Novel compounds with pendrin inhibitory activity and their medical uses

Abstract

The present invention relates to a novel compound having pendrin inhibitory activity and its medical use, and provides a compound represented by the following chemical formula 1, its E- or Z-isomer, its optical isomer, its precursor, a pharma- ceutically acceptable salt, a solvate, or a mixture of these two isomers, and a composition for preventing, ameliorating, or treating respiratory diseases and a diuretic composition utilizing the compound and its pendrin inhibitory activity. [Formula 1] TIFF2024522378000065.tif38142

Description

[Technical Field]

[0001] The present invention relates to a novel compound having pendrin inhibitory activity and its pharmaceutical use, and provides a compound represented by the following chemical formula 1, its E- or Z-isomer, its optical isomer, its precursor, a pharmaceutically acceptable salt thereof, a solvate thereof, or a mixture of these two isomers, and a composition for preventing, ameliorating, or treating respiratory diseases and a diuretic composition utilizing the pendrin inhibitory activity.

[0002] [ka] [Background technology]

[0003] Abnormal anion exchange is associated with a variety of human diseases. For example, plasma or urinary solute imbalance can indicate kidney, heart, or liver problems. Detection of Cl in cystic fibrosis - and HCO3 - Transport can alter the volume and composition of airway surface liquid, inducing diverse complications such as impaired immune function and CD disease pathogenesis. Therefore, the cellular mechanisms involved in anion exchange are of interest as potential therapeutic targets.

[0004] Pendrin (hereinafter also referred to as "PDS") is an anion exchanger encoded by the SLC26A4 (solute carrier family 26, member 4) gene, a member of the SLC26 gene family, and is expressed in various tissues, including inflamed airway epithelium, the inner ear, the thyroid gland, the adrenal gland, and the kidney. - HCO3 - , I - , O.H. - and SCN - and HCO2 -Pendrin is a plasma membrane protein expressed in the luminal membrane of airway epithelial cells. However, its expression is strongly upregulated in inflammatory airway diseases such as chronic obstructive pulmonary disease (COPD), allergic nasal salinity, asthma, Bordetella pertussis infection, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and the common cold caused by rhinovirus. Pendrin upregulation is observed when primary airway epithelial cells are cultured with IL-4, IL-13, and IL-17A. Interestingly, pendrin knockout (KO) improves airway inflammation in all mouse models of COPD, allergic rhinitis, asthma, Bordetella pertussis infection, and rhinovirus infection. The pathophysiological role of pendrin in airway inflammation has not been clearly elucidated. However, emerging evidence suggests that pendrin is involved in the regulation of airway surface liquid (ASL) volume conservation and mucus production in inflammatory airway diseases.

[0005] In primary cultures of mouse tracheal epithelial cells, IL-13-induced ASL volume increase was significantly greater in pendrin KO mice than in WT controls. In primary cultures of human nasal epithelial (HNE) cells from hearing-impaired patients carrying a pendrin mutant (DFNB4), IL-13-induced ASL volume increase was significantly greater than in normal controls. Furthermore, inhibition of pendrin with a pendrin inhibitor significantly increased IL-13-induced ASL volume in primary cultures of human bronchial epithelial cells. These findings suggest that downregulation of pendrin may have a beneficial effect on regulating ASL volume homeostasis in inflammatory airway diseases.

[0006] Excessive mucus production is a common feature of inflammatory airway diseases such as asthma and COPD. Overexpression of pendrin significantly increased MUC5AC gene expression in the human lung cancer cell line NCI-H292 and mouse lung tissue. IL-13 treatment significantly increased MUC5AC gene expression in HNE cells from normal subjects, but IL-13-induced MUC5AC upregulation was completely abolished in HNE cells from hearing-impaired patients harboring pendrin mutants. These findings suggest that downregulation of pendrin may be beneficial for the treatment of asthma and COPD.

[0007] As prior art, U.S. Patent Publication No. 2019 / 0054071 discloses a small molecule inhibitor of pendrin ion exchange, a compound represented by the following chemical formula I, and its pharmaceutical use as a respiratory disease treatment or diuretic.

[0008] [ka] Summary of the Invention [Problem to be solved by the invention]

[0009] The present invention is based on the discovery that certain novel compounds act as pendrin inhibitors and can be used as therapeutic agents for diseases associated with pendrin inhibitory activity or as diuretics.

[0010] Therefore, an object of the present invention is to provide a novel compound represented by the following chemical formula 1, a composition for preventing, improving or treating respiratory diseases and a diuretic composition based on its pendrin inhibitory activity.

[0011] Another object of the present invention is to provide a novel compound represented by the following chemical formula 1, a method for preventing, improving or treating respiratory diseases and a diuretic method based on its pendrin inhibitory activity. [Means for solving the problem]

[0012] In order to solve the above problems, the present invention provides a compound represented by the following chemical formula 1, its E- or Z-isomer, its optical isomer, its precursor, a pharmaceutically acceptable salt thereof, a solvate thereof, or a mixture of two isomers thereof:

[0013] [ka] In the above Chemical Formula 1, V 1 is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, aryl, alkylaryl having 1 to 10 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, heteroaryl, heterocycloalkyl, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 10 carbon atoms, alkynyl having 2 to 10 carbon atoms, C(O)OR 2 , C(O)R 2 , OR 2 and OCR 2 F2 is a heteroaryl having 5 to 10 carbon atoms and 1 to 3 nitrogen atoms substituted with one or more groups independently selected from the group consisting of A is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, aryl, alkylaryl having 1 to 10 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, heteroaryl, heterocycloalkyl, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 10 carbon atoms, alkynyl having 2 to 10 carbon atoms, or C(O)OR 2 , C(O)R 2 , OR 2 , OCR 2 F2 and OCOR 2 a heteroaryl having 5 to 7 carbon atoms and containing 1 to 3 nitrogen atoms, or a heterocycloalkyl having 5 to 7 carbon atoms and containing 1 to 3 heteroatoms, each substituted with one or more groups independently selected from the group consisting of V 2 is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, aryl, alkylaryl having 1 to 10 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, heteroaryl, heterocycloalkyl, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 10 carbon atoms, alkynyl having 2 to 10 carbon atoms, C(O)OR 2, C(O)R 2 , OR 2 , OCR 2 F2 and OCOR 2 aryl, alkyl having 1 to 10 carbon atoms, cycloalkyl having 5 to 7 carbon atoms, or C(O)OR substituted with one or more groups independently selected from the group consisting of 2 and R 1 is one or more independently selected from the group consisting of hydrogen, halogen, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 6 carbon atoms, and alkynyl having 2 to 6 carbon atoms, R 2 are independently selected from the group consisting of hydrogen, trifluoromethyl, trifluoromethoxy, aryl, aryl(alkyl having 1 to 10 carbon atoms), alkylaryl having 1 to 10 carbon atoms, heteroaryl, heteroaryl(alkyl having 1 to 10 carbon atoms), alkylheteroaryl having 1 to 10 carbon atoms, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, cycloalkyl and heterocycloalkyl having 3 to 6 carbon atoms; n is an integer of 1 to 5. According to a preferred embodiment of the present invention, in the above-mentioned Chemical Formula 1, V 1 is hydrogen, halogen, trifluoromethyl, cycloalkyl having 3 to 7 carbon atoms, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 10 carbon atoms, alkynyl having 2 to 10 carbon atoms, C(O)OR 2 , C(O)R 2 , OR 2 , OCR 2 F2 and OCOR 2 indolyl, isoindolyl, 3H-indole, 1H-indole, quinolyl, isoquinolyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, quinolidinyl, quinazolinyl, phthalazinyl, cinnolinyl, or naphthyridinyl substituted with one or more groups independently selected from the group consisting of A is pyrrolidinyl, piperidinyl, piperazinyl, or decahydroisoquinolinyl substituted by one or more groups independently selected from the group consisting of hydrogen, halogen, trifluoromethyl, cycloalkyl having 3 to 7 carbon atoms, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 10 carbon atoms, and alkynyl having 2 to 10 carbon atoms; V 2 is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, aryl, alkylaryl having 1 to 10 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, heteroaryl, heterocycloalkyl, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 10 carbon atoms, alkynyl having 2 to 10 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, C(O)OR 2 , C(O)R 2 , OR 2 and OCR 2 C(O)OR, C(O)OR, or C(O)OR substituted with one or more groups independently selected from the group consisting of F2 2 and R 1 is one or more independently selected from the group consisting of hydrogen, halogen, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 6 carbon atoms, and alkynyl having 2 to 6 carbon atoms, R 2 are independently selected from the group consisting of hydrogen, trifluoromethyl, aryl, aryl (alkyl having 1 to 10 carbon atoms), alkylaryl having 1 to 10 carbon atoms, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, and cycloalkyl having 3 to 6 carbon atoms; n is an integer of 1 to 5.

[0014] According to another preferred embodiment of the present invention, the compound represented by Chemical Formula 1, its E- or Z-isomer, its optical isomer, its precursor, a pharmaceutically acceptable salt, a solvate, or a mixture of two isomers thereof includes a compound represented by Chemical Formula 1a below, its E- or Z-isomer, its optical isomer, its precursor, a pharmaceutically acceptable salt, a solvate, or a mixture of two isomers thereof:

[0015] [ka] In the above chemical formula 1a, R 1 is one or more independently selected from the group consisting of hydrogen, halogen, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 6 carbon atoms, and alkynyl having 2 to 6 carbon atoms, R 3 is hydrogen, halogen, trifluoromethyl, cycloalkyl having 3 to 7 carbon atoms, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 10 carbon atoms, alkynyl having 2 to 10 carbon atoms, C(O)OR 2 , C(O)R 2 , OR 2 and OCR 2 F2, wherein R 4 is C(O)OR 2 , C(O)R 2 , OR 2 , OCR 2 F2 and OCOR 2 are groups independently selected from the group consisting of R 5 represents one or more groups independently selected from the group consisting of hydrogen, cycloalkyl having 3 to 7 carbon atoms, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 10 carbon atoms, and alkynyl having 2 to 10 carbon atoms; R 6 is hydrogen, halogen, trifluoromethyl, cycloalkyl having 3 to 7 carbon atoms, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 10 carbon atoms, alkynyl having 2 to 10 carbon atoms, C(O)OR 2 , C(O)R 2 , OR 2 and OCR 2 F2, wherein R 2 are independently selected from the group consisting of hydrogen, trifluoromethyl, aryl, aryl (alkyl having 1 to 10 carbon atoms), alkylaryl having 1 to 10 carbon atoms, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, and cycloalkyl having 3 to 6 carbon atoms; n is an integer of 1 to 5.

[0016] According to yet another preferred embodiment of the present invention, the compound represented by Chemical Formula 1, its E- or Z-isomer, its optical isomer, its precursor, a pharmaceutically acceptable salt, a solvate, or a mixture of two isomers thereof includes a compound represented by Chemical Formula 1b below, its E- or Z-isomer, its optical isomer, its precursor, a pharmaceutically acceptable salt, a solvate, or a mixture of two isomers thereof:

[0017] [ka] In the above chemical formula 1b, R 1 is one or more independently selected from the group consisting of hydrogen, halogen, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 6 carbon atoms, and alkynyl having 2 to 6 carbon atoms, R 3 is hydrogen, halogen, trifluoromethyl, cycloalkyl having 3 to 7 carbon atoms, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 10 carbon atoms, alkynyl having 2 to 10 carbon atoms, C(O)OR 2 , C(O)R 2 , OR 2 and OCR 2 F2, wherein R 4 is C(O)OR 2 , C(O)R 2 , OR 2 , OCR 2 F2 and OCOR 2 are groups independently selected from the group consisting of R 5 represents one or more groups independently selected from the group consisting of hydrogen, cycloalkyl having 3 to 7 carbon atoms, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 10 carbon atoms, and alkynyl having 2 to 10 carbon atoms; R 7represents one or more groups independently selected from the group consisting of hydrogen, halogen, trifluoromethyl, cycloalkyl having 3 to 7 carbon atoms, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 10 carbon atoms, and alkynyl having 2 to 10 carbon atoms; R 2 are independently selected from the group consisting of hydrogen, trifluoromethyl, aryl, aryl (alkyl having 1 to 10 carbon atoms), alkylaryl having 1 to 10 carbon atoms, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, and cycloalkyl having 3 to 6 carbon atoms; n is an integer of 1 to 5.

[0018] According to another preferred embodiment of the invention, the compound is: (1) 5-chloro-3-(2-oxo-2-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)-1H-indole-2-carboxylic acid; (2) 5-chloro-3-(2-oxo-2-(4-(2-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)-1H-indole-2-carboxylic acid; (3) 5-chloro-3-(2-(4-(2,6-dimethylphenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (4) 5-chloro-3-(2-(4-(2,4-dimethylphenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (5) 5-chloro-3-(2-(4-(3-methoxyphenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (6) 5-chloro-3-(2-(4-(2-chlorophenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (7) 5-chloro-3-(2-(4-(4-chlorophenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (8) 3-(2-(4-(2-bromophenyl)piperazin-1-yl)-2-oxoethyl)-5-chloro-1H-indole-2-carboxylic acid; (9) 3-(2-(4-(3-bromophenyl)piperazin-1-yl)-2-oxoethyl)-5-chloro-1H-indole-2-carboxylic acid; (10) 3-(2-(4-(4-bromophenyl)piperazin-1-yl)-2-oxoethyl)-5-chloro-1H-indole-2-carboxylic acid; (11) 5-chloro-3-(2-oxo-2-(4-(o-tolyl)piperazin-1-yl)ethyl)-1H-indole-2-carboxylic acid; (12) 5-chloro-3-(2-oxo-2-(4-(m-tolyl)piperazin-1-yl)ethyl)-1H-indole-2-carboxylic acid; (13) 5-chloro-3-(2-oxo-2-(4-(p-tolyl)piperazin-1-yl)ethyl)-1H-indole-2-carboxylic acid; (14) 3-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-oxoethyl)-5-chloro-1H-indole-2-carboxylic acid; (15) 5-chloro-3-(2-(4-(2-chloro-6-methylphenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (16) 5-chloro-3-(2-(4-(2-ethoxyphenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (17) 5-chloro-3-(2-(3-methyl-4-phenylpiperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (18) 5-chloro-3-(2-(4-(4-chlorophenyl)-2,2-dimethylpiperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (19) 5-chloro-3-(2-(4-(2-chloro-4-fluorophenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (20) 5-chloro-3-(2-(4-(2-chloro-5-methoxyphenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (21) 5-chloro-3-(2-(4-(2,4-dichlorophenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (22) (R)-5-chloro-3-(2-(2-methyl-4-phenylpiperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (23) 5-chloro-3-(2-(4-(2,4-difluorophenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (24) 5-chloro-3-(2-oxo-2-(4-(3,4,5-trichlorophenyl)piperazin-1-yl)ethyl)-1H-indole-2-carboxylic acid; (25) 5-chloro-3-(2-(4-(2-fluorophenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (26) 5-chloro-3-(2-(4-(3-chloro-2-methylphenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (27) 3-(2-(4-(4-carboxyphenyl)piperazin-1-yl)-2-oxoethyl)-5-chloro-1H-indole-2-carboxylic acid; (28) 3-(2-(4-(4-acetylphenyl)piperazin-1-yl)-2-oxoethyl)-5-chloro-1H-indole-2-carboxylic acid; (29) 5-chloro-3-(2-(4-(4-ethoxyphenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (30) 3-(2-(4-(4-(tert-butyl)phenyl)piperazin-1-yl)-2-oxoethyl)-5-chloro-1H-indole-2-carboxylic acid; (31) 3-(2-(4-(4-(tert-butyl)phenyl)piperazin-1-yl)-2-oxoethyl)-5-methyl-1H-indole-2-carboxylic acid; (32) 3-(2-(4-(4-(tert-butyl)phenyl)piperazin-1-yl-2-oxoethyl)-5,7-dimethyl-1H-indole-2-carboxylic acid; (33) 3-(2-(4-(2,6-dimethylphenyl)piperazin-1-yl)-2-oxoethyl)-5-methyl-1H-indole-2-carboxylic acid; (34) 3-(2-(4-(2,6-dimethylphenyl)piperazin-1-yl)-2-oxoethyl)-5,7-dimethyl-1H-indole-2-carboxylic acid; (35) 3-(2-(4-(2-chloro-6-methylphenyl)piperazin-1-yl)-2-oxoethyl)-5-methyl-1H-indole-2-carboxylic acid; (36) 3-(2-(4-(2-chloro-6-methylphenyl)piperazin-1-yl)-2-oxoethyl)-5,7-dimethyl-1H-indole-2-carboxylic acid; (37) 3-(2-(4-(2-chloro-6-methylphenyl)piperazin-1-yl)-2-oxoethyl)-5-fluoro-1H-indole-2-carboxylic acid; (38) 3-(2-(4-(2,6-dimethylphenyl)piperazin-1-yl)-2-oxoethyl)-5-fluoro-1H-indole-2-carboxylic acid; (39) 3-(2-(4-(4-(tert-butyl)phenyl)piperazin-1-yl)-2-oxoethyl)-5-fluoro-1H-indole-2-carboxylic acid; (40) 3-(2-(4-([1,1'-biphenyl]-4-yl)piperazin-1-yl)-2-oxoethyl)-5-chloro-1H-indole-2-carboxylic acid; or (41) 5-chloro-3-(2-(4-(2,5-dimethylphenyl)piperazin-1-yl-)-2-oxoethyl)-1H-indole-2-carboxylic acid.

[0019] In another aspect, the present invention provides a pharmaceutical composition for preventing or treating respiratory diseases, comprising the above-mentioned compound, its E- or Z-isomer, its optical isomer, its precursor, a pharmaceutically acceptable salt thereof, a solvate thereof, or a mixture of these two isomers as an active ingredient, and / or a health functional food for preventing or ameliorating respiratory diseases, comprising the same active ingredient.

[0020] According to one preferred embodiment of the present invention, the respiratory disease may be an inflammatory airway disease.

[0021] According to another preferred embodiment of the present invention, the inflammatory airway disease may be one or more selected from the group consisting of asthma, acute or chronic bronchitis, allergic rhinitis, acute respiratory infection, acute upper respiratory infection, cystic fibrosis, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), and chronic obstructive pulmonary disease (COPD).

[0022] According to yet another preferred embodiment of the present invention, the active ingredient can act as a pendrin inhibitor.

[0023] According to another preferred embodiment of the invention, the active ingredient is capable of preserving or increasing the volume of airway surface liquid (ASL).

[0024] According to yet another preferred embodiment of the present invention, the pharmaceutical composition may further comprise other pharmaceutical ingredients.

[0025] In another aspect, the present invention provides a diuretic pharmaceutical composition containing the above-mentioned compound, its E- or Z-isomer, its optical isomer, its precursor, a pharmaceutically acceptable salt thereof, a solvate thereof, or a mixture of these two isomers as an active ingredient, and / or a diuretic health functional food composition containing the same active ingredient.

[0026] According to one preferred embodiment of the invention, the composition may be co-administered with other diuretics.

[0027] According to another preferred embodiment of the present invention, the other diuretic is furosemide, and the composition and the furosemide may be administered in a weight ratio of about 1:10.

[0028] In another aspect, the present invention provides a method for preventing, ameliorating or treating a respiratory disease and a diuretic method, comprising the step of administering the above-mentioned compound, its E- or Z-isomer, its optical isomer, its precursor, a pharmaceutically acceptable salt thereof, a solvate thereof, or a mixture of the two isomers thereof. [Effects of the Invention]

[0029] The compound represented by Chemical Formula 1 according to the present invention, its E- or Z-isomer, its optical isomer, its precursor, its pharmaceutically acceptable salt, its solvate, or a mixture of the two isomers thereof acts as a pendrin inhibitor and is useful for the prevention, amelioration, or treatment of respiratory diseases, such as inflammatory airway diseases, particularly asthma or acute lung injury, and can also be used as a diuretic. [Brief explanation of the drawings]

[0030] [Figure 1] FIG. 1 shows changes in YFP fluorescence, illustrating the inhibitory effects of YPI-H05 and YPI-A4948 on the Cl − / I − exchange activity of pendrin in CHO-K1-YFP cells stably expressing human pendrin. [Figure 2] Figure 2 shows changes in YFP fluorescence, illustrating the inhibitory effects of YPI-H05 and YPI-A4948 on the Cl- / I-exchange activity of SLC26A3 in LN-215-YFP cells stably expressing human SLC26A3. [Figure 3]Figure 3 shows the effects of YPI-H05 and YPI-A4948 on the activity of the anion transporters SLC26A9, CFTR, and ANO1. (A) and (B) show YFP fluorescence changes illustrating the effect of YPI-H05 and YPI-A4948 on the Cl- / I-exchange activity of SLC26A9 in LN-215-YFP cells stably expressing human SLC26A9. (C) and (D) show YFP fluorescence changes illustrating the inhibitory effect of YPI-H05 and YPI-A4948 on the I-transport activity of CFTR in FRT-YFP cells stably expressing human CFTR. (E) and (F) show YFP fluorescence changes illustrating the inhibitory effect of YPI-H05 and YPI-A4948 on the I-transport activity of ANO1 in FRT-YFP cells stably expressing human ANO1. [Figure 4] The effect of YPI-H05 and YPI-A4948 on cell viability in CHO-K1 cells is shown in Figure 4. Cells were treated with YPI-H05 or YPI-A4948 for 24 hours, and cell viability was measured by MTS colorimetric assay (mean ± SEM, n = 3). [Figure 5] Figure 5 shows the effect of YPI-H05 on the reduction of airway surface liquid (ASL) by IL-4 treatment in differentiated primary cultured human nasal epithelial cells (HNE) (mean ± SEM, n = 3). *P < 0.05. [Figure 6] FIG. 6 shows the administration schedule designed to confirm the protective effect of YPI-A4948 before and after treatment in an LPS-induced acute lung injury model. [Figure 7] Figure 7 shows the suppressive effect of YPI-A4948 on the acute lung injury phenotype in an LPS-induced acute lung injury model. (A) shows the average mouse weight, (B) shows the total cell count in BALF, and (C) shows the protein concentration in BALF. [Figure 8]Figure 8 shows the reduction in lung injury before and after treatment with YPI-A4948 in an LPS-induced acute lung injury model. The upper panel shows the results of cytospin staining of BALF, and the lower panel shows the results of H&E lung tissue staining. [Figure 9] Figure 9 shows the diuretic effect of YPI-A4948 treatment in a mouse model. [Figure 10] FIG. 10 shows the administration schedule of adriamycin for establishing a mouse model of heart failure. [Figure 11] FIG. 11 shows the results of cardiac ultrasound examinations before and after administration of adriamycin. [Figure 12] FIG. 12 shows the diuretic effect of YPI-A4948 alone or co-administration of YPI-A4948 and furosemide in a mouse model of heart failure induced by adriamycin. [Figure 13a] FIG. 13a shows the effect of YPI-A4948 on the Cl − / SCN − exchange activity of pendrin in pendrin-overexpressing human alveolar epithelial cells (hAEC). [Figure 13b] Figure 13b shows the relationship between the levels of protein and mRNA expression and the concentration of YPI-A4948 after lipopolysaccharide (LPS) administration in human alveolar epithelial cells (hAEC). [Figure 14a] Figure 14a shows the inhibitory effect of YPI-A4948 treatment on acute lung injury in a mouse model of LPS-induced lung injury. From the top left, the dosing schedule, the Western blot analysis of pendrin (PDS) expression and its quantification, and graphs showing pendrin mRNA expression, total cell counts in bronchial lavage fluid (BALF), and BALF protein concentration. In Figures 14a and 14b, *P<0.05, **P<0.01, and ***P<0.001 were obtained by one-way analysis of variance with Bonferroni post-hoc test. [Figure 14b]Figure 14b shows graphs confirming the levels of four pulmonary inflammatory cytokines following YPI-A4948 treatment. In Figures 14a and 14b, *P<0.05, **P<0.01, and ***P<0.001 were determined by one-way analysis of variance with Bonferroni post-hoc test. [Figure 15a] Figures 15a and 15b show graphs confirming the effect of YPI-A4948 on the efficacy of LPS-induced lung injury in a mouse model with additional external anion supply. Figure 15a shows, from the top left, the administration schedule, lung injury score, total BALF cell count, and BALF protein concentration. Figure 15b shows, from the top left, the results of cytopathological staining of BALF, and the results of H&E staining of lung tissue. In Figures 15a and 15b, *P<0.05, **P<0.01, and ***P<0.001, respectively, and were calculated by one-way analysis of variance with Bonferroni post-hoc test. [Figure 15b] Figures 15a and 15b show graphs confirming the effect of YPI-A4948 on the efficacy of LPS-induced lung injury in a mouse model with additional external anion supply. Figure 15a shows, from the top left, the administration schedule, lung injury score, total BALF cell count, and BALF protein concentration. Figure 15b shows, from the top left, the results of cytopathological staining of BALF, and the results of H&E staining of lung tissue. In Figures 15a and 15b, *P<0.05, **P<0.01, and ***P<0.001, respectively, and were calculated by one-way analysis of variance with Bonferroni post-hoc test. [Figure 16]Figure 16 shows the effects of YPI-A4948 on the activity of anion transporters SLC26A3, SLC26A6, CFTR, and ANO1. (A) shows the YFP fluorescence change illustrating the effect of YPI-A4948 on the Cl- / I-exchange activity of SLC26A9 in LN-215-YFP cells stably expressing human SLC26A3. (B) shows the Cl- / I-exchange activity of SLC26A9 in LN-215-YFP cells stably expressing human SLC26A6. (C) shows YFP fluorescence changes illustrating the inhibitory effect of YPI-A4948 on the I-transport activity of CFTR in FRT-YFP cells stably expressing human CFTR. (D) shows YFP fluorescence changes illustrating the inhibitory effect of YPI-A4948 on the I-transport activity of ANO1 in FRT-YFP cells stably expressing human ANO1. DETAILED DESCRIPTION OF THE INVENTION

[0031] 1.Definition Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by those skilled in the art to which this invention belongs. The following references provide those skilled in the art with general definitions of many of the terms used herein: The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings set forth below unless otherwise specified.

[0032] Unless specifically stated or apparent from the context, the term "or" as used herein is to be understood as inclusive.

[0033] Unless otherwise specifically stated or apparent from the context, the term "about" used herein is understood to be within the general tolerance in the art, for example, within two standard deviations of the mean. About is understood to be within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the specified value. Unless otherwise apparent from the context, all numerical values ​​provided herein are modified by the term about.

[0034] The terms "active agent," "drug," and "pharmaceutical agent" are used interchangeably herein to refer to a chemical substance or compound that induces a desired pharmacological effect (e.g., reduced inflammation) when administered to a subject by any means described herein (e.g., any animal, including a human or non-human animal).

[0035] The term "additive" as used herein can refer to any additional component added to the compositions and formulas described herein. For example, the additional component is provided to be pharmaceutically acceptable for the particular condition being treated, and the additive can include an excipient (e.g., one or more excipients), an antioxidant (e.g., one or more antioxidants), a stabilizer (e.g., one or more stabilizers), a preservative (e.g., one or more preservatives), a pH adjusting and / or buffering agent (e.g., one or more pH adjusting and / or buffering agents), a tonicity adjusting agent (e.g., one or more tonicity adjusting agents), a thickening agent (e.g., one or more thickening agents), a suspending agent (e.g., one or more suspending agents), a binder (e.g., one or more binders), a viscosity increasing agent (e.g., one or more viscosity increasing agents), etc. The excipients may also include processing agents and drug delivery modifiers, enhancers, and combinations of any two or more thereof, such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, dextrose, hydroxypropyl-beta-cyclodextrin, polyvinylpyrrolidone, low-melting waxes, ion exchange resins, etc. Other suitable pharmaceutically acceptable excipients are described in "Remington's Pharmaceutical Sciences," Mack Pub. Co., New Jersey (1991), and "Remington: The Science and Practice of Pharmacy," Lippincott Williams & Wilkins, Philadelphia, 20th edition (2003) and 21st edition (2005), both of which are incorporated herein by reference. The excipients described in this invention can be used with any suitable drug.

[0036] The term "administration" as used herein means administration to a subject orally, by suppository, topical contact, intravenously, parenterally, intraperitoneally, intramuscularly, intralesionally, intrathecally, intranasally, intravitreally, or subcutaneously, or by implantation of a sustained-release device, e.g., a mini-osmotic pump. Administration may be by any route, including parenterally and transmucosally (e.g., oral, nasal, pulmonary, rectal, buccal, vaginal, ocular, and transdermal routes).

[0037] The terms "analog" and "derivative" are used interchangeably herein to refer to a compound that has the same core as the parent compound but differs from the parent compound in the absence or presence of one or more atoms and / or groups of atoms, and combinations thereof, and in the bond order. A derivative may differ from the parent compound, for example, in one or more substitutions present on the core, which may include one or more atoms, functional groups, or substructures. A derivative may also differ from the parent compound in the bond order between atoms within the core. In general, a derivative can be predicted, at least theoretically, to be formed from the parent compound by chemical and / or physical processes.

[0038] As used herein, the term "antioxidant" can refer to any artificial or natural substance that prevents or delays certain types of cell damage and / or oxidation. Antioxidants are found in many foods, including fruits and vegetables, and can also be used as dietary supplements. Exemplary antioxidants include beta-carotene, lutein, lycopene, selenium, vitamin A, vitamin C, and vitamin E. Other antioxidants known to those skilled in the art can also be used. The antioxidants described herein can be used in any suitable amount.

[0039] "Co-administration" means that a compound or composition described in the present invention is administered simultaneously, immediately before or after the administration of an additional therapeutic or active agent or additive described in the present invention. The compounds or compositions of the present invention may be administered alone or co-administered to a patient. Co-administration is understood to include simultaneous or sequential administration of compounds individually or in combination (one or more compounds or formulations). If desired, the formulation may also be combined with other active substances.

[0040] In the present invention, "comprises," "contains," and "having" and the like can have the meanings ascribed to them and can mean "comprises," and the like; "essentially comprises" or "essentially comprises" can likewise have the meanings ascribed to them, and the terms are open-ended, allowing for the presence of more than what is recited, as long as the basic or novel characteristics of the recited thing are not changed by the presence of more than what is recited, but prior art examples are excluded.

[0041] "Concurrent administration," as used herein, includes at least partial overlap in duration. For example, when two formulations (e.g., any formulation or class of formulations described herein that have bioactivity) are administered simultaneously, these administrations occur within a specific desired time period. Administration of the formulations can begin and end on the same day. Also, administration of one formulation can precede administration of a second formulation, as long as both formulations are administered at least once on the same day. Similarly, administration of one formulation can extend beyond administration of a second formulation, as long as both formulations are administered at least once on the same day. Bioactive agents / formulations do not have to be administered at the same time every day to be considered concurrent administration.

[0042] As used herein, an "effective amount" or "therapeutically effective amount" is an amount sufficient to affect a desired biological effect, such as beneficial results, including clinical outcomes. Therefore, the "effective amount" depends on the context in which it is applied. The effective amount will vary depending on factors known in the art, such as the disease state, age, sex, and weight of the individual being treated. Various divided doses may be administered daily, or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. Alternatively, the compositions / formulations of the present invention may be administered as frequently as necessary to achieve a therapeutic dose.

[0043] The term "gel" as used herein can refer to a substance that is not a readily flowable liquid, but is solid, i.e., not semi-solid. Gels can be formed from natural or synthetic materials. Gels are not ordered, but are slightly ordered, exhibiting birefringence, a liquid crystalline property. Gels can be administered topically.

[0044] The term "respiratory disease" as used herein has its usual medical meaning and includes, but is not limited to, asthma, acute or chronic bronchitis, allergic rhinitis, acute respiratory infection, acute upper respiratory infection, cystic fibrosis, acute respiratory distress syndrome (ARDS), acute lung injury (ALI) or chronic obstructive pulmonary disease (COPD), and closely related diseases and disorders of the respiratory system. As used herein, the term "inhibit" refers to preventing, reducing, slowing, or stopping. In one embodiment, a composition or compound is considered to inhibit the viability of at least one protein (e.g., pendrin) if the amount or rate of the step or reaction occurring in the presence of the compound or composition is reduced by at least about 10% when compared to the amount or rate in the absence of the compound or composition. In another embodiment, a composition or compound is considered to inhibit a step or reaction if the amount or rate of the step or reaction occurring in the presence of the compound or composition is reduced by at least about 20% when compared to the amount or rate in the absence of the compound or composition. In other embodiments, a compound or composition is considered to inhibit one or more proteins (e.g., pendrin) if the amount or rate of inhibition occurring in the presence of the compound or composition is reduced by at least about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 75%, or about 80% when compared to the amount or rate in the absence of the compound or composition. In other embodiments, the compound or composition is considered to inhibit the viability of one or more proteins, ie, to prevent their development.

[0045] As used herein, "intermittent administration" includes a period during which the formulation is administered (which is considered a "first administration period"), followed by a period during which the formulation is not taken or is taken at a lower dose (which is considered an "off-period"), followed by a period during which the formulation is again administered (which is considered a "second administration period"). Generally, the dosage level of the formulation during the second administration period will correspond to that administered during the first administration period, but can be increased or decreased as medically indicated.

[0046] A "jelly" according to the present invention comprises a gel, which is a semi-solid system consisting of a suspension of either small inorganic particles or large organic molecules in a structurally cohesive matrix permeated by a high proportion of liquid, usually a water-containing liquid.

[0047] As used herein, a "liquid" is a dosage form that is comprised of a composition in a liquid state. A liquid is pourable; it flows and behaves like a container at room temperature. A liquid exhibits Newtonian or pseudoplastic flow behavior.

[0048] In embodiments, a "semi-liquid" as used in the present invention can have all the properties of liquids and other formulations (ie, suspensions, emulsions, solutions, creams, gels, jellies, etc.).

[0049] The term "ointment" as used herein can refer to a thickened liquid or semi-liquid dosage form that can be used for the therapeutic treatment of a disease, syndrome, or condition.

[0050] As used herein, "pharmaceutically acceptable carriers" include any and all physiologically suitable solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The type of carrier can be selected based on the intended route of administration. Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile topical solutions or dispersions. The use of such media and formulations for pharmaceutically active substances is well known in the art. To the extent that any conventional media or formulation is incompatible with the composition (e.g., Formula 1, derivatives or analogs of Formula 1 described herein, or pharmaceutically acceptable salts, solvents, hydrates, or polymorphs thereof), its use in the compositions for the present invention is contemplated.

[0051] As used herein, a "pharmaceutical carrier" or "carrier" can additionally include pharmaceutically acceptable carriers, excipients, or stabilizers that are not toxic to cells or mammals at the dosages and concentrations employed. Physiologically acceptable carriers are sometimes aqueous pH buffered solutions. Examples of physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants, including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrins; chelating agents, such as EDTA; sugar alcohols, such as mannitol or sorbitol; salt-forming counterions, such as sodium; and / or Tween. TM , polyethylene glycol (PEG) and Pluronics TM Additionally, "pharmaceutically acceptable" means approved, or capable of being approved by a regulatory agency of a federal or state government or in a country other than the United States, or listed by the U.S. Food and Drug Administration or other generally recognized pharmacy for use in animals, and more particularly, in humans.

[0052] The term "pharmaceutically acceptable salt or complex" refers to a salt or complex of a compound represented by Formula 1 as specified below. Examples of such salts include, but are not limited to, base addition salts formed by the reaction of a compound represented by Formula 1 with an organic or inorganic base, such as a hydroxide, carbonate, or bicarbonate of a metal cation, such as those selected from the group consisting of alkali metals (e.g., sodium, potassium, or lithium) and alkaline earth metals (e.g., calcium or magnesium), or with a primary, secondary, or tertiary alkylamine. Amine salts derived from methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, morpholine, N-methyl-D-glucamine, N,N'-bis(phenylmethyl)-1,2-ethanediamine, tromethamine, ethanolamine, diethanolamine, ethylenediamine, N-methylmorpholine, procaine, piperidine, piperazine, and the like, are considered within the scope of the present invention.

[0053] As used herein, "salts" or "salt forms" or "pharmaceutically acceptable salts" also include base addition salts (formed with free carboxyl or other anionic groups) derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxide, and organic bases such as, for example, isopropylamine, trimethylamine, 2-ethylamino-ethanol, histidine, procaine, and the like. Such salts are formed as acid addition salts with any free cationic group and are commonly formed with inorganic acids such as, for example, hydrochloric acid, sulfuric acid, or phosphoric acid, or organic acids such as, for example, acetic acid, citric acid, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, tartaric acid, mandelic acid, and the like. Salts of the present invention can include amine salts formed by protonation of an amino group with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like. Salts of the present invention also include amine salts formed by protonation of an amino group with suitable organic acids such as, for example, p-toluenesulfonic acid, acetic acid, and the like.

[0054] The term "pH agent" or "buffer" used in the present invention can refer to a compound or buffer useful as a pH adjuster. These can include, but are not limited to, glycerol buffer, citrate buffer, borate buffer, acetate buffer, gluconate buffer, phosphate buffer, or citrate-phosphate buffer. The pH agent or buffer can be used in any suitable amount.

[0055] The term "preservative" as used herein can refer to a substance or chemical that prevents undesired chemical changes in the compounds or compositions or formulas described herein. Suitable preservatives include, for example, benzalkonium chloride, thimerosal, chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol, edetate disodium sorbate, onamer M polyquat, cetyl bromide, cetylpyridinium chloride, benzyl bromide, EDTA, phenylmercury nitrate, phenylmercury acetate, thimerosal, merthiolate, acetate and phenylmercury borate, polymyxin B sulfate, methyl and propylparaben, quaternary ammonium chloride, sodium benzoate, sodium propionate and sodium perborate, and other formulations known to those skilled in the art, or combinations thereof. Preservatives can be used in any suitable amount.

[0056] As used herein, the terms "prevent" or "prevention" and other grammatical equivalents include not only reducing the occurrence of symptoms, but also preventing the development, occurrence, interruption, or avoidance of disease or condition symptoms. Prevention can be complete (i.e., no detectable symptoms) or partial, with fewer symptoms observed than in the absence of treatment. The term additionally includes prophylactic benefit. To prevent a disease or condition, a composition is administered to a patient at risk of developing a particular disease or who, while not necessarily diagnosing such a disease, reports one or more physiological symptoms of the disease.

[0057] It is understood that the ranges provided herein are contractions to all values ​​within the range. For example, the range of 1 to 10 is understood to include any number, combination of numbers, or subrange from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, as well as all intermediate decimal values ​​between the recited integers, such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. In connection with subranges, "overlapping subranges" that extend from one of the range endpoints are specifically contemplated. For example, overlapping subranges of the exemplary range of 1 to 50 could include 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction. Ranges are expressed herein by "about" one particular value and / or "about" another particular value. When such a range is expressed, another aspect includes the one particular value and / or the other particular value. Similarly, when values ​​are expressed as approximations by the use of "about," it is understood that the particular value forms the other aspect. It is further understood that the endpoints of each range are significant in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are numerous values ​​disclosed herein, and that each value is also disclosed herein as "about" that particular value, in addition to the value itself. It is also understood that throughout the application, data are provided in a number of different formats, and such data represent endpoints and starting points and ranges for any combination of the data points. For example, if a specific data point "10" and a specific data point "15" are disclosed, not only are values ​​between 10 and 15 considered disclosed, but also values ​​greater than, equal to, less than, less than, equal to, and equal to 10 and 15. It is further understood that each unit between two specified units is disclosed. For example, if 10 and 15 are disclosed, 11, 12, 13, and 14 are also disclosed.

[0058] Additional excipients contemplated for use in embodiments of the present invention are available to those skilled in the art, and can be found, for example, in United States Pharmacopoeia Vol. XXII and National Formulary Vol. XVII, US Pharmacopoeia Convention, Inc., Rockville, Md. (1989), the relevant contents of which are incorporated herein by reference.

[0059] A "semi-solid gel" according to the present invention is a semi-solid. The apparent viscosity of a semi-solid formulation can increase with concentration.

[0060] As used herein, "sequential administration" includes administration of two formulations (e.g., compounds or compositions described herein) separately on the same day or not on the same day (e.g., occurring on consecutive days).

[0061] A "solution" according to the present invention may be a clear, homogeneous liquid dosage form containing one or more chemicals dissolved in a solvent or a mixture of solvents that are miscible with each other. A solution is a liquid formulation containing one or more dissolved chemicals in a suitable solvent or a mixture of solvents that are miscible with each other. Because the drug substance molecules are uniformly dispersed in the solution, the use of a solution as a dosage form generally provides assurance of a uniform dosage upon administration and good accuracy when the solution is diluted or mixed with another.

[0062] The term "solvent" as used herein refers to a liquid solvent, whether aqueous or non-aqueous. The choice of solvent depends, inter alia, on the solubility of the composition in the solvent and the mode of administration. Aqueous solvents may consist solely of water or of water and one or more miscible solvents, and may contain dissolved solutes such as sugars, buffers, salts, or other excipients. More commonly used non-aqueous solvents are short-chain organic alcohols such as methanol, ethanol, and propanol, short-chain ketones such as acetone, and polyalcohols such as glycerol.

[0063] "Subject" or "patient" means a human or non-human animal, such as a mammal. A "subject" can include any animal, including a horse, dog, cat, pig, goat, rabbit, hamster, monkey, guinea pig, rat, mouse, lizard, snake, sheep, cow, fish, and bird. A human subject can be referred to as a patient.

[0064] As used herein, a "suspension" is a liquid dosage form containing dispersed solid particles within a liquid vehicle.

[0065] As used herein, "viscosity" refers to the resistance of a fluid to flow. Viscosity agents that can be used in the present invention include, for example, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, other agents known to those skilled in the art, or combinations thereof.

[0066] The term "weight percentage" or "%(w / w)" refers to the percentage of a component in solution calculated based on the weight of the component and solvent. For example, a 1% (w / w) solution of a component would have 1 g of the component dissolved in 100 g of solvent. The term "volume percentage" or "%(v / v)" refers to the percentage of a component in solution calculated based on the volume of the component and solvent. For example, a 1% (v / v) solution of a component would have 1 ml of the component dissolved in 100 ml of solvent. The term "weight / volume percentage" or "%(w / v)" refers to the percentage of a component in solution calculated based on the weight of the component and the volume of the solvent. For example, a 1.0% (w / v) solution of a component would have 1 g of the component dissolved in 100 ml of solvent.

[0067] The term "syndrome" as used herein refers to a condition characterized by a group of symptoms or a series of related symptoms that occur together persistently. A syndrome (e.g., acute respiratory distress syndrome) can be a series of medical signs and symptoms that are related to each other and sometimes associated with a specific disease. In contrast, a disease can be a health condition with a clearly defined cause. However, a syndrome (from the Greek word meaning "running together") can induce multiple symptoms without an identifiable cause. They can suggest the possibility of an underlying disease or the possibility of a disease occurring.

[0068] As used herein, the terms "treat" or "treatment," and other grammatical equivalents, include alleviating, attenuating, ameliorating, or preventing a disease, condition (e.g., acute respiratory distress syndrome) or symptom, preventing additional symptoms, ameliorating or preventing the underlying metabolic cause of a symptom, inhibiting a disease or condition, e.g., arresting the development of a disease or condition, alleviating a disease or condition, regressing a disease or condition, alleviating a condition caused by a disease or condition, or ceasing the symptoms of a disease or condition, and are intended to include prevention. The term additionally includes achieving a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit refers to the eradication or amelioration of the underlying disorder being treated. Alternatively, a therapeutic benefit may be achieved by eradicating or ameliorating one or more physiological symptoms associated with the underlying disorder, such that an improvement is observed in the patient, even though the patient continues to suffer from the underlying disorder.

[0069] The term "health functional food" refers to a food or food supplement manufactured or processed as a raw material, functional ingredient, active pharmaceutical ingredient or additive useful for improving and / or nourishing and / or preserving the physiological functions of the human body.

[0070] The term "acute respiratory distress syndrome (ARDS)" refers to a medical condition that arises from critically ill patients with widespread inflammation in the lungs. ARDS is a clinical phenotype that can arise from a variety of pathologies, including pneumonia and sepsis. ARDS is characterized by widespread damage to cells that form the alveolar barrier, surfactant dysfunction, abnormal coagulation, and activation of the innate immune response.

[0071] The term "acute lung injury (ALI)" refers to an inflammatory syndrome and increased permeability associated with hypoxemia and the classic radiological appearance. At the most severe end of this spectrum is ARDS.

[0072] The term "airway surface liquid (ASL)" refers to the thin layer of fluid that coats the apical surface of the airway epithelium at the air interface. The ASL plays a central role in maintaining airway homeostasis. The volume, pH, and ionic balance of the ASL are directly involved in regulating antibacterial activity, ciliary function, and mucosal clearance.

[0073] The term "inflammatory airway disease" refers to a variety of inflammatory airway disorders, including asthma, acute or chronic bronchitis, allergic rhinitis, acute respiratory infections, acute upper respiratory infections, cystic fibrosis, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), chronic obstructive pulmonary disease (COPD), and the like.

[0074] The term "inhibitor" as used in the context of the present invention is defined as a molecule, two or more molecules, or a pharmaceutical composition that completely or partially inhibits the activity of a target or two or more targets to induce a desired biological effect. Non-limiting examples of targets include enzymes, receptors, ion-channels, or transporters (e.g., pendrin), etc. An "inhibitor" can reversibly or irreversibly inhibit a target, and reversible inhibition includes competitive inhibition, uncompetitive inhibition, non-competitive inhibition, and mixed inhibition.

[0075] The term "alkyl", when used alone or with other terms, refers to a monovalent alkyl group having 1 to 20 carbon atoms, straight or branched, C1-C 20Such terms include alkyl, and are exemplified by groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, tetrahydrogeranyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-octadecyl, n-nonadecyl, and n-eicosanyl. Preferably, these include C1-C9 alkyl, more preferably C1-C6 alkyl, and particularly preferably C1-C4 alkyl, which similarly refer to monovalent alkyl groups having 1 to 9 carbon atoms, monovalent alkyl groups having 1 to 6 carbon atoms, and monovalent alkyl groups having 1 to 4 carbon atoms, respectively.

[0076] The term "alkenyl", when used alone or with other terms, refers to a straight or branched chain C-C 20It may have any available number of double bonds in any available position, and the double bonds may be in either the (E) or (Z) configuration. Such terms are exemplified by groups such as vinyl, allyl, isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl, geranyl, 1-decenyl, 1-tetradecenyl, 1-octadecenyl, 9-octadecenyl, 1-eicosenyl, and 3,7,11,15-tetramethyl-1-hexadecenyl. Preferably, these include C2-C8 alkenyl, more preferably C2-C6 alkenyl. Among these, vinyl or ethenyl (-CH=CH2), n-2-propenyl (allyl, -CH2CH=CH2), isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-methyl-2-butenyl, and the like are particularly preferred.

[0077] The term "alkynyl" when used alone or with other terms refers to a straight or branched chain C-C 20 It includes alkynyl, which may have any available number of triple bonds in any available position. Such terms are exemplified by groups such as alkynyl groups having 2 to 20 carbon atoms and optionally having double or triple bonds, such as ethynyl (-C≡1-propynyl), 2-propynyl (propargyl: -CH≡C≡2-butynyl), 2-penten-4-ynyl, etc. In particular, these include C2-C8 alkynyl, more preferably C2-C6 alkynyl, etc. Preferably, it includes C2-C6 alkynyl, which denotes a group having 2 to 6 carbon atoms and having alkynyl unsaturation in at least 1 or 2 positions.

[0078] The term "heteroalkyl" refers to a C-C 12-alkyl, preferably C1-C6-alkyl, wherein at least one carbon is replaced by a heteroatom selected from O, N or S, including 2-methoxyethyl and the like.

[0079] The term "aryl" refers to an unsaturated aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., indenyl, naphthyl, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthyl). Aryl includes phenyl, naphthyl, anthryl, phenanthrenyl, and the like.

[0080] The term "C1-C6 alkylaryl" refers to an aryl group having a C1-C6 alkyl substituent, including methylphenyl, ethylphenyl, t-butylphenyl, and the like.

[0081] The term "aryl C1-C6 alkyl" refers to C1-C6 alkyl groups having an aryl substituent, including 3-phenylpropanyl, benzyl, and the like.

[0082] The term "heteroaryl" refers to a monocyclic heteroaromatic, or a bicyclic or tricyclic fused-ring heteroaromatic group. Specific examples of heteroaromatic groups include optionally substituted pyridyl, pyrrolyl, pyrimidinyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1H-pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indole, and benzimidazolyl. , imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxa-zolyl, quinolidinyl, quinazolinyl, phthalazinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl, xanthenyl, benzoquinolyl, benzo[d][1,3]dioxol-5-yl, 3,4-dihydro-1H-pyrano[4,3-c]pyridyl, quinolin-2(1H)-one, 4H-chromene, 1H-indole, and the like.

[0083] The term "C1-C6 alkyl heteroaryl" refers to heteroaryl groups having a C1-C6 alkyl substituent, including methylfuryl, t-butylfuryl, and the like.

[0084] The term "heteroaryl C1-C6 alkyl" refers to C1-C6 alkyl groups having a heteroaryl substituent, including furylmethyl and the like.

[0085] The term "C2-C6 alkenylaryl" refers to aryl groups having a C2-C6 alkenyl substituent, including vinylphenyl and the like.

[0086] The term "aryl C2-C6 alkenyl" refers to C2-C6 alkenyl groups having an aryl substituent, including phenyl vinyl and the like.

[0087] The term "C2-C6 alkenyl heteroaryl" refers to heteroaryl groups having a C2-C6 alkenyl substituent, including vinylpyridinyl and the like.

[0088] The term "heteroaryl C2-C6 alkenyl" refers to C1-C6 alkenyl groups having a heteroaryl substituent, including pyridinyl vinyl and the like.

[0089] The term "C3-C8-cycloalkyl" refers to a saturated carbocyclic group of 3 to 8 carbon atoms having a single ring (e.g., cyclohexyl) or multiple condensed rings (e.g., norbornyl). C3-C8-cycloalkyl includes cyclopentyl, cyclohexyl, norbornyl, and the like.

[0090] The term "heterocycloalkyl" refers to a C3-C8-cycloalkyl or multiple condensed ring as defined above, in which up to three carbon atoms are replaced by heteroatoms selected from the group consisting of O, S, and NR (where R is defined as hydrogen or methyl). Heterocycloalkyl includes lactams or lactones. Non-limiting examples include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, decahydroisoquinolinyl, octahydro-1H-pyrano[3,4-c]pyridinyl, 4-methylene-5(4H)-one, pyrrolidin-2-one, etc.

[0091] The term "C1-C6 alkyl C3-C8 cycloalkyl" refers to C3-C8 cycloalkyl groups having a C1-C6 alkyl substituent, including methylcyclopentyl and the like.

[0092] The term "C3-C8-cycloalkyl C1-C6 alkyl" refers to C1-C6 alkyl groups having a C3-C8-cycloalkyl substituent, including 3-cyclopentylpropyl and the like.

[0093] The term "C1-C6 alkyl heterocycloalkyl" refers to heterocycloalkyl groups having a C1-C6 alkyl substituent, including 4-methylpiperidinyl and the like.

[0094] The term "heterocycloalkyl C1-C6 alkyl" refers to C1-C6 alkyl groups having a heterocycloalkyl substituent, including (1-methylpiperidin-4-yl)methyl and the like.

[0095] The term "carboxy" refers to the group --C(O)OH.

[0096] The term "carboxy C1-C6 alkyl" refers to C1-C6 alkyl groups having a carboxy substituent, including 2-carboxyethyl and the like.

[0097] The term "acyl" refers to the group -C(O)R, including acetyl and the like, where R includes H, "alkyl," preferably "C1-C6 alkyl," "aryl," "heteroaryl," "C3-C8 cycloalkyl," "heterocycloalkyl," "aryl C1-C6 alkyl," "heteroaryl C1-C6 alkyl," "C3-C8 cycloalkyl C1-C6 alkyl," or "heterocycloalkyl C1-C6 alkyl."

[0098] The term "acyl C1-C6 alkyl" refers to C1-C6 alkyl groups having an acyl substituent, including 2-acetylethyl and the like.

[0099] The term "acylaryl" refers to aryl groups having an acyl substituent, including 2-acetylphenyl and the like.

[0100] The term "acyloxy" refers to the group -OC(O)R, including acetyloxy and the like, where R includes H, "C1-C6 alkyl", "C2-C6 alkenyl", "C2-C6 alkynyl", "C3-C8-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "aryl C1-C6 alkyl", "heteroaryl C1-C6 alkyl", "aryl C2-C6 alkenyl", "heteroaryl C2-C6 alkenyl", "aryl C2-C6 alkynyl", "heteroaryl C2-C6 alkynyl", "C3-C8-cycloalkyl C1-C6 alkyl", or "heterocycloalkyl C1-C6 alkyl".

[0101] The term "acyloxyC1-C6 alkyl" refers to C1-C6 alkyl groups having an acyloxy substituent, including 2-(ethylcarbonyloxy)ethyl and the like.

[0102] The term "alkoxy" refers to the group -OR, where R includes "C1-C6 alkyl," "aryl," "heteroaryl," "aryl C1-C6 alkyl," or "heteroaryl C1-C6 alkyl." Preferred alkoxy groups include, for example, methoxy, ethoxy, phenoxy, and the like.

[0103] The term "alkoxy C1-C6 alkyl" refers to C1-C6 alkyl groups having an alkoxy substituent, including methoxyethyl and the like.

[0104] The term "alkoxycarbonyl" refers to the group -C(O)OR, where R includes "C1-C6 alkyl," "aryl," "heteroaryl," "aryl C1-C6 alkyl," "heteroaryl C1-C6 alkyl," or "heteroalkyl."

[0105] The term "alkoxycarbonyl C1-C6 alkyl" refers to C1-C6 alkyl groups having an alkoxycarbonyl substituent, including 2-(benzyloxycarbonyl)ethyl and the like.

[0106] The term "aminocarbonyl" refers to the group -C(O)NRR', including N-phenylcarbonyl, where R and R' are independently H, C1-C6 alkyl, aryl, heteroaryl, "aryl C1-C6 alkyl," or "heteroaryl C1-C6 alkyl."

[0107] The term "aminocarbonyl C1-C6 alkyl" refers to alkyl groups having an aminocarbonyl substituent, including 2-(dimethylaminocarbonyl)ethyl, N-ethylacetamidyl, N,N-diethyl-acetamidyl, and the like.

[0108] The term "acylamino" refers to the group -NRC(O)R', including acetylamino, where R and R' are independently H, "C1-C6 alkyl", "C2-C6 alkenyl", "C2-C6 alkynyl", "C3-C8-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "aryl C1-C6 alkyl", "heteroaryl C1-C6 alkyl", "aryl C2-C6 alkenyl", "heteroaryl C2-C6 alkenyl", "aryl C2-C6 alkynyl", "heteroaryl C2-C6 alkynyl", "cycloalkyl C1-C6 alkyl", or "heterocycloalkyl C1-C6 alkyl".

[0109] The term "acylamino C1-C6 alkyl" refers to C1-C6 alkyl groups having an acylamino substituent, including 2-(propionylamino)ethyl and the like.

[0110] The term "ureido" refers to the group -NRC(O)NR'R'' where R, R', and R'' are independently H, "C1-C6 alkyl," "alkenyl," "alkynyl," "C3-C8 cycloalkyl," "heterocycloalkyl," "C1-C6 aryl," "heteroaryl," "aryl C1-C6 alkyl," "heteroaryl C1-C6 alkyl," "aryl C2-C6 alkenyl," "heteroaryl C2-C6 alkenyl," "aryl C2-C6 alkynyl," "heteroaryl C2-C6 alkynyl," "cycloalkyl C1-C6 alkyl," or "heterocycloalkyl C1-C6 alkyl," where R' and R'' together with the nitrogen atom to which they are attached can optionally form a 3- to 8-membered heterocycloalkyl ring.

[0111] The term "ureido C1-C6 alkyl" refers to C1-C6 alkyl groups having a ureido substituent, including 2-(N'-methylureido)ethyl and the like.

[0112] The term "carbamate" refers to the group -NRC(O)OR', where R and R' are independently "C1-C6 alkyl," "C2-C6 alkenyl," "C2-C6 alkynyl," "C3-C8-cycloalkyl," "heterocycloalkyl," "aryl," "heteroaryl," "C1-C6 alkylaryl," "heteroarylC1-C6 alkyl," "arylC2-C6 alkenyl," "heteroarylC2-C6 alkenyl," "arylC2-C6 alkynyl," "heteroarylC2-C6 alkynyl," "cycloalkylC1-C6 alkyl," or "heterocycloalkylC1-C6 alkyl," and R may be hydrogen.

[0113] The term "amino" refers to the group -NRR', where R and R' are independently H, "C1-C6 alkyl", "aryl", "heteroaryl", "C1-C6 alkylaryl", "C1-C6 alkylheteroaryl", "cycloalkyl", or "heterocycloalkyl", where R and R', together with the nitrogen atom to which they are attached, can optionally form a 3-8 membered heterocycloalkyl ring.

[0114] The term "aminoalkyl" refers to alkyl groups having an amino substituent, including 2-(1-pyrrolidinyl)ethyl and the like.

[0115] The term "ammonium" refers to the positively charged group -N + refers to RR'R'', where R, R', and R'' are independently "C1-C6 alkyl", "C1-C6 alkylaryl", "C1-C6 alkylheteroaryl", "cycloalkyl", or "heterocycloalkyl", where R and R', together with the nitrogen atom to which they are attached, optionally form a 3-8 membered heterocycloalkyl ring.

[0116] The term "ammonium alkyl" refers to alkyl groups having an ammonium substituent, including 1-ethylpyrrolidinium and the like.

[0117] The term "halogen" refers to fluoro, chloro, bromo and iodo atoms.

[0118] The term "sulfonyloxy" refers to the group -OSO2R, where R is selected from "C1-C6 alkyl", "C1-C6 alkyl" substituted with halogen, e.g., -OSO2CF3 group, "C2-C6 alkenyl", "alkynyl", "C3-C8 cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "aryl C1-C6 alkyl", "heteroaryl C1-C6 alkyl", "aryl C2-C6 alkenyl", "heteroaryl C2-C6 alkenyl", "aryl C2-C6 alkynyl", "heteroaryl C2-C6 alkynyl", "cycloalkyl C1-C6 alkyl", or "heterocycloalkylalkyl".

[0119] The term "sulfonyloxyC1-C6 alkyl" refers to alkyl groups having a sulfonyloxy substituent, including 2-(methylsulfonyloxy)ethyl and the like.

[0120] The term "sulfonyl" refers to the group "-S02R", where R is selected from "aryl", "heteroaryl", "C1-C6 alkyl", "C1-C6 alkyl" substituted with halogen, e.g., -S02CF3 group, "C2-C6 alkenyl", "C2-C6 alkynyl", "C3-C8 cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "arylC1-C6 alkyl", "heteroarylC1-C6 alkyl", "arylC2-C6 alkenyl", "heteroarylC2-C6 alkenyl", "arylC2-C6 alkynyl", "heteroarylC2-C6 alkynyl", "cycloalkylC1-C6 alkyl", or "heterocycloalkylC1-C6 alkyl".

[0121] The term "sulfonyl C1-C6 alkyl" refers to alkyl groups having a sulfonyl substituent, including 2-(methylsulfonyl)ethyl and the like.

[0122] The term "sulfinyl" refers to the group "-S(O)R", where R is selected from "alkyl" substituted with "alkyl" halogen, e.g., -SOCF3 group, "C2-C6 alkenyl", "C2-C6 alkynyl", "C3-C8 cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "aryl C1-C6 alkyl", "heteroaryl C1-C6 alkyl", "aryl C2-C6 alkenyl", "heteroaryl C2-C6 alkenyl", "aryl C2-C6 alkynyl", "heteroaryl C2-C6 alkynyl", "C3-C8-cycloalkyl C1-C6 alkyl", or "heterocycloalkyl C1-C6 alkyl".

[0123] The term "sulfinylalkyl" refers to alkyl groups having a sulfinyl substituent, including 2-(methylsulfinyl)ethyl and the like.

[0124] The term "sulfanyl" refers to the group -SR, where R is H, "C1-C6 alkyl," "C1-C6 alkyl" substituted with halogen, e.g., -SCF3 group, "C2-C6 alkenyl," "C2-C6 alkynyl," "C3-C8-cycloalkyl," "heterocycloalkyl," "aryl," "heteroaryl," "arylC1-C6 alkyl," "heteroarylC1-C6 alkyl," "arylC2-C6 alkenyl," "heteroarylC2-C6 alkenyl," "arylC2-C6 alkynyl," "alkynylheteroaryl," "cycloalkylC1-C6 alkyl," or "heterocycloalkylC1-C6 alkyl." Preferred sulfanyl groups include methylsulfanyl, ethylsulfanyl, and the like.

[0125] The term "sulfanyl C1-C6 alkyl" refers to C1-C5-alkyl groups having a sulfanyl substituent, including 2-(ethylsulfanyl)ethyl and the like.

[0126] The term "sulfonylamino" refers to the group -NRSO2R', where R and R' are independently "C1-C6 alkyl", "C2-C6 alkenyl", "C2-C6 alkynyl", "C3-C8-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "aryl C1-C6 alkyl", "heteroaryl C1-C6 alkyl", "aryl C2-C6 alkenyl", "heteroaryl C2-C6 alkenyl", "aryl C2-C6 alkynyl", "heteroaryl C2-C6 alkynyl", "C3-C8 cycloalkyl C1-C6 alkyl", or "heterocycloalkyl C1-C6 alkyl".

[0127] The term "sulfonylamino C1-C6 alkyl" refers to alkyl groups having a sulfonylamino substituent, including 2-(ethylsulfonylamino)ethyl and the like.

[0128] The term "aminosulfonyl" refers to the group -SONR-R', where R and R' are independently H, "C-C alkyl," "C-C alkenyl," "C-C alkynyl," "C-C cycloalkyl," "heterocycloalkyl," "aryl," "heteroaryl," "aryl C-C alkyl," "heteroaryl C-C alkyl," "aryl alkenyl," "heteroaryl C-C alkenyl," "aryl C-C alkynyl," "heteroaryl C-C alkynyl," "C-C cycloalkyl C-C alkyl," or "heterocycloalkyl C-C alkyl," where R and R', together with the nitrogen atom to which they are attached, optionally form a 3-8 membered heterocycloalkyl ring. Aminosulfonyl groups include cyclohexylaminosulfonyl, piperidinylsulfonyl, and the like.

[0129] The term "aminosulfonyl C1-C6 alkyl" refers to C1-C6 alkyl groups having an aminosulfonyl substituent, including 2-(cyclohexylaminosulfonyl)ethyl and the like.

[0130] Unless otherwise limited by the definition of an individual substituent, all of the foregoing substituents shall be understood to be optionally substituted.

[0131] Unless otherwise limited by the definition of the individual substituents, the term "substituted" refers to a group substituted with 1 to 5 substituents selected from the group consisting of "C1-C6 alkyl," "C2-C6 alkenyl," "C2-C6 alkynyl," "C3-C8 cycloalkyl," "heterocycloalkyl," "C1-C6 alkylaryl," "C1-C6 alkylheteroaryl," "C1-C6 alkylcycloalkyl," "C1-C6 alkylheterocycloalkyl," "amino," "aminosulfonyl," "ammonium," "acylamino," "aminocarbonyl," "aryl," "heteroaryl," "sulfinyl," "sulfonyl," "alkoxy," "alkoxycarbonyl," "carbamate," "sulfanyl," "halogen," trihalomethyl, cyano, hydroxy, mercapto, nitro, and the like.

[0132] 2.Compound A first aspect of the present invention relates to a compound represented by the following chemical formula 1, its E- or Z-isomer, its optical isomer, its precursor, a pharmaceutically acceptable salt thereof, a solvate thereof, or a mixture of two isomers thereof:

[0133] [ka] In the above Chemical Formula 1, V 1 is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, aryl, alkylaryl having 1 to 10 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, heteroaryl, heterocycloalkyl, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 10 carbon atoms, alkynyl having 2 to 10 carbon atoms, C(O)OR 2 , C(O)R 2 , OR 2 and OCR 2 F2 is a heteroaryl having 5 to 10 carbon atoms and 1 to 3 nitrogen atoms substituted with one or more groups independently selected from the group consisting of A is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, aryl, alkylaryl having 1 to 10 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, heteroaryl, heterocycloalkyl, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 10 carbon atoms, alkynyl having 2 to 10 carbon atoms, or C(O)OR 2 , C(O)R 2 , OR 2 , OCR 2 F2 and OCOR 2 a heteroaryl having 5 to 7 carbon atoms and containing 1 to 3 nitrogen atoms, or a heterocycloalkyl having 5 to 7 carbon atoms and containing 1 to 3 heteroatoms, each substituted with one or more groups independently selected from the group consisting of V 2is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, aryl, alkylaryl having 1 to 10 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, heteroaryl, heterocycloalkyl, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 10 carbon atoms, alkynyl having 2 to 10 carbon atoms, C(O)OR 2 , C(O)R 2 , OR 2 , OCR 2 F2 and OCOR 2 aryl, alkyl having 1 to 10 carbon atoms, cycloalkyl having 5 to 7 carbon atoms, or C(O)OR substituted with one or more groups independently selected from the group consisting of 2 and R 1 is one or more independently selected from the group consisting of hydrogen, halogen, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 6 carbon atoms, and alkynyl having 2 to 6 carbon atoms, R 2 are independently selected from the group consisting of hydrogen, trifluoromethyl, trifluoromethoxy, aryl, aryl(alkyl having 1 to 10 carbon atoms), alkylaryl having 1 to 10 carbon atoms, heteroaryl, heteroaryl(alkyl having 1 to 10 carbon atoms), alkylheteroaryl having 1 to 10 carbon atoms, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, cycloalkyl and heterocycloalkyl having 3 to 6 carbon atoms; n is an integer of 1 to 5.

[0134] More specifically, in the above Chemical Formula 1, V 1 is hydrogen, halogen, trifluoromethyl, cycloalkyl having 3 to 7 carbon atoms, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 10 carbon atoms, alkynyl having 2 to 10 carbon atoms, C(O)OR 2 , C(O)R 2 , OR 2 , OCR 2 F2 and OCOR 2indolyl, isoindolyl, 3H-indole, 1H-indole, quinolyl, isoquinolyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, quinolidinyl, quinazolinyl, phthalazinyl, cinnolinyl, or naphthyridinyl substituted with one or more groups independently selected from the group consisting of A is pyrrolidinyl, piperidinyl, piperazinyl, or decahydroisoquinolinyl substituted by one or more groups independently selected from the group consisting of hydrogen, halogen, trifluoromethyl, cycloalkyl having 3 to 7 carbon atoms, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 10 carbon atoms, and alkynyl having 2 to 10 carbon atoms; V 2 is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, aryl, alkylaryl having 1 to 10 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, heteroaryl, heterocycloalkyl, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 10 carbon atoms, alkynyl having 2 to 10 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, C(O)OR 2 , C(O)R 2 , OR 2 and OCR 2 C(O)OR or aryl having 5 to 7 carbon atoms substituted with one or more groups independently selected from the group consisting of F2 2 and R 2 are independently selected from the group consisting of hydrogen, trifluoromethyl, aryl, aryl (alkyl having 1 to 10 carbon atoms), alkylaryl having 1 to 10 carbon atoms, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, and cycloalkyl having 3 to 6 carbon atoms; n is an integer of 1 to 5.

[0135] More specifically, the present invention relates to a compound represented by the following chemical formula 1a, its E- or Z-isomer, its optical isomer, its precursor, its pharmaceutically acceptable salt, its solvate, or a mixture of the two isomers thereof:

[0136] [ka] In the above chemical formula 1a, R 1 is one or more independently selected from the group consisting of hydrogen, halogen, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 6 carbon atoms, and alkynyl having 2 to 6 carbon atoms, R 3 is hydrogen, halogen, trifluoromethyl, cycloalkyl having 3 to 7 carbon atoms, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 10 carbon atoms, alkynyl having 2 to 10 carbon atoms, C(O)OR 2 , C(O)R 2 , OR 2 and OCR 2 F2, wherein R 4 is C(O)OR 2 , C(O)R 2 , OR 2 , OCR 2 F2 and OCOR 2 are groups independently selected from the group consisting of R 5 represents one or more groups independently selected from the group consisting of hydrogen, cycloalkyl having 3 to 7 carbon atoms, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 10 carbon atoms, and alkynyl having 2 to 10 carbon atoms; R 6 is hydrogen, halogen, trifluoromethyl, cycloalkyl having 3 to 7 carbon atoms, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 10 carbon atoms, alkynyl having 2 to 10 carbon atoms, C(O)OR 2 , C(O)R 2 , OR 2 and OCR 2 F2, wherein R 2 are independently selected from the group consisting of hydrogen, trifluoromethyl, aryl, aryl (alkyl having 1 to 10 carbon atoms), alkylaryl having 1 to 10 carbon atoms, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, and cycloalkyl having 3 to 6 carbon atoms; n is an integer of 1 to 5.

[0137] More specifically, the present invention relates to a compound represented by the following chemical formula 1b, its E- or Z-isomer, its optical isomer, its precursor, its pharmaceutically acceptable salt, its solvate, or a mixture of the two isomers thereof:

[0138] [ka] In the above chemical formula 1b, R 1 is one or more independently selected from the group consisting of hydrogen, halogen, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 6 carbon atoms, and alkynyl having 2 to 6 carbon atoms, R 3 is hydrogen, halogen, trifluoromethyl, cycloalkyl having 3 to 7 carbon atoms, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 10 carbon atoms, alkynyl having 2 to 10 carbon atoms, C(O)OR 2 , C(O)R 2 , OR 2 and OCR 2 F2, wherein R 4 is C(O)OR 2 , C(O)R 2 , OR 2 , OCR 2 F2 and OCOR 2 are groups independently selected from the group consisting of R 5 represents one or more groups independently selected from the group consisting of hydrogen, cycloalkyl having 3 to 7 carbon atoms, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 10 carbon atoms, and alkynyl having 2 to 10 carbon atoms; R 7 represents one or more groups independently selected from the group consisting of hydrogen, halogen, trifluoromethyl, cycloalkyl having 3 to 7 carbon atoms, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 10 carbon atoms, and alkynyl having 2 to 10 carbon atoms; R 2are independently selected from the group consisting of hydrogen, trifluoromethyl, aryl, aryl (alkyl having 1 to 10 carbon atoms), alkylaryl having 1 to 10 carbon atoms, alkyl having 1 to 10 carbon atoms, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, and cycloalkyl having 3 to 6 carbon atoms; n is an integer of 1 to 5.

[0139] Hereinafter, preferred compounds include, but are not limited to, the compounds mentioned above. (1) 5-chloro-3-(2-oxo-2-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)-1H-indole-2-carboxylic acid; (2) 5-chloro-3-(2-oxo-2-(4-(2-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)-1H-indole-2-carboxylic acid; (3) 5-chloro-3-(2-(4-(2,6-dimethylphenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (4) 5-chloro-3-(2-(4-(2,4-dimethylphenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (5) 5-chloro-3-(2-(4-(3-methoxyphenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (6) 5-chloro-3-(2-(4-(2-chlorophenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (7) 5-chloro-3-(2-(4-(4-chlorophenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (8) 3-(2-(4-(2-bromophenyl)piperazin-1-yl)-2-oxoethyl)-5-chloro-1H-indole-2-carboxylic acid; (9) 3-(2-(4-(3-bromophenyl)piperazin-1-yl)-2-oxoethyl)-5-chloro-1H-indole-2-carboxylic acid; (10) 3-(2-(4-(4-bromophenyl)piperazin-1-yl)-2-oxoethyl)-5-chloro-1H-indole-2-carboxylic acid; (11) 5-chloro-3-(2-oxo-2-(4-(o-tolyl)piperazin-1-yl)ethyl)-1H-indole-2-carboxylic acid; (12) 5-chloro-3-(2-oxo-2-(4-(m-tolyl)piperazin-1-yl)ethyl)-1H-indole-2-carboxylic acid; (13) 5-chloro-3-(2-oxo-2-(4-(p-tolyl)piperazin-1-yl)ethyl)-1H-indole-2-carboxylic acid; (14) 3-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-oxoethyl)-5-chloro-1H-indole-2-carboxylic acid; (15) 5-chloro-3-(2-(4-(2-chloro-6-methylphenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (16) 5-chloro-3-(2-(4-(2-ethoxyphenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (17) 5-chloro-3-(2-(3-methyl-4-phenylpiperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (18) 5-chloro-3-(2-(4-(4-chlorophenyl)-2,2-dimethylpiperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (19) 5-chloro-3-(2-(4-(2-chloro-4-fluorophenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (20) 5-chloro-3-(2-(4-(2-chloro-5-methoxyphenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (21) 5-chloro-3-(2-(4-(2,4-dichlorophenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (22) (R)-5-chloro-3-(2-(2-methyl-4-phenylpiperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (23) 5-chloro-3-(2-(4-(2,4-difluorophenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (24) 5-chloro-3-(2-oxo-2-(4-(3,4,5-trichlorophenyl)piperazin-1-yl)ethyl)-1H-indole-2-carboxylic acid; (25) 5-chloro-3-(2-(4-(2-fluorophenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (26) 5-chloro-3-(2-(4-(3-chloro-2-methylphenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (27) 3-(2-(4-(4-carboxyphenyl)piperazin-1-yl)-2-oxoethyl)-5-chloro-1H-indole-2-carboxylic acid; (28) 3-(2-(4-(4-acetylphenyl)piperazin-1-yl)-2-oxoethyl)-5-chloro-1H-indole-2-carboxylic acid; (29) 5-chloro-3-(2-(4-(4-ethoxyphenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (30) 3-(2-(4-(4-(tert-butyl)phenyl)piperazin-1-yl)-2-oxoethyl)-5-chloro-1H-indole-2-carboxylic acid; (31) 3-(2-(4-(4-(tert-butyl)phenyl)piperazin-1-yl)-2-oxoethyl)-5-methyl-1H-indole-2-carboxylic acid; (32) 3-(2-(4-(4-(tert-butyl)phenyl)piperazin-1-yl-2-oxoethyl)-5,7-dimethyl-1H-indole-2-carboxylic acid; (33) 3-(2-(4-(2,6-dimethylphenyl)piperazin-1-yl)-2-oxoethyl)-5-methyl-1H-indole-2-carboxylic acid; (34) 3-(2-(4-(2,6-dimethylphenyl)piperazin-1-yl)-2-oxoethyl)-5,7-dimethyl-1H-indole-2-carboxylic acid; (35) 3-(2-(4-(2-chloro-6-methylphenyl)piperazin-1-yl)-2-oxoethyl)-5-methyl-1H-indole-2-carboxylic acid; (36) 3-(2-(4-(2-chloro-6-methylphenyl)piperazin-1-yl)-2-oxoethyl)-5,7-dimethyl-1H-indole-2-carboxylic acid; (37) 3-(2-(4-(2-chloro-6-methylphenyl)piperazin-1-yl)-2-oxoethyl)-5-fluoro-1H-indole-2-carboxylic acid; (38) 3-(2-(4-(2,6-dimethylphenyl)piperazin-1-yl)-2-oxoethyl)-5-fluoro-1H-indole-2-carboxylic acid; (39) 3-(2-(4-(4-(tert-butyl)phenyl)piperazin-1-yl)-2-oxoethyl)-5-fluoro-1H-indole-2-carboxylic acid; (40) 3-(2-(4-([1,1'-biphenyl]-4-yl)piperazin-1-yl)-2-oxoethyl)-5-chloro-1H-indole-2-carboxylic acid; or (41) 5-chloro-3-(2-(4-(2,5-dimethylphenyl)piperazin-1-yl-)-2-oxoethyl)-1H-indole-2-carboxylic acid.

[0140] The term "compound of the invention" and equivalent expressions herein include compounds of Formula 1 as set forth above, including their E- or Z-isomers, their optical isomers, their precursors, their pharmaceutically acceptable salts, their solvates, or mixtures of the two isomers, including those synthesized de novo.

[0141] The present invention is further illustrated by the following examples, which do not limit the scope of the invention in any way.

[0142] 3. Manufacturing method In the first aspect of the present invention, the present invention further provides methods for preparing compounds represented by Chemical Formula 1, Chemical Formula 1a, and Chemical Formula 1b. The synthesis method of YPI-A4948, a representative compound represented by Chemical Formula 1 of the present invention, is described in detail in Example 1, and the novel compounds of the present invention can be prepared based on the synthesis method described in Example 1.

[0143] In some embodiments, the base used during organic synthesis may be organic or inorganic. Non-limiting examples of organic bases include pyridine, trimethylamine, N,N-diisopropylethylamine (DIPEA), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Non-limiting examples of inorganic bases include sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and sodium hydride. These may be used alone or in combination, in stoichiometric amounts or in excess. Non-limiting examples of solvents that may be used include ethers (e.g., tetrahydrofuran (THF), diethyl ether, and 1,2-dimethoxyethane), alcohols (e.g., methanol, ethanol, propanol, and butanol), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dichloromethane (DCM), dichloroethane, water, and acetone. The solvents may be used alone or in combination.

[0144] 4. Compositions and Dosage Forms The present invention includes pharmaceutical compositions comprising the compounds described in the present invention and dosage forms suitable for administering the compounds described in the present invention. Any dosage form of the pharmaceutical composition suitable for administration by any medically acceptable means is included in the present invention. The pharmaceutical dosage form may include a pharmaceutically acceptable excipient or carrier and a pharmaceutically acceptable compound (composition) suitable for the means of administration.

[0145] The compounds described herein may be in dosage forms (including pharmaceutical compositions) with additives such as excipients (e.g., one or more excipients), antioxidants (e.g., one or more antioxidants), stabilizers (e.g., one or more stabilizers), preservatives (e.g., one or more preservatives), pH adjusting and / or buffering agents (e.g., one or more pH adjusting and / or buffering agents), tonicity adjusting agents (e.g., one or more tonicity adjusting agents), thickening agents (e.g., one or more thickening agents), suspending agents (e.g., one or more suspending agents), binders (e.g., one or more binders), viscosity increasing agents (e.g., one or more viscosity increasing agents), and the like, provided as additional pharmaceutically acceptable ingredients for the particular condition being treated. In some embodiments, the dosage forms can include a combination of additional ingredients (e.g., 2, 3, 4, 5, 6, 7, 8 or more additional ingredients) as described herein. In some embodiments, the additives can include processing agents and drug delivery modifiers, enhancers, and combinations of any two or more thereof, such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, dextrose, hydroxypropyl-beta-cyclodextrin, polyvinylpyrrolidone, low melting point waxes, ion exchange resins, and the like.

[0146] Other suitable pharmaceutically acceptable excipients are described in "Remington's Pharmaceutical Sciences," Mack Pub. Co., New Jersey (1991), and "Remington: The Science and Practice of Pharmacy," Lippincott Williams & Wilkins, Philadelphia, 20th edition (2003) and 21st edition (2005), which are incorporated herein by reference.

[0147] The dosage forms of the compositions described herein can be suitable for inhalation, nasal spray, intravenous injection, intramuscular injection, intravitreal injection, ointment, or oral administration consisting of solutions, suspensions, semi-liquids, semi-solids, gels, semi-solid gels, jellies, emulsions, ointments, tablets, liquids, and creams. Tablet forms can contain one or more of lactose, sucrose, mannitol, sorbitol, calcium phosphate, corn starch, potato starch, microcrystalline cellulose, gelatin, colloidal silicon dioxide, talc, magnesium stearate, stearic acid, and other excipients, colorants, fillers, binders, diluents, buffers, humectants, preservatives, flavorings, dyes, disintegrants, and pharmaceutically suitable carriers. Capsules can contain suitable excipients together with the compounds, or the compounds can be used alone in the capsule shell. All of these compound formulations can be administered singly, co-administered, intermittently, sequentially, or simultaneously.

[0148] 5. Administration The compositions of the present invention may be administered by any of the following methods: oral, parenteral, sublingual, transdermal, rectal, transmucosal, topical, inhalation, buccal, or intranasal administration, or any combination thereof. Parenteral administration includes, but is not limited to, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, intraspinal, and intraarterial. The compositions of the present invention may also be administered by implants, which allow for slow release of the composition as well as slow, controlled intravenous administration.

[0149] The dose administered to an individual in single or multiple doses will vary widely depending on a variety of factors, including pharmacokinetic properties, the condition and characteristics of the patient (sex, age, weight, health, size), the severity of symptoms, concurrent treatments, frequency of treatment, and the desired effect.

[0150] According to one embodiment of the present invention, the compounds according to the present invention and pharmaceutical dosage forms thereof can be administered alone or together with adjuvants useful in the treatment of respiratory disorders or diseases. According to another embodiment of the present invention, the compounds according to the present invention and pharmaceutical dosage forms thereof can be administered together with radiation therapy.

[0151] The present invention includes the administration of a compound according to the present invention or a pharmaceutical formulation thereof, in a therapeutically effective amount, to an individual prior to, concurrently with, or sequentially with other therapeutic or adjunctive agents (e.g., multi-drug therapy) useful in the treatment of cancer. Compounds according to the present invention or pharmaceutical formulations thereof administered simultaneously with said adjunctive agents can be administered in the same or different compositions and by the same or different routes of administration.

[0152] In one embodiment, the patient according to the present invention is a patient suffering from a respiratory disorder or disease such as bronchial asthma, bronchitis, allergic rhinitis, adult respiratory syndrome, cystic fibrosis, pulmonary viral infection (influenza), pulmonary hypertension, idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease (COPD).

[0153] In another embodiment, the compounds according to the present invention and pharmaceutical formulations thereof can be administered alone or in combination with one or more other diuretics, such as furosemide, torasemide, bumetanide, ethacrynic acid, or the like. The active ingredient may be selected from the group consisting of, but not limited to, benzodiazepine, benzophenone, benzocaine, benzodiazepine, benzocaine ...

[0154] Preferably, the compound according to the present invention or its pharmaceutical formulation is administered together with furosemide, and can be administered at an appropriate ratio taking into consideration the toxicity of each drug.For example, the compound according to the present invention or its pharmaceutical formulation and furosemide can be administered at a weight ratio of about 1:10, but is not limited thereto.

[0155] 6. Uses of the Compounds According to the Present Invention A second aspect of the present invention provides use of a compound represented by Chemical Formula 1, Chemical Formula 1a or Chemical Formula 1b, a mixture of compounds, or a pharmaceutical composition thereof for the prevention, amelioration, or treatment of a respiratory disease (inflammatory airway disease).

[0156] In one embodiment, the present invention provides the use of a compound of Formula 1, Formula 1a, or Formula 1b and pharmaceutical compositions thereof as a pendrin inhibitor.

[0157] In another embodiment, there is provided a use of a compound represented by Formula 1, Formula 1a, or Formula 1b and pharmaceutical compositions thereof for preserving or increasing airway surface liquid (ASL) volume.

[0158] In another embodiment, the present invention provides use for one or more respiratory diseases (inflammatory airway diseases) selected from the group consisting of asthma, acute or chronic bronchitis, allergic rhinitis, acute respiratory infections, acute upper respiratory infections, cystic fibrosis, acute respiratory distress syndrome (ARDS), acute lung injury (ALI) or chronic obstructive pulmonary disease (COPD).

[0159] In another embodiment, the present invention provides a use of a compound represented by Chemical Formula 1, Chemical Formula 1a or Chemical Formula 1b, a mixture of compounds, or a health functional food composition thereof as an active ingredient in a health functional food for the prevention or improvement of respiratory diseases (inflammatory airway diseases).

[0160] In another embodiment, the present invention provides a use of a compound represented by Chemical Formula 1, Chemical Formula 1a or Chemical Formula 1b as a pendrin inhibitor for preventing or improving respiratory diseases (inflammatory airway diseases) as an active ingredient in a health functional food, and a health functional food composition thereof.

[0161] In another embodiment, the present invention provides a use of a compound represented by Chemical Formula 1, Chemical Formula 1a, or Chemical Formula 1b and a pharmaceutical composition thereof, which is used as an active ingredient in a health functional food to preserve or increase the volume of airway surface liquid (ASL) for the prevention or improvement of respiratory diseases (inflammatory airway diseases).

[0162] In another embodiment, the present invention provides a use of the compound as an active ingredient in a health functional food for preventing or improving a respiratory disease (inflammatory airway disease), wherein the respiratory disease (inflammatory airway disease) is one or more selected from the group consisting of asthma, acute or chronic bronchitis, allergic rhinitis, acute respiratory infection, acute upper respiratory infection, cystic fibrosis, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), or chronic obstructive pulmonary disease (COPD).

[0163] A third aspect of the present invention provides a use of a compound, a mixture of compounds or a pharmaceutical composition thereof represented by Chemical Formula 1, Chemical Formula 1a or Chemical Formula 1b, which in other aspects exhibits a diuretic effect.

[0164] In another embodiment, the present invention provides a use of a compound, a mixture of compounds, or a health functional food composition thereof represented by Chemical Formula 1, Chemical Formula 1a, or Chemical Formula 1b, which exhibits diuretic effect, as an active ingredient in a health functional food.

[0165] Non-limiting examples of detailed experiments that do not limit the overall experiment are described in the present invention. The description of the present invention described in the present invention serves as an example, and those with general knowledge of the technology related to the present invention should understand that the present invention can be easily modified to other specific areas or forms without changing the technical idea or essential characteristics of the present invention. The described present invention is illustratively presented in the following examples, but is not limited thereto.

[0166] Compound names were generated using ChemDraw Professional V.15.1. The compounds according to the present invention include compounds represented by Formula 1, their tautomers, their geometric isomers (e.g., e, z isomers), their optically active forms as enantiomers, their regioisomers, and their racemic forms, as well as pharmaceutically acceptable salts thereof. The derivatives exemplified in this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be understood that when typical or preferred experimental conditions (i.e., reaction temperature, time, moles of reagents, solvents, etc.) are given, other experimental conditions can be used unless otherwise stated. Optimum reaction conditions will vary depending on the specific reactants or solvents used; such conditions can be determined by one skilled in the art using routine optimization procedures.

[0167] All references cited herein are incorporated herein by reference in their entirety. The present invention is not limited in scope by the specific embodiments described herein, which are intended as single illustrations of individual aspects of the invention; functionally equivalent methods and components are within the scope of the present invention. Indeed, various modifications of the present invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims. [Example]

[0168] [Example 1] Production of new compounds

[0169] The method for synthesizing the novel compound according to the present invention is as follows.

[0170] (1) 3-(carboxymethyl)-5-methyl-1H-indole-2-carboxylic acid [ka]

[0171] (a) 2-ketoglutaric acid, distilled water, refluxed at 100°C for 16 hours Distilled water was refluxed with 1 equivalent (3 g) of (4-chlorophenyl)hydrazine hydrochloride and 1.5 equivalents of 2-ketoglutaric acid at 100°C for 16 hours. After confirming the completion of the reaction, the mixture was cooled to room temperature and extracted three times with distilled water and ethyl acetate. The collected organic layer was dehydrated with sodium sulfate, and the sodium sulfate was removed using filter paper. The filtrate was distilled under reduced pressure.

[0172] (2) Ethyl 3-(2-ethoxy-2-oxoethyl)-5-methyl-1H-indole-2-carboxylate [ka]

[0173] (b) Concentrated sulfuric acid (95%), ethanol, reflux heating at 78°C for 16 hours The stock solution (3.5 g) obtained in the previous step was dissolved in ethanol, and then treated with 7 mL of concentrated sulfuric acid while carefully stirring using a glass rod. After all the concentrated sulfuric acid had been removed, the mixture was heated under reflux at 78°C for 16 hours. After confirming the completion of the reaction, it was distilled under reduced pressure. Distilled water and ethyl acetate were then added to the stock solution, which was then neutralized using sodium bicarbonate. After neutralization was complete, it was extracted three times using distilled water and ethyl acetate. The collected organic layer was dehydrated using sodium sulfate, and the sodium sulfate was removed using filter paper. The filtrate was distilled under reduced pressure and then purified using column chromatography. (The mobile phase was a mixed solution of ethyl acetate and n-hexane in a volume ratio of 1:10.)

[0174] (3) 2-(2-(ethoxycarbonyl)-5-methyl-1H-indol-3-yl)acetic acid [ka]

[0175] (c) Sodium hydroxide, tetrahydrofuran, ethanol, distilled water, -10°C, stirring for 16 hours The compound (1.6 g) purified in the previous step was dissolved in 20 mL of tetrahydrofuran and 20 mL of ethanol. Then, 1.1 equivalents of sodium hydroxide was dissolved in 4 mL of distilled water and treated. The mixture was stirred at -10°C for 16 hours using a low-temperature reactor. After confirming the completion of the reaction, the mixture was neutralized with 10% hydrochloric acid solution. It was then extracted three times using distilled water and ethyl acetate. The collected organic layer was dehydrated using sodium sulfate, and the sodium sulfate was removed using filter paper. The filtrate was distilled under reduced pressure and then purified using column chromatography (ethyl acetate:n-hexane = 1:10 → 1:1).

[0176] (4) Ethyl 3-(2-(4-(2-chloro-6-methylphenyl)piperazin-1-yl)-2-oxoethyl)-5-methyl-1H-indole-2-carboxylate [ka]

[0177] (d) Azabenzotriazole tetramethyluronium hexafluorophosphate, N,N-diisopropylethylamine, tetrahydrofuran, stirred at room temperature for 5 hours The compound (50 mg) purified in the previous step was dissolved in tetrahydrofuran and treated with 1.2 equivalents of phenylpiperazine, 1.1 equivalents of azabenzotriazole tetramethyluronium hexafluorophosphate (HATU), and 3 equivalents of N,N-diisopropylethylamine (DIPEA). The mixture was stirred at room temperature for 5 hours. After confirming the completion of the reaction, the product was distilled under reduced pressure and purified using column chromatography (ethyl acetate: n-hexane = 1:5).

[0178] (5) 3-(2-(4-(2-chloro-6-methylphenyl)piperazin-1-yl)-2-oxoethyl)-5-methyl-1H-indole-2-carboxylic acid (YPI-A4948) [ka]

[0179] (e) Lithium hydroxide, tetrahydrofuran, distilled water, stirred at room temperature for 16 hours The compound (70 mg) purified in the previous step was dissolved in tetrahydrofuran and then treated with 5 equivalents of lithium hydroxide dissolved in 5 mL of distilled water. After all the lithium hydroxide was treated, the mixture was stirred at room temperature for 16 hours. After confirming the completion of the reaction, the mixture was distilled under reduced pressure. After all the remaining solvent was removed, distilled water was added and the mixture was treated with 10% hydrochloric acid solution to precipitate the carboxylic acid. The precipitated carboxylic acid was filtered using filter paper and washed with distilled water for purification.

[0180] 1-1,5-chloro-3-(2-(4-(2,5-dimethylphenyl)piperazin-1-yl-)-2-oxoethyl)-1H-indole-2-carboxylic acid (YPI-H05) [ka]

[0181] 1-2,5-chloro-3-(2-oxo-2-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)-1H-indole-2-carboxylic acid (YPI-A4779) [ka]

[0182] 1 H NMR (300MHz, DMSO-d6) δ13.28(s, 1H), 11.79(s, 1H), 7.76-7.75(m, 1H), 7.54-7.51(m, 2H), 7.42-7. 40(m, 1H), 7.25-7.22(m, 1H), 7.09-7.07(m, 2H), 4.21(s, 2H), 3.78-3.62(m, 4H), 3.37-3.26(m, 4H). ESI(m / z) 464(MH-).

[0183] 1-3,5-chloro-3-(2-oxo-2-(4-(2-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)-1H-indole-2-carboxylic acid (YPI-A4781) [ka] 1H NMR (300MHz, DMSO-d6) δ13.28(s, 1H), 11.78(s, 1H), 7.77(m, 1H), 7.70-7.65(m, 2H), 7.53-7.51(m, 1H), 7. 44-7.41(m, 1H), 7.39-7.35(m, 1H), 7.27-7.24(m, 1H), 4.20(s, 2H), 3.74-3.59(m, 4H), 2.85-2.81(m, 4H). ESI (m / z) 466 (MH+), 464 (MH-).

[0184] 1-4,5-chloro-3-(2-(4-(2,6-dimethylphenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid (YPI-A4783) [ka]

[0185] 1H NMR (300MHz, DMSO-d6) δ13.26(s, 1H), 11.77(s, 1H), 7.76(m, 1H), 7.43-7.41(m, 1H), 7.26-7. 23(m, 1H), 6.97-6.89(m, 3H), 4.21(s, 2H), 3.66-3.58(m, 4H), 2.90-2.83(m, 4H), 2.18(s, 6H). ESI (m / z) 425 (MH+), 424 (MH-).

[0186] 1-5,5-chloro-3-(2-(4-(2,3-dimethylphenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid (YPI-A4799) [ka]

[0187] 1H NMR (300MHz, DMSO-d6) δ11.75(s, 1H), 7.70-7.69(m, 1H), 7.61-7.59(m, 1H), 7.05-7.03(m, 1H), 6.97-6.94(m, 1H), 6.8 4-6.82(m, 1H), 6.67-6.65(m, 1H), 4.38(s, 2H), 3.86-3.58(m, 4H), 2.61(s, 2H), 2.46(s, 2H), 2.16(s, 3H), 2.08(s, 3H). ESI (m / z) 425 (MH+), 424 (MH-).

[0188] 1-6,5-chloro-3-(2-(4-(2,4-dimethylphenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid (YPI-A4801) [ka]

[0189] 1H NMR (300MHz, DMSO-d6) δ11.56(s, 1H), 7.69(m, 1H), 7.51-7.49(m, 1H), 7.08-7.05(m, 1H), 6.93(m, 1H), 6.87- 6.85(m, 1H), 6.71-6.69(m, 1H), 4.34(s, 2H), 3.81-3.56(m, 4H), 2.62-2.50(m, 4H), 2.17(s, 3H), 2.15(s, 3H). ESI (m / z) 426 (MH+), 424 (MH-).

[0190] 1-7,5-chloro-3-(2-(4-(2-methoxyphenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid (YPI-A4876) [ka]

[0191] 1H NMR (300MHz, DMSO-d6) δ13.24(s, 1H), 11.75(s, 1H), 7.75-7.74(m, 1H), 7.43-7.40(m, 1H), 7. 26-7.22(m, 1H), 6.98-6.85(m, 4H), 4.19(s, 2H), 3.79(s, 3H), 3.75-3.60(m, 4H), 2.90(m, 4H). ESI(m / z) 426(MH-).

[0192] 1-8,5-chloro-3-(2-(4-(3-methoxyphenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid (YPI-A4877) [ka]

[0193] 1H NMR (300MHz, DMSO-d6) δ11.59(s, 1H), 7.71-7.70(m, 1H), 7.50-7.47(m, 1H), 7.11-7.03(m , 2H), 6.44-6.33(m, 3H), 4.33(s, 2H), 3.83-3.56(m, 4H), 3.68(s, 3H), 2.98-2.89(m, 4H). ESI (m / z) 428 (MH+), 426 (MH-).

[0194] 1-9,5-chloro-3-(2-(4-(4-methoxyphenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid (YPI-A4878) [ka]

[0195] 1H NMR (300MHz, DMSO-d6) δ11.55(s, 1H), 7.71-7.70(m, 1H), 7.49-7.46(m, 1H), 7.10-7.07(m , 1H), 6.82-6.74(m, 4H), 4.33(s, 2H), 3.84-3.57(m, 4H), 3.66(s, 3H), 2.84-2.74(m, 4H). ESI (m / z) 428 (MH+), 426 (MH-).

[0196] 1-10,5-chloro-3-(2-(4-(2-chlorophenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid (YPI-A4803) [ka]

[0197] 1H NMR (300MHz, DMSO-d6) δ11.57(s, 1H), 7.70(m, 1H), 7.53-7.51(m, 1H), 7.38-7.36(m, 1H), 7.23-7.21(m, 1H), 7.08-6.96(m, 3H), 4.35(s, 2H), 3.88-3.59(m, 4H), 2.80-2.69(m, 4H). ESI (m / z) 430(MH-), 432(MH-), 434(MH-).

[0198] 1-11,5-chloro-3-(2-(4-(4-chlorophenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid (YPI-A4843) [ka]

[0199] 1H NMR (300MHz, DMSO-d6) δ13.26(s, 1H), 11.75(s, 1H), 7.74(m, 1H), 7.42-7.40(m, 1H), 7. 25-7.22(m, 3H), 6.97-6.94(m, 2H), 4.20(s, 2H), 3.75-7.60(m, 4H), 3.12-3.08(m, 4H). ESI(m / z)432(MH+), 434(MH+), 436(MH+).

[0200] 1-12. 3-(2-(4-(2-bromophenyl)piperazin-1-yl)-2-oxoethyl)-5-chloro-1H-indole-2-carboxylic acid (YPI-A4844) [ka]

[0201] 1H NMR (300MHz, DMSO-d6) δ11.41(s, 1H), 7.69(m, 1H), 7.57-7.54(m, 1H), 7.49-7.46(m, 1H), 7.30-7.2 5(m, 1H), 7.06-7.03(m, 1H), 6.98-6.92(m, 2H), 4.36(s, 2H), 3.89-3.58(m, 4H), 2.79-2.66(m, 4H). ESI (m / z) 476 (MH+), 474 (MH-).

[0202] 1-13. 3-(2-(4-(3-bromophenyl)piperazin-1-yl)-2-oxoethyl)-5-chloro-1H-indole-2-carboxylic acid (YPI-A4845) [ka]

[0203] 1H NMR (300MHz, DMSO-d6) δ13.23(s, 1H), 11.75(s, 1H), 7.74(m, 1H), 7.42-7.39(m, 1H), 7.25-7.21( m, 1H), 7.19-7.09(m, 2H), 6.96-6.92(m, 2H), 4.20(s, 2H), 3.75-3.60(m, 4H), 3.17-3.13(m, 4H). ESI (m / z) 474(MH-), 476(MH-), 478(MH-).

[0204] 1-14. 3-(2-(4-(4-bromophenyl)piperazin-1-yl)-2-oxoethyl)-5-chloro-1H-indole-2-carboxylic acid (YPI-A4846) [ka]

[0205] 1H NMR (300MHz, DMSO-d6) δ11.49(s, 1H), 7.74(m, 1H), 7.39-7.37(m, 1H), 7.32-7.30(m, 2 H), 7.15-7.13(m, 1H), 6.86-6.84(m, 2H), 4.26(s, 2H), 3.80-3.57(m, 4H), 3.00(m, 4H). ESI(m / z)474(MH-), 476(MH-).

[0206] 1-15,5-Chloro-3-(2-oxo-2-(4-(o-tolyl)piperazin-1-yl)ethyl)-1H-indole-2-carboxylic acid (YPI-A4847) [ka]

[0207] 1H NMR (300MHz, DMSO-d6) δ11.51(s, 1H), 7.70-7.69(m, 1H), 7.52-7.49(m, 1H), 7.13-7.05(m, 3H), 6.9 4-6.89(m, 1H), 6.83-6.81(m, 1H), 4.35(s, 2H), 3.84-3.57(m, 4H), 2.66-2.54(m, 4H), 2.19(s, 3H). ESI (m / z) 412(MH+), 414(MH+), 410(MH-), 412(MH-).

[0208] 1-16,5-chloro-3-(2-oxo-2-(4-(m-tolyl)piperazin-1-yl)ethyl)-1H-indole-2-carboxylic acid (YPI-A4848) [ka]

[0209] 1H NMR (300MHz, DMSO-d6) δ13.23(s, 1H), 11.75(s, 1H), 7.74(m, 1H), 7.42-7.39(m, 1H), 7.25-7.21(m, 1 H), 7.12-7.07(m, 1H), 6.76-6.61(m, 3H), 4.20(s, 2H), 3.75-3.60(m, 4H), 3.07(m, 4H), 2.25(s, 3H). ESI (m / z) 412(MH+), 414(MH+), 410(MH-), 412(MH-).

[0210] 1-17,5-Chloro-3-(2-oxo-2-(4-(p-tolyl)piperazin-1-yl)ethyl)-1H-indole-2-carboxylic acid (YPI-A4849) [ka]

[0211] 1H NMR (300MHz, DMSO-d6) δ11.47(s, 1H), 7.70-7.69(m, 1H), 7.46-7.43(m, 1H), 7.09-7.05(m, 1H), 6.9 9-6.96(m, 2H), 6.75-6.73(m, 2H), 4.32(s, 2H), 3.83-3.56(m, 4H), 2.89-2.79(m, 4H), 2.17(s, 3H). ESI (m / z) 412(MH+), 414(MH+), 410(MH-), 412(MH-).

[0212] 1-18. 3-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-oxoethyl)-5-chloro-1H-indole-2-carboxylic acid (YPI-A4879) [ka]

[0213] 1H NMR (300MHz, DMSO-d6) δ13.22(s, 1H), 11.75(s, 1H), 7.73-7.72(m, 1H), 7.42-7.39( m, 1H), 7.25-7.21(m, 1H), 4.15(s, 2H), 3.60-3.44(m, 4H), 3.32(m, 4H), 1.41(s, 9H). ESI (m / z) 422(MH+), 424(MH+), 420(MH-), 422(MH-).

[0214] 1-19.5-Chloro-3-(2-(4-(2-chloro-6-methylphenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid (YPI-A4880) [ka]

[0215] 1H NMR (300MHz, DMSO-d6) δ13.30(s, 1H), 11.77(s, 1H), 7.77-7.76(m, 1H), 7.45-7.42(m, 1H), 7.27-7.16(m, 3H), 7 .08-7.03(m, 1H), 4.25(q, 2H, J=30.0Hz), 4.04-3.89(m, 2H), 3.51-3.04(m, 4H), 2.83-2.74(m, 2H), 2.29(s, 3H). ESI (m / z) 444(MH-), 446(MH-), 448(MH-).

[0216] 1-20.5-Chloro-3-(2-oxo-2-(4-(phenylpiperazin-1-yl)ethyl)-1H-indole-2-carboxylic acid (YPI-A4881) [ka]

[0217] 1H NMR (300MHz, DMSO-d6) δ11.67(s, 1H), 7.74-7.73(m, 1H), 7.41-7.38(m, 1H), 7.24-7.18(m , 3H), 6.94-6.91(m, 2H), 6.82-6.77(m, 1H), 4.22(s, 2H), 3.77-3.60(m, 4H), 3.07(m, 4H). ESI(m / z)396(MH-), 398(MH-).

[0218] 1-21.5-Chloro-3-(2-(4-(2-ethoxyphenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid (YPI-A4882) [ka]

[0219] 1H NMR (300MHz, DMSO-d6) δ13.33(s, 1H), 11.72(s, 1H), 7.75-7.74(m, 1H), 7.42-7.39(m, 1H), 7.25-7.21(m, 1H), 6.94-6.82(m, 4H), 4.20(s, 2H), 4.03(q, 2H, J=9.0Hz), 3.75-3.60(m, 4H), 2.92(m, 4H), 1.35(t, 3H, J=7.5Hz). ESI(m / z)442(MH+), 444(MH+), 440(MH-), 442(MH-).

[0220] 1-22,5-chloro-3-(2-(3-methyl-4-phenylpiperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid (YPI-A4883) [ka]

[0221] 1H NMR (300MHz, DMSO-d6) δ11.71(s, 1H), 7.76-7.73(m, 1H), 7.43-7.40(m, 1H), 7.24-7.19(m, 3H), 6.92- 6.86(m, 2H), 6.80-6.74(m, 1H), 4.40-3.99(m, 3H), 4.22(s, 2H), 3.55-2.87(m, 4H), 0.88-0.77(m, 3H). ESI (m / z) 412(MH+), 414(MH+), 410(MH-), 412(MH-).

[0222] 1-23.5-Chloro-3-(2-(4-(4-chlorophenyl)-2,2-dimethylpiperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid (YPI-A4884) [ka]

[0223] 1H NMR (300MHz, DMSO-d6) δ13.18(s, 1H), 11.73(s, 1H), 7.73(m, 1H), 7.43-7.40(m, 1H), 7.24-7. 15(m, 3H), 6.71-6.68(m, 2H), 4.15(s, 2H), 3.89-3.87(m, 2H), 3.33-3.25(m, 4H), 1.36(s, 6H). ESI (m / z) 458(MH-), 460(MH-), 462(MH-).

[0224] 1-24.5-Chloro-3-(2-(4-(2-chloro-4-fluorophenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid (YPI-A4885) [ka]

[0225] 1H NMR (300MHz, DMSO-d6) δ13.23(s, 1H), 11.74(s, 1H), 7.75-7.74(m, 1H), 7.44- 7.40(m, 2H), 7.25-7.16(m, 3H), 4.20(s, 2H), 3.78-3.62(m, 4H), 2.89(m, 4H). ESI (m / z) 448(MH-), 450(MH-), 452(MH-).

[0226] 1-25.5-Chloro-3-(2-(4-(2-chloro-5-methoxyphenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid (YPI-A4886) [ka]

[0227] 1H NMR (300MHz, DMSO-d6) δ13.22(s, 1H), 11.75(s, 1H), 7.75(m, 1H), 7.43-7.40(m, 1H), 7.33-7.30(m, 1 H), 7.26-7.22(m, 1H), 6.67-6.64(m, 2H), 4.20(s, 2H), 3.77-3.62(m, 4H), 3.75(s, 3H), 2.93(m, 4H). ESI (m / z) 460(MH-), 462(MH-), 464(MH-).

[0228] 1-26.5-Chloro-3-(2-(4-(2,4-dichlorophenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid (YPI-A4887) [ka]

[0229] 1H NMR (300MHz, DMSO-d6) δ11.70(s, 1H), 7.70-7.69(m, 1H), 7.58-7.55(m, 1H), 7.50-7.49(m, 1H), 7.28- 7.25(m, 1H), 7.08-7.04(m, 1H), 6.98-6.95(m, 1H), 4.36(s, 2H), 3.88-3.58(m, 4H), 2.79-2.67(m, 4H). ESI(m / z)464(MH-), 466(MH-), 468(MH-).

[0230] 1-27.(R)-5-chloro-3-(2-(2-methyl-4-phenylpiperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid (YPI-A4914) [ka]

[0231] 1H NMR (300MHz, DMSO-d6) δ13.19(s, 1H), 11.75(s, 1H), 7.73(m, 1H), 7.42-7.40(m, 1H), 7.22(m, 3H), 6.92-6.79(m, 3H), 4.64-4.03(m, 2H), 4.19(s, 2H), 3.59-2.78(m, 5H), 1.30-1.17(m, 3H). ESI(m / z)412(MH+), 414(MH+), 410(MH-), 412(MH-)

[0232] 1-28.5-Chloro-3-(2-(4-(2,4-difluorophenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid (YPI-A4915) [ka]

[0233] 1H NMR (300MHz, DMSO-d6) δ13.19(s, 1H), 11.75(s, 1H), 7.74(m, 1H), 7.43-7.40(m, 1H), 7. 25-7.18(m, 2H), 7.07-6.97(m, 2H), 4.19(s, 2H), 3.77-3.62(m, 4H), 2.94-2.90(m, 4H). ESI(m / z)432(MH-), 434(MH-).

[0234] 1-29.5-Chloro-3-(2-oxo-2-(4-(3,4,5-trichlorophenyl)piperazin-1-yl)ethyl)-1H-indole-2-carboxylic acid (YPI-A4916) [ka]

[0235] 1H NMR (300MHz, DMSO-d6) δ13.11(s, 1H), 11.75(s, 1H), 7.73(m, 1H), 7.42-7.40( m, 1H), 7.24-7.18(m, 3H), 4.19(s, 2H), 3.73-3.58(m, 4H), 3.27-3.21(m, 4H). ESI (m / z) 498 (MH-), 500 (MH-), 502 (MH-).

[0236] 1-30.5-Chloro-3-(2-(4-(2-fluorophenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid (YPI-A4917) [ka]

[0237] 1H NMR (300MHz, DMSO-d6) δ13.18(s, 1H), 11.74(s, 1H), 7.74(m, 1H), 7.43-7.40( m, 1H), 7.25-7.00(m, 5H), 4.20(s, 2H), 3.78-3.62(m, 4H), 2.98-2.95(m, 4H). ESI (m / z) 416(MH+), 418(MH+), 414(MH-), 416(MH-).

[0238] 1-31.5-Chloro-3-(2-(4-(3-chloro-2-methylphenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid (YPI-A4918) [ka]

[0239] 1H NMR (300MHz, DMSO-d6) δ11.76(s, 1H), 7.75(m, 1H), 7.41(m, 1H), 7.23-7.16(m, 3H), 6.98(m, 1H), 4.20(s, 2H), 3.77-3.63(m, 4H), 2.79-2.32(m, 4H), 1.36-0.80(m, 3H). ESI (m / z) 444(MH-), 446(MH-), 448(MH-).

[0240] 1-32. 3-(2-(4-(4-carboxyphenyl)piperazin-1-yl)-2-oxoethyl)-5-chloro-1H-indole-2-carboxylic acid (YPI-A4919) [ka]

[0241] 1H NMR (300MHz, DMSO-d6) δ12.77(s, 2H), 11.76(s, 1H), 7.81-7.75(m, 3H), 7.43-7.40(m, 1 H), 7.26-7.22(m, 1H), 6.99-6.96(m, 2H), 4.21(s, 2H), 3.79-3.62(m, 4H), 3.34(m, 4H). ESI(m / z)440(MH-), 442(MH-).

[0242] 1-33. 3-(2-(4-(4-acetylphenyl)piperazin-1-yl)-2-oxoethyl)-5-chloro-1H-indole-2-carboxylic acid (YPI-A4920) [ka]

[0243] 1H NMR (300MHz, DMSO-d6) δ13.23(s, 1H), 11.75(s, 1H), 7.83-7.81(m, 2H), 7.74(m, 1H), 7.42-7.40(m, 1 H), 7.24-7.22(m, 1H), 6.98-6.96(m, 2H), 4.20(s, 2H), 3.78-3.62(m, 4H), 3.32(m, 4H), 2.46(s, 3H). ESI(m / z)438(MH-), 440(MH-).

[0244] 1-34,5-Chloro-3-(2-(4-(4-ethoxyphenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid (YPI-A4921) [ka]

[0245] 1H NMR (300MHz, DMSO-d6) δ11.53(s, 1H), 7.72(m, 1H), 7.42-7.40(m, 1H), 7.15-7.13(m, 1H), 6.82-6.74(m , 4H), 4.27(s, 2H), 3.91(q, 2H, J=6.0Hz), 3.79-3.57(m, 4H), 2.85-2.83(m, 4H), 1.27(t, 3H, J=6.0Hz). ESI(m / z)442(MH+), 444(MH+), 440(MH-), 442(MH-).

[0246] 1-35. 3-(2-(4-(4-(tert-butyl)phenyl)piperazin-1-yl)-2-oxoethyl)-5-chloro-1H-indole-2-carboxylic acid (YPI-A4943) [ka]

[0247] 1H NMR (300MHz, DMSO-d6) δ13.23(s, 1H), 11.76(s, 1H), 7.74(m, 1H), 7.42-7.40(m, 1H), 7.24-7. 22(m, 3H), 6.88-6.86(m, 2H), 4.20(s, 2H), 3.75-3.60(m, 4H), 3.05-3.02(m, 4H), 1.24(s, 9H). ESI(m / z)452(MH-), 454(MH-).

[0248] 1-36. 3-(2-(4-(4-(tert-butyl)phenyl)piperazin-1-yl)-2-oxoethyl)-5-methyl-1H-indole-2-carboxylic acid (YPI-A4944) [ka]

[0249] 1H NMR (300MHz, DMSO-d6) δ12.99(s, 1H), 11.41(s, 1H), 7.42(s, 1H), 7.30-7.28(m, 1H), 7.24-7.22(m, 2H), 7.07- 7.05(m, 1H), 6.87-6.85(m, 2H), 4.17(s, 2H), 3.75-3.60(m, 4H), 3.02-3.01(m, 4H), 2.35(s, 3H), 1.23(s, 9H). ESI (m / z) 434 (MH+), 432 (MH-).

[0250] 1-37. 3-(2-(4-(4-(tert-butyl)phenyl)piperazin-1-yl-2-oxoethyl)-5,7-dimethyl-1H-indole-2-carboxylic acid (YPI-A4945) [ka]

[0251] 1H NMR (300MHz, DMSO-d6) δ11.16(s, 1H), 724(m, 2H), 7.21(s, 1H), 6.87(s, 1H), 6.84(m, 2H) ), 4.17(s, 2H), 3.75-3.59(m, 4H), 3.02(m, 4H), 2.46(s, 3H), 2.31(s, 3H), 1.23(s, 9H). ESI (m / z) 448 (MH+), 446 (MH-).

[0252] 1-38. 3-(2-(4-(2,6-dimethylphenyl)piperazin-1-yl)-2-oxoethyl)-5-methyl-1H-indole-2-carboxylic acid (YPI-A4946) [ka]

[0253] 1H NMR (300MHz, DMSO-d6) δ13.04(s, 1H), 11.42(s, 1H), 7.46(s, 1H), 7.31-7.29(m, 1H), 7.09-7.06(m, 1 H), 6.95-6.91(m, 3H), 4.19(s, 2H), 3.66-3.57(m, 4H), 2.89-2.79(m, 4H), 2.37(s, 3H), 2.16(s, 6H). ESI (m / z) 406 (MH+), 404 (MH-).

[0254] 1-39. 3-(2-(4-(2,6-dimethylphenyl)piperazin-1-yl)-2-oxoethyl)-5,7-dimethyl-1H-indole-2-carboxylic acid (YPI-A4947) [ka]

[0255] 1H NMR (300MHz, DMSO-d6) δ13.01(s, 1H), 11.21(s, 1H), 7.28(s, 1H), 6.97-6.91(m, 3H), 6.87(s, 1 H), 4.18(s, 2H), 3.66-3.57(m, 4H), 2.88-2.81(m, 4H), 2.47(s, 3H), 2.33(s, 3H), 2.16(s, 6H). ESI (m / z) 420 (MH+), 418 (MH-).

[0256] 1-40. 3-(2-(4-(2-chloro-6-methylphenyl)piperazin-1-yl)-2-oxoethyl)-5-methyl-1H-indole-2-carboxylic acid (YPI-A4948) [ka]

[0257] 1H NMR (300MHz, DMSO-d6) δ11.37(s, 1H), 7.45(s, 1H), 7.30-7.28(m, 1H), 7.19-7.14(m, 2H), 7.07-7.03(m, 2H) ), 4.20(q, 2H, J=12Hz), 4.00-3.90(m, 2H), 3.18-3.02(m, 4H), 2.81-2.70(m, 2H), 2.36(s, 3H), 2.27(s, 3H). ESI (m / z) 426(MH+), 428(MH+), 424(MH-), 426(MH-).

[0258] 1-41. 3-(2-(4-(2-chloro-6-methylphenyl)piperazin-1-yl)-2-oxoethyl)-5,7-dimethyl-1H-indole-2-carboxylic acid (YPI-A4949) [ka]

[0259] 1H NMR (300MHz, DMSO-d6) δ12.97(s, 1H), 11.20(s, 1H), 7.27(s, 1H), 7.20-7.15(m, 2H), 7.07-7.02(m, 1H), 6.87(s, 1H), 4.18(q, 2H, J=15Hz), 3.96-3.89(m, 2H), 3.22-3.06(m, 4H), 2.81-2.73(m, 2H), 2.47(s, 3H), 2.33(s, 3H), 2.28(s, 3H). ESI (m / z) 440(MH+), 442(MH+), 438(MH-), 440(MH-).

[0260] 1-42. 3-(2-(4-(2-chloro-6-methylphenyl)piperazin-1-yl)-2-oxoethyl)-5-fluoro-1H-indole-2-carboxylic acid (YPI-A4963) [ka]

[0261] 1H NMR (300MHz, DMSO-d6) δ13.23(s, 1H), 11.67(s, 1H), 7.47-7.39(m, 2H), 7.20-7.03(m, 4H), 4.23(q, 2H, J=30Hz), 3.50-3.47(m, 2H), 3.22-3.02(m, 4H), 2.82-2.73(m, 2H), 2.28(s, 3H). ESI(m / z)430(MH+), 432(MH+), 428(MH-), 430(MH-).

[0262] 1-43. 3-(2-(4-(2,6-dimethylphenyl)piperazin-1-yl)-2-oxoethyl)-5-fluoro-1H-indole-2-carboxylic acid (YPI-A4964) [ka]

[0263] 1H NMR (300MHz, DMSO-d6) δ13.12(s, 1H), 11.66(s, 1H), 7.46-7.40(m, 2H), 7.14-7.09(m, 1 H), 6.95-6.90(m, 3H), 4.20(s, 2H), 3.65-3.57(m, 4H), 2.88-2.81(m, 4H), 2.16(s, 6H). ESI (m / z) 410 (MH+), 408 (MH-).

[0264] 1-44. 3-(2-(4-(4-(tert-butyl)phenyl)piperazin-1-yl)-2-oxoethyl)-5-fluoro-1H-indole-2-carboxylic acid (YPI-A4965) [ka]

[0265] 1H NMR (300MHz, DMSO-d6) δ13.21(s, 1H), 11.66(s, 1H), 7.45-7.38(m, 2H), 7.25-7.22(m, 2H), 7. 13-7.07(m, 1H), 6.88-6.85(m, 2H), 4.18(s, 2H), 3.75-3.61(m, 4H), 3.03(m, 4H), 1.24(s, 9H). ESI (m / z) 438 (MH+), 436 (MH-).

[0266] 1-45. 3-(2-(4-([1,1'-biphenyl]-4-yl)piperazin-1-yl)-2-oxoethyl)-5-chloro-1H-indole-2-carboxylic acid (YPI-A4966) [ka]

[0267] 1H NMR (300MHz, DMSO-d6) δ11.76(s, 1H), 7.75(m, 1H), 7.62-7.53(m, 4H), 7.43-7.39(m, 3 H), 7.28-7.22(m, 2H), 7.05-7.02(m, 2H), 4.22(s, 2H), 3.78-3.63(m, 4H), 3.16(m, 4H). ESI (m / z) 474(MH+), 476(MH+), 472(MH-), 474(MH-).

[0268] [Example 2] Confirmation of pendrin inhibitory activity of new compounds

[0269] 2-1.Cell culture Chinese hamster ovary (CHO)-K1 cells were cultured in DMEM medium containing 10% fetal bovine serum (FBS), 100 units / ml penicillin, and 100 μg / ml streptomycin. CHO-K1 cells were stably transfected with pcDNA3.1 encoding the halide sensor YFP-H148Q / I152L / F46L and human wild-type (WT) pendrin.

[0270] 2-2. Compound Pendrin Cl - / I - Exchange inhibitory activity evaluation 2 x 10 CHO-K1 cells expressing human WT pendrin and YFP-F46L / H148Q / I152L per well 4 Cells were plated into 96-well microplates at a density of 1000 μL each and cultured for 48 hours. Each well of the cell-cultured 96-well plate was washed twice with 200 μL of PBS and filled with 50 μL of HEPES buffer solution (140 mM NaCl, 5 mM KCl, 1 mM MgCl, 1 mM CaCl, 10 mM glucose, and 10 mM HEPES (pH 7.4)). Test compounds (1 μL) were added at final concentrations of 1, 3, 10, 30, and 100 μM. After 10 minutes of incubation at 37°C, the 96-well plate was placed in a FLUOstar Omega microplate reader (BMG Labtech, Ortenberg, Germany) for fluorescence analysis. Pendrin-mediated I was measured by continuously recording fluorescence (400 ms per point) for 1 second (baseline). -After analyzing each well individually for iodide influx, 50 μL of NaI-substituted HEPES buffer solution (NaI was used instead of NaCl) was added using a liquid injector in 1 s, and YFP fluorescence was recorded for 5 s. The initial iodide influx rate was determined from the initial slope of fluorescence by nonlinear regression after iodide injection.

[0271] The pendrin inhibitory activity (% inhibition) of the 45 compounds of Example 1 at different concentrations is shown in Table 1.

[0272] [Table 1]

[0273] [Example 3] Confirmation of the function of new compounds as pendrin inhibitors

[0274] 3-1.Cell culture Chinese hamster ovary (CHO)-K1 cells were cultured in DMEM medium containing 10% fetal bovine serum (FBS), 100 units / ml penicillin, and 100 μg / ml streptomycin. CHO-K1 cells were stably transfected with pcDNA3.1 encoding the halide sensor YFP-H148Q / I152L / F46L and human wild-type (WT) pendrin.

[0275] 3-2. Pendrin Cl - / I - Exchange activity evaluation 2 x 10 CHO-K1 cells expressing human WT pendrin and YFP-F46L / H148Q / I152L per well 4Cells were plated into 96-well microplates at a density of 1000 μL each and cultured for 48 hours. Each well of the cell-cultured 96-well plate was washed twice with 200 μL of PBS and filled with 50 μL of HEPES buffer solution (140 mM NaCl, 5 mM KCl, 1 mM MgCl, 1 mM CaCl, 10 mM glucose, and 10 mM HEPES (pH 7.4)). Test compounds (1 μL) were added to a final concentration of 50 μM. After 10 minutes of incubation at 37°C, the 96-well plate was placed in a FLUOstar Omega microplate reader (BMG Labtech, Ortenberg, Germany) for fluorescence analysis. Pendrin-mediated I was measured by continuously recording fluorescence (400 ms per point) for 1 second (baseline). - After analyzing each well individually for iodide influx, 50 μL of NaI-substituted HEPES buffer solution (NaI was used instead of NaCl) was added using a liquid injector in 1 s, and YFP fluorescence was recorded for 5 s. The initial iodide influx rate was determined from the initial slope of fluorescence by nonlinear regression after iodide injection.

[0276] As a result, as shown in Figure 1, both the novel pendrin inhibitors YPI-H05 and YPI-A4948 inhibited pendrin-induced Cl - / I - Anion exchange was inhibited in a concentration-dependent manner. 50 =570nM) was compared with YPI-05 (IC 50 = 2.7 μM), showing approximately 5-fold higher efficacy.

[0277] [Example 4] Confirmation of the effect of new compounds on SLC26A3 activity

[0278] 4-1.Cell culture LN-215 cells were cultured in DMEM medium containing 10% fetal bovine serum (FBS), 100 units / ml penicillin, and 100 μg / ml streptomycin. LN-215 cells were stably transfected with pcDNA3.1 encoding the halide sensor YFP-H148Q / I152L / F46L and human wild-type (WT)-SLC26A3.

[0279] 4-2.SLC26A3 Cl - / I - Exchange activity evaluation 2 × 10 LN-215 cells expressing human WT SLC26A3 and YFP-F46L / H148Q / I152L per well 4 Cells were plated into 96-well microplates at a density of 100 μL each and cultured for 48 hours. Each well of the cultured 96-well plate was washed twice with 200 μL of PBS and filled with 50 μL of HEPES buffer solution (140 mM NaCl, 5 mM KCl, 1 mM MgCl, 1 mM CaCl, 10 mM glucose, and 10 mM HEPES (pH 7.4)). Test compounds (1 μL) were added to a final concentration of 100 μM. After 10 minutes of incubation at 37°C, the 96-well plate was placed in a FLUOstar Omega microplate reader (BMG Labtech, Ortenberg, Germany) for fluorescence analysis. SLC26A3-mediated I was measured by continuously recording fluorescence (400 ms per point) for 1 second (baseline). - After analyzing each well individually for iodide influx, 50 μL of NaI-substituted HEPES buffer solution (NaI was used instead of NaCl) was added using a liquid injector in 1 s, and YFP fluorescence was recorded for 5 s. The initial iodide influx rate was determined from the initial slope of fluorescence by nonlinear regression after iodide injection.

[0280] The novel pendrin inhibitors YPI-H05 and YPI-A4948 inhibit Cl-mediated cleavage by SLC26A3, the anion exchanger closest to pendrin (SLC26A4) in the SLC26A family. - / I -As a result of examining the effect on anion exchange, as shown in Figure 2, YPI-H05 (IC 50 = 3.8 μM) inhibited pendrin and SLC26A3 with similar potency. However, YPI-A4948 (IC 50 = 11.4 μM) was approximately 18-fold more selective for pendrin than SLC26A3. Therefore, YPI-A4948 is a highly selective pendrin inhibitor.

[0281] [Example 5] Confirmation of the effects of new compounds on the activity of SLC26A9, CFTR, and ANO1

[0282] 5-1.Cell culture Chinese hamster ovary (CHO)-K1 or LN-215 cells were cultured in DMEM / F-12 medium containing 10% fetal bovine serum (FBS), 100 units / ml penicillin, and 100 μg / ml streptomycin. CHO-K1 or LN-215 cells were stably transfected with pcDNA3.1 encoding the halide sensor YFP-H148Q / I152L / F46L and human wild-type (WT)-SLC26A9. Fisher rat thyroid (FRT) cells stably transfected with YFP-H148Q / I152L / F46L and human wild-type (WT)-CFTR or human wild-type (WT)-ANO1 were cultured in DMEM / F-12 medium containing 10% fetal bovine serum (FBS), 100 units / ml penicillin, and 100 μg / ml streptomycin.

[0283] 5-2. Activity evaluation of SLC26A9, CFTR, and ANO1 LN-215 cells expressing human WT SLC26A9 and YFP-F46L / H148Q / I152L and 2 × 10 FRT cells expressing human WT CFTR or ANO1 and YFP-F46L / H148Q / I152L were cultured at 2 × 10 per well. 4Cells were plated into 96-well microplates at a density of 100 μL each and cultured for 48 hours. Each well of the cultured 96-well plate was washed twice with 200 μL of PBS and filled with 50 μL of HEPES buffer solution (140 mM NaCl, 5 mM KCl, 1 mM MgCl, 1 mM CaCl, 10 mM glucose, and 10 mM HEPES (pH 7.4)). Test compounds (1 μL) were added to a final concentration of 100 μM. For CFTR activity assessment, 10 μM forskolin was added to activate CFTR. After 10 minutes of incubation at 37°C, the 96-well plate was placed in a FLUOstar Omega microplate reader (BMG Labtech, Ortenberg, Germany) for fluorescence analysis. SLC29A9-mediated I activity was assessed by continuously recording fluorescence (400 ms per point) for 1 s (baseline). - After analyzing each well individually for influx of CFTR, 50 μL of NaI-substituted HEPES buffer solution (NaI was used instead of NaCl) was added using a liquid injector in 1 s, and YFP fluorescence was recorded for 6 s. CFTR-mediated I was assessed by continuously recording fluorescence (400 ms per point) for 2 s (baseline) to assess CFTR activity. - After analyzing each well individually for influx of I, 50 μL of NaI-substituted HEPES buffer solution (NaI was used instead of NaCl) was added using a liquid injector in 2 seconds, and YFP fluorescence was recorded for 8 seconds. ANO1-mediated I was measured by continuously recording fluorescence (400 ms per point) for 1 second (baseline) to assess ANO1 activity. - After analyzing each well individually for iodide influx, 50 μL of NaI-substituted HEPES buffer solution (NaI was used instead of NaCl) containing ATP (200 μM) was added using a liquid injector in 1 s, and YFP fluorescence was recorded for 6 s. The initial iodide influx rate was determined from the initial slope of fluorescence by nonlinear regression after iodide injection.

[0284] We investigated the effects of the novel pendrin inhibitors YPI-H05 and YPI-A4948 on SLC26A9, a member of the SLC26A family, and the representative anion transporters CFTR and ANO1. As shown in Figure 3, both YPI-H05 and YPI-A4948 completely inhibited SLC26A9 activity at 100 μM. For CFTR, YPI-H05 inhibited approximately 50% of activity at 100 μM, while YPI-A4948 had almost no effect on CFTR activity at 100 μM. For ANO1, YPI-H05 inhibited approximately 80% of activity at 30 μM, while YPI-A4948 only weakly inhibited ANO1 activity at 30 μM. Therefore, we confirmed that YPI-A4948 is a highly selective pendrin-specific inhibitor.

[0285] [Example 6] Confirmation of the effect of new compounds on cell viability

[0286] 6-1.Cell culture Chinese hamster ovary (CHO)-K1 cells were cultured in DMEM medium containing 10% fetal bovine serum (FBS), 100 units / ml penicillin, and 100 μg / ml streptomycin.

[0287] 6-2. Cell viability measurement Cell viability was measured using the CellTiter 96® AQueous One Solution Cell Proliferation Assay Kit (Promega, Madison, WI, USA). CHO-K1 cells were cultured in 96-well plates for 24 hours in medium supplemented with 10% FBS, then treated with compound or vehicle. After 24 hours, the medium was completely removed and MTS assay was performed according to the manufacturer's protocol. Formazan absorbance was measured at 490 nm using an Infinite M200 microplate reader (Tecan, Austria).

[0288] The cytotoxicity of the novel pendrin inhibitors YPI-H05 and YPI-A4948 was assessed using CHO-K1 cells. As shown in Figure 4, neither YPI-H05 nor YPI-A4948 exhibited cytotoxicity at 30 μM. Even at 100 μM, YPI-H05 and YPI-A4948 showed a change in viability of less than 10%. Therefore, YPI-H05 and YPI-A4948 were confirmed to have very low cytotoxicity.

[0289] [Example 7] Confirmation of the recovery function of ASL damaged by IL-4, a novel compound

[0290] 7-1.Cell culture For differentiation of primary cultures of human nasal epithelial cells, 2 x 10 cells 5 cells / cm 2 The cells were cultured at a density of 1000 μm in transwells (Transwell, Costar Co., Cambridge, MA). They were cultured in a 1:1 mixture of Dulbecco's modified Eagle's medium (Lonza) and bronchial epithelial growth medium (Lonza) supplemented with the following growth factors, with the medium replaced every 2–3 days. The cells were cultured submerged in the medium for the first 7 days, and then the top of the transwell was exposed to air for the rest of the culture period. After establishing an air-liquid interface (ALI), the cells were cultured for 21 days to allow differentiation. The cell culture device was maintained at 5% CO2 and 37°C throughout the culture process.

[0291] 7-2. Airway surface liquid (ASL) volume assessment Vehicle, IL-4 (10 ng / ml), and YPI-H05 (30 μM) were added to the basal fluid of transwells containing differentiated NHE cells expressing normal pendrin. The cells were then cultured for 48 hours in an incubator at 37°C under 5% CO2. After incubation, a 10 mm diameter circular filter paper was placed in the luminal side of the transwell and left for 10 seconds to absorb the airway surface liquid. The volume change of the airway surface liquid was measured using a precision electronic balance based on the increased weight of the filter paper.

[0292] As a result, as shown in Figure 5, the novel pendrin inhibitor YPI-H05 significantly increased the volume of airway surface liquid (ASL), which was significantly reduced by pendrin expression upregulated by IL-4 treatment in differentiated respiratory epithelial cells (HNE cells). This confirmed that YPI-H05 is a pendrin inhibitor that can exert its pharmacological effects on human respiratory epithelial cells.

[0293] [Example 8] Efficacy of novel compounds in LPS-induced acute lung injury model

[0294] Wild-type male C57BL / 6N mice, 8-10 weeks old and weighing 20-24 g, were purchased from Orient Bio Co., Ltd. (Seongnam, Korea). As shown in Table 2, the mice were divided into five groups and treated with the samples according to the administration schedule shown in Figure 6.

[0295] [Table 2]

[0296] Specifically, LPS (Escherichia coli O111:B4, Sigma) (10 mg / kg) dissolved in 50 μL PBS was administered intranasally (intranasally). Control mice received 50 μL of sterile PBS intranasally. For pretreatment, YPI-A4948 dissolved in 50 μL DMSO was administered intraperitoneally (ip) at doses of 0.1 mg / kg, 1.0 mg / kg, and 10 mg / kg, respectively, 1 hour before LPS inhalation. For posttreatment, YPI-A4948 was administered intraperitoneally at doses of 0.1 mg / kg, 1.0 mg / kg, and 10 mg / kg, respectively, 12 hours after LPS inhalation. Vehicle control groups received 50 μL DMSO intraperitoneally at the same time points as pretreatment and posttreatment. Mice were euthanized 48 hours after LPS inhalation, and the lungs were removed.

[0297] As a result, as shown in Figure 7, the mice in the group treated with YPI-A4948 before and after LPS inhalation had significantly reduced total cell counts and protein concentration levels in BALF compared with the mice in the group treated with vehicle before and after LPS inhalation.

[0298] We also performed BALF cytospin staining and H&E lung tissue staining to observe the extent of lung injury. As shown in Figure 8, mice treated with YPI-A4948 before and after LPS inhalation showed significantly reduced lung injury compared with mice treated with vehicle before and after LPS inhalation.

[0299] [Example 9] Confirmation of diuretic effect of new compounds

[0300] Wild-type male C57BL / 6N mice, 8 weeks old and weighing 20-24 g, were purchased from Orient Bio Inc. (Seongnam, Korea). Prior to the experiment, water and food were restricted, and bladder stimulation was used to induce urination. YPI-A4948 dissolved in DMSO at a stock concentration of 100 mg / ml was intraperitoneally injected twice, 3 hours apart, to final concentrations of 0.001 mg / kg / 100 ul, 0.005 mg / kg / 100 ul, 0.001 mg / kg / 100 ul, 0.05 mg / kg / 100 ul, 0.1 mg / kg / 100 ul, 0.5 mg / kg / 100 ul, and 1 mg / kg / 100 ul (1% DMSO + DW). Six hours later, urine output was measured in each group.

[0301] As a result, as shown in FIG. 9, when YPI-A4948 was administered alone at various concentrations, a diuretic effect was observed from 0.01 mg / kg, confirming the potential of pendrin inhibitors as diuretics.

[0302] [Example 10] Confirmation of diuretic effect of new compounds in heart failure models

[0303] 10-1. Establishment of a mouse model of heart failure Wild-type male C57BL / 6N mice, 8 weeks old and weighing 20-24 g, were purchased from Orient Bio Inc. (Seongnam, Korea). Cardiac ultrasound examination was performed before adriamycin administration. As shown in Figure 10, 5 mg / kg adriamycin was then administered intraperitoneally once a week for a total of 5 weeks, and the mice's body weight before administration was measured. After 5 weeks, cardiac ultrasound examination was performed to confirm whether heart failure had been induced.

[0304] As shown in Figure 11, the left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (FS) were significantly reduced after administration of adriamycin, verifying that a heart failure model had been established.

[0305] 10-2. Confirmation of diuretic effect by treatment with new compounds YPI-A4948 was dissolved in DMSO at a stock concentration of 100 mg / ml to prepare final concentrations of 0.1 mg / kg / 100 μl, 0.5 mg / kg / 100 μl, and 1 mg / kg / 100 μl (1% DMSO + DW). Mice with heart failure were placed in metabolic cages and water and food restricted. Before administration, the bladders of the mice were stimulated, and YPI-A4948 was administered intraperitoneally twice, once every 3 hours for 6 hours. In other groups, YPI-A4948 was administered with 0.5 mg / kg and 1 mg / kg furosemide to confirm the effects of coadministration with other diuretics. Urine was collected from each group after 6 hours.

[0306] As shown in Figure 12, when YPI-A4948 was administered alone at various concentrations, a diuretic effect was observed at 1 mg / kg, and when 0.5 mg / kg YPI-A4948 was coadministered with 1.0 mg / kg furosemide, an additive effect was observed, confirming the potential of pendrin inhibitors as diuretics in a mouse model of heart failure.

[0307] [Example 11] Effect of YPI-A4948 on pendrin activity in human alveolar epithelial cells (hAEC)

[0308] Figure 13a shows the change in YFP fluorescence intensity when pendrin-overexpressing human alveolar epithelial cells (hAECs) were treated with a novel pendrin inhibitor, YPI-A4948, at concentrations ranging from 0.3 μM to 30 μM, compared to before YPI-A4948 treatment. - / SCN - Measure human wild-type pendrin-mediated Cl exchange capacity - / SCN - Exchange activity IC 50The concentration of pendrin in the IL-16 cells was confirmed to be 0.9 μM. Furthermore, as shown in Figure 13b, after pretreatment with YPI-A4948 in vitro, the protein expression of SLC26A4 (pendrin), which was overexpressed and induced by LPS treatment, was dose-dependently suppressed by YPI-A4948. However, the mRNA expression of pendrin, which was increased by LPS in vitro, was not statistically significantly reduced by YPI-A4948.

[0309] [Example 12] Effect of pendrin inhibition on LPS-induced lung injury in mice

[0310] Lipopolysaccharide (LPS, 200 μg / head) dissolved in 50 μL PBS was intranasally instilled into C57BL / 6N mice. YPI-A4948 (1 and 10 μg / kg) was administered intravenously twice, 6 and 12 hours after LPS instillation. Mice were euthanized 24 hours after LPS inhalation, and the lungs were removed.

[0311] Immune cell capture was confirmed by injecting 1 mL of PBS into the excised lungs and then re-extracting the PBS to obtain bronchoalveolar lavage fluid (BALF). Lung injury parameters were measured by ELISA after lung tissue lysis. Pendrin protein expression levels were confirmed by Western blot analysis and quantified using a shadowmeter (mean ± SEM, n = 3 per group). Pendrin mRNA levels were extracted from lung tissue and determined by real-time quantitative PCR (mean ± SEM, n = 3 per group). IL-1β, MIP-2, IL-6, and TNF-α levels were measured by ELISA in lung tissue lysates (mean ± SEM, n = 4-7 mice per group).

[0312] As shown in Figure 14a, after LPS inhalation, mice treated with YPI-A4948 showed significantly reduced pendrin mRNA and protein, total BALF cell count, and BALF protein levels compared to mice treated with LPS alone. Furthermore, YPI-A4948 showed comparable efficacy to the positive control group, dexamethasone (3 mg / kg), at a dose 300-3000 times lower.

[0313] Furthermore, as shown in Figure 14b, the pulmonary inflammatory cytokines IL-1β, IL-6, MIP-2, and TNF-α were statistically significantly reduced after treatment of mice with YPI-A4948.

[0314] [Example 13] The role of anions in LPS-induced lung injury model treated with YPI-A4948

[0315] We investigated the effect of YPI-A4948 on the efficacy of LPS-induced lung injury in mice in response to anion supply.

[0316] Specifically, lipopolysaccharide (LPS, 200 μg / head) dissolved in 50 μL PBS was instilled intranasally, and 6 hours after LPS inhalation, YPI-A4948 was administered intravenously once at 5 μg / kg. - , HCO3 - , SCN - Anions were administered intranasally. 24 hours after LPS inhalation, the animals were euthanized, and the lungs were removed. Lung tissue was then subjected to H&E staining to assess the extent of lung injury. Bronchoalveolar lavage fluid (BALF) was extracted as described in Example 12 to measure total cell counts, BALF protein concentration, and cytopathological staining using Diff-Quik Stain. Data presented are mean ± SEM (n = 3-5 mice per group). Scale bars for H&E and cytopathological staining images taken at 400x magnification are 50 μm.

[0317] As a result, as shown in Figures 15a and 15b, the lung injury-improving effect of YPI-A4948 was only enhanced by SCN among the three anions administered. - This indicates that SCN is attenuated by LPS-induced lung injury. - We confirmed that anions induce lung injury via pendrin and play an important role in the underlying mechanisms. We confirmed that administration of YPI-A4948 reduced lung injury, and SCN - The association with anions was demonstrated.

[0318] [Example 14] Confirmation of the effects of new compounds on the activity of SLC26A3, SLC26A6, CFTR, and ANO1

[0319] For SLC26A3 and SLC26A6, the transporter proteins and halide-sensitive YFP were expressed in LN-215 cells, and the activity of each transporter protein was measured. For CFTR, WT-CFTR and halide-sensitive YFP were expressed in CHO-K1 cells, and the activity of CFTR was measured. For ANO1, ANO1 and halide-sensitive YFP were expressed in FRT cells, and the activity of CFTR was measured. For CFTR, the adenylyl cyclase activator forskolin was treated at 10 μM for 10 minutes to increase intracellular cyclic AMP and activate CFTR, and then the assay was performed. For ANO1, ATP was immediately added at 100 μM to activate intracellular Ca. 2+ The other procedures were the same as in Example 5.

[0320] The results are shown in Figure 16. The effects of the novel pendrin inhibitor YPI-A4948 on SLC26A4 (Pendrin) and its related proteins, SLC26A3 and SLC26A6 (A6), in the SLC26A family, as well as on representative anion transporters, CFTR and ANO1 anion channels, were examined. As shown in Figure 16, YPI-A4948 did not inhibit the activity of SLC26A6 at all, but showed only an IC 50 The Cl concentration of SLC26A4 (Pendrin) was confirmed to be 10.6 μM. - / I - Exchange IC 50 This is considered to be a significant difference compared to 0.55 μM. In the case of CFTR, YPI-A4948 had almost no effect on CFTR activity at 100 μM. In the case of ANO1 activity, YPI-A4948 weakly inhibited ANO1 activity at 30 μM. Therefore, YPI-A4948 was confirmed to be a highly selective pendrin-specific inhibitor.

Claims

1. A compound selected from the group consisting of the following compounds (1) to (28) and (30) to (40), its E- or Z-isomer, its optical isomer, its pharmaceutically acceptable salt, its solvate, or a mixture of two isomers thereof: (1) 5-chloro-3-(2-oxo-2-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)-1H-indole-2-carboxylic acid; (2) 5-chloro-3-(2-oxo-2-(4-(2-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)-1H-indole-2-carboxylic acid; (3) 5-chloro-3-(2-(4-(2,6-dimethylphenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (4) 5-chloro-3-(2-(4-(2,4-dimethylphenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (5) 5-chloro-3-(2-(4-(3-methoxyphenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (6) 5-chloro-3-(2-(4-(2-chlorophenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (7) 5-chloro-3-(2-(4-(4-chlorophenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (8) 3-(2-(4-(2-bromophenyl)piperazin-1-yl)-2-oxoethyl)-5-chloro-1H-indole-2-carboxylic acid; (9) 3-(2-(4-(3-bromophenyl)piperazin-1-yl)-2-oxoethyl)-5-chloro-1H-indole-2-carboxylic acid; (10) 3-(2-(4-(4-bromophenyl)piperazin-1-yl)-2-oxoethyl)-5-chloro-1H-indole-2-carboxylic acid; (11) 5-chloro-3-(2-oxo-2-(4-(o-tolyl)piperazin-1-yl)ethyl)-1H-indole-2-carboxylic acid; (12) 5-chloro-3-(2-oxo-2-(4-(m-tolyl)piperazin-1-yl)ethyl)-1H-indole-2-carboxylic acid; (13) 5-chloro-3-(2-oxo-2-(4-(p-tolyl)piperazin-1-yl)ethyl)-1H-indole-2-carboxylic acid; (14) 3-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-oxoethyl)-5-chloro-1H-indole-2-carboxylic acid; (15) 5-chloro-3-(2-(4-(2-chloro-6-methylphenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (16) 5-chloro-3-(2-(4-(2-ethoxyphenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (17) 5-chloro-3-(2-(3-methyl-4-phenylpiperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (18) 5-chloro-3-(2-(4-(4-chlorophenyl)-2,2-dimethylpiperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (19) 5-chloro-3-(2-(4-(2-chloro-4-fluorophenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (20) 5-chloro-3-(2-(4-(2-chloro-5-methoxyphenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (21) 5-chloro-3-(2-(4-(2,4-dichlorophenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (22) (R)-5-chloro-3-(2-(2-methyl-4-phenylpiperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (23) 5-chloro-3-(2-(4-(2,4-difluorophenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (24) 5-chloro-3-(2-oxo-2-(4-(3,4,5-trichlorophenyl)piperazin-1-yl)ethyl)-1H-indole-2-carboxylic acid; (25) 5-chloro-3-(2-(4-(2-fluorophenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (26) 5-chloro-3-(2-(4-(3-chloro-2-methylphenyl)piperazin-1-yl)-2-oxoethyl)-1H-indole-2-carboxylic acid; (27) 3-(2-(4-(4-carboxyphenyl)piperazin-1-yl)-2-oxoethyl)-5-chloro-1H-indole-2-carboxylic acid; (28) 3-(2-(4-(4-acetylphenyl)piperazin-1-yl)-2-oxoethyl)-5-chloro-1H-indole-2-carboxylic acid; (30) 3-(2-(4-(4-(tert-butyl)phenyl)piperazin-1-yl)-2-oxoethyl)-5-chloro-1H-indole-2-carboxylic acid; (31) 3-(2-(4-(4-(tert-butyl)phenyl)piperazin-1-yl)-2-oxoethyl)-5-methyl-1H-indole-2-carboxylic acid; (32) 3-(2-(4-(4-(tert-butyl)phenyl)piperazin-1-yl)-2-oxoethyl)-5,7-dimethyl-1H-indole-2-carboxylic acid; (33) 3-(2-(4-(2,6-dimethylphenyl)piperazin-1-yl)-2-oxoethyl)-5-methyl-1H-indole-2-carboxylic acid; (34) 3-(2-(4-(2,6-dimethylphenyl)piperazin-1-yl)-2-oxoethyl)-5,7-dimethyl-1H-indole-2-carboxylic acid; (35) 3-(2-(4-(2-chloro-6-methylphenyl)piperazin-1-yl)-2-oxoethyl)-5-methyl-1H-indole-2-carboxylic acid; (36) 3-(2-(4-(2-chloro-6-methylphenyl)piperazin-1-yl)-2-oxoethyl)-5,7-dimethyl-1H-indole-2-carboxylic acid; (37) 3-(2-(4-(2-chloro-6-methylphenyl)piperazin-1-yl)-2-oxoethyl)-5-fluoro-1H-indole-2-carboxylic acid; (38) 3-(2-(4-(2,6-dimethylphenyl)piperazin-1-yl)-2-oxoethyl)-5-fluoro-1H-indole-2-carboxylic acid; (39) 3-(2-(4-(4-(tert-butyl)phenyl)piperazin-1-yl)-2-oxoethyl)-5-fluoro-1H-indole-2-carboxylic acid; and (40) 3-(2-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-2-oxoethyl)-5-chloro-1H-indole-2-carboxylic acid.

2. A pharmaceutical composition for preventing or treating a respiratory disease, comprising the compound according to claim 1, its E- or Z-isomer, its optical isomer, a pharmaceutically acceptable salt thereof, a solvate thereof, or a mixture of two such isomers as an active ingredient.

3. The pharmaceutical composition of claim 2, wherein the respiratory disease is an inflammatory airway disease.

4. 4. The pharmaceutical composition of claim 3, wherein the inflammatory airway disease is one or more selected from the group consisting of asthma, acute or chronic bronchitis, allergic rhinitis, acute respiratory infection, acute upper respiratory infection, cystic fibrosis, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), and chronic obstructive pulmonary disease (COPD).

5. The pharmaceutical composition of claim 2, wherein the active ingredient acts as a pendrin inhibitor.

6. 3. The pharmaceutical composition of claim 2, wherein the active ingredient preserves or increases the volume of airway surface liquid (ASL).

7. The pharmaceutical composition of claim 2 further comprising other pharmaceutical ingredients.

8. A health functional food for preventing or improving respiratory diseases, comprising the compound according to claim 1, its E- or Z-isomer, its optical isomer, a pharmaceutically acceptable salt thereof, a solvate thereof, or a mixture of these two isomers as an active ingredient.

9. A diuretic pharmaceutical composition comprising the compound according to claim 1, its E- or Z-isomer, its optical isomer, a pharmaceutically acceptable salt thereof, a solvate thereof, or a mixture of the two isomers thereof as an active ingredient.

10. 10. The pharmaceutical composition of claim 9, which is co-administered with another diuretic.

11. The pharmaceutical composition of claim 10, wherein the other diuretic is furosemide, and the pharmaceutical composition and the furosemide are administered in a weight ratio of 1:

10.

12. A diuretic health functional food composition comprising the compound according to claim 1, its E- or Z-isomer, its optical isomer, a pharmaceutically acceptable salt thereof, a solvate thereof, or a mixture of the two isomers thereof as an active ingredient.

13. 10. A method for preventing, ameliorating, or treating a respiratory disease, comprising administering to a non-human individual the compound of claim 1, its E- or Z-isomer, its optical isomer, a pharmaceutically acceptable salt thereof, a solvate thereof, or a mixture of the two isomers thereof.

14. 10. A method of diuresis, comprising administering to a non-human individual the compound of claim 1, its E- or Z-isomer, its optical isomer, its pharmaceutically acceptable salt, its solvate, or a mixture of the two isomers.

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