Composition for preventing and treating renal failure (RF)

Abstract

The present invention relates to a pharmaceutical composition for preventing and treating renal failure, comprising a compound represented by formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient; methods of preventing and treating renal failure using the compounds; the use of said compounds for the prevention and treatment of renal failure; and an application of the compound in preparation of drugs for preventing and treating renal failure.

Description

Technical Field

[0001] The present disclosure relates to a pharmaceutical composition for preventing and treating renal failure, the pharmaceutical composition comprising a compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient; a method for preventing and treating renal failure using the compound; the use of the compound for preventing and treating renal failure; and the use of the compound in the preparation of a drug for preventing and treating renal failure. Background Art

[0002] Renal failure (RF) can be classified into acute renal failure (also known as acute kidney injury) and chronic renal failure (also known as chronic kidney disease), in a state where kidney function cannot proceed normally.

[0003] Acute renal failure has many etiologies and can be divided into three types. First, there is no problem with the kidneys themselves, but there is a situation where the blood supply to the kidneys decreases due to the overall decline of the body's functions. Secondly, there is a situation where urine cannot be produced due to abnormalities in the kidneys themselves, and finally, the urinary tract and bladder that excrete urine are blocked. Chronic renal failure is caused by polycystic kidney disease, glomerulonephritis, diabetes, hypertension, etc., and refers to a continuous decline in kidney function for at least three months. Chronic renal failure is divided into five stages according to the degree of kidney injury and functional decline. If not properly treated, chronic renal failure will deteriorate to end-stage renal failure.

[0004] The treatment of renal failure lies in preventing kidney diseases that cause continuous degradation of kidney function and reducing the incidence of end-stage renal failure by reducing the disease progression rate in cases where kidney function begins to deteriorate chronically. To treat the diseases that cause renal failure, therapeutic agents for hypertension or diabetes are used, but in many cases, the primary disease cannot be identified because the disease has progressed severely (Lancet 2012; 379: 165 - 180, Kidney Int 2012; 81: 351 - 362).

[0005] Therefore, there is no appropriate treatment for renal failure. Since steroids and immunosuppressive drugs can cause a decline in kidney function, there is still a highly unmet medical need for the development of novel drugs capable of preventing and treating renal failure.

[0006] Prior Art References

[0007] Patent Documents

[0008] (Patent Document 1) Korean Unexamined Patent Publication No. 10 - 2017 - 0017792

[0009] Non-Patent Documents

[0010] (Non - Patent Document 1) Hou Qing et al., Front Pharmacol. July 14, 2022; 13:938391

[0011] (Non - Patent Document 2) Seung Seob Son et al., Sci Rep. January 26, 2021; 11(1):2191

[0012] (Non - Patent Document 3) Xingying Chen et al., Am J Physiol Renal Physiol. December 2020 Summary of the Invention

[0013] Technical Problem

[0014] The present disclosure can provide a pharmaceutical composition for preventing and treating renal failure, the pharmaceutical composition containing a compound represented by formula I, its optical isomer or its pharmaceutically acceptable salt as an active ingredient.

[0015] The present disclosure can provide a method for preventing and treating renal failure, which includes administering to an individual a compound represented by the above formula I, its optical isomer or its pharmaceutically acceptable salt.

[0016] The present disclosure can provide the use of a compound represented by the above formula I, its optical isomer or its pharmaceutically acceptable salt for preventing and treating renal failure.

[0017] The present disclosure can provide the use of a compound represented by the above formula I, its optical isomer or its pharmaceutically acceptable salt in the preparation of a drug for preventing and treating renal failure.

[0018] Technical Solution

[0019] Details are described as follows. At the same time, each description and implementation scheme disclosed in the present invention can also be applied to other descriptions and their implementation schemes respectively. In other words, each combination of various elements disclosed in the present invention falls within the scope of the present invention. In addition, it cannot be considered that the scope of the present invention is limited to the specific descriptions described below.

[0020] The present disclosure can provide a pharmaceutical composition for preventing and treating renal failure (RF), the pharmaceutical composition containing a compound represented by the following formula I, its optical isomer or its pharmaceutically acceptable salt as an active ingredient.

[0021] [Formula I]

[0022]

[0023] In formula I,

[0024] wherein L1, L2 or L3 are each independently a bond or -(C1 - C2 alkylene)-;

[0025] R1 is -CX2H or -CX3;

[0026] R2 is -NR A R B 、-OR C 、 {in At least one H in the alkyl group may be substituted by: -X, -OH, -O(C1-C4 alkyl), -NR D R E , -(C1-C4 alkyl), -CF3, -CF2H, -CN, -aryl, -heteroaryl, -(C1-C4 alkyl)-aryl or -(C1-C4 alkyl)-heteroaryl, [wherein at least one H of -aryl, -heteroaryl, -(C1-C4 alkyl)-aryl or -(C1-C4 alkyl)-heteroaryl may be substituted by -X, -OH, -CF3 or -CF2H]};

[0027] R3 is -H, -(C1-C4 alkyl), -(C1-C4 alkyl)-O(C1-C4 alkyl), -(C1-C4 alkyl)-C(=O)-O(C1-C4 alkyl), -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), -aryl, -heteroaryl, -adamantyl,

[0028] {wherein at least one H of -(C1-C4 alkyl) may be substituted with -X or -OH,

[0029] At least one H of the -aryl or -heteroaryl group may be independently substituted by -X, -OH, -O(C1-C4 alkyl), -OCF3, -O-aryl, -NR D R E , -(C1-C4 alkyl), -CF3, -CF2H, -C(=O)-(C1-C4 alkyl), -C(=O)-O(C1-C4 alkyl), -C(=O)-NR D R E , -S(=O)2-(C1-C4 alkyl), aryl, heteroaryl, [in At least one H of D R E , -CF3 or -CF2H substituted],

[0030] -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), adamantyl, At least one H of can be independently replaced by -X, -OH or -(C1-C4 alkyl) respectively;

[0031] Y1, Y2 and Y4 are each independently -CH2-, -NR F -, -O-, -C(=O)- or -S(=O)2-;

[0032] Y3 is -CH- or -N-;

[0033] Z1 to Z4 are each independently N or CR Z , {wherein at least three of Z1 to Z4 cannot be N simultaneously, and R Z is -H, -X or -O(C1-C4 alkyl)};

[0034] Z5 and Z6 are each independently -CH2- or -O-;

[0035] Z7 and Z8 are each independently =CH- or =N-;

[0036] Z9 is -NR G - or -S-;

[0037] R A and R B are each independently -H, -(C1-C4 alkyl), -(C1-C4 alkyl)-OH, -(C1-C4 alkyl)-NR D R E , -aryl, -(C1-C4 alkyl)-aryl, -heteroaryl, -(C1-C4 alkyl)-heteroaryl, -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl) or {wherein at least one H of the -(C1-C4 alkyl), -(C1-C4 alkyl)-OH or -(C1-C4 alkyl)-NR D R E can be replaced by -X,

[0038] at least one H of the -aryl, -(C1-C4 alkyl)-aryl, -heteroaryl, -(C1-C4 alkyl)-heteroaryl, -(C3-C7 cycloalkyl) or -(C2-C6 heterocycloalkyl) can be replaced by the following: -X, -OH, -O(C1-C4 alkyl), -(C1-C4 alkyl), -CF3, -CF2H or -CN,

[0039] At least one H can be replaced by the following: -X, -OH, -O(C1-C4 alkyl), -(C1-C4 alkyl), -CF3, -CF2H, -CN, -(C2-C6 heterocycloalkyl), -aryl, -(C1-C4 alkyl)-aryl, -heteroaryl or -heteroaryl-(C1-C4 alkyl)};

[0040] R C is -(C1-C4 alkyl), -aryl, -(C1-C4 alkyl)-aryl, -heteroaryl or -(C1-C4 alkyl)-heteroaryl {wherein at least one H of -(C1-C4 alkyl) can be replaced by -X or -OH, and at least one H of -aryl, -(C1-C4 alkyl)-aryl, -heteroaryl or -(C1-C4 alkyl)-heteroaryl can be replaced by -X, -OH, -CF3 or -CF2H};

[0041] R D and R E are each independently -H, -(C1-C4 alkyl), -aryl or -(C1-C4 alkyl)-aryl {wherein at least one H of -(C1-C4 alkyl) can be replaced by -X or -OH, and at least one H of -aryl or -(C1-C4 alkyl)-aryl can be replaced by -X, -OH, -CF3 or -CF2H};

[0042] R F is -H, -(C1-C6 alkyl), -(C1-C4 alkyl)-OH, -(C1-C4 alkyl)-O-(C1-C4 alkyl), -C(=O)-(C1-C4 alkyl), -C(=O)-O(C1-C4 alkyl), -(C1-C4 alkyl)-C(=O)-O(C1-C4 alkyl), -(C1-C4 alkyl)-NR D R E 、-S(=O)2-(C1-C4 alkyl), -aryl, -(C1-C4 alkyl)-aryl, -(C2-C4 alkenyl)-aryl, -heteroaryl, -(C1-C4 alkyl)-heteroaryl, -C(=O)-(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl) or -(C1-C4 alkyl)-C(=O)-(C2-C6 heterocycloalkyl)

[0043] {wherein -(C1-C4 alkyl), -(C1-C4 alkyl)-OH, -(C1-C4 alkyl)-O-(C1-C4 alkyl), -C(=O)-(C1-C4 alkyl), -C(=O)-O(C1-C4 alkyl), -(C1-C4 alkyl)-C(=O)-O(C1-C4 alkyl), -(C1-C4 alkyl)-NR D R EAt least one H of -S(=O)2-(C1-C4 alkyl) may be replaced by -X,

[0044] At least one H of -aryl, -(C1-C4 alkyl)-aryl, -(C2-C4 alkenyl)-aryl, -heteroaryl, -(C1-C4 alkyl)-heteroaryl, -C(=O)-(C3-C7 cycloalkyl), -C2-C6 heterocycloalkyl or -(C1-C4 alkyl)-C(=O)-(C2-C6 heterocycloalkyl) may be replaced by -X, -OH, -CF3 or -CF2H};

[0045] R G is -H or -(C1-C4 alkyl);

[0046] Q is -O- or a bond;

[0047] is a single bond or a double bond {provided that, is a double bond and Y1 is =CH-};

[0048] a to e are each independently an integer of 0, 1, 2, 3 or 4 {provided that a and b cannot be 0 at the same time, and c and d cannot be 0 at the same time};

[0049] X are each independently F, Cl, Br or I.

[0050] In the pharmaceutical composition according to the present disclosure, the compound represented by formula I may be as follows:

[0051] L1, L, or L3 are each independently a bond or -(C1-C2 alkylene)-;

[0052] R1 is -CX2H or -CX3;

[0053] R2 is -NR A R B 、-OR C 、

[0054] {wherein at least one H of may be replaced by -X, -OH, -NR D R E 、-(C1-C4 alkyl)};

[0055] R3 is -(C1-C4 alkyl), -(C3-C7 cycloalkyl), -aryl, -heteroaryl, -adamantyl,

[0056] {wherein at least one H of -aryl or -heteroaryl may be independently replaced by the following: -X, -O(C1-C4 alkyl), -OCF3, -O-aryl, -NR DR E , -(C1-C4 alkyl), -CF3, -S(=O)2-(C1-C4 alkyl), -aryl, -heteroaryl, [in At least one H can be -NR D R E or -(C1-C4 alkyl) substituted],

[0057] At least one H of each of the following may be independently substituted by -(C1-C4 alkyl)};

[0058] Y1, Y2 and Y4 are each independently -CH2-, -NR F -, -O-, -C(=O)- or -S(=O)2-;

[0059] Y3 is -CH- or -N-;

[0060] Z1 to Z4 are each independently N or CR Z {At least three of Z1 to Z4 cannot be N at the same time, and R Z is -H, -X or -O(C1-C4 alkyl)};

[0061] Z5 and Z6 are each independently -CH2- or -O-;

[0062] Z7 and Z8 are each independently ═CH- or ═N-;

[0063] Z9-NR G -or-S-;

[0064] R A and R B Each is independently -H, -(C1-C4 alkyl), -(C1-C4 alkyl)-OH, -(C1-C4 alkyl)-NR D R E , -aryl, -(C1-C4 alkyl)-aryl, -(C3-C7 cycloalkyl) or

[0065] {in At least one H of the group may be substituted by -X, -(C1-C4 alkyl), -CF3, -(C2-C6 heterocycloalkyl), -(C1-C4 alkyl)-aryl, -heteroaryl or heteroaryl-(C1-C4 alkyl)};

[0066] R C is -(C1-C4 alkyl) or -aryl;

[0067] R D and RE Each independently is -H, -(C1-C4 alkyl) or -(C1-C4 alkyl)-aryl;

[0068] R F is -H, -(C1-C6 alkyl), -(C1-C4 alkyl)-OH, -(C1-C4 alkyl)-O-(C1-C4 alkyl), -C(=O)-(C1-C4 alkyl), -C(=O)-O(C1-C4 alkyl), -(C1-C4 alkyl)-C(=O)-O(C1-C4 alkyl), -(C1-C4 alkyl)-NR D R E , -S(=O)2-(C1-C4 alkyl), -aryl, -(C1-C4 alkyl)-aryl, -(C2-C4 alkenyl)-aryl, -heteroaryl, -(C1-C4 alkyl)-heteroaryl, -C(=O)-(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl) or -(C1-C4 alkyl)-C(=O)-(C2-C6 heterocycloalkyl)

[0069] {wherein at least one H of -(C1-C4 alkyl) or -C(=O)-O(C1-C4 alkyl) may be replaced by -X,

[0070] at least one H of -aryl may be replaced by -X};

[0071] R G is -(C1-C4 alkyl);

[0072] Q is -O- or a bond;

[0073] is a single bond or a double bond {provided that is a double bond and Y1 is -CH-};

[0074] a to e are each independently an integer of 0, 1, 2, 3 or 4 {provided that a and b cannot be 0 at the same time, and c and d cannot be 0 at the same time};

[0075] X is each independently F, Cl, Br or I.

[0076] In the pharmaceutical composition according to the present disclosure, the compound represented by formula I may be the compound represented by formula Ia:

[0077] [Formula Ia]

[0078]

[0079] In formula Ia,

[0080] R2 is

[0081] R3 is -aryl {wherein at least one H of -aryl can each independently be replaced by -X};

[0082] Y1 is -O- or -S(=O)2-;

[0083] Z1 is N or CR Z {wherein R Z is -X};

[0084] a and b are each independently an integer of 0, 1, 2, 3 or 4 {wherein a and b cannot be 0 at the same time};

[0085] X is each independently F, Cl, Br or I.

[0086] In the pharmaceutical composition according to the present disclosure, the compound represented by formula Ia can be as follows:

[0087] R2 is

[0088] R3 is -phenyl {wherein at least one H of -phenyl can each independently be replaced by -F or -Cl};

[0089] Y1 is -O- or -S(=O)2-;

[0090] Z1 is N or CF.

[0091] In the pharmaceutical composition according to the present disclosure, the compound represented by formula I can be shown in Table A below:

[0092] [Table A]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099] [[ID=6)]]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122] According to the present disclosure, a pharmaceutical composition containing the compounds (compounds 1 to 450) in Table A above, their optical isomers, or their pharmaceutically acceptable salts as active ingredients can prevent and treat renal failure.

[0123] In the pharmaceutical composition according to the present disclosure, the compound represented by Formula I can be shown in Table B below:

[0124] [Table B]

[0125]

[0126] According to the present disclosure, pharmaceutical compositions containing the compounds in Table B above (Compounds 40, 43, 239, 285, 295 and / or 296), optical isomers thereof, or pharmaceutically acceptable salts thereof as active ingredients can prevent and treat renal failure.

[0127] In the present disclosure, the compound represented by the above Formula I, Compounds 1 to 450, optical isomers thereof, or pharmaceutically acceptable salts thereof may be prepared by the method disclosed in Korean Unexamined Patent Application Publication No. 10-2017-0017792, but is not limited thereto.

[0128] In the pharmaceutical composition according to the present disclosure, the compound represented by the above formula I, compound 1 to 450, its optical isomer or its pharmaceutically acceptable salt can contain at least one asymmetric carbon, and therefore can exist as a racemic mixture, a single enantiomer (optical isomer), a diastereomeric mixture and a single diastereomer. Such isomers can be separated by splitting according to the prior art (e.g., column chromatography, HPLC, etc.). Alternatively, isomers can be synthesized using a series of known optically pure starting materials and / or reagent stereospecifics. In particular, the isomers can be optical isomers (enantiomers).

[0129] In the present disclosure, the term "pharmaceutically acceptable" may refer to being physiologically acceptable when administered to an individual and generally not causing gastrointestinal disturbances, allergic reactions such as dizziness, or other reactions similar thereto.

[0130] The pharmaceutically acceptable salts according to embodiments of the present invention can be prepared by conventional methods known to those skilled in the art.

[0131] Pharmaceutically acceptable salts according to embodiments of the present invention may include, for example: inorganic ion salts prepared from calcium, potassium, sodium, magnesium, etc.; inorganic acid salts prepared from hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, sulfuric acid, hydroiodic acid, etc.; organic acid salts prepared from acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, etc.; sulfonates prepared from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, etc.; amino acid salts prepared from glycine, arginine, lysine, etc.; amine salts prepared from trimethylamine, triethylamine, ammonia, pyridine, picoline, etc.; and the like, but are not limited thereto. In an embodiment of the present invention, the salt may include hydrochloric acid, trifluoroacetic acid, citric acid, bromic acid, maleic acid, phosphoric acid, sulfuric acid, tartaric acid, or a mixture thereof.

[0132] As used herein, "renal failure (RF)" refers to a state in which the function of the kidneys to filter waste products from the blood and properly maintain the body's water concentration and electrolyte content is reduced or lost.

[0133] Renal failure can be divided into two categories: acute renal failure and chronic renal failure. Acute renal failure refers to a disease condition in which the excretion of waste products in the body is problematic due to a rapid decline in renal function, leading to the accumulation of uremic toxins and imbalance of water and electrolytes. Chronic renal failure refers to a disease condition in which renal tissue is damaged and renal function has declined for at least three months.

[0134] The causes of acute renal failure can include hypotension, urinary tract obstruction, certain drugs, muscle degeneration, hemolytic uremic syndrome, etc., while the causes of chronic renal failure can include diabetes, hypertension, nephrotic syndrome, polycystic kidney disease, etc.

[0135] In an embodiment of the present invention, renal failure can be caused by various reasons and is not limited thereto.

[0136] In an embodiment of the present invention, in order to evaluate the effect of the compounds according to the present disclosure in preventing and treating renal failure, a chronic renal failure model is used, in which metabolites accumulate in the kidneys through an adenine diet, causing its dysfunction, but the renal failure of the present invention is not limited thereto.

[0137] In an embodiment of the present invention, in order to confirm the effect of the compound of formula I, compounds 1 to 450, their optical isomers or their pharmaceutically acceptable salts according to the present disclosure in preventing and treating renal failure, the relative fibrosis area and the tubulointerstitial fibrosis score are selected to evaluate renal fibrosis, but the evaluation of renal fibrosis is not limited thereto.

[0138] In an embodiment of the present invention, in order to confirm the effect of the compound of formula I, compounds 1 to 450, their optical isomers or their pharmaceutically acceptable salts according to the present disclosure in preventing and treating renal failure, the glomerulosclerosis (GS) index is selected to evaluate nephropathy, but the evaluation of nephropathy is not limited thereto.

[0139] In an embodiment of the present invention, in order to confirm the effect of the compound of formula I, compounds 1 to 450, their optical isomers or their pharmaceutically acceptable salts according to the present disclosure in preventing and treating renal failure, it has been confirmed that the acetylation of tubulin is increased, but it is not limited thereto.

[0140] In an embodiment of the present invention, in order to confirm the effect of the compound of formula I, compounds 1 to 450, their optical isomers or their pharmaceutically acceptable salts according to the present disclosure in preventing and treating renal failure, the change in the expression of type I collagen α1 (COL1A1) is selected to evaluate renal fibrosis, but it is not limited thereto.

[0141] In an embodiment of the present invention, to confirm the effect of the compound of formula I, compounds 1 to 450, their optical isomers or their pharmaceutically acceptable salts according to the present disclosure in preventing and treating renal failure, the change in blood urea nitrogen (BUN) concentration was selected to evaluate renal function, but the evaluation of renal function is not limited thereto.

[0142] As used herein, the term "prevention" may refer to all actions of inhibiting or delaying the occurrence of renal failure diseases by administering the compound of formula I, compounds 1 to 450, their optical isomers or their pharmaceutically acceptable salts according to the present disclosure.

[0143] As used herein, the term "treatment" may refer to all actions of improving or causing a favorable change in the symptoms of individuals suspected of having renal failure diseases and those who have developed the diseases by administering the compound of formula I, compounds 1 to 450, their optical isomers or their pharmaceutically acceptable salts according to the present disclosure; all actions of preventing the symptoms of individuals suspected of having renal failure diseases and those who have developed the diseases from further deteriorating; and all actions capable of preventing or delaying the progression of renal failure.

[0144] In the present disclosure, a pharmaceutical composition comprising the compound represented by formula I, compounds 1 to 450, their optical isomers or their pharmaceutically acceptable salts may have the effect of preventing and treating renal failure.

[0145] In an embodiment of the present invention, a pharmaceutical composition comprising the compound represented by formula I, compounds 1 to 450, their optical isomers or their pharmaceutically acceptable salts may have the effect of preventing and treating acute renal failure and / or chronic renal failure.

[0146] In an embodiment of the present invention, a pharmaceutical composition comprising the compound represented by formula I, compounds 1 to 450, their optical isomers or their pharmaceutically acceptable salts may have the effect of preventing and treating the decline or impairment of renal function caused by chronic renal failure.

[0147] In an embodiment of the present invention, a pharmaceutical composition comprising the compound represented by formula I, compounds 1 to 450, their optical isomers or their pharmaceutically acceptable salts may delay or inhibit the progression of renal failure. For example, the pharmaceutical composition according to an embodiment of the present invention may inhibit or delay the progression of renal failure to end-stage renal failure as much as possible, may prevent a patient from undergoing dialysis or kidney transplantation, or may delay the rate at which renal failure reaches such a state.

[0148] In an embodiment of the present invention, a pharmaceutical composition comprising the compound represented by formula I, compounds 1 to 450, their optical isomers or their pharmaceutically acceptable salts may have the effect of preventing and treating renal fibrosis caused by chronic renal failure.

[0149] In an embodiment of the present invention, a pharmaceutical composition comprising a compound represented by Formula I, Compounds 1 to 450, their optical isomers, or pharmaceutically acceptable salts thereof can improve renal fibrosis, can delay or inhibit the progression of renal fibrosis, and can slow down the rate of renal fibrosis.

[0150] In an embodiment of the present invention, a pharmaceutical composition comprising a compound represented by Formula I, Compounds 1 to 450, their optical isomers, or pharmaceutically acceptable salts thereof can exhibit a pharmacological effect resulting from the TGF-β / SMAD mechanism associated with chronic renal failure, but is not limited thereto.

[0151] In an embodiment of the present invention, a pharmaceutical composition comprising a compound represented by Formula I, Compounds 1 to 450, their optical isomers, or pharmaceutically acceptable salts thereof can improve renal fibrosis, or delay or inhibit the progression of renal fibrosis, and slow down the progression rate of renal fibrosis associated with renal failure (acute renal failure and chronic renal failure). For example, a pharmaceutical composition comprising a compound represented by Formula I, Compounds 1 to 450, their optical isomers, or pharmaceutically acceptable salts thereof can slow down the progression rate of renal fibrosis in an animal model of adenine-induced chronic renal failure induced by an adenine diet ( Figure 1 ).

[0152] In an embodiment of the present invention, a pharmaceutical composition comprising a compound represented by Formula I, Compounds 1 to 450, their optical isomers, or pharmaceutically acceptable salts thereof can improve glomerulosclerosis, or delay or inhibit the progression of glomerulosclerosis, and slow down the progression rate of glomerulosclerosis associated with renal failure (acute renal failure and chronic renal failure). For example, a pharmaceutical composition comprising a compound represented by Formula I, Compounds 1 to 450, their optical isomers, or pharmaceutically acceptable salts thereof can slow down the progression rate of glomerulosclerosis in an animal model of adenine-induced chronic renal failure induced by an adenine diet ( Figure 2 ).

[0153] In an embodiment of the present invention, a pharmaceutical composition comprising a compound represented by Formula I, Compounds 1 to 450, their optical isomers, or pharmaceutically acceptable salts thereof can increase the acetylation of tubulin in chronic renal failure. For example, a pharmaceutical composition comprising a compound represented by Formula I, Compounds 1 to 450, their optical isomers, or pharmaceutically acceptable salts thereof can increase the acetylation of tubulin in an animal model of adenine-induced chronic renal failure ( Figure 3 ).

[0154] In an embodiment of the present invention, a pharmaceutical composition comprising a compound represented by Formula I, Compounds 1 to 450, an optical isomer thereof, or a pharmaceutically acceptable salt thereof can inhibit the increase of type I collagen α1 (COL1A1) in chronic renal failure. For example, a pharmaceutical composition comprising a compound represented by Formula I, Compounds 1 to 450, an optical isomer thereof, or a pharmaceutically acceptable salt thereof can inhibit the increase of type I collagen α1 in an animal model with adenine-induced chronic renal failure( Figure 4 ).

[0155] In an embodiment of the present invention, a pharmaceutical composition comprising a compound represented by Formula I, Compounds 1 to 450, an optical isomer thereof, or a pharmaceutically acceptable salt thereof can reduce blood urea nitrogen (BUN) in chronic renal failure to improve renal function, or delay or inhibit the decline of renal function, and delay the rate of decline of renal function( Figure 5 ). For example, a pharmaceutical composition comprising a compound represented by Formula I, Compounds 1 to 450, an optical isomer thereof, or a pharmaceutically acceptable salt thereof can reduce blood urea nitrogen (BUN) in an animal model with adenine-induced chronic renal failure.

[0156] In an embodiment of the present invention, a pharmaceutical composition can be administered to an individual suffering from renal failure, and the renal failure of the individual can be caused by other diseases. The diseases that can cause renal failure can include at least one selected from the following: hypotension, urinary tract obstruction, acute renal failure, acute pyelonephritis, chronic pyelonephritis, IgA nephropathy, muscle degeneration, hemolytic uremic syndrome, glomerulopathy (e.g., nephritic syndrome, acute late glomerulonephritis, chronic glomerulonephritis, nephrotic syndrome, etc.), hereditary nephropathy (e.g., polycystic kidney disease), diabetes, hypertension, heart disease, and liver disease.

[0157] In an embodiment of the present invention, a pharmaceutical composition can be administered to an individual suffering from chronic renal failure, and the chronic renal failure of the individual can be caused by other diseases. The diseases that can cause renal failure can include at least one selected from the following: diabetes, hypertension, nephrotic syndrome, nephritic syndrome, hereditary nephropathy (e.g., polycystic kidney disease), heart disease, and liver disease. The compound represented by Formula I, Compounds 1 to 450, an optical isomer thereof, or a pharmaceutically acceptable salt thereof according to the present disclosure can exhibit a preventive and therapeutic effect on renal failure at a level similar to, substantially the same as, or superior to that of conventionally known drugs for the prevention and treatment of renal failure.

[0158] In addition to the compounds represented by Formula I above, Compounds 1 to 450, their optical isomers or their pharmaceutically acceptable salts, the pharmaceutical compositions of the present disclosure may further comprise at least one pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers may be carriers conventionally used in the art, particularly including but not limited to lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methyl paraben, propyl paraben, talc, magnesium stearate, minerals or oils. In addition to the above components, the pharmaceutical compositions of the present invention may further comprise lubricants, humectants, sweeteners, flavoring agents, emulsifying agents, suspending agents, preservatives, dispersing agents, stabilizers, etc. Furthermore, the pharmaceutical compositions of the present disclosure may be formulated into oral dosage forms, such as tablets, powders, granules, pills, capsules, suspensions, emulsions, oral liquids, oils, syrups, etc., as well as external forms, suppositories or sterile solutions for injection by using pharmaceutically acceptable carriers and excipients, and may thus be prepared in unit dosage forms or by inserting into multi-dose containers. Such preparations may be prepared according to conventional methods for formulation in the art or the methods disclosed in Remington's Pharmaceutical Science (19th Edition, 1995), and may be formulated into various preparations depending on each disease or component.

[0159] Non-limiting examples of preparations for oral administration using the pharmaceutical compositions of the present disclosure may include tablets, troches, lozenges, aqueous suspensions, oily suspensions, preformed powders, granules, emulsions, hard capsules, soft capsules, syrups, elixirs, etc. In order to formulate the pharmaceutical compositions according to the embodiments of the present invention into preparations for oral administration, the following may be used: binders such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose, gelatin, etc.; excipients such as dicalcium phosphate, etc.; disintegrants such as corn starch, sweet potato starch, etc.; lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate, polyethylene glycol wax, etc., among which sweeteners, flavoring agents, syrups, etc. may also be used. In addition, in the case of capsules, liquid carriers such as fatty oils, etc. may also be used in addition to the materials mentioned above.

[0160] Non-limiting examples of parenteral preparations using the pharmaceutical composition according to an embodiment of the present invention may include injectable solutions, suppositories, powders for respiratory inhalation, aerosol agents for spraying, ointments, dusting powders, oils, creams, etc. In order to formulate the pharmaceutical composition according to an embodiment of the present invention into a preparation for parenteral administration, the following may be used: sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, topical preparations, etc. As the non-aqueous solvents and suspensions, but not limited to the following may be used: propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, etc.

[0161] The pharmaceutical composition according to an embodiment of the present invention can be administered orally or parenterally according to a targeting method, for example, intravenous administration, subcutaneous administration, intraperitoneal administration or topical administration, specifically oral administration, but not limited thereto.

[0162] The daily dose of the compound represented by Formula I according to the present disclosure, Compounds 1 to 450, their optical isomers or their pharmaceutically acceptable salts can specifically be about 0.1 mg / kg to about 10,000 mg / kg, about 1 mg / kg to about 8,000 mg / kg, about 5 mg / kg to about 6,000 mg / kg or about 10 mg / kg to about 4,000 mg / kg, and more specifically about 50 mg / kg to about 2,000 mg / kg, but not limited thereto, and can also be administered once a day or several times a day by dividing the daily dose of the compound.

[0163] The pharmaceutically effective dose and the effective dose of the pharmaceutical composition according to an embodiment of the present invention may vary depending on the method for formulating the pharmaceutical composition, the mode of administration, the administration time, the administration route, etc., and can be diversified according to various factors, including the type and degree of the reaction to be achieved by administering the pharmaceutical composition, the type of individual receiving the administration, the age, weight, general health condition, disease symptoms or severity, gender, diet and excretion of the individual, the components of other pharmaceutical compositions used for the corresponding individual simultaneously or at different times, etc., as well as other similar factors well known in the pharmaceutical field, and those skilled in the art can easily determine and prescribe the effective dose for the intended treatment.

[0164] The pharmaceutical composition according to an embodiment of the present invention can be administered once a day or several times a day by dividing the daily dose of the composition. The pharmaceutical composition of the present disclosure can be administered as a single therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with conventional therapeutic agents. Considering all of the above factors, the pharmaceutical composition of the present disclosure can be administered in the following amounts: the maximum effect can be achieved with the minimum amount without side effects, and this amount can be easily determined by those skilled in the art to which the present invention pertains.

[0165] Even when used alone, the pharmaceutical composition according to an embodiment of the present invention can still exhibit excellent effects, but can be further used in combination with various methods such as hormone therapy, drug therapy, etc. to improve the treatment efficiency.

[0166] The present disclosure can provide a method for preventing and treating renal failure, which comprises administering to an individual a compound represented by Formula I above, Compounds 1 to 450, their optical isomers or their pharmaceutically acceptable salts.

[0167] The present disclosure can provide a method for preventing and treating renal failure, which comprises administering to an individual the above Compounds 40, 43, 239, 285, 295 and / or 296, their optical isomers or their pharmaceutically acceptable salts.

[0168] In the preventive and treatment methods of the present disclosure, the above terms "renal failure", "prevention" and "treatment" can be the same as those described above.

[0169] As used herein, the term "administering" can refer to introducing a predetermined substance into an individual by an appropriate method.

[0170] As used herein, the term "individual" can refer to all animals that may develop or have developed renal failure, such as rats, mice, livestock, etc., including humans, and more particularly refers to mammals, including humans, but is not limited thereto.

[0171] The method for preventing and treating renal failure of the present disclosure can comprise administering a therapeutically effective amount of a compound represented by Formula I above, Compounds 1 to 450, their optical isomers or their pharmaceutically acceptable salts.

[0172] As used herein, the term "therapeutically effective amount" can refer to an amount sufficient to treat a disease with a reasonable risk / benefit ratio applicable to medical treatment and without causing side effects, and such amount can be determined by those skilled in the art according to factors including the patient's gender, age, weight and health status, type of disease, severity, drug activity, drug sensitivity, method of administration, time of administration, route of administration, excretion rate, treatment period, drugs used in combination or simultaneously, and other factors well known in the medical field. Preferably, a specific therapeutically effective amount is applied differently to a certain patient depending on various factors, including the type and degree of response achieved thereby, the specific composition (including the presence of other preparations used in some cases), the patient's age, weight, general health status, gender and diet, time of administration, route of administration, excretion rate of the composition, treatment period, and drugs used in combination with or simultaneously with a specific composition, as well as other similar factors well known in the pharmaceutical field.

[0173] The methods for preventing and treating renal failure according to the present disclosure may include not only treating the disease itself before its symptoms appear, but also inhibiting or avoiding such symptoms by administering a compound represented by Formula I above, Compounds 1 to 450, their optical isomers, or pharmaceutically acceptable salts thereof. When controlling the disease, the prophylactic or therapeutic dose of a certain active ingredient may vary depending on the nature and severity of the disease or disorder, as well as the route of administration of the active ingredient. The dose and frequency thereof may vary depending on the age, weight, and response of the individual patient. Reasonably considering such factors, those skilled in the art can easily select an appropriate dose and usage.

[0174] In addition, the methods for preventing and treating renal failure according to the present disclosure may further include administering a therapeutically effective amount of an additional active agent together with a compound represented by Formula I above, Compounds 1 to 450, their optical isomers, or pharmaceutically acceptable salts thereof, which additional active agent contributes to the prevention and treatment of the disease, and the additional active agent may exhibit a synergistic or additive effect together with a compound represented by Formula I above, Compounds 1 to 450, their optical isomers, or pharmaceutically acceptable salts thereof.

[0175] Matters mentioned in the pharmaceutical compositions according to the present disclosure also apply to the prevention and treatment methods if they are not contradictory to each other.

[0176] The present disclosure may provide the use of a compound represented by Formula I above, Compounds 1 to 450, their optical isomers, or pharmaceutically acceptable salts thereof for preventing and treating renal failure.

[0177] The present disclosure may provide the use of the above Compounds 40, 43, 239, 285, 295, and / or 296, their optical isomers, or pharmaceutically acceptable salts thereof for preventing and treating renal failure.

[0178] The present disclosure may provide the use of a compound represented by Formula I above, Compounds 1 to 450, their optical isomers, or pharmaceutically acceptable salts thereof in the preparation of a medicament for preventing and treating renal failure.

[0179] The present disclosure may provide the use of a compound represented by the above Compounds 40, 43, 239, 285, 295, and / or 296, their optical isomers, or pharmaceutically acceptable salts thereof in the preparation of a medicament for preventing and treating renal failure.

[0180] In the prophylactic and therapeutic uses according to the present disclosure, the above terms "renal failure", "prevention", and "treatment" may be the same as those described above.

[0181] For the preparation of a drug, the compound represented by Formula I above, Compounds 1 to 450, their optical isomers or their pharmaceutically acceptable salts can be mixed with pharmaceutically acceptable adjuvants, diluents, carriers, etc., and can be prepared into a combined preparation together with other active agents, thereby providing a synergistic effect.

[0182] Matters mentioned in the pharmaceutical compositions, preventive and therapeutic methods, and uses of the present disclosure can be equally applicable if they are not contradictory to each other.

[0183] Beneficial effects

[0184] The compound represented by Formula I of the present disclosure, Compounds 1 to 450, their optical isomers or their pharmaceutically acceptable salts, and a pharmaceutical composition containing the same as an active ingredient can be advantageously used for preventing and treating renal failure. Description of the drawings

[0185] Figure 1 Shows the measurement results of the degree of fibrosis of the kidneys obtained by collecting mouse kidneys 14 days after an adenine diet in an animal model of adenine-induced chronic renal failure. A pharmaceutical composition containing the compound represented by Formula I, Compounds 1 to 450, their optical isomers or their pharmaceutically acceptable salts can reduce the fibrosis occurring in an animal model of renal failure.

[0186] Figure 2 Shows the measurement results of the degree of glomerulosclerosis of the kidneys obtained by collecting mouse kidneys 14 days after an adenine diet in an animal model of adenine-induced chronic renal failure. A pharmaceutical composition containing the compound represented by Formula I, Compounds 1 to 450, their optical isomers or their pharmaceutically acceptable salts can reduce the glomerulosclerosis occurring in an animal model of renal failure.

[0187] Figure 3 Shows the measurement results of the degree of tubulin acetylation in mouse kidney tissues 14 days after an adenine diet in an animal model of adenine-induced chronic renal failure. A pharmaceutical composition containing the compound represented by Formula I, Compounds 1 to 450, their optical isomers or their pharmaceutically acceptable salts can increase the tubulin acetylation in the kidneys of an animal model of renal failure.

[0188] Figure 4 Shows the measurement results of the expression level of COL1A1 in mouse kidney tissues 14 days after an adenine diet in an animal model of adenine-induced chronic renal failure. A pharmaceutical composition containing the compound represented by Formula I, Compounds 1 to 450, their optical isomers or their pharmaceutically acceptable salts can reduce the increased COL1A1 expression in an animal model of renal failure.

[0189] Figure 5 The measurement results of the blood urea nitrogen (BUN) concentration in blood obtained by collecting the blood of mice 14 days after an adenine diet in an animal model with adenine-induced chronic renal failure are shown. A pharmaceutical composition containing a compound represented by Formula I, Compounds 1 to 450, their optical isomers, or their pharmaceutically acceptable salts can reduce the level of increased blood urea nitrogen (BUN) in an animal model with renal failure.

[0190] Detailed Description of Exemplary Embodiments

[0191] The present disclosure is described in detail with reference to the examples below. However, the examples are for illustrative purposes only, and it is obvious to those skilled in the art that the scope of the present invention is not limited to the examples disclosed below.

[0192] Preparation Example 1. Synthesis of Compound 43 N-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl) methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide

[0193] [Step 1] N-Phenylthiomorpholine-4-carboxamide 1,1-dioxide

[0194]

[0195] Phosgene (4.780 g, 16.107 mmol) was added to a solution of aniline (3.000 g, 32.213 mmol) and N,N-diisopropylethylamine (33.439 mL, 193.278 mmol) in dichloromethane (100 mL) at 0 °C, and the mixture was stirred at the same temperature. Thiomorpholine 1,1-dioxide (4.790 g, 35.434 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for an additional 16 hours. Subsequently, water was added to the reaction mixture, and then the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (anhydrous MgSO4), filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 40 g column; methanol / dichloromethane = 2%) and concentrated to obtain the title compound as a yellow solid (1.325 g, 16.2%).

[0196] [Step 2] Synthesis of Methyl 6-((1,1-dioxo-N-phenylthiomorpholine-4-carboxamido)methyl)nicotinate

[0197]

[0198] At 0 °C, a solution of N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (1.000 g, 3.932 mmol) and sodium hydride (60.00%, 0.157 g, 3.932 mmol) in N,N-dimethylformamide (10 mL) prepared in Step 1 was stirred for 1 hour and mixed with methyl 4-(bromomethyl)-3-fluorobenzoate (0.905 g, 3.932 mmol). The reaction mixture was stirred for an additional 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure to remove the solvent, water was added to the concentrate, and then it was extracted with ethyl acetate. The organic layer was washed with brine, dried (anhydrous MgSO4), filtered, and concentrated under reduced pressure. The crude product was crystallized with methanol (20 mL) at room temperature. The resulting precipitate obtained by filtration was washed with methanol and dried to give the title compound as a brown solid (0.816 g, 51.4%).

[0199] [Step 3] Synthesis of N-((5-hydrazinecarbonyl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide

[0200]

[0201] At room temperature, methyl 6-((1,1-dioxo-N-phenylthiomorpholine-4-carboxamido)methyl)nicotinate (0.816 g, 2.023 mmol) prepared in Step 2 and hydrazine monohydrate (1.910 mL, 40.451 mmol) were mixed in ethanol (10 mL), then heated at 100 °C for 1 hour under microwave and cooled to room temperature to terminate the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent. The crude product was crystallized with dichloromethane (20 mL) at room temperature. The resulting precipitate obtained by filtration was washed with dichloromethane and dried to give the title compound as a light brown solid (0.560 g, 68.6%).

[0202] [Step 4] Synthesis of N-((5-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide

[0203]

[0204] At room temperature, a solution of N-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (0.260 g, 0.644 mmol) and triethylamine (0.178 mL, 1.289 mmol) in dichloromethane (2 mL) was mixed with difluoroacetic anhydride (0.087 mL, 0.580 mmol). The reaction mixture was stirred at the same temperature for 16 h. Subsequently, water was added to the reaction mixture, which was then extracted with dichloromethane. The mixture was passed through a plastic frit to remove the solid residue and the aqueous layer, and the collected organic layer was concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 0% to 5%) to give the title compound as a white foam (0.156 g, 50.3%).

[0205] [Step 5] Synthesis of Compound 43

[0206]

[0207] A mixture of N-((5-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (0.156 g, 0.324 mmol) and 1-methoxy-N-triethylammonium sulfonyl-methanimidate (Burgess reagent, 0.116 g, 0.486 mmol) in tetrahydrofuran (2 mL) was heated at 15*C under microwave for 30 min and cooled to room temperature to terminate the reaction. Subsequently, water was added to the reaction mixture, which was then extracted with dichloromethane. The biphasic mixture was passed through a plastic frit to remove the solid residue and the aqueous layer, and the collected organic layer was concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g column; methanol / dichloromethane = 3%) to give the title compound as a colorless oil (0.078 g, 51.9%).

[0208] 1 H NMR (400 MHz, CDCl3) δ 9.23 (d, 1H, J = 2.2 Hz), 8.38 (dd, 1H, J = 8.2, 2.2 Hz), 7.54 (d, 1H, J = 8.2 Hz), 7.41 - 7.31 (m, 2H), 7.19 (ddd, 3H, J = 6.4, 3.0, 1.6 Hz), 6.94 (m, 1H), 5.10 (s, 2H), 3.72 (dd, 4H, J = 6.9, 3.7 Hz), 2.97 - 2.90 (m, 4H); LRMS (ES) m / z 464.2 (M + +1).

[0209] Synthesis Example 2. Synthesis of Compound 40 N-(4-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)- N-phenylthiomorpholine-4-carboxamide 1,1-dioxide

[0210] [Step 1] Methyl 4-((1,1-dioxido-N-phenylthiomorpholine-4-carboxamido)methyl)-3-fluorobenzoate

[0211]

[0212] A solution of N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (1.000 g, 3.932 mmol) and sodium hydride (60.00%, 0.189 g, 4.719 mmol) in N,N-dimethylformamide (30 mL) was mixed with methyl 4-(bromomethyl)-3-fluorobenzoate (1.020 g, 4.129 mmol) at 0 °C and stirred at room temperature for 18 h. Subsequently, saturated aqueous sodium bicarbonate was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried (anhydrous MgSO4), filtered and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 40 g column; ethyl acetate / hexane = 0% to 50%) to give the title compound, methyl 4-((1,1-dioxido-N-phenylthiomorpholine-4-carboxamido)methyl)-3-fluorobenzoate, as a white solid (1.240 g, 75.0%).

[0213] [Step 2] N-(2-Fluoro-4-(hydrazinecarbonyl)benzyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide

[0214]

[0215] A solution of the methyl 4-((1,1-dioxido-N-phenylthiomorpholine-4-carboxamido)methyl)-3-fluorobenzoate (1.240 g, 2.949 mmol) prepared in Step 1 and hydrazine monohydrate (2.786 mL, 58.983 mmol) in ethanol (15 mL) was stirred at 120 °C for 1 h and cooled to room temperature to terminate the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent, and saturated aqueous sodium bicarbonate was added to the concentrate, followed by extraction with dichloromethane. The biphasic mixture was passed through a plastic sintered funnel to remove the solid residue and the aqueous layer, and the collected organic layer was concentrated under reduced pressure. The crude title compound, N-(2-fluoro-4-(hydrazinecarbonyl)benzyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (1.240 g, 100.0%, white solid), was used without further purification.

[0216] [Step 3] N-(4-(2-(2,2-Difluoroacetyl)hydrazine-1-carbonyl)-2-fluorobenzyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide

[0217]

[0218] At room temperature, a solution of N-(2-fluoro-4-(hydrazinecarbonyl)benzyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (0.615 g, 1.463 mmol), triethylamine (0.304 mL, 2.194 mmol) and difluoroacetic anhydride (0.164 mL, 1.316 mmol) in dichloromethane (10 mL) was stirred for 18 hours. Subsequently, saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with brine, dried (anhydrous MgSO4), filtered and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 24 g column; methanol / dichloromethane = 0% to 3%) to give the title compound N-(4-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)-2-fluorobenzyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide as a white solid (0.462 g, 63.4%).

[0219] [Step 4] Synthesis of Compound 40

[0220]

[0221] A mixture of N-(4-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)-2-fluorobenzyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (0.462 g, 0.927 mmol) and 1-methoxy-N-triethylammonium sulfonyl-methanimidate (Burgess reagent, 0.331 g, 1.390 mmol) in tetrahydrofuran (10 mL) was heated at 150 °C for 30 minutes under microwave and cooled to room temperature to terminate the reaction. Subsequently, saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with dichloromethane. The biphasic mixture was passed through a plastic sintered funnel to remove the solid residue and the aqueous layer, and the collected organic layer was concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12 g column; ethyl acetate / hexane = 0% to 50%) to give the title compound N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide as a white solid (0.337 g, 75.7%).

[0222] 11H NMR (400 MHz, CDCl3) δ 7.87 - 7.85 (m, 1H), 7.75 - 7.72 (m, 1H), 7.67 - 7.64 (m, 1H), 7.38 - 7.34 (m, 2H), 7.25 - 7.20 (m, 1H), 7.13 - 7.10 (m, 2H), 7.03 - 6.77 (m, 1H), 4.92 (s, 2H), 3.71 - 3.67 (m, 4H), 2.77 - 2.74 (m, 4H); LRMS (ES) m / z 481.1 (M + + 1).

[0223] Synthesis Example 3. Synthesis of Compound 239 N-(3-chlorophenyl)-N-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2- yl)pyridin-2-yl)methyl)thiomorpholine-4-carboxamide 1,1-dioxide

[0224] [Step 1] Synthesis of N-(3-chlorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide

[0225]

[0226] A solution of 1-chloro-3-isocyanatobenzene (1.000 g, 6.512 mmol) and thiomorpholine 1,1-dioxide (0.871 g, 6.447 mmol) in diethyl ether (20 mL) was stirred at room temperature for 18 h. The precipitate was filtered, washed with diethyl ether and dried to give the title compound as a white solid (1.811 g, 96.3%).

[0227] [Step 2] Synthesis of methyl 6-((N-(3-chlorophenyl)-1,1-dioxothiomorpholine-4-carboxamido)methyl)nicotinate

[0228]

[0229] To a solution of N-(3-chlorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.200 g, 0.693 mmol) prepared in Step 1 in N,N-dimethylformamide (5 mL) at 0 °C was added sodium hydride (60.00%, 0.028 g, 0.693 mmol). The reaction mixture was stirred at the same temperature for 1 h, 6-(bromomethyl)methyl nicotinate (0.159 g, 0.693 mmol) was added at the same temperature, and the mixture was stirred for another 2 h. Subsequently, water was added to the reaction mixture, and then it was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried (anhydrous MgSO4), filtered and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, 12 g column; methanol / dichloromethane = 0% to 5%) and concentrated to give the title compound as a brown oil (0.261 g, 86.0%).

[0230] [Step 3] Synthesis of N-(3-chlorophenyl)-N-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)thiomorpholine-4-carboxamide 1,1-dioxide

[0231]

[0232] At room temperature, methyl 6-((N-(3-chlorophenyl)-1,1-dioxothiomorpholine-4-carboxamido)methyl)nicotinate (0.261 g, 0.596 mmol) prepared in Step 2 and hydrazine monohydrate (0.290 mL, 5.958 mmol) were mixed in ethanol (2 mL). Then, the mixture was stirred at 110 °C for 18 hours and cooled to room temperature to terminate the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent. Subsequently, water was added to the obtained concentrate, and then it was extracted with dichloromethane. The biphasic mixture was passed through a plastic sintered funnel to remove the solid residue and the aqueous layer, and the collected organic layer was concentrated under reduced pressure. The residue was purified and concentrated by chromatography (SiO2, 4 g column; methanol / dichloromethane = 5% to 15%) to obtain the title compound as a brown oil (0.261 g, 100.0%).

[0233] [Step 4] Synthesis of Compound 239

[0234]

[0235] At room temperature, N-(3-chlorophenyl)-N-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.261 g, 0.596 mmol) prepared in Step 3, triethylamine (0.415 mL, 2.980 mmol) and 2,2-difluoroacetic anhydride (0.195 mL, 1.788 mmol) were mixed in tetrahydrofuran (2 mL). Then, the obtained solution was stirred at 80 °C for 18 hours and cooled to room temperature to terminate the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent. Subsequently, water was added to the obtained concentrate, and then it was extracted with dichloromethane. The biphasic mixture was passed through a plastic sintered funnel to remove the solid residue and the aqueous layer, and the collected organic layer was concentrated under reduced pressure. The residue was purified and concentrated by chromatography (SiO2, 4 g column; methanol / dichloromethane = 0% to 3%) to obtain the title compound as a yellow foam (0.087 g, 29.3%).

[0236] 11H NMR (400 MHz, CDCl3) δ 9.27 (dd, 1H, J = 2.2, 0.8 Hz), 8.43 (dd, 1H, J = 8.2, 2.2 Hz), 7.55 (dd, 1H, J = 8.2, 0.9 Hz), 7.31 (t, 1H, J = 8.0 Hz), 7.23 (t, 1H, J = 2.1 Hz), 7.21 - 7.10 (m, 2H), 7.10 (t, 1H), 5.12 (s, 2H), 3.75 (t, 4H, J = 5.3 Hz), 3.06 - 2.99 (m, 4H); LRMS (ES) m / z 498.3 (M + + 1).

[0237] Synthesis Example 4. Synthesis of Compound 285: N-(4-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenz yl)-N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide

[0238] [Step 1] N-(4-Fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide

[0239]

[0240] A solution of 1-fluoro-4-isocyanatobenzene (0.500 g, 3.647 mmol) in diethyl ether (10 mL) was mixed with thiomorpholine 1,1-dioxide (0.493 g, 3.647 mmol) at 0 °C and stirred at the same temperature for 1 h. The reaction mixture was stirred at room temperature for an additional 4 h. The precipitate was collected by filtration, washed with diethyl ether, and dried to give N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.920 g, 92.7%) as a white solid.

[0241] [Step 2] Methyl 3-fluoro-4-((N-(4-fluorophenyl)-1,1-dioxothiomorpholine-4-carbonylamino)methyl)benzoate

[0242]

[0243] The solution of N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.300 g, 1.102 mmol) and sodium hydride (60.00%, 0.048 g, 1.212 mmol) prepared in Step 1 in N,N-dimethylformamide (5 mL) was stirred at 0 °C for 2 h and mixed with methyl 4-(bromomethyl)-3-fluorobenzoate (0.299 g, 1.212 mmol). The reaction mixture was stirred at room temperature for an additional 17 h and quenched at room temperature by the addition of water (2 mL, stirred for 10 min). Subsequently, water was added to the reaction mixture, and then it was extracted with dichloromethane. The biphasic mixture was passed through a plastic sintered funnel to remove the solid residue and the aqueous layer, and the collected organic layer was concentrated under reduced pressure. The crude product was crystallized with dichloromethane (3 mL) at room temperature. The resulting precipitate was filtered, washed with dichloromethane, and dried to give methyl 3-fluoro-4-((N-(4-fluorophenyl)-1,1-dioxothiomorpholine-4-carboxamido)methyl)benzoate (0.212 g, 43.9%) as a white solid.

[0244] [Step 3] N-(2-Fluoro-4-(hydrazinocarbonyl)benzyl)-N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide

[0245]

[0246] Methyl 3-fluoro-4-((N-(4-fluorophenyl)-1,1-dioxothiomorpholine-4-carboxamido)methyl)benzoate (0.212 g, 0.484 mmol) prepared in Step 2 and hydrazine monohydrate (0.470 mL, 9.670 mmol) were mixed in ethanol (4 mL) at room temperature, then heated at 120 °C under microwave for 1 h and cooled to room temperature to terminate the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent. Subsequently, water was added to the reaction mixture, and then it was extracted with dichloromethane. The biphasic mixture was passed through a plastic sintered funnel to remove the solid residue and the aqueous layer, and the collected organic layer was concentrated under reduced pressure. The residue was diluted with diethyl ether (5 mL) and ethyl acetate (1 mL) and stirred at ambient temperature. The resulting precipitate was collected by filtration, washed with hexane, and dried to give N-(2-fluoro-4-(hydrazinocarbonyl)benzyl)-N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.179 g, 84.4%) as a white solid.

[0247] [Step 4] Synthesis of Compound 285

[0248]

[0249] At room temperature, a solution of N-(2-fluoro-4-(hydrazinocarbonyl)benzyl)-N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.100 g, 0.228 mmol) and triethylamine (0.095 mL, 0.684 mmol) in dichloromethane (4 mL) was mixed with 2,2-difluoroacetic anhydride (0.028 mL, 0.228 mmol), and the mixture was stirred at the same temperature for 17 h. Subsequently, saturated aqueous sodium bicarbonate was added to the reaction mixture, and then the mixture was extracted with dichloromethane. The biphasic mixture was passed through a plastic sintered funnel to remove solid residues and the aqueous layer, and the collected organic layer was concentrated under reduced pressure. The residue was chromatographed (SiO2, 4 g column; ethyl acetate / hexane = 20% to 50%) to give N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.053 g, 46.6%) as a white solid.

[0250] 1 H NMR (400 MHz, CDCl3) δ 7.90 (dd, 1H, J = 8.0, 1.6 Hz), 7.77 (dd, 1H, J = 10.1, 1.6 Hz), 7.69 (t, 1H, J = 7.6 Hz), 7.14 - 6.81 (m, 5H), 4.90 (s, 2H), 3.74 - 3.71 (m, 4H), 2.85 - 2.82 (m, 4H); LRMS (ES) m / z 499.3 (M + +1).

[0251] Synthesis Example 5. Synthesis of Compound 295 N-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl) methyl)-N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide

[0252] [Step 1] Methyl 6-((N-(4-fluorophenyl)-1,1-dioxothiomorpholine-4-carboxamido)methyl)nicotinate

[0253]

[0254] At 0 °C, a solution of N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.500 g, 1.836 mmol) (Compound 285) prepared in Step 1 of Synthesis Example 4 and sodium hydride (60.00%, 0.081 g, 2.020 mmol) in N,N-dimethylformamide (10 mL) was stirred for 30 minutes and mixed with methyl 6-(bromomethyl)nicotinate (0.465 g, 2.020 mmol). The reaction mixture was stirred at room temperature for an additional 5 hours and quenched at room temperature by the addition of water (5 mL, stirred for 10 minutes). Subsequently, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried (anhydrous MgSO4), filtered and concentrated under reduced pressure. Methyl 6-((N-(4-fluorophenyl)-1,1-dioxothiomorpholine-4-carboxamido)methyl)nicotinate (0.450 g, 58.1%, brown solid) was used without further purification.

[0255] [Step 2] N-(4-Fluorophenyl)-N-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)thiomorpholine-4-carboxamide 1,1-dioxide

[0256]

[0257] At room temperature, methyl 6-((N-(4-fluorophenyl)-1,1-dioxothiomorpholine-4-carboxamido)methyl)nicotinate (0.150 g, 0.356 mmol) prepared in Step 1 and hydrazine monohydrate (0.346 mL, 7.118 mmol) were mixed in ethanol (5 mL), and then stirred at 100 °C for 17 hours and cooled to room temperature. The precipitate was collected by filtration, washed with ethanol, and dried to give N-(4-fluorophenyl)-N-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.111 g, 74.0%) as a pale yellow solid.

[0258] [Step 3] N-((5-(2-(2,2-Difluoroacetyl)hydrazine-1-carbonyl)pyridin-2-yl)methyl)-N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide

[0259]

[0260] At room temperature, a solution of N-(4-fluorophenyl)-N-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.111 g, 0.263 mmol) and triethylamine (0.110 mL, 0.790 mmol) in dichloromethane (5 mL) was mixed with 2,2-difluoroacetic anhydride (0.065 mL, 0.527 mmol), and the mixture was stirred at the same temperature for 1 h. Subsequently, water was added to the reaction mixture, and then it was extracted with dichloromethane. The biphasic mixture was passed through a plastic sintered funnel to remove the solid residue and the aqueous layer, and the collected organic layer was concentrated under reduced pressure. The crude product (0.082 g, 62.3%, yellow solid) was used without further purification.

[0261] [Step 4] Synthesis of Compound 295

[0262]

[0263] At room temperature, N-((5-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)pyridin-2-yl)methyl)-N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.082 g, 0.164 mmol) prepared in Step 3 and 1-methoxy-N-triethylammonium sulfonyl-methanimidate (Burgess reagent, 0.117 g, 0.493 mmol) were mixed in tetrahydrofuran (5 mL), then stirred at 70 °C for 5 h, cooled to room temperature, filtered to remove the solid, and concentrated under reduced pressure. The residue was chromatographed (SiO2, 4 g column; methanol / dichloromethane = 0% to 10%) to give N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.015 g, 19.0%) as a white solid.

[0264] 1 H NMR (400 MHz, CDCl3) δ 9.27 (d, 1H, J = 1.6 Hz), 8.43 (dd, 1H, J = 8.2, 2.2 Hz), 7.58 (d, 2H, J = 8.2 Hz), 7.25 - 7.21 (m, 2H), 7.10 - 6.84 (m, 3H), 5.08 (s, 2H), 3.73 (t, 4H, J = 5.1 Hz), 2.98 (t, 4H, J = 5.2 Hz); LRMS (ES) m / z 482.1 (M + +1).

[0265] Synthesis Example 6. Synthesis of Compound 296 N-((5-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl) methyl)-N-(3-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide

[0266] [Step 1]Methyl 6-((N-(3-fluorophenyl)-1,1-dioxothiomorpholine-4-carboxamido)methyl)nicotinate

[0267]

[0268] A solution of 1-fluoro-3-isocyanatobenzene (0.500 g, 3.647 mmol) in diethyl ether (10 mL) was mixed with thiomorpholine 1,1-dioxide (0.493 g, 3.647 mmol) at 0 °C and stirred at the same temperature for 1 h. The reaction mixture was stirred for an additional 4 h at room temperature. The precipitate was collected by filtration, washed with diethyl ether, and dried to give N-(3-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.870 g, 87.6%) as a white solid.

[0269] A solution of N-(3-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.500 g, 1.836 mmol) and sodium hydride (60.00%, 0.081 g, 2.020 mmol) in N,N-dimethylformamide (10 mL) was stirred at 0 °C for 30 min and mixed with methyl 6-(bromomethyl)nicotinate (0.465 g, 2.020 mmol). The reaction mixture was stirred for an additional 5 h at room temperature and quenched at room temperature by the addition of water (5 mL, stirred for 10 min). Subsequently, water was added to the reaction mixture, and then it was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried (anhydrous MgSO4), filtered, and concentrated under reduced pressure. Methyl 6-((N-(3-fluorophenyl)-1,1-dioxothiomorpholine-4-carboxamido)methyl)nicotinate (0.450 g, 58.1%, brown solid) was used without further purification.

[0270] [Step 2]N-(3-fluorophenyl)-N-((5-(hydrazinocarbonyl)pyridin-2-yl)methyl)thiomorpholine-4-carboxamide 1,1-dioxide

[0271]

[0272] Methyl 6-((N-(3-fluorophenyl)-1,1-dioxothiomorpholine-4-carboxamido)methyl)nicotinate (0.150 g, 0.356 mmol) prepared in Step 1 and hydrazine monohydrate (0.346 mL, 7.118 mmol) were mixed in ethanol (5 mL) at room temperature, then stirred at 100 °C for 17 h and cooled to room temperature. The precipitate was collected by filtration, washed with ethanol, and dried to give N-(3-fluorophenyl)-N-((5-(hydrazinocarbonyl)pyridin-2-yl)methyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.113 g, 75.3%) as a pale yellow solid.

[0273] [Step 3] N-((5-(2-(2,2-Difluoroacetyl)hydrazine-1-carbonyl)pyridin-2-yl)methyl)-N-(3-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide

[0274]

[0275] A solution of N-(3-fluorophenyl)-N-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.113 g, 0.268 mmol) and triethylamine (0.112 mL, 0.804 mmol) in dichloromethane (5 mL) prepared in Step 2 was mixed with 2,2-difluoroacetic anhydride (0.067 mL, 0.536 mmol) at room temperature and stirred at the same temperature for 1 h. Subsequently, water was added to the reaction mixture, which was then extracted with dichloromethane. The biphasic mixture was passed through a plastic sintered funnel to remove solid residues and the aqueous layer, and the collected organic layer was concentrated under reduced pressure. N-((5-(2-(2,2-Difluoroacetyl)hydrazine-1-carbonyl)pyridin-2-yl)methyl)-N-(3-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.090 g, 67.2%, yellow solid) was used without further purification.

[0276] [Step 4] Synthesis of Compound 296

[0277]

[0278] N-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)-N-(3-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.090 g, 0.180 mmol) prepared in Step 3 and 1-methoxy-N-triethylammonium sulfonyl-methanimidate (Burgess reagent, 0.129 g, 0.541 mmol) were mixed in tetrahydrofuran (5 mL) at room temperature, then stirred at 70 °C for 5 h, cooled to room temperature, filtered to remove solids, and concentrated under reduced pressure. The residue was chromatographed (SiO2, 4 g column; methanol / dichloromethane = 0% to 10%) to give N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-(3-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.044 g, 50.7%) as a white solid.

[0279] 11H NMR (400 MHz, CDCl3) δ 9.28 (d, 1H, J = 1.6 Hz), 8.46 (dd, 1H, J = 8.2, 2.2 Hz), 7.58 (d, 1H, J = 8.2 Hz), 7.37 - 7.32 (m, 1H), 7.10 - 6.92 (m, 4H), 5.14 (s, 2H), 3.76 (t, 4H, J = 5.1 Hz), 3.03 (t, 4H, J = 5.2 Hz); LRMS (ES) m / z 482.3 (M + + 1).

[0280] <Example 1> Confirmation of the preventive or therapeutic effect on renal failure 1

[0281] Through this experiment, an attempt was made to confirm the effect of the compounds of the present disclosure on renal function related to renal fibrosis and glomerulosclerosis.

[0282] Six-week-old C57BL / 6J mice were fed a 0.2% adenine diet for two weeks to prepare an animal model with chronic renal failure. The compound of Example 1 (Compound 43) was orally administered to the mice with adenine-induced chronic renal failure twice a day for two weeks (experimental group, Compound 43). Meanwhile, for the induction group (vehicle), a vehicle was orally administered to the mice with adenine-induced chronic renal failure twice a day, and a vehicle was orally administered to normal mice (control) twice a day.

[0283] The animals were provided with a standard diet (Central Lab Animal, Inc.), a 0.2% adenine diet (ENVIGO), and unlimited water, and were housed in a controlled environment at a temperature of (22 ± 2°C), a humidity of (44% - 56%), and a 12-hour light-dark cycle. All experimental procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of the Korea CKD Laboratory Animal Center and were conducted accordingly (IACUC animal research protocol approval number: S-21-037).

[0284] Each group was classified as shown in Table 1 below.

[0285] [Table 1]

[0286]

[0287] In an animal model of adenine-induced chronic renal failure, the compound of formula I (compound 43 of Preparation Example 1) was repeatedly administered to the experimental group twice daily for two weeks, in combination with a 0.2% adenine diet. Two weeks after the administration, the kidneys were obtained by sacrificing the mice.

[0288] To determine the degree of renal fibrosis, the kidneys of the mice were fixed in 10% neutral buffered formalin (NBF) to allow paraffin to infiltrate the kidney tissues of the mice, followed by embedding, and then the corresponding blocks were sagittally sectioned to a thickness of 4 μm, and thus Masson's trichrome staining was performed, and then images were captured using an image analyzer (NIS-Elements BR 5.11.01 (Nikon)). Regarding the relative fibrosis area, the average value was calculated by measuring the positive area compared to the total area, and the evaluation was performed as follows: when the tubulointerstitial fibrosis was normal, the tubulointerstitial fibrosis score was 0; when it was less than or equal to 10%, it was 1; when it was greater than 10% and less than or equal to 25%, it was 2; when it was greater than 25% and less than or equal to 75%, it was 3; when it was greater than or equal to 75%, it was 4.

[0289] To determine the glomerulosclerosis of the kidneys, the kidneys of the mice were fixed in 10% neutral buffered formalin (NBF) to allow paraffin to infiltrate the kidney tissues of the mice, followed by embedding, and then the corresponding blocks were sagittally sectioned to a thickness of 4 μm, and thus periodic acid Schiff (PAS) staining was performed, and then images were captured using an image analyzer (NIS-Elements BR 5.11.01 (Nikon)). Regarding the glomerulosclerosis (GS) index, depending on the number of glomeruli showing the corresponding lesions, the evaluation was performed as follows: when normal, it was 0; when less than 25%, it was 1; when greater than or equal to 25% but less than 50%, it was 2; when greater than or equal to 50% but less than 75%, it was 3; when the lesions were visible throughout, it was 4.

[0290] All results were presented as mean ± SEM and analyzed using GraphPad Prism 5 (GraphPad Software, Inc., USA), and statistical analysis was performed by one-way ANOVA (multiple comparisons).

[0291] The analysis results of the relative fibrosis area, tubulointerstitial fibrosis score, and glomerulosclerosis score are shown in Figure 1 and Figure 2 In the above Figure 1 and Figure 2 the error bars can refer to ±SEM (standard error of the mean) (vehicle vs. each group), **p < 0.01, ****p < 0.0001).

[0292] As confirmed from the above Figure 1 and Figure 2 it can be seen that Compound 43 (Preparation Example 1) reduces renal fibrosis and alleviates renal sclerosis in an animal model with renal failure.

[0293] Therefore, it can be seen that the compounds of the present disclosure can be advantageously used for the prevention and treatment of renal failure diseases.

[0294] <Example 2> Confirmation 2 of the preventive or therapeutic effect of renal failure

[0295] Through this experiment, the change in the level of acetylated α-tubulin (Ace-tub) according to the administration of the compounds of the present disclosure was measured to confirm the preventive and therapeutic effects of the compounds of the present disclosure on renal failure.

[0296] Six-week-old C57BL / 6J mice were fed a 0.2% adenine diet for two weeks to prepare an animal model with chronic renal failure. The mice with adenine-induced chronic renal failure were orally administered Preparation Example 1 (Compound 43) twice a day for two weeks (experimental group, Compound 43). Meanwhile, for the induction group (vehicle), the vehicle was orally administered to the mice with adenine-induced chronic renal failure twice a day, and the vehicle was orally administered to the mice in the normal group (control) twice a day.

[0297] The animals were provided with a standard diet (Central Lab Animal, Inc.), a 0.2% adenine diet (ENVIGO), and unlimited water, and were housed in a controlled environment at a temperature of (22 ± 2°C), a humidity of (44% - 56%), and a 12-hour light-dark cycle. All experimental procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of the CKD Experimental Animal Center in Korea and were conducted accordingly (IACUC animal research protocol approval number: S-21-037).

[0298] Each group was classified as shown in Table 2 below.

[0299] [Table 2]

[0300]

[0301] To confirm the preventive and therapeutic effects of the compounds of Formula I according to the present disclosure on renal failure diseases, the expression of acetyl-α-tubulin in mice with adenine-induced chronic renal failure was analyzed, and the results are shown in Figure 3 below.

[0302] In an animal model of adenine-induced chronic renal failure, the compound of formula I (Compound 43 of Preparation Example 1) was repeatedly administered to the experimental group once daily for two weeks, in combination with a 0.2% adenine diet. After two weeks of administration, the kidneys of the mice were homogenized using RIPA buffer and then centrifuged at 13,000 rpm for 20 minutes at 4°C. After centrifugation, the supernatant was transferred to a new tube, and the protein concentration was measured using a BCA Protein Assay Kit (PIERCE). 20 μg of protein was loaded onto a NuPAGE Bis-Tris gel (Invitrogen), and then the proteins in the gel were transferred to a nitrocellulose membrane using iBlot 2 Gel Transfer. Thereafter, acetylated α-tubulin (Ace-tub) and α-tubulin (α-tub) antibodies were added to a 3% bovine serum albumin (BSA) solution and incubated with the nitrocellulose membrane at 4°C. After incubation, protein expression was measured using a detection reagent (Thermo Scientific) and a ChemiDocTM MP (BIO-RAD, 12003154) device, and analysis was performed using BIO-RAD's Image Lab software (version 5.0).

[0303] All results are expressed as mean ± SEM and were analyzed using GraphPad Prism 5 (GraphPad Software, Inc., USA), and statistical analysis was performed using one-way ANOVA (multiple comparisons).

[0304] The analysis results of Ace-tub and α-tub are shown in Figure 3 In Figure 3 the error bars represent ± SEM (standard error of the mean) (vehicle vs. each group, **p < 0.05, ****p < 0.0001).

[0305] As shown above in Figure 3 it was confirmed that Compound 43 (Preparation Example 1) increased the acetylation of tubulin in an animal model of renal failure.

[0306] Therefore, it can be seen that the compounds of the present disclosure can be advantageously used for the prevention and treatment of renal failure diseases.

[0307] <Example 3> Confirmation of the preventive or therapeutic effect on renal failure 3

[0308] Through this experiment, the degree of change in the expression of type I collagen α1 (COL1A1) related to fibrosis according to the administration of the compounds of the present disclosure was identified to confirm the preventive and therapeutic effects of the compounds of the present disclosure on renal failure.

[0309] Six-week-old C57BL / 6J mice were fed a 0.2% adenine diet for two weeks to prepare an animal model with chronic renal failure. The compound of Example 1 (Compound 43) was orally administered to the mice with adenine-induced chronic renal failure twice a day for two weeks (experimental group, Compound 43). Meanwhile, for the induction group, a carrier was orally administered to the mice with adenine-induced chronic renal failure twice a day, and a carrier was orally administered to the mice in the normal group (control) twice a day.

[0310] The animals were provided with a standard diet (Central Lab Animal, Inc.), a 0.2% adenine diet (ENVIGO), and unlimited water, and were housed in a controlled environment at a temperature of (22 ± 2°C), a humidity of (44% - 56%), and a 12-hour light-dark cycle. All experimental procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of the CKD Experimental Animal Center in Korea and were conducted accordingly (IACUC animal research protocol approval number: S-21-037).

[0311] Each group was classified as shown in Table 3 below.

[0312] [Table 3]

[0313]

[0314] The expression of type I collagen α1 (COL1A1) related to renal fibrosis was analyzed to confirm the effect of the compound of Formula I according to the present disclosure in preventing and treating renal failure diseases.

[0315] In the animal model with adenine-induced chronic renal failure, the compound of Formula I (Compound 43 of Preparation Example 1) was repeatedly administered to the experimental group once a day for two weeks, in combination with a 0.2% adenine diet. After two weeks of administration, the kidneys of the mice were homogenized using RIPA buffer, and then centrifuged at 13,000 rpm for 20 minutes at 4°C. After centrifugation, the supernatant was transferred to a new tube, and the protein concentration was measured using a BCA protein assay kit (PIERCE). 20 μg of protein was loaded onto a NuPAGE Bis-Tris gel (Invitrogen), and then the protein in the gel was transferred to a nitrocellulose membrane using iBlot 2 Gel Transfer. Thereafter, COL1A1 and GAPDH antibodies were added to a 3% bovine serum albumin (BSA) solution and incubated with the nitrocellulose membrane at 4°C. After incubation, the protein expression was measured using a detection reagent (ThermoScientific) and a ChemiDocTM MP (BIO-RAD, 12003154) device, and analyzed using BIO-RAD's Image Lab software (version 5.0).

[0316] All results are expressed as mean ± SEM and analyzed using GraphPad Prism 5 (GraphPad Software, Inc., USA), and statistical analysis is performed using one-way ANOVA (multiple comparisons).

[0317] The expression of COL1A1 was analyzed to compare the degree of renal fibrosis in each group, and the results are shown below Figure 4 in. Figure 4 In, error bars represent ±SEM (standard error of the mean) (vehicle vs. each group, **p < 0.01, ****p < 0.0001).

[0318] As Figure 4 shown in, it was observed that Compound 43 (Preparation Example 1) decreased the expression of COL1A1 in mice with chronic renal failure.

[0319] Therefore, it can be seen that the compounds according to the present disclosure have an effect of inhibiting renal fibrosis in patients with renal failure and are thus advantageously used for preventing or treating renal failure diseases.

[0320] <Example 4> Confirmation of the preventive or therapeutic effect on renal failure 4

[0321] Through this experiment, an attempt was made to confirm the effect of the compounds of the present disclosure on renal function related to renal failure.

[0322] Six-week-old C57BL / 6J mice were fed a 0.2% adenine diet for two weeks to prepare an animal model with chronic renal failure. Preparation Example 1 (Compound 43) was orally administered to the mice with adenine-induced chronic renal failure twice a day for two weeks (experimental group, Compound 43). At the same time, for the induction group (vehicle), a vehicle was orally administered to the mice with adenine-induced chronic renal failure twice a day, and a vehicle was orally administered to the mice in the normal group (control) twice a day.

[0323] The animals were provided with a standard diet (Central Lab Animal, Inc.), a 0.2% adenine diet (ENVIGO), and unlimited water, and were housed in a controlled environment at a temperature of (22 ± 2°C), a humidity of (44% - 56%), and a 12-hour light-dark cycle. All experimental procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of the CKD Experimental Animal Center in Korea and were conducted accordingly (IACUC animal research protocol approval number: S-21-037).

[0324] Each group was classified as shown in Table 4 below.

[0325] [Table 4]

[0326]

[0327] In an animal model of adenine-induced chronic renal failure, the compound of formula I (Compound 43 of Preparation Example 1) was repeatedly administered to the experimental group twice daily for two weeks, in combination with a 0.2% adenine diet. Two weeks after administration, the blood of the mice was placed in EDTA-treated tubes and centrifuged to determine the concentration of blood urea nitrogen (BUN). The plasma, which was the supernatant, was transferred to new tubes. The plasma was added to sample cups using a biochemical analyzer (HITACHI-7020), and the BUN concentration was measured using a blood urea nitrogen (BUN) reagent (WAKO, 416-55192, 416-55292).

[0328] All results are presented as mean ± SEM and were analyzed using GraphPad Prism 5 (GraphPad Software, Inc., USA), and statistical analysis was performed using one-way ANOVA (multiple comparisons).

[0329] The results of the determination of the blood urea nitrogen (BUN) concentration are shown below Figure 5 in. In Figure 5 it, the error bars represent ±SEM (standard error of the mean) (vehicle vs. each group, ****p < 0.0001).

[0330] As confirmed from the above Figure 5 it can be seen that Compound 43 (Preparation Example 1) reduces the BUN concentration in mice with chronic renal failure.

[0331] Therefore, it can be seen that the compounds according to the present disclosure have the effect of improving the renal function of patients with renal failure, and can thus be advantageously used for the prevention or treatment of renal failure diseases.

[0332] The present disclosure provides the following pharmaceutical compositions, prevention and treatment methods, and prevention and treatment uses:

[0333] Item 1. A pharmaceutical composition for preventing and treating renal failure, comprising a compound represented by the above formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0334] Item 2. The pharmaceutical composition according to Item 1, wherein the compound represented by the above formula I is at least one selected from Compounds 1 to 450 described in Table A mentioned above.

[0335] Item 3. The pharmaceutical composition according to Item 1 or 2, wherein the compound represented by the above formula I is at least one selected from the following: Compound 40, Compound 43, Compound 239, Compound 285, Compound 295, and Compound 296 described in Table B mentioned above.

[0336] Item 4. A method for preventing and treating renal failure, which comprises administering to an individual a compound represented by formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as described in any one of Items 1 to 3.

[0337] Item 5. Use of a compound represented by formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as described in any one of Items 1 to 3 for preventing and treating renal failure.

[0338] Item 6. Use of a compound represented by formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as described in any one of Items 1 to 3 in the preparation of a medicament for preventing and treating renal failure.

[0339] Item 7. The pharmaceutical composition according to any one of Items 1 to 3, the method according to Item 4, or the use according to Item 5 or 6, wherein the renal failure is at least one selected from acute renal failure and chronic renal failure.

[0340] Item 8. The pharmaceutical composition according to any one of Items 1 to 3, wherein the pharmaceutical composition is administered orally.

[0341] Item 9. The method according to Item 4 or the use according to Item 5 or 6, wherein the compound represented by formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as described in any one of Items 1 to 3 is administered orally.

[0342] Although specific parts of the present invention have been described in detail above, it will be apparent to those skilled in the art that such detailed descriptions are only for illustrative embodiments and should not be construed as limiting the scope of the present invention. Therefore, it should be understood that the substantial scope of the present invention is defined by the scope of the appended claims and their equivalents.

Claims

1. A pharmaceutical composition for preventing and treating renal failure, which comprises a compound represented by the following formula I, its optical isomer or its pharmaceutically acceptable salt as an active ingredient: [Formula I] In Formula I, wherein L1, L2 or L3 are each independently a bond or -(C1-C2 alkylene)-; R1 is -CX2H or -CX3; R2 is -NR A R B , -OR C , {wherein at least one H of D R E can be substituted by the following: -X, -OH, -O(C1-C4 alkyl), -NR D R E , -(C1-C4 alkyl), -CF3, -CF2H, -CN, -aryl, -heteroaryl, -(C1-C4 alkyl)-aryl or -(C1-C4 alkyl)-heteroaryl, [wherein at least one H of the said -aryl, -heteroaryl, -(C1-C4 alkyl)-aryl or -(C1-C4 alkyl)-heteroaryl can be substituted by -X, -OH, -CF3 or -CF2H]}; R3 is -H, -(C1-C4 alkyl), -(C1-C4 alkyl)-O(C1-C4 alkyl), -(C1-C4 alkyl)-C(=O)-O(C1-C4 alkyl), -(C3-C7 cycloalkyl), -(C2-C6 heteroalkyl), -aryl, -heteroaryl, -adamantyl, {wherein at least one H of -(C1-C4 alkyl) can be substituted by -X or -OH, At least one H of -aryl or -heteroaryl may each independently be substituted by: -X, -OH, -O(C1-C4 alkyl), -OCF3, -O-aryl, -NR D R E , -(C1-C4 alkyl), -CF3, -CF2H, -C(=O)-(C1-C4 alkyl), -C(=O)-O(C1-C4 alkyl), -C(=O)-NR D R E , -S(=O)2-(C1-C4 alkyl), aryl, heteroaryl, [wherein at least one H of D R E may be substituted by -X, -(C1-C4 alkyl), -NR D R E , -CF3 or -CF2H], -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), adamantyl, at least one H of which may each independently be substituted by -X, -OH or -(C1-C4 alkyl)}; Y1, Y2 and Y4 are each independently -CH2-, -NR F -, -O-, -C(=O)- or -S(=O)2-; Y3 is -CH- or -N-; Z1 to Z4 are each independently N or CR Z , where at least three of Z1 to Z4 cannot be N simultaneously, and R Z is -H, -X or -O(C1-C4 alkyl)}; Z5 and Z6 are each independently -CH2- or -O-; Z7 and Z8 are each independently =CH- or =N-; Z9 is -NR G - or -S-; R A and R B each independently is -H, -(C1-C4 alkyl), -(C1-C4 alkyl)-OH, -(C1-C4 alkyl)-NR D R E , -aryl, -(C1-C4 alkyl)-aryl, -heteroaryl, -(C1-C4 alkyl)-heteroaryl, -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl) or wherein at least one H of said -(C1-C4 alkyl), -(C1-C4 alkyl)-OH or -(C1-C4 alkyl)-NR D R E can be replaced by -X, at least one H of said -aryl, -(C1-C4 alkyl)-aryl, -heteroaryl, -(C1-C4 alkyl)-heteroaryl, -(C3-C7 cycloalkyl) or -(C2-C6 heterocycloalkyl) can be substituted by the following: -X, -OH, -O(C1-C4 alkyl), -(C1-C4 alkyl), -CF3, -CF2H or -CN, At least one H may be replaced by the following: -X, -OH, -O(C1-C4 alkyl), -(C1-C4 alkyl), -CF3, -CF2H, -CN, -(C2-C6 heterocycloalkyl), -aryl, -(C1-C4 alkyl)-aryl, -heteroaryl or -heteroaryl-(C1-C4 alkyl)}; R C is -(C1-C4 alkyl), -aryl, -(C1-C4 alkyl)-aryl, -heteroaryl or -(C1-C4 alkyl)-heteroaryl, {wherein at least one H of -(C1-C4 alkyl) can be replaced by -X or -OH, and at least one H of -aryl, -(C1-C4 alkyl)-aryl, -heteroaryl or -(C1-C4 alkyl)-heteroaryl can be replaced by -X, -OH, -CF3 or -CF2H}; R D and R E each independently is -H, -(C1-C4 alkyl), -aryl or -(C1-C4 alkyl)-aryl, {wherein at least one H of -(C1-C4 alkyl) may be replaced by -X or -OH, and at least one H of -aryl or -(C1-C4 alkyl)-aryl may be replaced by -X, -OH, -CF3 or -CF2H}; R F is -H, -(C1-C6 alkyl), -(C1-C4 alkyl)-OH, -(C1-C4 alkyl)-O-(C1-C4 alkyl), -C(=O)-(C1-C4 alkyl), -C(=O)-O(C1-C4 alkyl), -(C1-C4 alkyl)-C(=O)-O(C1-C4 alkyl), -(C1-C4 alkyl)-NR D R E , -S(=O)2-(C1-C4 alkyl), -aryl, -(C1-C4 alkyl)-aryl, -(C2-C4 alkenyl)-aryl, -heteroaryl, -(C1-C4 alkyl)-heteroaryl, -C(=O)-(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl) or -(C1-C4 alkyl)-C(=O)-(C2-C6 heterocycloalkyl) wherein at least one H of -(C1-C4 alkyl), -(C1-C4 alkyl)-OH, -(C1-C4 alkyl)-O-(C1-C4 alkyl), -C(=O)-(C1-C4 alkyl), -C(=O)-O(C1-C4 alkyl), -(C1-C4 alkyl)-C(=O)-O(C1-C4 alkyl), -(C1-C4 alkyl)-NR D R E or -S(=O)2-(C1-C4 alkyl) may be substituted by -X, at least one H of -aryl, -(C1-C4 alkyl)-aryl, -(C2-C4 alkenyl)-aryl, -heteroaryl, -(C1-C4 alkyl)-heteroaryl, -C(=O)-(C3-C7 cycloalkyl), -C2-C6 heterocycloalkyl or -(C1-C4 alkyl)-C(=O)-(C2-C6 heterocycloalkyl) can be substituted by -X, -OH, -CF3 or -CF2H}; R G is -H or -(C1-C4 alkyl); Q is -O- or a bond; is a single bond or a double bond, provided that is a double bond and Y1 is =CH-}; a to e are each independently an integer of 0, 1, 2, 3 or 4 {provided that a and b cannot be 0 at the same time, and c and d cannot be 0 at the same time}; X is each independently F, Cl, Br or I.

2. The pharmaceutical composition according to claim 1, wherein in the compound represented by Formula I, L1, L2 or L3 are each independently a bond or -(C1-C2 alkylene)-; R1 is -CX2H or -CX3; R2 is -NR A R B 、-OR C 、 {wherein at least one H of D R E can be substituted by -X, -OH, -NR R, -(C1-C4 alkyl)}; R3 is -(C1-C4 alkyl), -(C3-C7 cycloalkyl), -aryl, -heteroaryl, -adamantyl, At least one H of the -aryl or -heteroaryl may each independently be substituted by: -X, -O(C1-C4 alkyl), -OCF3, -O-aryl, -NR D R E , -(C1-C4 alkyl), -CF3, -S(=O)2-(C1-C4 alkyl), -aryl, -heteroaryl, [wherein at least one H may be substituted by -NR D R E or -(C1-C4 alkyl)], at least one H may each independently be substituted by -(C1-C4 alkyl); Y1, Y2, and Y4 are each independently -CH2-, -NR F -, -O-, -C(=O)-, or -S(=O)2-; Y3 is -CH- or -N-; Z1 to Z4 are each independently N or CR Z {wherein at least three of Z1 to Z4 cannot be N simultaneously, and R Z is -H, -X or -O(C1-C4 alkyl)}; Z5 and Z6 are each independently -CH2- or -O-; Z7 and Z8 are each independently =CH- or =N-; Z9 is -NR G - or -S-; R A and R B each independently is -H, -(C1-C4 alkyl), -(C1-C4 alkyl)-OH, -(C1-C4 alkyl)-NR D R E , -aryl, -(C1-C4 alkyl)-aryl, -(C3-C7 cycloalkyl) or {wherein at least one H may be replaced by: -X, -(C1-C4 alkyl), -CF3, -(C2-C6 heterocycloalkyl), -(C1-C4 alkyl)-aryl, -heteroaryl or heteroaryl-(C1-C4 alkyl)}; R C is -(C1-C4 alkyl) or -aryl; R D and R E each independently is -H, -(C1-C4 alkyl) or -(C1-C4 alkyl)-aryl; R F is -H, -(C1-C6 alkyl), -(C1-C4 alkyl)-OH, -(C1-C4 alkyl)-O-(C1-C4 alkyl), -C(=O)-(C1-C4 alkyl), -C(=O)-O(C1-C4 alkyl), -(C1-C4 alkyl)-C(=O)-O(C1-C4 alkyl), -(C1-C4 alkyl)-NR D R E , -S(=O)2-(C1-C4 alkyl), -aryl, -(C1-C4 alkyl)-aryl, -(C2-C4 alkenyl)-aryl, -heteroaryl, -(C1-C4 alkyl)-heteroaryl, -C(=O)-(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl) or -(C1-C4 alkyl)-C(=O)-(C2-C6 heterocycloalkyl) {wherein at least one H of -(C1-C4 alkyl) or -C(=O)-O(C1-C4 alkyl) can be substituted by -X, at least one H of -aryl can be substituted by -X}; R G is -(C1-C4 alkyl); Q is -O- or a bond; is a single bond or a double bond {provided that is a double bond and Y1 is -CH-}; a to e are each independently an integer of 0, 1, 2, 3 or 4 {provided that a and b cannot be 0 at the same time, and c and d cannot be 0 at the same time}; X is each independently F, Cl, Br or I.

3. The pharmaceutical composition according to claim 1, wherein the compound represented by Formula I is a compound represented by Formula Ia: [Formula Ia] In Formula Ia, wherein, R2 is R3 is -aryl {wherein at least one H of -aryl can be independently substituted by -X}; Y1 is -O- or -S(=O)2-; Z1 is N or CR Z {wherein R Z is -X}; a and b are each independently an integer of 0, 1, 2, 3 or 4 {wherein a and b cannot be 0 at the same time}; X is each independently F, Cl, Br or I.

4. The pharmaceutical composition according to claim 1, wherein in the compound represented by Formula Ia, R2 is R3 is -phenyl {wherein at least one H of -phenyl is independently replaced by -F or -Cl}; Y1 is -O- or -S(=O)2-; Z1 is N or CF.

5. A pharmaceutical composition for preventing and treating renal failure, which comprises a compound having the structure of the following [Table A], its optical isomer or its pharmaceutically acceptable salt as an active ingredient: [Table A] 6. A pharmaceutical composition for preventing and treating renal failure, which comprises a compound having the structure of the following [Table B], its optical isomer or its pharmaceutically acceptable salt as an active ingredient: [Table B] 7. The pharmaceutical composition according to claim 6, wherein the renal failure is at least one selected from acute renal failure and chronic renal failure.

8. The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition is administered orally.

9. A method for preventing and treating renal failure, which comprises administering to an individual the compound represented by Formula I, its optical isomer or its pharmaceutically acceptable salt, wherein the compound represented by the above Formula I is the same as the compound in claim 1.

10. A method for preventing and treating renal failure, which comprises administering to an individual a compound having the structure of [Table A] in claim 5, its optical isomer or its pharmaceutically acceptable salt.

11. A method for preventing and treating renal failure, which comprises administering to an individual a compound having the following structure of [Table B], its optical isomer or its pharmaceutically acceptable salt: [Table B] 12. The method according to claim 11, wherein the renal failure is at least one selected from acute renal failure and chronic renal failure.

13. Use of the compound represented by Formula I, its optical isomer or its pharmaceutically acceptable salt for preventing and treating renal failure, wherein the compound represented by the above Formula I is the same as the compound in claim 1.

14. Use of a compound having the structure of [Table A] in claim 5, its optical isomer or its pharmaceutically acceptable salt for preventing and treating renal failure.

15. Use of a compound having the following structure of [Table B], its optical isomer or its pharmaceutically acceptable salt for preventing and treating renal failure: [Table B] 16. The use according to claim 15, wherein the renal failure is at least one selected from acute renal failure and chronic renal failure.

17. Use of the compound represented by Formula I, its optical isomer or its pharmaceutically acceptable salt in the preparation of a drug for preventing and treating renal failure, wherein the compound represented by the above Formula I is the same as the compound in claim 1.

18. Use of the compound having the structure of [Table A] according to claim 5, its optical isomer or its pharmaceutically acceptable salt in the preparation of a drug for preventing and treating renal failure.

19. Use of a compound having the following structure of [Table B], its optical isomer or its pharmaceutically acceptable salt in the preparation of a drug for preventing and treating renal failure: [Table B] 20. The use according to claim 19, wherein the renal failure is at least one selected from acute renal failure and chronic renal failure.

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