaneously hydrogen)

R7 and R8 are, independently of each other, hydrogen; Or a hydroxycarbonyl group (provided that R7 and R8 can not be simultaneously hydrogen),

R9 is hydrogen or a C1 to C6 alkyl group.

In the compound of the formula (1) of the present invention, preferred compounds or salts thereof are as follows:

4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

4 - (((2-chlorophenylethyl) (7-fluorobenzo [d] thiazol-2-yl) amino) methyl) benzoic acid;

4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (3-fluorophenyl) ethyl] amino} methyl) benzoic acid;

4 - {[[2- (4-chlorophenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino] methyl} benzoic acid;

4 - {[[2- (3-chlorophenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino] methyl} benzoic acid;

4 - (((7-fluorobenzo [d] thiazol-2-yl) (4-methylphenylethyl) amino) methyl) benzoic acid;

4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (3-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (4-fluorophenyl) ethyl] amino} methyl) benzoic acid;

4 - {[[2- (4-ethoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino] methyl} benzoic acid;

4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (4-propoxyphenyl) ethyl] amino} methyl) benzoic acid;

4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (4-isopropoxyphenyl) ethyl] amino} methyl) benzoic acid;

4 - {[(7-Fluorobenzo [d] thiazol-2-yl) {2- [4- (methylsulfanyl) phenyl] ethyl} amino] methyl} benzoic acid;

4 - {[(7-Fluorobenzo [d] thiazol-2-yl) {2- [3- (methylsulfanyl) phenyl] ethyl} amino] methyl} benzoic acid;

4 - ({[2- (2,5-dimethoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

4 - ({[2- (3,4-dimethoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (2-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (3-methylphenyl) ethyl] amino} methyl) benzoic acid;

4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (4-isobutoxyphenyl) ethyl] amino} methyl) benzoic acid;

4 - {[[2- (4-cyclopropylmethoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino] methyl} benzoic acid;

4 - {[(7-Fluorobenzo [d] thiazol-2-yl) {2- [4- (methylamino) phenyl] ethyl} amino] methyl} benzoic acid;

4 - {[{2- [4- (dimethylamino) phenyl] ethyl} (7-fluorobenzo [d] thiazol-2-yl) amino] methyl} benzoic acid;

4 - {[(7-fluorobenzo [d] thiazol-2-yl) (2-phenylethyl) amino] methyl} benzoic acid;

4 - {[[2- (4-cyclohexylmethoxyphenyl) ethyl] - (7-fluorobenzo [d] thiazol-2-yl) amino] methyl} benzoic acid;

4 - {[[2- (4-cyclobutylmethoxyphenyl) ethyl] - (7-fluorobenzo [d] thiazol-2-yl) amino] methyl} benzoic acid;

4 - ({[2- (4-ethoxy-3-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

4 - ({(7-Fluorobenzo [d] thiazol-2-yl) [2- (2-fluoro-4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

4 - ({[2- (2,4-dimethoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (3-fluoro-4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

4 - ({[2- (3-chloro-4-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

4 - {[[2- (4-sec-butoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino] methyl} benzoic acid;

4 - {[[2- (4-ethylaminophenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino] methyl} benzoic acid;

4 - ({[2- (4-ethylphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

4 - {[(7-Fluorobenzo [d] thiazol-2-yl) {2- [4- (propan-2-yl) phenyl] ethyl} amino] methyl} benzoic acid;

4 - ({[2- (2,3-difluorophenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

4 - ({[2- (2,5-difluorophenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (3,4,5-trifluorophenyl) ethyl] amino} methyl) benzoic acid;

4 - ({[2- (3-bromo-4-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

4 - ({[2- (2,4-dichlorophenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

4 - ({[2- (2,4-difluorophenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (2-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (2-fluorophenyl) ethyl] amino} methyl) benzoic acid;

4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (3-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

4 - ({[2- (2,3-difluoro-4-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

Methyl} -5- (propan-2-yl) phenyl] ethyl} amino] methyl} -1H-pyrazolo [ Benzoic acid;

4 - ({[2- (2,5-difluoro-4-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

4 - ({[2- (2-chloro-4-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (4-methoxy-2,3-dimethylphenyl) ethyl] amino} methyl) benzoic acid;

4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (4-methoxy-2,5-dimethylphenyl) ethyl] amino} methyl) benzoic acid;

4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (4-methoxy-3-methylphenyl) ethyl] amino} methyl) benzoic acid;

4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (4-methoxy-2-methylphenyl) ethyl] amino} methyl) benzoic acid;

4 - ({[2- (2,6-difluoro-4-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

4- (1 - {(7-Fluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} ethyl) benzoic acid;

4- (1 - {(7-fluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} propyl) benzoic acid;

4- (1 - {(7-Fluorobenzo [d] thiazol-2-yl) [2- (3-fluoro-4-methoxyphenyl) ethyl] amino} ethyl) benzoic acid;

4- (1 - {[2- (3-bromo-4-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} ethyl) benzoic acid;

4- (1 - {[2- (2,4-difluorophenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} ethyl) benzoic acid;

4- (1 - {[2- (2,3-difluorophenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} ethyl) benzoic acid;

4- (1 - {(7-Fluorobenzo [d] thiazol-2-yl) [2- (3,4,5-trifluorophenyl) ethyl] amino} ethyl) benzoic acid;

4- (1 - {[2- (2,4-dichlorophenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} ethyl) benzoic acid;

4- (1 - {[2- (2,3-difluoro-4-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} ethyl) benzoic acid;

4- (1 - {[2- (2,5-Difluoro-4-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} ethyl) benzoic acid;

2- {4-methoxy-2-methyl-5- (propan-2-yl) phenyl] ethyl} amino] Ethyl} benzoic acid;

4- (1 - {(7-Fluorobenzo [d] thiazol-2-yl) [2- (4-methoxy-2,3-dimethylphenyl) ethyl] amino} ethyl) benzoic acid;

4- (1 - {(7-Fluorobenzo [d] thiazol-2-yl) [2- (4-methoxy-2,5-dimethylphenyl) ethyl] amino} ethyl) benzoic acid;

4- (1 - {(7-Fluorobenzo [d] thiazol-2-yl) [2- (4-methoxy-3-methylphenyl) ethyl] amino} ethyl) benzoic acid;

4- (1 - {(7-Fluorobenzo [d] thiazol-2-yl) [2- (4-methoxy-2-methylphenyl) ethyl] amino} ethyl) benzoic acid;

4- (1 - {[2- (2,6-Difluoro-4-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} ethyl) benzoic acid;

4- (1 - {[2- (2,3-difluoro-4-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} propyl) benzoic acid;

4- (1 - {[2- (2,5-Difluoro-4-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} propyl) benzoic acid;

4- (1 - {[2- (2-chloro-4-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} propyl) benzoic acid;

4- (1 - {(7-Fluorobenzo [d] thiazol-2-yl) [2- (4-methoxy-2,3-dimethylphenyl) ethyl] amino} propyl) benzoic acid;

4- (1 - {(7-Fluorobenzo [d] thiazol-2-yl) [2- (4-methoxy-2,5-dimethylphenyl) ethyl] amino} propyl) benzoic acid;

4- (1 - {(7-Fluorobenzo [d] thiazol-2-yl) [2- (4-methoxy-3-methylphenyl) ethyl] amino} propyl) benzoic acid;

4- (1 - {(7-Fluorobenzo [d] thiazol-2-yl) [2- (4-methoxy-2-methylphenyl) ethyl] amino} propyl) benzoic acid;

4- (1 - {[2- (2,6-Difluoro-4-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} propyl) benzoic acid;

2- {4-methoxy-2-methyl-5- (propan-2-yl) phenyl] ethyl} amino] Propyl} benzoic acid;

4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) -2-hydroxybenzoic acid;

3-chloro-4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

4 - ({[2- (4-methoxyphenyl) ethyl] (6-nitro-benzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

4 - ({[2- (4-methoxyphenyl) ethyl] (7-nitro-benzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

4 - ({(6-amino-benzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

4 - ({(7-amino-benzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

4 - ({(7-chloro-benzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

4 - ({(6-chloro-benzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

4 - ({(5-chloro-benzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

4 - ({(5,6-difluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

4 - {[[2- (4-methoxyphenyl) ethyl] (5,6,7-trifluoro benzo [d] thiazol-2-yl) amino] methyl} benzoic acid;

4 - ({(6-chloro-7-fluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

4 - {[[2- (4-methoxyphenyl) ethyl] (7-trifluoromethyl-benzo [d] thiazol-2-yl) amino] methyl} benzoic acid;

4 - ({(6,7-difluorobenzo [d] thiazol-2-yl) - [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

4 - ({(5-bromo-benzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

4 - ({(6-fluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

4 - ({(5,7-difluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

4 - ({(7-fluoro-6-methyl-benzo [d] thiazol-

Methyl} benzoic acid;

4 - ({(4,6-difluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

4 - ({[2- (4-methoxyphenyl) ethyl] (7-methyl-benzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

4 - ({[2- (4-methoxyphenyl) ethyl] (6-methyl-benzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

4 - ({[2- (4-methoxyphenyl) ethyl] (5-methyl-benzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

4- (1 - {(5,7-difluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} ethyl) benzoic acid;

4- (1 - {(5,6-difluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} ethyl) benzoic acid;

4- (1 - {[2- (4-methoxyphenyl) ethyl] (5,6,7-trifluoro benzo [d] thiazol-2-yl) amino} ethyl) benzoic acid;

4- (1- {6-chloro-7-fluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} ethyl) benzoic acid;

4- (1 - {(5-bromo-benzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} ethyl) benzoic acid;

4- (1 - {(6,7-difluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} ethyl) benzoic acid;

4- (1- {7-Fluoro-6-methyl-benzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} ethyl) benzoic acid;

4- (1 - {[2- (4-methoxyphenyl) ethyl] [7- (trifluoromethyl) -benzo [d] thiazol-2-yl] amino} ethyl) benzoic acid;

4- (1 - {(5-chloro-benzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} ethyl) benzoic acid;

4- (1- {6-chloro-benzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} ethyl) benzoic acid;

4- (1 - {(7-chloro-benzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} ethyl) benzoic acid;

4- (1 - {[2- (4-methoxyphenyl) ethyl] (7-methyl-benzo [d] thiazol-2-yl) amino} ethyl) benzoic acid;

4- (1 - {[2- (4-methoxyphenyl) ethyl] (6-methyl-benzo [d] thiazol-2-yl) amino} ethyl) benzoic acid;

4- (1 - {[2- (4-methoxyphenyl) ethyl] (5-methyl-benzo [d] thiazol-2-yl) amino} ethyl) benzoic acid;

4- (1 - {(5-fluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} ethyl) benzoic acid;

4- (1 - {(4,6-difluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} ethyl) benzoic acid;

4 - ({(6-Bromo-benzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

4- (1 - {(6-Bromo-benzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} ethyl) benzoic acid;

2 - {(4-carboxybenzyl) [2- (4-methoxyphenyl) ethyl] amino} benzo [d] thiazole-6-carboxylic acid;

2 - {(4-carboxybenzyl) [2- (4-methoxyphenyl) ethyl] amino} benzo [d] thiazole-7-carboxylic acid;

4 - ({[2- (4-methoxyphenyl) ethyl] [6- (trifluoromethyl) benzo [d] thiazol-2-yl] amino} methyl) benzoic acid;

4 - ({[2- (4-methoxyphenyl) ethyl] [5- (trifluoromethyl) benzo [d] thiazol-2-yl] amino} methyl) benzoic acid;

4 - ({[7-fluoro-6- (trifluoromethyl) benzo [d] thiazol-2-yl] [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

4- (1 - {(5,7-Difluorobenzo [d] thiazol-2-yl) [2- (3-fluoro-4-methoxyphenyl) ethyl] amino} ethyl) benzoic acid;

4- (1 - {[2- (4-methoxyphenyl) ethyl] [6- (trifluoromethyl) benzo [d] thiazol-2-yl] amino} ethyl) benzoic acid;

4- (1 - {[2- (4-methoxyphenyl) ethyl] [5- (trifluoromethyl) benzo [d] thiazol-2-yl] amino} ethyl) benzoic acid; And

4- (1 - {[7-fluoro-6- (trifluoromethyl) benzo [d] thiazol-2-yl] [2- (4-methoxyphenyl) ethyl] amino} ethyl) benzoic acid.

In the present invention, a more preferred example of the compound represented by the formula (1) may be a compound having a structure represented by the following formula (1-1).

≪ Formula 1-1 >

In Formula 1-1,

R1 is hydrogen; Or a halogen group,

R4 is hydrogen; A halogen group; Or a C1 to C6 alkoxy group

R7 is hydrogen; Or a hydroxycarbonyl group.

In one embodiment of the present invention, among the compounds represented by the general formula (1), compounds which share the structure of the general formula (1-1), particularly 4 - ({(7-fluorobenzo [ (3-methoxyphenyl) ethyl] amino} methyl) benzoic acid, to an in vivo disease model for a variety of immune cell migration (and infiltration) -related diseases And the effect of preventing and treating the disease was confirmed. The compound of formula 2 is also referred to herein as 'BC-KI-00053'.

(2)

The compound of the formula (1) or a salt thereof may have a substituent including an asymmetric atom, and the compound of the formula (1) or a salt thereof may exist as an optical isomer such as (R), (S), or racemic (RS) . Accordingly, unless otherwise indicated, the compound of Formula 1 or its salt includes all optical isomers such as (R), (S), or racemic (RS).

The compound of formula (I) of the present invention may be in the form of a pharmaceutically acceptable salt. The salts may be formed with conventional acid addition salts such as salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid and organic acids such as citric acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, Salts derived from organic acids such as benzoic acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, glutamic acid or aspartic acid. The salt may also be in the form of a conventional metal salt, for example, an alkali metal salt such as lithium, sodium, or potassium; Alkaline earth metal salts such as calcium or magnesium salts; Or chromium salts. Also included are salts formed with suitable organic ligands, such as quaternary ammonium salts, including dicyclohexylamine or N-methyl-D-glucamine salts and amino acid salts formed with arginine, lysine and the like.

In the present invention, the term "immune cell" preferably means monocytes or macrophages.

The term "diseases related to immune cell migration" in the present invention is not particularly limited as long as it is known in the art that excessive immune cell migration (or invasion) is a major mechanism of onset, Fibrosis disease, inflammatory disease, and Alport syndrome.

The specific type of the cardiovascular disease is not particularly limited, and examples thereof include hypertension (including inflammatory complications due to hypertension), pulmonary arterial hypertension, atherosclerosis, angina pectoris, myocardial infarction, ischemic cerebrovascular disease, arteriosclerosis, It can be chosen from the group.

Examples of the fibrotic diseases include, but are not limited to, scleroderma, rheumatoid arthritis, Crohn's disease, ulcerative colitis, myelofibrosis, The present invention relates to a method for the treatment and prophylaxis of pulmonary fibrosis, hepathic fibrosis, liver cirrhosis, kidney fibrosis, glomerulosclerosis, myofibrosis, cardiac fibrosis, interstitial fibrosis, pancreatic fibrosis, Myocardial fibrosis, endometrial myocardial fibrosis, peritoneal fibrosis, peritoneal fibrosis, advanced fibrotic fibrosis, fibrotic fibrosis, endothelial fibrosis, endothelial fibrosis, Systemic lupus erythematosu, hereditary fibrosis, infectious fibrosis, irritative fibrosis, chronic autoimmune fibrosis, organ transplantation Fibrosis due to inadequate antigenicity, fibrosis of surgical operation, fibrosis due to hyperlipidemia, fibrosis due to obesity, diabetic fibrosis, fibrosis due to hypertension, and fibrosis occlusion during stenting.

In the present invention, the type of the inflammatory disease is not particularly limited, but is preferably an autoimmune disease, inflammatory bowel disease, dermatitis (for example, atopic dermatitis, eczema, psoriasis), diabetic eye disease Retinopathy, etc.), peritonitis, osteomyelitis, meningitis, meningitis, encephalitis, pancreatitis, traumatic shock, bronchial asthma, rhinitis, sinusitis, otitis media, pneumonia, gastritis, enteritis, cystic fibrosis, (Such as diabetic neuropathy, multiple sclerosis, etc.), gout, diabetes mellitus, etc.), hepatitis (such as cirrhosis, non-alcoholic steatohepatitis, etc.), nephritis (diabetic renal failure), arthritis (psoriatic arthritis, osteoarthritis, Inflammatory bowel disease, spondylitis, Reiter's syndrome, nodular polyarteritis, vasculitis, Lou Gehrig's disease, Wegener's granulomatosis, hypercytokinemia, rheumatoid multiple myalgia, arthritic cell arteritis, Arthropathy, caustic gout, non-articular rheumatism, bursitis, hay fever, suppurative tongue (tennis elbow), Charcot's joint, hemarthrosis, Henoch-Schönlein purpura, hypertrophic osteoarthritis, Hyperparathyroidism, hyperparathyroidism, hyperkeratosis, familial Mediterranean fever, Bechart's disease, systemic lupus erythematosus, systemic lupus erythematosus, systemic lupus erythematosus, systemic lupus erythematosus, Chronic obstructive pulmonary disease, acute lung injury, and bronchopulmonary dysplasia (bronchopulmonary dysplasia), bronchial asthma, multiple sclerosis, multiple sclerosis, multiple sclerosis, septicemia, septic shock, acute respiratory distress syndrome, multiple organ failure, chronic obstructive pulmonary disease, -pulmonary dysplasia), and also includes chronic inflammatory diseases.

In the present invention, autoimmune diseases Rheumatoid arthritis, systemic scleroderma, systemic lupus erythematosus, psoriasis, asthma, ulcerative colitis, Behcet's disease, Crohn's disease, multiple sclerosis, dermatomyositis, colitis, vasculitis, arthritis, granulomatosis, organ specific autoimmune lesions, ulcerative colitis And GvHD (graft-versus-host disease).

The chronic inflammatory diseases refer to the types of inflammatory diseases mentioned above and they include chronic conditions. Examples of the chronic inflammatory diseases include asthma, atopic dermatitis, eczema, psoriasis, osteoarthritis, gout, But are not limited to, psoriatic arthritis, cirrhosis, nonalcoholic fatty liver disease, chronic obstructive pulmonary disease, rhinitis, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy and multiple sclerosis.

The pharmaceutical composition according to the present invention may be formulated into a suitable form together with a compound of the above-mentioned formula (I) or a pharmaceutically acceptable salt thereof alone or together with a pharmaceutically acceptable carrier, and may further contain an excipient or diluent can do. &Quot; Pharmaceutically acceptable " as used herein refers to a nontoxic composition that is physiologically acceptable and does not normally cause an allergic reaction such as gastrointestinal disorder, dizziness, or the like when administered to humans.

The pharmaceutically acceptable carrier may further include, for example, a carrier for oral administration or a carrier for parenteral administration. Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. In addition, it may contain various drug delivery materials used for oral administration. In addition, the carrier for parenteral administration may contain water, a suitable oil, a saline solution, an aqueous glucose and a glycol, and may further contain a stabilizer and a preservative. Suitable stabilizers include antioxidants such as sodium hydrogen sulfite, sodium sulfite or ascorbic acid. Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. The pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, etc. in addition to the above components. Other pharmaceutically acceptable carriers and preparations may be those known in the art.

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. Parenteral administration methods include, but are not limited to, intravenous, intraperitoneal, intracerebral, subcutaneous, intramuscular, intravenous, intraarterial, intrathecal, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, But are not limited to, injection or infusion by intranasal, intestinal, topical, sublingual, rectal, or intralesional routes, or injection or infusion by a sustained release system as described below. For example, the compound of Formula 1 may be administered systemically or locally.

The pharmaceutical composition of the present invention can be formulated into oral preparations or parenteral administration preparations according to the administration route as described above.

In the case of a preparation for oral administration, the composition of the present invention may be formulated into a powder, a granule, a tablet, a pill, a sugar, a tablet, a liquid, a gel, a syrup, a slurry, . For example, an oral preparation can be obtained by combining the active ingredient with a solid excipient, then milling it, adding suitable auxiliaries, and then processing the mixture into a granular mixture. Examples of suitable excipients include, but are not limited to, sugars including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol and maltitol, and starches including corn starch, wheat starch, rice starch and potato starch, Cellulose such as methylcellulose, sodium carboxymethylcellulose and hydroxypropylmethyl-cellulose and the like, fillers such as gelatin, polyvinylpyrrolidone and the like. In addition, crosslinked polyvinylpyrrolidone, agar, alginic acid or sodium alginate may optionally be added as a disintegrant. Further, the pharmaceutical composition of the present invention may further comprise an anti-coagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent and an antiseptic agent.

In the case of a preparation for parenteral administration, it can be formulated by a method known in the art in the form of injection, cream, lotion, external ointment, oil, moisturizer, gel, aerosol and nasal aspirate. These formulations are described in commonly known formulations of all pharmaceutical chemistries.

 The total effective amount of the composition of the present invention may be administered to a patient in a single dose and may be administered by a fractionated treatment protocol administered over a prolonged period of time in multiple doses. In the pharmaceutical composition of the present invention, the content of the active ingredient may be varied depending on the degree of the disease. Preferably, the total preferred dose of the pharmaceutical composition of the present invention may be from about 0.01 μg to about 10,000 mg, and most preferably from about 0.1 μg to 500 mg, per kilogram of patient body weight per day. However, the dosage of the pharmaceutical composition may be determined depending on various factors such as the formulation method, administration route and frequency of treatment, as well as the patient's age, body weight, health condition, sex, severity of disease, diet and excretion rate, It will be possible to determine the appropriate effective dose of the composition of the present invention by those of ordinary skill in the art in view of this point. The pharmaceutical composition according to the present invention is not particularly limited to the formulation, administration route and administration method as long as the effect of the present invention is exhibited.

The present invention provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention or treatment of diseases related to immune cell migration.

The present invention provides a method for treating immune cell migration-related diseases, which comprises administering to a subject in need thereof an effective amount of a composition comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

The 'effective amount' of the present invention refers to an amount that, when administered to an individual, indicates an effect of improving, treating, preventing, detecting, diagnosing or inhibiting immune cell migration-related diseases of an immune cell migration-related disease, , Preferably mammals, especially humans, and may be cells, tissues, organs, etc., derived from animals. The subject may be a patient requiring the effect.

The term " treatment " of the present invention broadly refers to ameliorating symptoms of immune cell migration-related diseases or immune cell migration-related diseases, which includes curing, substantially preventing, or ameliorating conditions And includes, but is not limited to, relieving, curing or preventing one or most of the symptoms resulting from immune cell migration related diseases.

The term "comprising" of the present invention is used synonymously with "containing" or "characterized" and does not exclude additional component elements or method steps not mentioned in the composition or method . The term " consisting of " is intended to exclude additional elements, steps or components not otherwise mentioned. The term " consisting essentially of " is intended to encompass component elements or steps, etc., which, in addition to the component elements or steps described, do not materially affect their underlying properties,

The compound of formula (I) can control the migration of immune cells, and thus has a remarkable effect in prevention, improvement and treatment of diseases related to immune cell migration.

Figure 1a shows the results of a transwell migration assay comparing the effects of collagen (Col), fibronectin (FN) and laminin (LN) on the migration of immune cells (monocytes / macrophages) Microscopic images of migrating cells are shown.

FIG. 1B is a graphical representation of the number of cells in the microscope image of FIG. 1A.

2a shows the results of a transwell migration assay comparing the effects of various laminin subtypes (LN111, LN211, LN221, LN411, LN421, LN511, LN521) on the migration of immune cells (monocytes / macrophages) , Which shows a microscopic image of the migrating cell.

FIG. 2B is a graph showing the number of cells in a microscopic image of FIG. 2A.

FIG. 3 shows the result of Western blotting that KRS increases in the monocyte / macrophage membrane by the treatment with LN421.

FIG. 4A shows a microscope image of migrating cells as a result of comparing the effect of KRS expression on LN421-specific monocyte / macrophage migration with a Transwell cell migration assay.

FIG. 4B is a graph showing the number of cells in a microscopic image of FIG. 4A. FIG.

FIG. 5 shows that the increase in KRS level in the cell membrane region by treatment with LN421 was markedly lowered by treatment with the compounds having the structure of Formula 1 (typically, BC-KI-00053 compound) .

FIG. 6A shows the results of transwell cell migration assays in which monocyte / macrophage migration was significantly inhibited in a concentration-dependent manner by treatment with compounds having the structure of Chemical Formula 1 (typically, BC-KI-00053 compound) Microscopic images of migrating cells are shown.

FIG. 6B is a graph showing the number of cells in a microscopic image of FIG. 6A.

FIG. 7a shows fluorescence microscopic observation of the degree of infiltration of monocytes, macrophages and Langerhans cells by BC-KI-00053 compound treatment in an acute inflammatory reaction (ear skin wound model) And the lower end represents BC-KI-00053 100 mg / kg administration group, the green part represents monocytes, macrophages and Langerhans cells, the red part represents the labeled blood vessels for CD31, skin wound position).

FIG. 7B is a graphical representation of the degree of monocyte / macrophage infiltration in a skin wound peripheral region indicated by a blue circle in the fluorescence microscope image of FIG. 7A.

Figure 8a is a schematic representation of a triad (bile duct, hepatic artery, hepatic vein) occlusion procedure for the production of hepatic ischemia-reperfusion injury model.

FIG. 8B shows fluorescence microscopic observation of the degree of infiltration of mononuclear cells, macrophages and Cooper cells according to BC-KI-00053 compound treatment in a hepatic ischemia-reperfusion injury model (the upper part of the figure shows the vehicle-treated group, 100-mg / kg administered group BC-KI-00053), green indicates the monocyte, macrophage and Cooper cell, and red indicates the labeled blood vessel for CD31).

FIG. 8C is a graph showing the degree of mononuclear / macrophage infiltration in the fluorescence microscope image of FIG. 8B quantified by the time point after ischemia-reperfusion injury. The red bar was the vehicle-treated group, and the green bar was the quantified value in the BC-KI-00053 100 mg / kg group.

FIG. 9A is a graph showing an experimental method and schedule of an experiment for preparing an animal model of liver fibrosis with CCl ₄ (carbon tetrachloride) and evaluating the therapeutic effect of BC-KI-00053 compound.

FIG. 9b shows the result of evaluating the effect of BC-KI-00053 in an animal model of liver fibrosis induced by CCl ₄ (carbon tetrachloride), wherein the degree of fibrosis in the liver surface and liver was observed by fluorescence microscopy in each experimental group (In the upper part of each figure, the liver surface is imaged, and the lower part is an image of the liver inside. Collagen in the green part and hepatocyte in the red part).

Figure 10a shows right ventricular end-systolic pressure (RVESP) changes by administration of BC-KI-00053 compound in a pulmonary arterial hypertension (PAH) model (MCT: monocrotaline treated pulmonary arterial hypertension (PAH) model, Tx25mpk : 25 mg / kg BC-KI-00053 in the PAH model, and 50 mg / kg BC-KI-00053 in the Tx50mpk: PAH model).

Figure 10b shows changes in left ventricular end-systolic pressure (LVESP) by administering BC-KI-00053 compounds in a pulmonary arterial hypertension (PAH) model (MCT: monocrotaline treated pulmonary arterial hypertension (PAH) model, Tx25mpk : 25 mg / kg BC-KI-00053 in the PAH model, and 50 mg / kg BC-KI-00053 in the Tx50mpk: PAH model).

FIG. 10C shows the result of IHC staining that the immune cell migration and infiltration of lung tissue were reduced by administration of the BC-KI-00053 compound in a pulmonary arterial hypertension (PAH) model.

Figure 11a shows the body weight and body weight change of the vehicle-treated group and the BC-KI-00053 treated group in the superimposed hypertension FHH rats during the experimental period (numbers in parentheses are used to calculate average data in each group (The same applies hereinafter).

FIG. 11B shows the results of measurement of MAP changes according to treatment with BC-KI-00053 in FHH rats which are superimposed hypertension.

FIG. 11C shows the results of measurement of changes in proteinuria (urinary protein excretion) by BC-KI-00053 treatment in FHH rats, which are superimposed hypertension.

FIG. 11D shows the results of measurement of changes in plasma creatinine concentration according to BC-KI-00053 treatment in FHH rats that are superimposed hypertension.

FIG. 11E shows the results of an evaluation of the glomerular microscope image (upper image) and the degree of glomerulosclerosis in the vehicle treatment group (control) and the BC-KI-00053 treatment group in the superimposed hypertension FHH rats Graphs (numbers in the graph indicate the number of images used to measure actual results).

FIG. 11f shows a microscopic image (upper image) and degree of cortical fibrosis of the cortical fibrosis in the vehicle-treated group and BC-KI-00053 treated group in the superimposed hypertension FHH rats (Bottom graph) (the numbers in the graph indicate the number of images used to measure actual results).

FIG. 11g shows a microscopic image (upper image) and the degree of water quality fibrosis of the water-quality fibrosis of the vehicle-treated group (control) and BC-KI-00053 treated group in the superimposed hypertension FHH rats (Bottom graph) (the numbers in the graph indicate the number of images used to measure actual results).

Figure 11h shows a microscopic image (top image, right ventricular insertion point) and degree of cardiac fibrosis for cardiac fibrosis in the vehicle treatment group and BC-KI-00053 treatment group in FHH rats with superimposed hypertension The results are quantified and shown (bottom graph).

FIG. 11I shows the result of IHC staining that immune cell migration and infiltration of renal tissue was reduced by administering BC-KI-00053 compound in FHH rats, which are superimposed hypertension.

Figure 12a shows the baseline body weight and experimental period of vehicle-treated group and BC-KI-00053 treated group in Dahl salt-sensitive (SS) rats which induced hypertension, proteinuria, glomerular sclerosis and kidney stromal fibrosis through high salt (HS) (The numbers in parentheses indicate the number of animals used to calculate the average data in each group, and so on).

FIG. 12B shows the results of measurement of MAP changes according to treatment with BC-KI-00053 in Dahl salt-sensitive (SS) rats that induced hypertension through high salt (HS) diet.

Figure 12c shows the change in the degree of proteinuria (urinary protein excretion) following treatment with BC-KI-00053 in Dahl salt-sensitive (SS) rats that induced proteinuria, glomerular sclerosis and kidney stromal fibrosis via high salt (HS) This is a result.

FIG. 12d shows the results of measurement of plasma creatinine concentration according to BC-KI-00053 treatment in Dahl salt-sensitive (SS) rats which induced hypertension, proteinuria, glomerular sclerosis and kidney stromal fibrosis through high salt (HS) .

Figure 12e shows the vehicle treatment (control) and BC-KI-00053 treatment groups in Dahl salt-sensitive (SS) rats that induced hypertension, proteinuria, glomerular sclerosis and renal stromal fibrosis via high salt (HS) (Upper graph) and glomerulosclerosis (lower graph). (The numbers in the graph indicate the number of images used in the actual measurement).

Figure 12f shows the vehicle treatment and BC-KI-00053 treatment in Dahl salt-sensitive (SS) rats that induced hypertension, proteinuria, glomerular sclerosis and kidney stromal fibrosis via high salt (HS) (Upper graph) and the degree of cortical fibrosis (lower graph) (the numbers in the graph indicate the number of images used in the actual measurement).

Figure 12g shows the results of the vehicle treatment and BC-KI-00053 treatment in Dahl salt-sensitive (SS) rats that induced hypertension, proteinuria, glomerular sclerosis and kidney stromal fibrosis via high salt (HS) (Upper graph) and water quality fibrosis (bottom graph) (the numbers in the graph indicate the number of images used in actual measurement).

Figure 12h shows the results of the vehicle treatment and BC-KI-00053 treatment in Dahl salt-sensitive (SS) rats that induced hypertension, proteinuria, glomerular sclerosis and kidney stromal fibrosis via high salt (HS) (Upper image, right ventricle insertion point) and degree of cardiac fibrosis (bottom graph).

Figure 12i shows immunocyte migration and invasion of renal tissues by administration of the compound BC-KI-00053 in Dahl salt-sensitive (SS) rats which induced hypertension, proteinuria, glomerular sclerosis and kidney stromal fibrosis via high salt (HS) And IHC staining.

FIG. 13 shows the results of evaluating the leukocyte infiltration and the degree of fibrosis reduction in the kidney when the control substance or BC-KI-00053 compound was treated in an animal model of Alport syndrome. CD45, a marker of leukocyte infiltration, was stained green and collagen I, a marker of fibrosis, was stained red.

Hereinafter, the present invention will be described in detail.

However, the following examples are illustrative of the present invention, and the present invention is not limited to the following examples.

Example 1: Identification of the role of laminin signal in immune cell migration and invasion

Among the various extracellular matrices (ECMs), we have identified which promotes the migration and invasion of monocytes / macrophages. Transwell migration assay was performed using collagen (Col), fibronectin and laminin as the extracellular matrix, and the specific experimental method is as follows. Transwell (Corning, # 3421-5mm) was coated with gelatin (0.5mg / ml) and RAW 264.7 cells (1x10 ⁵ cells / well) were seeded in the top chamber. Serum Free DMEM (500 μl) containing 10 μg / ml of laminin (laminin mixture, Biolamina), Fibronectin or Collagen was added to the bottom chamber. After 24 hours, 70% methanol was fixed for 30 min and stained with 50% hematoxylin for 30 min. Non-migrating cells on the top of the membrane were removed with a cotton swab, and the membrane was mounted on a slide. The migrating cells present on the underside of the membrane were observed and quantified on a high magnification microscope.

Experimental results As shown in FIGS. 1A and 1B, it was confirmed that laminin among various extracellular matrix promotes the migration of monocytes / macrophages most strongly. In other words, it was confirmed that the migration of monocytes / macrophages reacted strongly to the laminin (LN) signal in ECM (extracellular matrix).

Example 2 Immune Cell Migration and Infiltration by Laminin Subtypes

The effect of laminin subtype on immune cell migration and invasion was evaluated. A transwell migration assay was performed in the same manner as in Example 1 using 1 μg / ml of LN111, LN211, LN221, LN411, LN421, LN511, and LN521 as various laminin subtype proteins (purchased from Biolamina) Respectively. The specific sequence of the laminin subtypes is determined by the? 4 chain of SEQ ID No. 4, the? 2 chain of SEQ ID No. 10, the? 5 chain of SEQ ID No. 11, the? 2 chain of SEQ ID No. 6, the? 1 chain of SEQ ID No. 12, , The? 1 chain of SEQ ID NO: 8 can be referred to.

Experimental Results As shown in FIGS. 2A and 2B, monocytes / macrophages specifically reacted with the α4β2γ1 subtype (LN421) among the laminin. In other words, it was confirmed that the migration of monocytes / macrophages was specific to LN421 among laminin.

Example 3: Cell membrane migration of KRS by laminin treatment in immune cells

RAW 264.7 cells (2x10 ⁶ cells) were plated on 100-well plates and cultured for 18 hr. Then, the cells were harvested at 0 h, 12 h, and 24 h after treatment with 1 μg / ml of LN421 in serum free DMEM media. Using the ProteoExtract Subcellular Proteome Extraction Kit (Calbiotech, cat # 539790), the RAW 264.7 cell protein was separated into cytosol and membrane fraction. The resulting protein was electrophoresed, transferred to a PVDF membrane (Milipore) and blocked with 3% skim milk. Then KRS was detected by Western blotting. Specifically, KRS polyclonal antibody (rabbit, Neomics, Co. Ltd. # NMS-01-0005) antibody was added and bound for 1 hour. Unbound antibody was removed and reacted by addition of anti-rabbit secondary antibody (ThermoFisher Scientific, # 31460). After reacting the secondary antibody, the substrate was film-sensitized with ECL reagent in a dark room. The sensitized band was identified as a band corresponding to the size of KRS as compared to a standard molecular marker. Antibodies against Na + / K + ATPase (Abcam, ab76020) and tubulin (Santa Cruz SC-5286) were used to identify the plasma membrane and cytosol markers, respectively.

As shown in FIG. 3, it was confirmed that when LN421 was treated with monocytes / macrophages, the KRS detection amount was slightly increased in the cytosol region, compared with the decrease in the KRS detection amount. These results suggest that KRS, which is expressed in the cytoplasmic region of monocytes / macrophages, is migrated to the cell membrane region by LN421 treatment, and KRS is specifically increased in the immune cell membrane region It is thought to be an important pathological phenomenon for diseases related to immune cell migration and invasion.

Example 4: Effect of KRS on LN421-dependent immune cell migration and invasion

In order to examine whether KRS affects LN421-specific monocyte / macrophage migration, LN421 was treated with each of the macrophages transfected to overexpress KRS and the macrophages transfected so as to inhibit expression of KRS, A transwell migration assay was performed. As a control, the KRS-like protein leucyl-tRNA synthetase (LRS, SEQ ID NO: 3) was used.

Specifically, KRS or LRS overexpressing macrophages were constructed as follows: KRS-Myc and LRS-Myc inserted in pCDNA3 were transfected (48hrs) into Raw 264.7 cells using Turbofect (Thermo Fisher Scientific). Cells transfected with Ev (empty vector, pCDNA3) -Myc as a negative control were prepared.

KRS or LRS expression inhibition macrophages were constructed as follows: Si-KRS (SEQ ID NO: 13) and Si-LRS (SEQ ID NO: 14) were transfected with Raw 264.7 cells using Lipofectamin (Thermo Fisher Scientific) 72 hrs). Cells transfected with si-control (si-RNA duplex with medium GC content (Invitrogen, Cat No. 12935-300) as negative control) were prepared.

Whether or not KRS or LRS overexpression or inhibition of expression was properly performed in the transfected cells was confirmed by Western blotting of each protein (data not shown).

Transwell migration assay was performed in the same manner as in Example 1 using 1 쨉 g / ml of Laminin 421 for each of the transformed macrophages.

As shown in FIGS. 4A and 4B, KRS overexpression effectively increased LN421-specific monocyte / macrophage migration, while conversely, reduction of KRS expression using si-RNA effectively reduced LN421-specific monocyte / macrophage migration Respectively. In contrast, the expression of leucyl-tRNA synthetase (LRS), a KRS-like protein, did not affect monocyte / macrophage migration. This suggests that LN421-dependent migration of monocytes / macrophages is strongly affected by KRS expression.

Example  5: Selection of compounds that inhibit migration of immune cells without side effects Of KRS  Transfer inhibitor compounds to cell membrane

From the results of Examples 3 and 4, not only the expression level of KRS in LN421-dependent migration of monocytes / macrophages but also the intracellular behavior of KRS significantly influenced KRS, The increase of KRS specifically in the immune cell membrane region was considered to be an important pathological phenomenon for diseases related to immune cell migration and invasion. Therefore, we tried to verify that the suppression of this pathological behavior of KRS is applicable as one of therapeutic strategies of diseases related to immune cell migration and invasion. On the other hand, under normal conditions, KRS is an organ necessary for the synthesis of proteins in cells. Therefore, the strategy of simply increasing or decreasing the amount of KRS is likely to be inadequate as a practical treatment strategy due to concerns about adverse effects on normal function of the body. Therefore, the inventors of the present invention examined whether various known compounds known to affect activity, intracellular dynamics and expression in various aspects of KRS can specifically inhibit migration to monocytes / macrophages without side effects.

As a result, the present inventors confirmed that the compounds having the core structure of the formula (1) inhibit the migration of KRS to the cell membrane and inhibit LN431-specific monocyte / macrophage migration. This confirmation was specifically performed by the following in vitro experiments. In the present invention, the compounds represented by the formula (1) are prepared and prepared according to Korean Patent Laid-Open No. 10-2018-0006167.

To examine the effect of various KRS inhibitors on cell membrane permeability, RAW 264.7 cells (2x10 ⁶ cells) were added to 100-well plates and incubated for 18 hours. Laminin 421 1 μg / ml and treated with 100 nM of various KRS inhibitors for 12 h. After harvesting, RAW 264.7 cell protein was separated into cytosol and membrane fraction using ProteoExtract Subcellular Proteome Extraction Kit (Calbiotech, Cat # 539790). The resulting protein was electrophoresed, transferred to a PVDF membrane (Milipore) and blocked with 3% skim milk. Thereafter, KRS was detected by Western blotting, and a specific method was performed in the same manner as in <Example 3>.

Thus, the substance identified as inhibiting the migration of KRS to the cell membrane was treated with LN421-treated macrophages to perform a transwell migration assay. These results confirmed the inhibitory effect of KRS on the movement of LN421-specific monocytes / macrophages by inhibition of migration to the cell membrane. Specifically, Transwell (Corning, # 3421-5mm) was coated with gelatin (0.5mg / ml) and RAW 264.7 cells (1x10 ⁵ cells / well) were seeded in a top chamber. 500 μl of Serum Free DMEM containing 1 μg / ml of Laminin 421 (LN421, Biolamina) was added to the bottom chamber. Then, DMSO or KRS inhibitor compound (in DMSO) was treated with various concentrations (30 nM, 100 nM, 300 nM, 1 μM and 3 μM, respectively) in the upper chamber. After 24 hours, 70% methanol was fixed for 30 min and stained with 50% hematoxylin for 30 min. Non-migrating cells on the top of the membrane were removed with a cotton swab, and the membrane was mounted on a slide. The migrating cells present on the underside of the membrane were observed and quantified on a high magnification microscope.

FIGS. 5, 6A and 6B are graphs showing the results of comparison between the BC-KI-00053 compound (4 - ({(7-fluorobenzo [d] thiazol- - yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid). As shown in FIG. 5, it was confirmed that the level of KRS increased in the cell membrane region by the treatment with LN421, which was significantly lowered by treatment with BC-KI-00053. This means that the level of KRS that has been transferred to the cell membrane of monocytes / macrophages by laminin (LN421) is reduced.

Also, as shown in FIGS. 6A and 6B, it was confirmed that the migration of monocytes / macrophages was remarkably inhibited depending on the concentration of BC-KI-00053 (a compound inhibiting migration of KRS to cell membrane).

In the following in vivo experiments for diseases related to immune cell migration, experiments were conducted on the basis of the BC-KI-00053 compound.

Example  6: in vivo In an acute inflammatory reaction KRS  Effect of cell membrane migration inhibitor on monocyte / macrophage infiltration

6-1. ear skin wound model

To investigate the effect of KRS cell membrane migration inhibitor on mononuclear cell infiltration in acute inflammatory reaction, ear skin wound model using CX3CR1-GFP mouse (Stock # 005582, Jackson Laboratory (Bar Harbor, USA)) was prepared. Monocytes, macrophages and Langerhans cells in CX3R1-GFP mice appear green. D-2, D-1, D-0, and D-3 were administered to mice for 2 days from the first day of imaging for a total of 4 days, either vehicle or BC-KI-00053 (100 mg / kg, D + 1). The vehicle used was a mixture of Corn oil: Polyethylene glycol 400: Tween 80: Methyl cellulose (1%) = 20: 30: 1: 49. The ear skin was punctured with a 31G syringe (at time D-0) to induce an acute inflammatory response. Alexa Flour 555 conjugated anti-CD31 antibody was used to label blood vessels (identified in red). A confocal microscope was used as the imaging equipment.

As shown in FIGS. 7A and 7B, in the vehicle-treated control group, it was confirmed that monocytes and macrophages were gathered around the wound area (ear hole area) marked with a white circle and infiltrated to a considerably wide range at a high level (Blue circle). In contrast, the level of monocyte and macrophage infiltration was significantly reduced in mice administered BC-KI-00053. 7a and 7b, green dots scattered around the normal tissues rather than the main lesion (blue circles) were resident macrophage Langerhans cells. In the vehicle and BC-KI-00053 treated groups, Langerhans cell , It was judged that only migration of migratory macrophages was inhibited by the treatment of BC-KI-00053. From the above results, it was confirmed that migration and infiltration of immune cells due to acute inflammatory reaction were inhibited by administration of KRS cell membrane migration inhibitor (particularly, BC-KI-00053), indicating that the compound of the present invention inhibited the pro- It is possible to inhibit excessive migration of immune cells that secrete cain and thus to exhibit preventive or therapeutic effects on inflammatory diseases.

6-2. Liver Ischemia-Reperfusion Injury Model

Liver Ischemia-Reperfusion Injury Model was constructed using CX3CR1-GFP mouse to investigate the effect of KRS cell membrane migration inhibitor on monocyte infiltration in ischemic immune response. In CX3CR1-GFP mice, monocytes, macrophages and kupffer cells appear green. (D-2, D-1, D-0) were administered to mice for 3 days from the day two days before imaging, either vehicle or BC-KI-00053 (100 mg / kg; As the vehicle, Corn oil: Polyethylene glycol 400: Tween80: Methyl cellulose (1%) = 20: 30: 1: 49 was used. Triad (bile duct, hepatic artery, hepatic vein) occlusion was performed using a 6-0 suture on the third day of oral administration (D-0) as shown in FIG. Triad occlusion was performed for 30 min to induce acute inflammation, with 3 g of Eppendorf tube hanging from both ends of the suture. Immediately after reperfusion (0 h) and after 24 h of ischemic inflammation, the suture was removed and the blood vessels were labeled with anti-CD31 antibody conjugated with Alexa Flour 555 for repeated imaging ). Two - photon microscope was used as imaging equipment.

Experimental Results As shown in FIGS. 8B and 8C, in a control mouse treated only with a vehicle, a large number of mononuclear cells / macrophages were recruited into a wound site (recruitment site) after 24 hours of reperfusion . On the other hand, in the BC-KI-00053 treated group, the degree of monocyte and macrophage infiltration was significantly reduced. In FIG. 8C, the red bar is the result of quantification in the vehicle-administered group and the green bar is the quantification in the BC-KI-00053 100 mg / kg group. On the other hand, the very bright green cells scattered around the normal tissue mainly seen at 0 h in reperfusion are kupffer cells which are resident macrophages. After 24 hours of reperfusion, kupffer cells in both vehicle and BC-KI-00053 treated groups , It was judged that only migration of migratory macrophages was inhibited by the treatment of BC-KI-00053. That is, the KRS cell membrane migration inhibitor (especially BC-KI-00053) exerts an excellent effect of inhibiting only monocyte / macrophage infiltration to the liver induced by ischemia.

Example  7: In vivo  For liver fibrosis KRS  Identification of pharmacological effects of cell membrane migration inhibitors

Actin-DsRed (Stock no. # 006051, Jackson Laboratory (Bar Harbor, USA)) Hepatocytes appear red in mice. To induce liver fibrosis, CCl ₄ (carbon tetrachloride) was dissolved in corn oil and injected intraperitoneally at a concentration of 20% twice a week for a total of 6 weeks. The vehicle and BC-KI-00053 (100 mg / kg) were administered daily, orally, and for 3 weeks from the time three weeks had elapsed since the start of CCl ₄ administration. The vehicle used was a mixture of Corn oil: Polyethylene glycol 400: Tween 80: Methyl cellulose (1%) = 20: 30: 1: 49. The animal groups were constructed as shown in Table 1 below.

The degree of fibrosis on the surface and inside of the liver (30-50 μm depth) was detected by SHG (Second Harmonic Generation) technique (Excitation: 780 nm, Detection: 390 nm).

division		Material treatment state	Number of experimental animals
Control group	(One)	Cone oil administration animals (normal animals) + vehicle administration	One
	(2)	Cone oil-administered animals (normal animals) + BC-KI-00053 administration	One
Experimental group	(3)	CCl 4 liver fibrosis animal model + vehicle administration	2
	(4)	CCl 4 liver fibrosis animal model + BC-KI-00053 administration	3

In the group to which BC-KI-00053 was administered to normal animals (the animal of (2) in Table 1), no weight loss was observed and no other symptoms were caused in the liver. Therefore, the BC-KI-00053 compound was considered to be innocuous in vivo . In the fibrotic animal model, animals receiving the vehicle (animals in Table 1 (3)) died prematurely due to the toxicity of CCl ₄ at 4 weeks after the start of the experiment. Specifically, as shown in FIG. 9A, one of the mice died on the 24th day and the other one died on the 32nd day of the 6-week experimental period, and they showed significant weight loss. The pre-terminated experimental group was used for data comparisons after completion of all experiments using the liver surface and internal fibrosis data obtained at 2 weeks and 4 weeks before they died.

In general, severe fibrosis is observed in the shape of a linear rather than a rounded (curly) shape. As shown in FIG. 9B, significant fibrosis was observed on the surface of the liver (upper part (0 mu m) of FIG. 9B) after administration of CCl ₄ for 2 weeks or 4 weeks. Particularly, in the group administered with CCl ₄ for 4 weeks, And the portal-portal septa was found, and it was confirmed that severe fibrosis progressed considerably. In addition, similar fibrosis patterns were observed in the liver (lower end (30-48 μm) of FIG. 9B) and necrosis of hepatocytes was observed. While (4 one animal group in Table 1) in the liver surface and fibrosis of the inner CCl ₄ to 6 weeks of administration three weeks treated animal group a BC-KI-00053 of the process to all significantly reduced CCl ₄ 2 ju group It was confirmed that capsular collagen appeared almost similar to normal individuals, and hepatocyte necrosis was also significantly reduced. In Fig. 9B, green represents collagen (fibrosis), and red represents liver cells. These experimental results indicate that the KRS cell membrane movement inhibitor (particularly, BC-KI-00053) provided by the present invention is excellent in inhibiting fibrosis.

Example 8: In vivo  Identification of pharmacological effects of KRS cell membrane migration inhibitors on pulmonary arterial hypertension (PAH)

Experimental Method

1. Pulmonary arterial hypertension (PAH) model preparation and test substance administration

To induce PAH in 6-week-old female SD rats (Oriental Bio), 60 mg / kg of MCT (monocrotaline), which induces pulmonary arterial hypertension, was injected subcutaneously through selective pulmonary artery injury. (25 mg / kg, once daily) or BC-KI-00053 (25 or 50 mg / kg, dissolved in vehicle, Once a day) was orally administered for 3 weeks. The vehicle used was a mixture of Corn oil: Polyethylene glycol 400: Tween 80: Methyl cellulose (1%) = 20: 30: 1: 49.

2. Measurement of blood flow and blood pressure

After 3 weeks, the animals were anesthetized with isoflurane and blood flow and pressure were measured using an MPVS Cardiovascular Pressure and Volume System (MPVS Ultra, manufacturer: Millar Instruments). Right ventricular end-systolic pressure (RVESP) and end-diastolic pressure, left ventricular systolic pressure, and end-  ratpressurecatheter, manufactured by Millar Instruments). Cardiac output was measured using a perivascular blood flow probe (Transonic  Flowprobes, manufactured by Millar Instruments), and the experimental technique was carried out in the same manner as described in the following documents: Pacher P, Nagayama T, Mukhopadhyay P, Batkai S, Kassta. Measurement of cardiac function using pressure-volume conductance catheter technique in mice and rats. Nat Protoc 2008; 3 (9): 1422-34.

3. Immunohistochemistry (IHC)

IHC staining for monocyte / macrophage marker CD68 was performed using the lung tissue of each experimental group. The collected lungs were fixed to paraformaldehyde (PFA) according to a conventional procedure, and then infiltrated with paraffin through water, dehydration, and transparency. Rat lung tissue paraffin block was cut to a thickness of 6 μm and slides were made. Then, dyeing was carried out as follows. First, xylene treatment for 5 minutes was followed by 2 minutes of 2 minutes, 95% ethanol, 90% ethanol, 70% ethanol and DW in 100% ethanol for 2 minutes and washed with PBS for 5 minutes (2 times). After treatment with 0.3% H ₂ O ₂ (10 min), the samples were washed twice with PBS for 5 min. After immersing in 0.01M citrate buffer (pH 6.0) for 3 minutes and 30 seconds, it was cooled for 10 seconds, heated for 10 minutes, and then incubated for 20 minutes at room temperature. And then washed three times for 5 minutes with PBS-T (0.03% Triton-X). Thereafter, the cells were blocked with 2% BSA and 2% goat serum in PBS at 4 ° C for 30 minutes. Anti-CD68 antibody (1: 200, Abcam, ab31630) was treated overnight at 4 ° C. After washing with PBS-T 3 times for 5 minutes, the cells were treated with polymer-HRP amti-mouse envision kit (DAKO) for 1 hour at 4 ° C. After washing three times for 5 minutes with PBS-T, 1 ml of DAB substrate buffer and 20 μl of DAB chromogen were added to the tissue. After 10 minutes, the cells were rinsed twice with a third DW every 2 minutes. The stained tissue was treated with Mayer's hematoxylin (Sigma) for 1 min and then treated with 70% ethanol, 90% ethanol, 95% ethanol and 100% ethanol for 2 min for 2 min each. Finally, xylene treatment was performed 3 times for 5 minutes, followed by mounting using a mounting solution and observation with an optical microscope.

Experiment result

Pulmonary arterial hypertension is caused by narrowing of the pulmonary artery, resulting in an increase in right ventricular pressure, resulting in right ventricular failure. In addition, when the compensatory mechanism is destroyed by persistent hypertension, right ventricular enlargement occurs following right ventricular hypertrophy. In addition, it has been shown that the left ventricular end-diastolic volume and cardiac output decrease (Lee et al., Clinical Characteristics and Prognostic Factors of Patients with Severe Pulmonary Hypertension, Korean Circulation J 2007; 37 : 265-270 ). As a result, pulmonary hypertension is mainly related to the right ventricle, but it is also related to the function of the left ventricle.

As shown in FIG. 10A, RVESP (right ventricular systolic pressure) was increased in the PAH animal model, and BC-KI-00053 treatment significantly decreased RVESP concentration-dependently. In particular, the RVESP lowering effect in the BC-KI-00053 50 mg / kg treated group was similar to that of sildenafil, one of the standard treatments.

In addition, there was no decrease in LVESP after treatment with BC-KI-00053, and in the group administered with BC-KI-00053 at 50 mg / kg, LVESP was increased as shown in FIG. 10B But not statistically significant. This is in contrast to sildenafil, which is used to treat pulmonary arterial hypertension, as well as pulmonary artery enlargement as well as systemic arterial dilation leading to reduced systemic blood pressure. In other words, BC-KI-00053 showed a lower tendency to affect systemic artery pressure compared to sildenafil, and this effect indicates that there is a concern about the risk of hypotension when sildenafil is administered in a clinical setting When considered, this would be an advantageous characteristic of the therapeutic agent. In addition, severe pulmonary hypertension can be accompanied by low cardiac output and systemic hypotension as right ventricular failure occurs. In contrast, BC-KI-00053 may be used at higher concentrations to improve cardiac output and systemic blood pressure by improving pulmonary arterial hypertension. If the cardiac output and systemic blood pressure decrease, the patient may experience general weakness or dizziness. Therefore, improvement of these symptoms can be expected through improvement of cardiac output and systemic blood pressure.

In summary, administration of the KRS cell membrane migration inhibitor (especially BC-KI-00053) provided by the present invention not only shows the therapeutic effect and symptom relief of PAH but also has a relatively low risk of side effects of existing therapeutic drugs Respectively.

As shown in FIG. 10C, IHC staining of monocyte / macrophage marker CD68 using the lung tissue of each experimental group showed that monocyte / macrophage infiltration occurred in the lung of pulmonary arterial hypertension (PAH) mice at a high level Respectively. On the other hand, it was confirmed that the treatment of KRS cell membrane migration inhibitor (especially BC-KI-00053) provided by the present invention clearly reduced the invasion of lung tissue of monocytes / macrophages, Was found to be significantly better than sildenafil.

Example  9: in vivo  Hypertension-induced proteinuria, glomerulosclerosis, renal and cardiac fibrosis KRS  Identification of pharmacological effects of cell membrane migration inhibitors

9-1. It is a superimposed hypertension. FHH In the rats KRS  Effects of cell membrane migration inhibitors on hypertension, kidney damage, cardiac damage and fibrosis

Experimental Method

Experiments were performed using male FHH rats aged 9-12 weeks. These animals were obtained from the University of Mississippi Medical Center and approved by the American Association for Accreditation of Laboratory Animal Care (AAALAC). All protocols have been approved by the Institutional Animal Care and Use Committee of the University of Mississippi Medical Center. The rats were fed free of food and water and these rats were provided with a refined AIN-76 rodent feed containing 0.4% NaCl (Dyets, Bethlehem, PA) after weaning. Fawn-hooded hypertensive (FHH) rats are a genetic model of spontaneous hypertension associated with glomerular filtration and proteinuria. To facilitate glomerular injury in the rats, a single (unilateral) kidney extraction was performed and a DOCA strip was implanted.

Specifically, FHH rats were anesthetized with isoflurane and a telemetry transmitter (model TA11PAC40, Data Sciences International, St. Paul, Minn.) Was purchased from Williams, JM et al. Am J Physiol Regul As described in Integr Comp Physiol (2012). Briefly, surgery was performed under 2 to 3% isoflurane-O ₂ , and the catheter of the device was inserted into the left femoral artery and was guided upstream to the aorta. The body of the telemetry unit was placed in the lateral cavity of the left leg and closed with muscle tissue. The skin was then sutured. Animals were given Baytril (10 mg / kg) and rimadyl (5 mg / kg), a long-acting analgesic, to control surgical pain to prevent infection. After surgery, the rats were housed in individual cages in a quiet, air-conditioned room environment with a 12: 12-h contrast cycle and took one week to fully recover from surgery. Then, the mean arterial blood pressure (MAP) and proteinuria were measured for 4 hours (10 am to 2 pm) before the rats were housed in a metabolic cage. Proteolysis was measured using the Bradford method and BSA (Bio-Rad Laboratories, Hercules, Calif.) As a standard.

One week after the insertion of the transmitter, the rats were housed in Wang, X. et al. Lt; RTI ID = 0.0 &gt; Am J & lt; / RTI &gt; Physiol Renal Physiol (2016). Briefly, the rats were anesthetized with 2-3% isoflurane-O ₂ , and the right side was incised in aseptic condition. Gently lifting the right kidney, tightly tied the thread around the renal vessels and ureters. The kidney vessels and the distal end of the ureter were excised and kidneys were removed. The incised portion was sutured with successive subcutaneous stitches, and then the skin was further sutured. After the right kidney of the rats was removed, DOCA pellet (200 mg, Innovative Research of America) was transplanted subcutaneously into the neck.

After single kidney extraction and DOCA transplantation, the rats had recovery time of 3 days. Groups 1 (n = 15) were then randomized to gavage to provide BC (n = 15), which was previously provided with distilled water in rats, converted to water containing 1% NaCl and randomly divided into two groups: -KI-00053 (25 mg / kg daily) was treated; In Group 2 (n = 15), vehicle (corn oil, polyethylene glycol 400, Tween 80 and methylcellulose) of the same volume (2.5 ml / kg per day) was directly administered to the gastrointestinal tract. Blood pressure and proteinuria were measured weekly for 3 weeks in the experimental group. At the end of the experiment, rats were anesthetized with isoflurane and blood samples were taken to determine creatinine levels. The rats were then flushed through 50 ml of 0.9% NaCl through the aorta and perfused with 20 ml of 4% paraformaldehyde. Kidneys and hearts were collected for histological evaluation.

The paraffin slices were stained with Masson's trichrome to measure glomerular injury and renal interstitial fibrosis. Images were obtained using a Nikon DS-Fi1 color camera (Nikon, Melville, NY) and a Nikon Eclipse 55i microscope with NIS-Elements D 3.0 software. The degree of glomerular injury was evaluated by the experimenter from 0 to 4+ for 30-40 glomeruli / slices without prejudice. 0 represents normal glomeruli, 1+ represents 1-25% loss, 2+ represents 26-50% loss, 3+ represents 51-75% loss, 4+ represents capillary blood vessels within tuft And the loss is 75% or more. Cortical and aquatic fibrosis were analyzed using NIS-Elements automatic measurement software after thresholding to determine the percentage of images stained blue. Immunohistochemical staining (IHC) on CD68, a monocyte / macrophage marker, was also performed on the kidney tissue in the same manner as in Example 8 above.

Statistics: Each data is expressed as mean ± SEM. Comparisons between the groups were analyzed by a two-tailed test. P value <0.05 was considered statistically significant.

Experiment result

There was no difference in baseline body weight between Vehicle-treated group and BC-KI-00053 treated group (control group 309.57 ± 4.14 g, experimental group 304.7 ± 5.39 g, P> 0.05). Body weight decreased by about 10% in vehicle or BC-KI-00053 treated rats during the study period, but there was no statistically difference between the two groups (Fig. 11a).

MAP data measured via telemetry in control and experimental FHH rats is shown in Figure 11b. There was no difference in the baseline MAP between the two groups (120.50 ± 0.91mmHg in the control group, 120.1 ± 0.62mmHg in the experimental group, P> 0.05). MAP was rapidly increased in both groups after conversion to 1% NaCl feed with DOCA pellet implantation after single kidney resection. Vehicle-treated group showed a larger MAP than BC-KI-00053 treated group. After 1 week of treatment, the MAP of BC-KI-00053 treated group was statistically lower than that of vehicle treated group (control group 184.34 ± 2.46 mmHg, experimental group 174.4 ± 3.83 mmHg, P <0.05). The MAP results in the vehicle-treated group after 2 weeks of treatment seemed to be relatively stable compared to the results of the first week. The MAP of the BC-KI-00053 treated group showed a temporary, but a further decrease, and there was a significant difference between the two groups (184.22 ± 4.21 mmHg in the control group and 168.8 ± 3.74 mmHg in the control group, P <0.05). After 3 weeks, the mean MAP difference between the two groups was further increased (control: 195.30 ± 3.68 mmHg, experimental group: 176.9 ± 5.83 mmHg, P <0.05).

Data for proteinuria in control and experimental FHH rats is shown in Figure 11c. There was no difference in the baseline proteinuria between the two groups (52.75 ± 6.99 mg / day in the control group and 51.0 ± 4.9 mg / day in the test group, P> 0.05). After conversion to 1% NaCl feed with DOCA pellet implantation after single kidney resection, proteinuria increased steadily in both groups. After 2 weeks of treatment with the test substance, proteinuria in the BC-KI-00053 treated group was statistically lower (472.99 ± 53.81 mg / day in the control group, 285.5 ± 47.48 mg / day in the control group, P <0.05) (675.61 ± 49.91 mg / day in the control group, 433.1 ± 60.59 mg / day in the control group, P <0.05)

Data for plasma creatinine levels in control and experimental FHH rats are presented in Figure 11d. Vehicle-treated plasma creatinine levels were significantly higher in the BC-KI-00053 treated group (0.65 ± 0.04 mg / dL in the control group and 0.48 ± 0.02 mg / dL in the control group, P <0.05).

Conversion of FHH rats to single-kidney resection followed by DOCA pellet implantation and conversion to 1% NaCl feed significantly affected glomerular and coronary lesions morphologically (Figs. 11e, 11f, and 11g). The mean glomerular injury score showed a significant reduction in the extent of injury in the BC-KI-00053 treated rats (3.16 ± 0.04 in the control group, 1.49 ± 0.05, P <0.05 in the test group). In addition, significant fibrosis was significantly reduced in BC-KI-00053 treated group compared to significant fibrosis in vehicle treated group. Specifically, in the BC-KI-00053 treated rats, the cortical fibrosis was significantly less (19.46 ± 1.18% in the control group, 5.79 ± 0.48% in the test group, P <0.05) (17.69 ± 1.07% in the control group, 7.40 ± 0.56% in the experimental group, P <0.05).

As shown in the slice samples stained with Sirius red (FIG. 11h), control rats showed significant cardiac fibrosis, especially at the right ventricular insertion point. In contrast, rats treated with BC-KI-00053 significantly decreased the rate of cardiac fibrosis (31.97 ± 2.62% in the control group and 9.14 ± 2.18% in the control group, P <0.05).

As a result of confirming the degree of macrophage infiltration, as shown in FIG. 11i, IHC staining of CD68, a monocyte / macrophage marker, was performed using kidney tissue. As a result, in the kidney tissue of the control group (vehicle treated), mononuclear / macrophage infiltration Of the total population. In contrast, treatment of the KRS cell membrane migration inhibitor (especially BC-KI-00053) provided by the present invention was found to significantly reduce renal tissue infiltration of monocytes / macrophages.

9-2. SS In the rat KRS  Effects of cell membrane migration inhibitors on hypertension, kidney damage, cardiac damage and fibrosis

Experiments were performed using male SS rats aged 9-12 weeks. These animals were obtained from the University of Mississippi Medical Center and approved by the American Association for Accreditation of Laboratory Animal Care (AAALAC). All protocols have been approved by the Institutional Animal Care and Use Committee of the University of Mississippi Medical Center. The rats were fed free of food and water and these rats were provided with a refined AIN-76 rodent feed containing 0.4% NaCl (Dyets, Bethlehem, PA) after weaning. Dahl salt-sensitive (SS) rats are animal models that rapidly induce severe hypertension, proteinuria, glomerular sclerosis and renal stromal fibrosis when high salt (HS) diets are administered.

SS rats were anesthetized with isoflurane and telemetry transmitters (Model TA11PAC40, Data Sciences International, St. Paul, Minn.) Were aseptically transplanted in the same manner as described above. After surgery, the rats were housed in individual cages in a quiet, air-conditioned room environment with a 12: 12-h contrast cycle and took one week to fully recover from surgery. The baseline MAP (mean arterial blood pressure) was then measured before rats were housed in a metabolic cage to measure urine protein excretion. Proteolysis was measured using the Bradford method and BSA (Bio-Rad Laboratories, Hercules, Calif.) As a standard.

The rats were then randomly divided into two groups: Group 1 (n = 15) was treated with BC-KI-00053 (25 mg / kg daily) via gastrointestinal tract gavage; In Group 2 (n = 15), vehicle (corn oil, polyethylene glycol 400, Tween 80 and methylcellulose) of the same volume (2.5 ml / kg per day) was directly administered to the gastrointestinal tract. At the same time as the material treatment, feeds were changed to HS feed containing 8% NaCl (Dyets, Bethlehem, PA) and blood pressure and proteinuria were measured at 7, 14 and 21 days after feeding HS feed. At the end of the experiment, rats were anesthetized with isoflurane and blood samples were taken to determine creatinine levels. The rats were then flushed through 50 ml of 0.9% NaCl through the aorta and perfused with 20 ml of 4% paraformaldehyde. Kidneys and hearts were collected for histological evaluation.

Paraffin sections, and the degree of glomerular injury, cortex, and water fibrosis were performed in the same manner as described above. Immunohistochemical staining (IHC) on CD68, a monocyte / macrophage marker, was also performed on the kidney tissue in the same manner as in Example 8 above.

Statistics: Each data is expressed as mean ± SEM. Comparisons between the groups were analyzed by a two-tailed test. P value <0.05 was considered statistically significant.

Experiment result

There was no difference in baseline body weight between Vehicle-treated group and BC-KI-00053 treated group (337.92 ± 9.86 g in control group, 350.13 ± 9.173 g in experimental group, P> 0.05). There was no statistically significant difference between the two groups during the entire study period (Fig. 12A), although body weight was maintained or slightly increased in vehicle or BC-KI-00053 treated rats.

MAP data measured via telemetry in control and experimental SS rats is shown in Figure 12B. There was no difference in the baseline MAP between the two groups (122.13 ± 2.31 mmHg in the control group, 123.45 ± 2.36 mmHg in the experimental group, P> 0.05). When the feed of SS rats was changed to HS feed, the MAP increased continuously in both groups. Vehicle-treated group showed a larger MAP than BC-KI-00053 treated group. After 2 weeks of treatment, the MAP of BC-KI-00053 treated group was statistically decreased (178.51 ± 3.71 mmHg in the control group, 164.43 ± 3.00 mmHg in the control group, P <0.05) (Control group, 201.65 ± 2.54 mmHg, 178.48 ± 3.49 mmHg, P <0.05).

Data for proteinuria in control and experimental SS rats are shown in Figure 12c. There was no difference in the baseline proteinuria between the two groups (133.82 ± 10.50 mg / day in the control group, 113.27 ± 8.06 mg / day in the experimental group, P> 0.05). When the feed of SS rats was changed to HS feed, proteinuria increased rapidly in both groups. In the vehicle-treated group, proteinuria was significantly increased compared to BC-KI-00053 treated group. After 1 week of treatment with the test substance, proteinuria in the BC-KI-00053 treated group was statistically lower than that of vehicle treated group (control group 469.08 ± 24.82 mg / day, 302.86 ± 29.76 mg / day, P <0.05) . After 2 weeks of treatment with the test substance, proteinuria levels in the BC-KI-00053 treated group and the vehicle treated group still differed significantly (control group 675.61 ± 59.67 mg / day, test group 510.64 ± 42.42 mg / day, P <0.05) (752.97 ± 57.80 mg / day in the control group, 524.55 ± 44.70 mg / day in the control group, P <0.05)

Data for plasma creatinine concentration in control and experimental SS rats is shown in Figure 12d. Vehicle-treated plasma creatinine levels were significantly higher in the BC-KI-00053 treated group (0.60 ± 0.02 mg / dL in the control group and 0.55 ± 0.01 mg / dL in the control group, P <0.05).

HS diet significantly affected glomerular and coronary damage morphologically to SS rats (Figures 12e, 12f, 12g). The mean glomerular injury score showed a significant decrease in the degree of injury in the BC-KI-00053 treated rats (2.82 ± 0.05 in the control group, 1.34 ± 0.04 in the test group, P <0.05). In addition, significant fibrosis was significantly reduced in BC-KI-00053 treated group compared to significant fibrosis in vehicle treated group. Specifically, in the BC-KI-00053 treated rats, the cortical fibrosis was significantly less (19.48 ± 0.96% in the control group, 6.47 ± 0.46% in the test group, P <0.05) (23.49 ± 0.99% in the control group, 12.33 ± 0.78% in the experimental group, P <0.05).

As shown in the slice samples stained with Sirius red (FIG. 12h), control rats showed significant cardiac fibrosis, especially at the right ventricular insertion point. In contrast, rats treated with BC-KI-00053 significantly reduced the rate of cardiac fibrosis (18.60 ± 0.93% in the control group, 6.63 ± 0.94% in the test group, P <0.05).

As a result of confirming the degree of macrophage infiltration, as shown in FIG. 12i, IHC staining for CD68, a monocyte / macrophage marker, was performed using kidney tissue. As a result, in the kidney tissue of the control (vehicle treated) mononuclear / macrophage infiltration Of the total population. In contrast, treatment of the KRS cell membrane migration inhibitor (especially BC-KI-00053) provided by the present invention was found to significantly reduce renal tissue infiltration of monocytes / macrophages.

Example  10: KRS  Cell membrane migration inhibitor  in vivo Alport  Of fibrosis of kidney and immune cell infiltration in animal model

Experiments were conducted using a 129 Sv / J mouse (Boys town hospital). Experimental animals were divided into (i) 129 Sv / J wild type mouse control (0.5% methylcellulose suspension) administration group, (ii) 129 Sv / J knockout mouse. Cosgrove D et al., Genes Dev. 1996 Dec 1 ; And (iii) 129 Sv / J Alport mice were administered with BC-KI-00053. Each dose group consists of two mice. In the BC-KI-00053-treated group, the cells were dissolved in 0.5% methylcellulose suspension and orally administered at a concentration of 100 mg / kg, and fibrosis of the kidney and invasion of the immune cells were evaluated. Each animal group was treated with a control substance or drug for a total of 4 weeks once daily from 3 weeks of age. After 4 weeks of drug treatment, renal paraffin sections were stained with collagen I (fibrosis markers) and CD45, and the extent of leukocyte infiltration was observed. Fibrosis and infiltration confirmation were performed in the same manner as in the above-described embodiments.

As can be seen from FIG. 13, it was confirmed that leukocyte infiltration and fibrosis progressed remarkably in the kidney when the control substance (vehicle, 0.5% methylcellulose) was administered to Alport mouse. On the contrary, leukocyte infiltration was decreased and fibrosis was decreased to normal (wild-type mouse-control substance-treated group) level in Alport mouse kidney treated with BC-KI-00053.

As described above, the present invention relates to a novel use of benzo [d] thiazole derivatives having a specific structure disclosed in the present invention, and more particularly to a novel use of benzo [d] thiazole Derivatives for the prevention or treatment of diseases related to immune cell migration. The compound of formula (I) is capable of regulating the migration of immune cells, and thus has a very remarkable effect in prevention, improvement and treatment of diseases related to immune cell migration.

Claims (14)

1. A pharmaceutical composition for preventing or treating immune cell migration-related diseases comprising, as an active ingredient, a compound of the following formula (1) or a pharmaceutically acceptable salt thereof:

   &Lt; Formula 1 >

   

   In this formula,

   R1, R2, and R3 are, independently of each other, hydrogen; A halogen group; A nitro group; An amino group; A C1-C6 alkyl group optionally substituted by halogen; Or a hydroxycarbonyl group (provided that R1, R2, and R3 can not be hydrogen at the same time)

   R4, R5, and R6 are, independently of each other, hydrogen; A halogen group; A C1 to C6 alkyl group; A C1 to C6 alkoxy group optionally substituted with C3 to C6 cycloalkyl; A C1-C6 alkylsulfanyl group; Or a mono- or di-C 1 -C 6 alkylamino group,

   R7 and R8 are, independently of each other, hydrogen; A hydroxyl group; A halogen group; Or a hydroxycarbonyl group (provided that R7 and R8 can not be simultaneously hydrogen),

   R9 is hydrogen or a C1 to C6 alkyl group.
2. The compound according to claim 1, wherein the compound of formula (1)

   R1, R2, and R3 are, independently of each other, hydrogen; Or a halogen group (provided that R1, R2, and R3 can not be hydrogen at the same time)

   R4, R5, and R6 are, independently of each other, hydrogen; A halogen group; Or a C1 to C6 alkoxy group (provided that R4, R5, and R6 can not be simultaneously hydrogen)

   R7 and R8 are, independently of each other, hydrogen; Or a hydroxycarbonyl group (provided that R7 and R8 can not be simultaneously hydrogen),

   And R9 is hydrogen or a C1 to C6 alkyl group.

   A pharmaceutical composition for preventing or treating immune cell migration-related diseases.
3. The compound according to claim 1, wherein the compound of formula (1)

   4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - (((2-chlorophenylethyl) (7-fluorobenzo [d] thiazol-2-yl) amino) methyl) benzoic acid;

   4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (3-fluorophenyl) ethyl] amino} methyl) benzoic acid;

   4 - {[[2- (4-chlorophenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino] methyl} benzoic acid;

   4 - {[[2- (3-chlorophenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino] methyl} benzoic acid;

   4 - (((7-fluorobenzo [d] thiazol-2-yl) (4-methylphenylethyl) amino) methyl) benzoic acid;

   4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (3-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (4-fluorophenyl) ethyl] amino} methyl) benzoic acid;

   4 - {[[2- (4-ethoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino] methyl} benzoic acid;

   4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (4-propoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (4-isopropoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - {[(7-Fluorobenzo [d] thiazol-2-yl) {2- [4- (methylsulfanyl) phenyl] ethyl} amino] methyl} benzoic acid;

   4 - {[(7-Fluorobenzo [d] thiazol-2-yl) {2- [3- (methylsulfanyl) phenyl] ethyl} amino] methyl} benzoic acid;

   4 - ({[2- (2,5-dimethoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

   4 - ({[2- (3,4-dimethoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

   4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (2-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (3-methylphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (4-isobutoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - {[[2- (4-cyclopropylmethoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino] methyl} benzoic acid;

   4 - {[(7-Fluorobenzo [d] thiazol-2-yl) {2- [4- (methylamino) phenyl] ethyl} amino] methyl} benzoic acid;

   4 - {[{2- [4- (dimethylamino) phenyl] ethyl} (7-fluorobenzo [d] thiazol-2-yl) amino] methyl} benzoic acid;

   4 - {[(7-fluorobenzo [d] thiazol-2-yl) (2-phenylethyl) amino] methyl} benzoic acid;

   4 - {[[2- (4-cyclohexylmethoxyphenyl) ethyl] - (7-fluorobenzo [d] thiazol-2-yl) amino] methyl} benzoic acid;

   4 - {[[2- (4-cyclobutylmethoxyphenyl) ethyl] - (7-fluorobenzo [d] thiazol-2-yl) amino] methyl} benzoic acid;

   4 - ({[2- (4-ethoxy-3-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

   4 - ({(7-Fluorobenzo [d] thiazol-2-yl) [2- (2-fluoro-4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({[2- (2,4-dimethoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

   4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (3-fluoro-4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({[2- (3-chloro-4-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

   4 - {[[2- (4-sec-butoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino] methyl} benzoic acid;

   4 - {[[2- (4-ethylaminophenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino] methyl} benzoic acid;

   4 - ({[2- (4-ethylphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

   4 - {[(7-Fluorobenzo [d] thiazol-2-yl) {2- [4- (propan-2-yl) phenyl] ethyl} amino] methyl} benzoic acid;

   4 - ({[2- (2,3-difluorophenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

   4 - ({[2- (2,5-difluorophenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

   4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (3,4,5-trifluorophenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({[2- (3-bromo-4-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

   4 - ({[2- (2,4-dichlorophenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

   4 - ({[2- (2,4-difluorophenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

   4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (2-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (2-fluorophenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (3-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({[2- (2,3-difluoro-4-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

   Methyl} -5- (propan-2-yl) phenyl] ethyl} amino] methyl} -1H-pyrazolo [ Benzoic acid;

   4 - ({[2- (2,5-difluoro-4-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

   4 - ({[2- (2-chloro-4-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

   4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (4-methoxy-2,3-dimethylphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (4-methoxy-2,5-dimethylphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (4-methoxy-3-methylphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (4-methoxy-2-methylphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({[2- (2,6-difluoro-4-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

   4- (1 - {(7-Fluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} ethyl) benzoic acid;

   4- (1 - {(7-fluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} propyl) benzoic acid;

   4- (1 - {(7-Fluorobenzo [d] thiazol-2-yl) [2- (3-fluoro-4-methoxyphenyl) ethyl] amino} ethyl) benzoic acid;

   4- (1 - {[2- (3-bromo-4-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} ethyl) benzoic acid;

   4- (1 - {[2- (2,4-difluorophenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} ethyl) benzoic acid;

   4- (1 - {[2- (2,3-difluorophenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} ethyl) benzoic acid;

   4- (1 - {(7-Fluorobenzo [d] thiazol-2-yl) [2- (3,4,5-trifluorophenyl) ethyl] amino} ethyl) benzoic acid;

   4- (1 - {[2- (2,4-dichlorophenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} ethyl) benzoic acid;

   4- (1 - {[2- (2,3-difluoro-4-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} ethyl) benzoic acid;

   4- (1 - {[2- (2,5-Difluoro-4-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} ethyl) benzoic acid;

   2- {4-methoxy-2-methyl-5- (propan-2-yl) phenyl] ethyl} amino] Ethyl} benzoic acid;

   4- (1 - {(7-Fluorobenzo [d] thiazol-2-yl) [2- (4-methoxy-2,3-dimethylphenyl) ethyl] amino} ethyl) benzoic acid;

   4- (1 - {(7-Fluorobenzo [d] thiazol-2-yl) [2- (4-methoxy-2,5-dimethylphenyl) ethyl] amino} ethyl) benzoic acid;

   4- (1 - {(7-Fluorobenzo [d] thiazol-2-yl) [2- (4-methoxy-3-methylphenyl) ethyl] amino} ethyl) benzoic acid;

   4- (1 - {(7-Fluorobenzo [d] thiazol-2-yl) [2- (4-methoxy-2-methylphenyl) ethyl] amino} ethyl) benzoic acid;

   4- (1 - {[2- (2,6-Difluoro-4-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} ethyl) benzoic acid;

   4- (1 - {[2- (2,3-difluoro-4-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} propyl) benzoic acid;

   4- (1 - {[2- (2,5-Difluoro-4-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} propyl) benzoic acid;

   4- (1 - {[2- (2-chloro-4-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} propyl) benzoic acid;

   4- (1 - {(7-Fluorobenzo [d] thiazol-2-yl) [2- (4-methoxy-2,3-dimethylphenyl) ethyl] amino} propyl) benzoic acid;

   4- (1 - {(7-Fluorobenzo [d] thiazol-2-yl) [2- (4-methoxy-2,5-dimethylphenyl) ethyl] amino} propyl) benzoic acid;

   4- (1 - {(7-Fluorobenzo [d] thiazol-2-yl) [2- (4-methoxy-3-methylphenyl) ethyl] amino} propyl) benzoic acid;

   4- (1 - {(7-Fluorobenzo [d] thiazol-2-yl) [2- (4-methoxy-2-methylphenyl) ethyl] amino} propyl) benzoic acid;

   4- (1 - {[2- (2,6-Difluoro-4-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} propyl) benzoic acid;

   2- {4-methoxy-2-methyl-5- (propan-2-yl) phenyl] ethyl} amino] Propyl} benzoic acid;

   4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) -2-hydroxybenzoic acid;

   3-chloro-4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({[2- (4-methoxyphenyl) ethyl] (6-nitro-benzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

   4 - ({[2- (4-methoxyphenyl) ethyl] (7-nitro-benzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

   4 - ({(6-amino-benzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({(7-amino-benzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({(7-chloro-benzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({(6-chloro-benzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({(5-chloro-benzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({(5,6-difluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - {[[2- (4-methoxyphenyl) ethyl] (5,6,7-trifluoro benzo [d] thiazol-2-yl) amino] methyl} benzoic acid;

   4 - ({(6-chloro-7-fluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - {[[2- (4-methoxyphenyl) ethyl] (7-trifluoromethyl-benzo [d] thiazol-2-yl) amino] methyl} benzoic acid;

   4 - ({(6,7-difluorobenzo [d] thiazol-2-yl) - [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({(5-bromo-benzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({(6-fluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({(5,7-difluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({(7-Fluoro-6-methyl-benzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({(4,6-difluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({[2- (4-methoxyphenyl) ethyl] (7-methyl-benzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

   4 - ({[2- (4-methoxyphenyl) ethyl] (6-methyl-benzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

   4 - ({[2- (4-methoxyphenyl) ethyl] (5-methyl-benzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

   4- (1 - {(5,7-difluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} ethyl) benzoic acid;

   4- (1 - {(5,6-difluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} ethyl) benzoic acid;

   4- (1 - {[2- (4-methoxyphenyl) ethyl] (5,6,7-trifluoro benzo [d] thiazol-2-yl) amino} ethyl) benzoic acid;

   4- (1- {6-chloro-7-fluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} ethyl) benzoic acid;

   4- (1 - {(5-bromo-benzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} ethyl) benzoic acid;

   4- (1 - {(6,7-difluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} ethyl) benzoic acid;

   4- (1- {7-Fluoro-6-methyl-benzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} ethyl) benzoic acid;

   4- (1 - {[2- (4-methoxyphenyl) ethyl] [7- (trifluoromethyl) -benzo [d] thiazol-2-yl] amino} ethyl) benzoic acid;

   4- (1 - {(5-chloro-benzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} ethyl) benzoic acid;

   4- (1- {6-chloro-benzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} ethyl) benzoic acid;

   4- (1 - {(7-chloro-benzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} ethyl) benzoic acid;

   4- (1 - {[2- (4-methoxyphenyl) ethyl] (7-methyl-benzo [d] thiazol-2-yl) amino} ethyl) benzoic acid;

   4- (1 - {[2- (4-methoxyphenyl) ethyl] (6-methyl-benzo [d] thiazol-2-yl) amino} ethyl) benzoic acid;

   4- (1 - {[2- (4-methoxyphenyl) ethyl] (5-methyl-benzo [d] thiazol-2-yl) amino} ethyl) benzoic acid;

   4- (1 - {(5-fluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} ethyl) benzoic acid;

   4- (1 - {(4,6-difluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} ethyl) benzoic acid;

   4 - ({(6-Bromo-benzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4- (1 - {(6-Bromo-benzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} ethyl) benzoic acid;

   2 - {(4-carboxybenzyl) [2- (4-methoxyphenyl) ethyl] amino} benzo [d] thiazole-6-carboxylic acid;

   2 - {(4-carboxybenzyl) [2- (4-methoxyphenyl) ethyl] amino} benzo [d] thiazole-7-carboxylic acid;

   4 - ({[2- (4-methoxyphenyl) ethyl] [6- (trifluoromethyl) benzo [d] thiazol-2-yl] amino} methyl) benzoic acid;

   4 - ({[2- (4-methoxyphenyl) ethyl] [5- (trifluoromethyl) benzo [d] thiazol-2-yl] amino} methyl) benzoic acid;

   4 - ({[7-fluoro-6- (trifluoromethyl) benzo [d] thiazol-2-yl] [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4- (1 - {(5,7-Difluorobenzo [d] thiazol-2-yl) [2- (3-fluoro-4-methoxyphenyl) ethyl] amino} ethyl) benzoic acid;

   4- (1 - {[2- (4-methoxyphenyl) ethyl] [6- (trifluoromethyl) benzo [d] thiazol-2-yl] amino} ethyl) benzoic acid;

   4- (1 - {[2- (4-methoxyphenyl) ethyl] [5- (trifluoromethyl) benzo [d] thiazol-2-yl] amino} ethyl) benzoic acid; And

   (4-methoxyphenyl) ethyl] amino} ethyl) benzoic acid, which is used in the synthesis of 4- (1 - {[7-fluoro-6- (trifluoromethyl)

   Lt; RTI ID = 0.0 &gt; of: &lt; / RTI &gt;
4. The compound according to claim 1, wherein the compound of formula (1)

   4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - (((2-chlorophenylethyl) (7-fluorobenzo [d] thiazol-2-yl) amino) methyl) benzoic acid;

   4 - (((7-fluorobenzo [d] thiazol-2-yl) (4-methylphenylethyl) amino) methyl) benzoic acid;

   4 - {[[2- (4-ethoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino] methyl} benzoic acid;

   4 - {[(7-Fluorobenzo [d] thiazol-2-yl) {2- [4- (methylsulfanyl) phenyl] ethyl} amino] methyl} benzoic acid;

   4 - {[(7-Fluorobenzo [d] thiazol-2-yl) {2- [3- (methylsulfanyl) phenyl] ethyl} amino] methyl} benzoic acid;

   4 - ({[2- (3,4-dimethoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

   4 - {[[2- (4-cyclopropylmethoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino] methyl} benzoic acid;

   4 - {[(7-Fluorobenzo [d] thiazol-2-yl) {2- [4- (methylamino) phenyl] ethyl} amino] methyl} benzoic acid;

   4 - {[{2- [4- (dimethylamino) phenyl] ethyl} (7-fluorobenzo [d] thiazol-2-yl) amino] methyl} benzoic acid;

   4 - ({(7-Fluorobenzo [d] thiazol-2-yl) [2- (2-fluoro-4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (3-fluoro-4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({[2- (3-chloro-4-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

   4 - ({[2- (4-ethylphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

   4 - ({[2- (2,3-difluoro-4-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

   4 - ({[2- (2,5-difluoro-4-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

   4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (4-methoxy-2,5-dimethylphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (4-methoxy-3-methylphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (4-methoxy-2-methylphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({[2- (2,6-difluoro-4-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

   4- (1 - {(7-Fluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} ethyl) benzoic acid;

   4- (1 - {(7-fluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} propyl) benzoic acid;

   4- (1 - {[2- (2,3-difluoro-4-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} ethyl) benzoic acid;

   4- (1 - {[2- (2,5-Difluoro-4-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} ethyl) benzoic acid;

   4- (1 - {(7-Fluorobenzo [d] thiazol-2-yl) [2- (4-methoxy-2,3-dimethylphenyl) ethyl] amino} ethyl) benzoic acid;

   4- (1 - {(7-Fluorobenzo [d] thiazol-2-yl) [2- (4-methoxy-2,5-dimethylphenyl) ethyl] amino} ethyl) benzoic acid;

   4- (1 - {(7-Fluorobenzo [d] thiazol-2-yl) [2- (4-methoxy-3-methylphenyl) ethyl] amino} ethyl) benzoic acid;

   4- (1 - {(7-Fluorobenzo [d] thiazol-2-yl) [2- (4-methoxy-2-methylphenyl) ethyl] amino} ethyl) benzoic acid;

   4- (1 - {[2- (2,6-Difluoro-4-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} ethyl) benzoic acid;

   4- (1 - {[2- (2,3-difluoro-4-methoxyphenyl) ethyl] (7-fluorobenzo [d] thiazol-2-yl) amino} propyl) benzoic acid;

   4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) -2-hydroxybenzoic acid;

   3-chloro-4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({[2- (4-methoxyphenyl) ethyl] (6-nitro-benzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

   4 - ({[2- (4-methoxyphenyl) ethyl] (7-nitro-benzo [d] thiazol-2-yl) amino} methyl) benzoic acid;

   4 - ({(6-amino-benzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({(7-amino-benzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({(7-chloro-benzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({(6-chloro-benzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({(5-chloro-benzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({(5,6-difluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - {[[2- (4-methoxyphenyl) ethyl] (5,6,7-trifluoro benzo [d] thiazol-2-yl) amino] methyl} benzoic acid;

   4 - ({(6-chloro-7-fluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - {[[2- (4-methoxyphenyl) ethyl] (7-trifluoromethyl-benzo [d] thiazol-2-yl) amino] methyl} benzoic acid;

   4 - ({(6,7-difluorobenzo [d] thiazol-2-yl) - [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({(5-bromo-benzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({(6-fluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({(5,7-difluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({(7-Fluoro-6-methyl-benzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({(4,6-difluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4- (1 - {(7-chloro-benzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} ethyl) benzoic acid;

   4 - ({[2- (4-methoxyphenyl) ethyl] [5- (trifluoromethyl) benzo [d] thiazol-2-yl] amino} methyl) benzoic acid;

   4- (1 - {(5,7-Difluorobenzo [d] thiazol-2-yl) [2- (3-fluoro-4-methoxyphenyl) ethyl] amino} ethyl) benzoic acid; And

   Benzo [d] thiazol-2-yl] amino} ethyl) benzoic acid, which is used in the synthesis of 4- (1 - {[2- (4- methoxyphenyl) ethyl]

   Lt; RTI ID = 0.0 &gt; of: &lt; / RTI &gt;
5. The compound according to claim 1, wherein the compound of formula (1)

   4 - ({(7-fluorobenzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid;

   4 - ({(7-chloro-benzo [d] thiazol-2-yl) [2- (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid; And

   (4-methoxyphenyl) ethyl] amino} methyl) benzoic acid was used in place of 4 - {[(5,7-difluorobenzo [d] thiazol-

   Lt; RTI ID = 0.0 &gt; of: &lt; / RTI &gt;
6. The pharmaceutical composition according to claim 1, wherein the disease associated with immune cell migration is selected from the group consisting of cardiovascular diseases, fibrotic diseases, inflammatory diseases and Alport syndrome.
7. [Claim 7] The pharmaceutical composition according to claim 6, wherein the cardiovascular disease is selected from the group consisting of hypertension, pulmonary arterial hypertension, atherosclerosis, angina pectoris, myocardial infarction, ischemic cerebrovascular disease, arteriosclerosis and mesothelioma.
8. 7. The method of claim 6, wherein the fibrotic disease is selected from the group consisting of scleroderma, rheumatoid arthritis, Crohn's disease, ulcerative colitis, myelofibrosis, pulmonary fibrosis, The present invention relates to a method of treating hepatic fibrosis, hepatic fibrosis, liver cirrhosis, kidney fibrosis, glomerulosclerosis, myofibrosis, cardiac fibrosis, interstitial fibrosis, pancreatic fibrosis, Atherosclerotic fibrosis, peritoneal fibrosis, peritoneal fibrosis, advanced massive fibrosis, idiopathic fibrotic syndrome, fibrotic syndrome, fibrosis, Systemic lupus erythematosus, hereditary fibrosis, infectious fibrosis, irritative fibrosis, chronic autoimmunity fibrosis, fibrosis due to antigen failure during organ transplantation, surgery Fibrotic complications of alcohol, fibrosis caused by hyperlipidemia, fibrosis caused by obesity, diabetes, fibrosis, the pharmaceutical composition being selected from the group consisting of occlusion due to fibrosis and fibrosis during stenting due to high blood pressure.
9. 7. The method of claim 6, wherein the inflammatory disease is selected from the group consisting of autoimmune disease, inflammatory bowel disease, dermatitis, diabetic eye disease, peritonitis, osteomyelitis, cachexia, meningitis, encephalitis, pancreatitis, trauma shock, bronchial asthma, rhinitis, Inflammatory bowel disease, pneumonia, gastritis, enteritis, cystic fibrosis, stroke, bronchitis, bronchiolitis, hepatitis, nephritis, arthritis, neuritis, gout, spondylitis, lighter syndrome, nodular polyarteritis, vasculitis, Lou Gehrig's disease, Wegener's granulomatosis, hypercytokinemia ), Rheumatoid arthritis, rheumatoid arthritis, arthritic multiple myalgia, arthritic arthritis, calcific gout, non-articular rheumatism, bursitis, hay fever, pharyngitis, Charcot's joint, hemarthrosis, - Schrein's purpura, hypertrophic osteoarthritis, multisymmetric hematoma, surcoilosis, hemochromatosis, sickle cell disease and other hemochromatosis, Hypertriglyceridemia, septic shock, acute respiratory distress syndrome, multiple organ dysfunction, multiple sclerosis, multiple sclerosis, multiple sclerosis, multiple sclerosis, multiple sclerosis, multiple sclerosis, hypogammaglobulinemia, hyperparathyroidism, Chronic bronchitis, chronic obstructive pulmonary disease, acute lung injury, and broncho-pulmonary dysplasia.
10. 10. The method of claim 9, wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, systemic scleroderma, systemic lupus erythematosus, psoriasis, asthma, ulcerative colitis, Bechther's disease, Crohn's disease, multiple sclerosis, dermatomyositis, , Long-term specific autoimmune lesions, ulcerative colitis, and graft-versus-host disease.
11. The use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prophylaxis or treatment of diseases related to immune cell migration;

    &Lt; Formula 1 >

    

    In this formula,

    R1, R2, and R3 are, independently of each other, hydrogen; A halogen group; A nitro group; An amino group; A C1-C6 alkyl group optionally substituted by halogen; Or a hydroxycarbonyl group (provided that R1, R2, and R3 can not be hydrogen at the same time)

    R4, R5, and R6 are, independently of each other, hydrogen; A halogen group; A C1 to C6 alkyl group; A C1 to C6 alkoxy group optionally substituted with C3 to C6 cycloalkyl; A C1-C6 alkylsulfanyl group; Or a mono- or di-C 1 -C 6 alkylamino group,

    R7 and R8 are, independently of each other, hydrogen; A hydroxyl group; A halogen group; Or a hydroxycarbonyl group (provided that R7 and R8 can not be simultaneously hydrogen),

    R9 is hydrogen or a C1 to C6 alkyl group.
12. 12. The compound according to claim 11, wherein the compound of formula (1)

    R1, R2, and R3 are, independently of each other, hydrogen; Or a halogen group (provided that R1, R2, and R3 can not be hydrogen at the same time)

    R4, R5, and R6 are, independently of each other, hydrogen; A halogen group; Or a C1 to C6 alkoxy group (provided that R4, R5, and R6 can not be simultaneously hydrogen)

    R7 and R8 are, independently of each other, hydrogen; Or a hydroxycarbonyl group (provided that R7 and R8 can not be simultaneously hydrogen),

    R9 is hydrogen or a C1 to C6 alkyl group.
13. A method for treating immune cell migration-related diseases, which comprises administering to a subject in need thereof an effective amount of a composition comprising a compound of the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:

    &Lt; Formula 1 >

    

    In this formula,

    R1, R2, and R3 are, independently of each other, hydrogen; A halogen group; A nitro group; An amino group; A C1-C6 alkyl group optionally substituted by halogen; Or a hydroxycarbonyl group (provided that R1, R2, and R3 can not be hydrogen at the same time)

    R4, R5, and R6 are, independently of each other, hydrogen; A halogen group; A C1 to C6 alkyl group; A C1 to C6 alkoxy group optionally substituted with C3 to C6 cycloalkyl; A C1-C6 alkylsulfanyl group; Or a mono- or di-C 1 -C 6 alkylamino group,

    R7 and R8 are, independently of each other, hydrogen; A hydroxyl group; A halogen group; Or a hydroxycarbonyl group (provided that R7 and R8 can not be simultaneously hydrogen),

    R9 is hydrogen or a C1 to C6 alkyl group.
14. 14. The compound according to claim 13, wherein the compound of formula (1)

    R1, R2, and R3 are, independently of each other, hydrogen; Or a halogen group (provided that R1, R2, and R3 can not be hydrogen at the same time)

    R4, R5, and R6 are, independently of each other, hydrogen; A halogen group; Or a C1 to C6 alkoxy group (provided that R4, R5, and R6 can not be simultaneously hydrogen)

    R7 and R8 are, independently of each other, hydrogen; Or a hydroxycarbonyl group (provided that R7 and R8 can not be simultaneously hydrogen),

    And R9 is hydrogen or a C1 to C6 alkyl group.

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