Composition for preventing and treating renal failure

Abstract

The present invention relates to a pharmaceutical composition for preventing and treating renal failure, which comprises, as an active ingredient, a compound represented by formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof; a method for preventing and treating renal failure using said compound; use of said compound for preventing and treating renal failure; and use of said compound in the manufacture of a medicament for preventing and treating renal failure.

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition for preventing and treating renal failure, which comprises, as an active ingredient, a compound represented by formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof; a method for preventing and treating renal failure using said compound; use of said compound for preventing and treating renal failure; and use of said compound in the manufacture of a medicament for preventing and treating renal failure. [Background technology]

[0002] Renal failure (RF) is a condition in which the kidneys are no longer able to perform their functions adequately, and can be classified into acute renal failure and chronic renal failure.

[0003] Acute renal failure has a variety of causes, but can be broadly classified into three types. First, there may be no abnormality found in the kidneys themselves, but a lack of blood flow to the kidneys due to a decline in overall bodily function. Second, abnormalities may occur in the kidneys themselves, preventing urine production and causing blockage of the urethra and bladder, through which urine is ultimately excreted. Chronic renal failure is caused by polycystic kidney disease, glomerulonephritis, diabetes, hypertension, etc., and refers to a persistent decline in kidney function for three months or more. Chronic renal failure is classified into five stages depending on the degree of kidney damage and the degree of decline in function, and if not properly managed, it can worsen to end-stage renal failure.

[0004] The treatment of renal failure aims to prevent kidney disease that causes persistent deterioration of kidney function, or, once chronic deterioration of kidney function has begun, to slow the rate of progression and reduce the incidence of end-stage renal failure. Drug therapy is used to treat the underlying disease, but once the condition has progressed, it is often impossible to identify the underlying disease (Lancet 2012;379:165-180, Kidney Int 2012;81:351-362).

[0005] Therefore, there is currently no appropriate treatment for renal failure, and because steroids and immunosuppressants can cause a decline in renal function, there is a significant unmet medical need, and there is a strong demand for the development of drugs that can prevent and treat this. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Republic of Korea Patent Publication No. 10-2017-0017792 [Non-patent literature]

[0007] [Non-Patent Document 1] Qing Hou et al.,Front Pharmacol.2022 Jul 14;13:938391 [Non-patent document 2] Seung Seob Son et al.,Sci Rep.2021 Jan 26;11(1):2191 [Non-patent document 3] Xingying Chen et al.,Am J PhysiolRenal Physiol.2020 Dec Summary of the Invention [Problem to be solved by the invention]

[0008] The present invention provides a pharmaceutical composition for preventing and treating renal failure, which comprises, as an active ingredient, a compound represented by formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0009] The present invention provides a method for preventing and treating renal failure, which comprises administering to an individual a compound represented by the above formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0010] The present invention provides use of a compound represented by the above formula I, an optical isomer thereof or a pharmaceutically acceptable salt thereof for the prevention and treatment of renal failure.

[0011] The present invention provides use of a compound represented by the above formula I, an optical isomer thereof or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention and treatment of renal failure. [Means for solving the problem]

[0012] The present invention will be described in detail below. Each description and embodiment disclosed in the present invention can be applied to each of the other descriptions and embodiments. That is, all combinations of the various elements disclosed in the present invention fall within the scope of the present invention. Furthermore, the scope of the present invention is not limited to the specific description described below.

[0013] The present invention provides a compound represented by formula I: [ka]

[0014] In the above 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 ,

[0015] [ka] and

[0016] {where: [ka] One or more H in the formula (I) may be -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 one or more H of the -aryl, -heteroaryl, -(C1-C4 alkyl)-aryl, or -(C1-C4 alkyl)-heteroaryl may be replaced by -X, -OH, -CF3, or -CF2H;

[0017] 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 cycloheteroalkyl), -aryl, -heteroaryl, -adamantyl; [ka] and

[0018] wherein one or more H of -(C1-C4 alkyl) may be replaced with -X or -OH; One or more H in -aryl or -heteroaryl are each independently selected from -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, [ka] may be substituted with, [ka] One or more H in the formula (I) may be -X, -(C1-C4 alkyl), -NR D R E , -CF3, or -CF2H],

[0019] -(C3-C7 cycloalkyl), -(C2-C6 cycloheteroalkyl), adamantyl, [ka] one or more H may each independently be replaced with -X, -OH, or -(C1-C4 alkyl);

[0020] Y1, Y2 and Y4 each independently represent -CH2-, -NR F -, -O-, -C(=O)-, or -S(=O)2-; Y3 is -CH- or -N-; Z1 to Z4 each independently represent N or CR Z where Z1 to Z4 cannot be three or more Ns at the same time, 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-NR G -or-S-;

[0021] R A and R B are each independently -H, -(C1-C4 alkyl), -(C1-C4 alkyl)-OH, or -(C1-C4 alkyl)-NR D R E , -aryl, -(C1-C4 alkyl)-aryl, -heteroaryl, -(C1-C4 alkyl)-heteroaryl, -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), or [ka] and

[0022] {wherein —(C1-C4 alkyl), —(C1-C4 alkyl)-OH, or —(C1-C4 alkyl)-NR D R E one or more H may be replaced by -X;

[0023] one or more H of -aryl, -(C1-C4 alkyl)-aryl, -heteroaryl, -(C1-C4 alkyl)-heteroaryl, -(C3-C7 cycloalkyl), or -(C2-C6 heterocycloalkyl) may be replaced with -X, -OH, -O(C1-C4 alkyl), -(C1-C4 alkyl), -CF3, -CF2H, or -CN;

[0024] [ka] wherein one or more H may be replaced by -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);

[0025] R C is -(C1-C4 alkyl), -aryl, -(C1-C4 alkyl)-aryl, -heteroaryl, or -(C1-C4 alkyl)-heteroaryl {wherein one or more H of -(C1-C4 alkyl) may be replaced with -X or -OH, and one or more H of -aryl, -(C1-C4 alkyl)-aryl, -heteroaryl, or -(C1-C4 alkyl)-heteroaryl may be replaced with -X, -OH, -CF3, or -CF2H};

[0026] R D and R Eare each independently -H, -(C1-C4 alkyl), -aryl, or -(C1-C4 alkyl)-aryl {wherein one or more H of -(C1-C4 alkyl) may be replaced with -X or -OH, and one or more H of -aryl or -(C1-C4 alkyl)-aryl may be replaced with -X, -OH, -CF3, or -CF2H};

[0027] 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);

[0028] {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 E or -S(=O) One or more H of 2-(C1-C4 alkyl) may be replaced by -X; one or more H in -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 with -X, -OH, -CF3 or -CF2H};

[0029] R G is -H or -(C1-C4 alkyl); Q is -O- or a bond;

[0030] [ka] is a single or double bond {provided that: [ka] is a double bond, then Y1 is =CH-};

[0031] a to e are each independently an integer of 0, 1, 2, 3, or 4 {provided that a and b cannot both be zero, and c and d cannot both be zero}; A method for treating renal failure (Renal failure) comprising, as an active ingredient, a compound represented by formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is independently F, Cl, Br, or I. The present invention provides a pharmaceutical composition for the prevention and treatment of Recurrent Fatal and Recurrent Syndrome (RF).

[0032] In the pharmaceutical composition according to the present invention, the compound represented by formula I is L1, L2, or L3 are each independently a bond or -(C1-C2 alkylene)-; R1 is -CX2H or -CX3;

[0033] R2 is -NR A R B , -OR C , [ka] and

[0034] {where: [ka] One or more H in the group is -X, -OH, -NR D R E , optionally substituted with -(C1-C4 alkyl)};

[0035] R3 is -(C1-C4 alkyl), -(C3-C7 cycloalkyl), -aryl, -heteroaryl, -adamantyl, [ka] and

[0036] wherein one or more H of -aryl or -heteroaryl are each independently -X, -O(C1-C4 alkyl), -OCF3, -O-aryl, -NR D R E , -(C1-C4 alkyl), -CF3, -S(=O)2-(C1-C4 alkyl), -aryl, -heteroaryl, [ka] may be substituted with, [ka] One or more H in -NR D R E or -(C1-C4 alkyl)],

[0037] [ka] one or more H may each independently be substituted with -(C1-C4 alkyl);

[0038] Y1, Y2 and Y4 each independently represent -CH2-, -NR F -, -O-, -C(=O)- or -S(=O)2-; Y3 is -CH- or -N-; Z1 to Z4 each independently represent N or CR Z where Z1 to Z4 cannot be three or more Ns at the same time, 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-NR G -or-S-;

[0039] R A and R B are each independently -H, -(C1-C4 alkyl), -(C1-C4 alkyl)-OH, or -(C1-C4 alkyl)-NR D R E , -aryl, -(C1-C4 alkyl)-aryl, -(C3-C7 cycloalkyl), or [ka] and

[0040] {where: [ka] wherein one or more H may be replaced by -X, -(C1-C4 alkyl), -CF3, -(C2-C6 heterocycloalkyl), -(C1-C4 alkyl)-aryl, -heteroaryl, or heteroaryl-(C1-C4 alkyl);

[0041] R C is -(C1-C4 alkyl) or -aryl; R D and R E are each independently -H, -(C1-C4 alkyl) or -(C1-C4 alkyl)-aryl; R F is -H, -(C1-C6 alkyl), -(C1-C4 alkyl)-OH, -(C 1-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);

[0042] wherein one or more H of —(C1-C4 alkyl) or —C(═O)—O(C1-C4 alkyl) may be replaced by —X; -one or more H in aryl may be replaced by -X}; R G is -(C1-C4 alkyl); Q is -O- or a bond;

[0043] [ka] is a single or double bond {provided that: [ka] is a double bond, then Y1 is -CH-};

[0044] a to e are each independently an integer of 0, 1, 2, 3, or 4 {provided that a and b cannot both be zero, and c and d cannot both be zero}; Each X is independently F, Cl, Br, or I.

[0045] In the pharmaceutical composition according to the present invention, the compound represented by the above formula I may be a compound represented by the following formula Ia: [ka]

[0046] In the above formula Ia, R2 is [ka] and;

[0047] R3 is -aryl {wherein one or more H of -aryl may each independently be replaced with -X}; Y1 is -O- or -S(=O)2-; Z1 is N or CR Z where R Z is -X}; a and b are each independently an integer of 0, 1, 2, 3, or 4 {provided that a and b cannot both be zero}; Each X is independently F, Cl, Br, or I.

[0048] In the pharmaceutical composition according to the present invention, the compound represented by formula Ia is R2 is [ka] and;

[0049] R3 is -phenyl {wherein one or more H of -phenyl may each independently be replaced with -F or -Cl}; Y1 is -O- or -S(=O)2-; Z1 is N or CF.

[0050] In the pharmaceutical composition according to the present invention, the compound represented by the above formula I may be a compound listed in Table A below.

[0051] [Table 1]

[0052] [Table 2]

[0053] [Table 3]

[0054] [Table 4]

[0055] [Table 5]

[0056] [Table 6]

[0057] [Table 7]

[0058] Table 8

[0059] Table 9

[0060] Table 10

[0061] Table 11

[0062] Table 12

[0063] Table 13

[0064] Table 14

[0065] Table 15

[0066] Table 16

[0067] Table 17

[0068] Table 18

[0069] Table 19

[0070] Table 20

[0071] Table 21

[0072] Table 22

[0073] Table 23

[0074] Table 24

[0075] Table 25

[0076] Table 26

[0077] Table 27

[0078] Table 28

[0079] [Table 29]

[0080] According to the present invention, a pharmaceutical composition containing, as an active ingredient, a compound in the above table (compounds 1 to 450), an optical isomer thereof, or a pharmaceutically acceptable salt thereof is effective in preventing and treating renal failure. It is possible.

[0081] In the pharmaceutical composition according to the present invention, the compound represented by the above formula I may be a compound listed in Table B below.

[0082] [Table 30]

[0083] According to the present invention, a pharmaceutical composition comprising, as an active ingredient, a compound of Table B above (compounds 40, 43, 239, 285, 295, and / or 296), an optical isomer thereof, or a pharmaceutically acceptable salt thereof, can prevent and treat renal failure.

[0084] In the present invention, the compound represented by the above formula I, compounds 1 to 450, their optical isomers or pharmaceutically acceptable salts thereof can be prepared by, but not limited to, the method disclosed in Korean Patent Publication No. 10-2017-0017792.

[0085] In the present invention, the compounds represented by Formula I above, Compounds 1 to 450, their optical isomers, or pharmaceutically acceptable salts thereof may contain one or more asymmetric carbon atoms, and may therefore exist as racemic mixtures, single enantiomers (optical isomers), diastereomeric mixtures, or single diastereomers. These isomers can be separated by conventional techniques, such as column chromatography or HPLC. Alternatively, they can be stereospecifically synthesized using optically pure starting materials and / or reagents of known sequence. Specifically, the isomers may be optical isomers.

[0086] In the present invention, the term "pharmaceutically acceptable" may mean physiologically tolerable and not normally causing gastrointestinal upset, allergic reactions such as dizziness, or similar reactions when administered to an individual.

[0087] The pharmaceutically acceptable salts of the present invention may be prepared by conventional methods known to those skilled in the art. Examples of the pharmaceutically acceptable salts of the present invention include, but are not limited to, inorganic ion salts prepared with calcium, potassium, sodium, magnesium, etc.; inorganic acid salts prepared with hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, sulfuric acid, hydroiodic acid, etc.; organic acid salts prepared with 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, carboxylic acid, vanillic acid, etc.; sulfonate salts prepared with methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, etc.; amino acid salts prepared with glycine, arginine, lysine, etc.; and amine salts prepared with trimethylamine, triethylamine, ammonia, pyridine, picoline, etc. In the present invention, preferred salts include hydrochloric acid, trifluoroacetic acid, citric acid, bromic acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid.

[0088] In the present invention, the term "renal failure (RF)" refers to a condition in which the kidneys' ability to filter unnecessary waste products from the blood and maintain an appropriate level of water and electrolytes in the body is reduced or lost.

[0089] Renal failure is classified as acute renal failure or chronic renal failure. Acute renal failure occurs when kidney function suddenly declines, causing problems with the excretion of waste products from the body, resulting in the accumulation of uric toxins and an imbalance of fluids and electrolytes. Chronic renal failure refers to a condition in which kidney tissue is damaged, causing a decline in the kidney's ability to remove waste products, and persists for more than three months. The causes of acute renal failure may be hypotension, urethral obstruction, certain drugs, muscle breakdown, hemolytic uremic syndrome, etc., and the causes of chronic renal failure may be diabetes, hypertension, nephrotic syndrome, polycystic kidney disease, etc. In the embodiment of the present invention, the renal failure may be caused by various factors, and is not limited thereto.

[0090] In an embodiment of the present invention, a chronic renal failure model in which metabolic products accumulate in the kidney due to an adenine diet and functional abnormalities occur was used to confirm the preventive and therapeutic effects of the compound of the present invention on renal failure, but the renal failure of the present invention is not limited thereto.

[0091] In an embodiment of the present invention, to confirm the preventive and therapeutic effects of the compound of Formula I, compounds 1 to 450, their optical isomers, or pharmaceutically acceptable salts thereof on renal failure, the relative fibrosis area and tubulointerstitial fibrosis score were selected to evaluate renal fibrosis, but the evaluation of renal fibrosis is not limited thereto. In an embodiment of the present invention, to confirm the preventive and therapeutic effects of the compound of formula I, compounds 1 to 450, their optical isomers, or pharmaceutically acceptable salts thereof on renal failure, glomerulosclerosis (GS) was selected as an indicator for evaluating renal damage, but the evaluation of renal damage is not limited thereto.

[0092] In an embodiment of the present invention, an increase in acetylation of tubulin protein was confirmed to confirm the preventive and therapeutic effects of the compound of formula I according to the present invention, compounds 1 to 450, their optical isomers, or pharmaceutically acceptable salts thereof on renal failure, but is not limited thereto.

[0093] In an embodiment of the present invention, to confirm the preventive and therapeutic effects of the compound of formula I according to the present invention, compounds 1 to 450, their optical isomers, or pharmaceutically acceptable salts thereof on renal failure, the degree of change in the expression of collagen type I alpha 1 (COL1A1), which is used to evaluate renal fibrosis, was confirmed, but is not limited to this.

[0094] In an embodiment of the present invention, to confirm the preventive and therapeutic effects of the compound of formula I on renal failure, the change in blood urea nitrogen (BUN) concentration was measured to evaluate renal function, but the evaluation of renal function is not limited thereto.

[0095] In the present invention, the term "prevention" means any action of suppressing or delaying the onset of renal failure disease by administering the compound of formula I of the present invention, compounds 1 to 450, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0096] In the present invention, the term "treatment" means any action that improves or favorably changes the symptoms of an individual suspected of or having developed renal failure, any action that prevents further deterioration of the symptoms of an individual suspected of or having developed renal failure, and any action that can prevent or slow the progression of renal failure, by administering the compound of formula I of the present invention, compounds 1-450, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0097] In 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 exhibit prophylactic and therapeutic effects on renal failure.

[0098] In an embodiment of the present invention, a pharmaceutical composition comprising a compound represented by formula I, compounds 1 to 450, an optical isomer, or a pharmaceutically acceptable salt thereof may exhibit preventive and therapeutic effects against acute renal failure and / or chronic renal failure.

[0099] 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 may exhibit preventive and therapeutic effects against decreased or impaired renal function due to chronic renal failure.

[0100] 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 delay or inhibit the progression of renal failure. For example, the pharmaceutical composition according to the embodiment of the present invention can inhibit or delay as much as possible the progression of renal failure to end-stage renal failure, thereby preventing a patient from reaching a state requiring dialysis or a kidney transplant, or can slow the rate of progression to such a state.

[0101] 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 may exhibit preventive and therapeutic effects against renal fibrosis due to chronic renal failure.

[0102] 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 improve renal fibrosis, or delay or inhibit the progression of renal fibrosis, thereby slowing the rate of renal fibrosis.

[0103] 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 may exhibit efficacy and effectiveness in chronic renal failure through, but not limited to, the mechanism of action of TGF-β / SMAD.

[0104] In an embodiment of the present invention, a pharmaceutical composition containing a compound represented by Formula I, compounds 1 to 450, their optical isomers, or a pharmaceutically acceptable salt thereof can improve renal fibrosis in renal failure (acute renal failure and chronic renal failure), or delay or inhibit the progression of renal fibrosis, thereby slowing the rate of progression of renal fibrosis. For example, a pharmaceutical composition containing a compound represented by Formula I, compounds 1 to 450, their optical isomers, or a pharmaceutically acceptable salt thereof can slow the rate of progression of renal fibrosis caused by dietary adenine in an animal model of adenine-induced chronic renal failure (Figure 1).

[0105] In an embodiment of the present invention, a pharmaceutical composition containing a compound represented by Formula I, compounds 1 to 450, their optical isomers, or a pharmaceutically acceptable salt thereof can improve glomerulosclerosis in renal failure (acute renal failure and chronic renal failure), or can delay or inhibit the progression of glomerulosclerosis, thereby slowing the rate of progression of glomerulosclerosis. For example, a pharmaceutical composition containing a compound represented by Formula I, compounds 1 to 450, their optical isomers, or a pharmaceutically acceptable salt thereof can slow the rate of progression of glomerulosclerosis caused by dietary adenine in an animal model of adenine-induced chronic renal failure (Figure 2).

[0106] In an embodiment of the present invention, a pharmaceutical composition containing a compound represented by Formula I, Compounds 1 to 450, an optical isomer thereof, or a pharmaceutically acceptable salt thereof can increase acetylation of tubulin protein in chronic renal failure. For example, a pharmaceutical composition containing a compound represented by Formula I, Compounds 1 to 450, an optical isomer thereof, or a pharmaceutically acceptable salt thereof can increase acetylation of tubulin protein in an adenine-induced chronic renal failure animal model (Figure 3).

[0107] In an embodiment of the present invention, a pharmaceutical composition containing a compound represented by Formula I, Compounds 1 to 450, an optical isomer thereof, or a pharmaceutically acceptable salt thereof can suppress the increase in collagen type I alpha 1 (COL1A1) in chronic renal failure. For example, a pharmaceutical composition containing a compound represented by Formula I, Compounds 1 to 450, an optical isomer thereof, or a pharmaceutically acceptable salt thereof can suppress the increase in collagen type I alpha 1 (COL1A1) in an adenine-induced chronic renal failure animal model (Figure 4).

[0108] 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 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 in renal function, thereby slowing the rate of decline in renal function (Figure 5). For example, a pharmaceutical composition comprising a compound represented by formula I, compounds 1 to 450, their optical isomers, or a pharmaceutically acceptable salt thereof can reduce blood urea nitrogen (BUN) in an animal model of adenine-induced chronic renal failure. It can reduce blood urea nitrogen (BUN).

[0109] In an embodiment of the present invention, the pharmaceutical composition can be administered to the subject suffering from renal failure, and the renal failure of the subject can be caused by other diseases.The disease that can cause renal failure can be at least one selected from the group consisting of hypotension, urethral obstruction, acute renal failure, acute pyelonephritis, chronic pyelonephritis, IgA nephropathy, muscle breakdown, hemolytic uremic syndrome, glomerular disease (for example, nephritic syndrome, acute progressive glomerulonephritis, chronic glomerulonephritis, nephrotic syndrome, etc.), hereditary renal disease (for example, polycystic kidney disease), diabetes, hypertension, heart disease and liver disease.

[0110] In an embodiment of the present invention, the pharmaceutical composition can be administered to a subject suffering from chronic renal failure, which may be caused by another disease. The disease that may cause renal failure can be at least one selected from the group consisting of diabetes, hypertension, nephrotic syndrome, nephritic syndrome, hereditary kidney disease (e.g., polycystic kidney disease), heart disease, and liver disease. The compound represented by Formula I of the present invention, compounds 1 to 450, their optical isomers, or pharmaceutically acceptable salts thereof can exhibit preventive or therapeutic effects for renal failure at a level similar to or substantially identical to, or superior to, those of conventionally known drugs for the prevention and treatment of renal failure.

[0111] The pharmaceutical compositions of the present invention may further contain one or more pharmaceutically acceptable carriers in addition to the compound represented by Formula I, Compounds 1-450, their optical isomers, or pharmaceutically acceptable salts thereof. Pharmaceutically acceptable carriers are those commonly used in the art, and may include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidine, cellulose, water, syrup, methylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, minerals, or oils. The pharmaceutical compositions of the present invention may further contain, in addition to the above ingredients, lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, dispersing agents, stabilizers, etc. The pharmaceutical compositions of the present invention can be formulated using pharmaceutically acceptable carriers and excipients into the form of tablets, powders, granules, pills, capsules, suspensions, emulsions, oral liquids, oils, syrups and other oral preparations, external preparations, suppositories, or sterile injection solutions, and can be manufactured in unit dose forms or in multi-volume containers. The formulations can be prepared by conventional methods used in the art or by methods described in Remington's Pharmaceutical Sciences (1999). thThey can be produced by the methods disclosed in "Therapeutic Agents for the Treatment of Diabetes" (ed., 1995), and can be formulated into various preparations depending on the disease or component.

[0112] Non-limiting examples of oral administration formulations using the pharmaceutical composition of the present invention include tablets, troches, lozenges, aqueous suspensions, oily suspensions, prepared powders, granules, emulsions, hard capsules, soft capsules, syrups, and elixirs. To formulate the pharmaceutical composition of the present invention for oral administration, binders such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose, or gelatin; excipients such as dibasic calcium phosphate; disintegrants such as corn starch or sweet potato starch; lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate, or polyethylene glycol wax may be used, as well as sweeteners, flavorings, syrups, and the like. Furthermore, in the case of capsules, liquid carriers such as oils and fats may also be used in addition to the above-mentioned substances.

[0113] Non-limiting examples of parenteral formulations using the pharmaceutical composition of the present invention include injection solutions, suppositories, powders for respiratory inhalation, aerosols for spraying, ointments, powders for application, oils, creams, etc. To formulate the pharmaceutical composition of the present invention for parenteral administration, a sterile aqueous solution, a non-aqueous solvent, a suspension, an emulsion, a freeze-dried preparation, an external preparation, etc. may be used, and examples of the non-aqueous solvent and suspension include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.

[0114] The pharmaceutical composition of the present invention may be administered orally or parenterally, for example, intravenously, subcutaneously, intraperitoneally or topically, depending on the intended method, and may be administered orally, but is not limited thereto.

[0115] The daily dose of the compound represented by formula I, compounds 1 to 450, their optical isomers, and pharmaceutically acceptable salts of the present invention may be, specifically, about 0.1 to 10,000 mg / kg, about 1 to 8,000 mg / kg, about 5 to 6,000 mg / kg, or about 10 to 4,000 mg / kg, or more specifically, about 50 to 2,000 mg / kg, but is not limited to these, and may be administered once a day or in divided doses.

[0116] The pharmaceutically effective amount and effective dosage of the pharmaceutical composition of the present invention may vary depending on the method for formulating the pharmaceutical composition, the mode of administration, the administration time and / or the administration route, etc., and may vary depending on various factors including the type and degree of response to be achieved by administering the pharmaceutical composition, the type, age, weight, general health condition, symptoms and degree of disease, sex, diet, excretion, drugs administered simultaneously or at different times to the individual, other components of the composition, etc., as well as similar factors well known in the pharmaceutical field. A person of ordinary skill in the art can easily determine and prescribe an effective dosage for the intended treatment.

[0117] The pharmaceutical composition of the present invention may be administered once a day or in divided doses. The pharmaceutical composition of the present invention may be administered as a single therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. Taking all of the above factors into consideration, the minimum amount that produces the maximum effect without side effects may be administered, which can be easily determined by those skilled in the art to which the present invention pertains.

[0118] The pharmaceutical composition of the present invention can exhibit excellent effects even when used alone, but may also be used in combination with various methods such as hormone therapy and drug therapy to further improve therapeutic efficiency.

[0119] The present invention provides a method for preventing and treating renal failure, which comprises administering to an individual a compound represented by the above formula I, compounds 1 to 450, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. The present invention provides a method for preventing and treating renal failure, which comprises administering to an individual the above-mentioned compounds 40, 43, 239, 285, 295 and / or 296, an optical isomer thereof or a pharmaceutically acceptable salt thereof.

[0120] In the above-mentioned preventive and therapeutic methods of the present invention, the terms "renal failure," "prevention," and "treatment" are the same as those defined above.

[0121] In the present invention, the term "administration" means introducing a given substance into an individual by an appropriate method.

[0122] In the present invention, the term "individual" refers to any animal, including humans, such as mice, rats, livestock, etc., that has or may have renal failure, and specifically refers to humans. The animal may be a mammal, including, but not limited to, a mammal.

[0123] The method for preventing and treating renal failure of the present invention may involve administering a therapeutically effective amount of a compound represented by the above formula I, compounds 1 to 450, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0124] In the present invention, the term "therapeutically effective amount" refers to an amount applicable to medical treatment and sufficient to treat a disease at a reasonable benefit / risk ratio without causing side effects, which may be determined by one skilled in the art depending on factors including the patient's sex, age, weight, health condition, type and severity of the disease, drug activity, drug sensitivity, administration method, administration time, administration route, excretion rate, treatment period, co-administered or concomitant drugs, and other factors well known in the medical field. It is preferable that a specific therapeutically effective amount for a particular patient be determined depending on various factors, such as the type and degree of response to be achieved, the specific composition, including whether a different formulation is used, the patient's age, weight, general health condition, sex, and diet, administration time, administration route, and excretion rate of the composition, treatment period, drugs used together with or concomitantly with the specific composition, and similar factors well known in the medical field.

[0125] The method for preventing and treating renal failure of the present invention involves administering a compound represented by Formula I, Compounds 1-450, an optical isomer thereof, or a pharmaceutically acceptable salt thereof to not only treat the disease itself before symptoms appear, but also inhibit or prevent its onset. In managing disease, the prophylactic or therapeutic dose of a particular active ingredient will vary depending on the characteristics and severity of the disease or condition and the route by which the active ingredient is administered. The dose and frequency of doses will vary depending on the age, weight, and response of the individual patient. Appropriate dosage regimens can be readily selected by those of ordinary skill in the art, taking these factors into consideration as a matter of course.

[0126] In addition, the method for preventing and treating renal failure of the present invention may further comprise administering, together with the compound represented by the above formula I, compounds 1 to 450, their optical isomers, or pharmaceutically acceptable salts thereof, an additional active agent useful for the prevention and treatment of the disease in a therapeutically effective amount, and the additional active agent can exert a synergistic or additive effect together with the compound represented by the above formula I, compounds 1 to 450, their optical isomers, or pharmaceutically acceptable salts thereof.

[0127] The contents described in relation to the pharmaceutical composition of the present invention are also applicable to the above-mentioned prevention and treatment methods, unless they are mutually inconsistent.

[0128] The present invention provides use of the compounds represented by the above formula I, compounds 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof for the prevention and treatment of renal failure. The present invention provides use of the above compounds 40, 43, 239, 285, 295 and / or 296, their optical isomers or pharmaceutically acceptable salts thereof for the prevention and treatment of renal failure. The present invention provides use of the compound represented by the above formula I, compounds 1 to 450, an optical isomer thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention and treatment of renal failure. The present invention provides the use of the above compounds 40, 43, 239, 285, 295 and / or 296, their optical isomers or pharmaceutically acceptable salts thereof in the manufacture of a medicament for the prevention and treatment of renal failure.

[0129] In the above-mentioned preventive and therapeutic uses of the present invention, the terms "renal failure," "prevention," and "treatment" are the same as those defined above.

[0130] To produce a drug, the compound represented by the above formula I, compounds 1 to 450, their optical isomers, or their pharmaceutically acceptable salts may be mixed with pharmaceutically acceptable adjuvants, diluents, carriers, etc., and produced as a combined preparation together with other active ingredients, which can have a synergistic effect.

[0131] The matters stated in the pharmaceutical compositions, methods of treatment and uses of the present invention are equally applicable unless they contradict each other. [Effects of the Invention]

[0132] The compounds of the present invention represented by formula I, compounds 1 to 450, their optical isomers or pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing them as active ingredients can be effectively used in the prevention and treatment of renal failure. [Brief explanation of the drawings]

[0133] [Figure 1] 1 shows the results of measuring intrarenal fibrosis in mouse kidneys collected from an adenine-induced chronic renal failure animal model after feeding the mouse with an adenine diet for 14 days. Pharmaceutical compositions containing the compound represented by Formula I, compounds 1 to 450, optical isomers thereof, or pharmaceutically acceptable salts thereof can reduce fibrosis in the renal failure animal model. [Figure 2]2 shows the results of measuring the degree of glomerular sclerosis in the kidneys of mice that were fed an adenine diet for 14 days in an adenine-induced chronic renal failure animal model. Pharmaceutical compositions containing the compound represented by Formula I, compounds 1 to 450, optical isomers thereof, or pharmaceutically acceptable salts thereof can reduce glomerular sclerosis in the renal failure animal model. [Figure 3] Figure 3 shows the results of confirming tubulin acetylation in the kidneys of mice in an adenine-induced chronic renal failure animal model after feeding an adenine diet for 14 days. Pharmaceutical compositions containing the compound represented by Formula I, compounds 1 to 450, optical isomers thereof, or pharmaceutically acceptable salts thereof can increase tubulin acetylation in the kidneys of an animal model of renal failure. [Figure 4] Figure 4 shows the results of confirming COL1A1 expression in the kidneys of mice after feeding an adenine diet for 14 days to an animal model of adenine-induced chronic renal failure. Pharmaceutical compositions containing the compound represented by Formula I, compounds 1 to 450, optical isomers thereof, or pharmaceutically acceptable salts thereof can reduce increased COL1A1 expression in an animal model of renal failure. [Figure 5] 5 shows the results of measuring blood urea nitrogen (BUN) levels in blood collected from mice in an adenine-induced chronic renal failure animal model after feeding an adenine diet for 14 days. Pharmaceutical compositions containing the compound represented by Formula I, compounds 1 to 450, optical isomers thereof, or pharmaceutically acceptable salts thereof can reduce increased blood urea nitrogen levels in the renal failure animal model. DETAILED DESCRIPTION OF THE INVENTION

[0134] The present invention will be described in more detail below with reference to examples. It will be obvious to those skilled in the art that these embodiments are intended to illustrate the present invention and should not be construed as limiting the scope of the present invention.

[0135] 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

[0136] [Step 1] Synthesis of N-phenylthiomorpholine-4-carboxamide 1,1-dioxide [ka]

[0137] To a solution of aniline (3.000 g, 32.213 mmol) and N,N-diisopropylethylamine (33.439 mL, 193.278 mmol) in methylene chloride (100 mL) at 0 °C, triphosgene (4.780 g, 16.107 mmol) was added and stirred at the same temperature. Thiomorpholine 1,1-dioxide (4.790 g, 35.434 mmol) was added to the reaction mixture, which was then stirred at room temperature for an additional 16 hours. Water was poured into the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 40 g cartridge; methanol / methylene chloride = 2%) and concentrated to give the title compound (1.325 g, 16.2%) as a yellow solid.

[0138] [Step 2] Synthesis of methyl 6-((1,1-dioxide-N-phenylthiomorpholine-4-carboxamido)methyl)nicotinate [ka]

[0139] A solution of N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (1.000 g, 3.932 mmol) prepared in Step 1 and sodium hydride (60.00%, 0.157 g, 3.932 mmol) in N,N-dimethylformamide (10 mL) was stirred at 0 °C for 1 h. Methyl 4-(bromomethyl)-3-fluorobenzoate (0.905 g, 3.932 mmol) was added and stirred at room temperature for an additional 2 h. The reaction mixture was evaporated under reduced pressure, and the concentrate was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was crystallized from methanol (20 mL) at room temperature, filtered, and the resulting solid was washed with methanol and dried to give the title compound (0.816 g, 51.4%) as a brown solid.

[0140] [Step 3] Synthesis of N-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide [ka]

[0141] A mixture of methyl 6-((1,1-dioxide-N-phenylthiomorpholine-4-carboxamido)methyl)nicotinate (0.816 g, 2.023 mmol) prepared in Step 2 and hydrazine hydrate (1.910 mL, 40.451 mmol) in ethanol (10 mL) at room temperature was heated at 100°C by microwave irradiation for 1 hour, and then the temperature was lowered to room temperature to complete the reaction. The reaction mixture was subjected to reduced pressure to remove the solvent, and the concentrate was crystallized from methylene chloride (20 mL) at room temperature and filtered. The resulting solid was washed with methylene chloride and dried to give the title compound (0.560 g, 68.6%) as a pale brown solid.

[0142] [Step 4] Synthesis of N-((5-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide [ka]

[0143] Difluoroacetic anhydride (0.087 mL, 0.580 mmol) was added to a solution of N-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (0.260 g, 0.644 mmol) prepared in Step 3 and triethylamine (0.178 mL, 1.289 mmol) in methylene chloride (2 mL) at room temperature, and the mixture was stirred at the same temperature for 16 hours. The reaction mixture was poured into water, extracted with methylene chloride, filtered through a plastic frit, and the solid residue and aqueous layer were removed. The extract was then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / methylene chloride = 0% → 5%) and concentrated to give the title compound (0.156 g, 50.3%) as a white foam.

[0144] [Step 5] Synthesis of compound 43 [ka]

[0145] 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) prepared in Step 4 and 1-methoxy Di-N-triethylammoniosulfonylmethanimidate (Burgess reagent, 0.116 g, 0.486 mmol) was mixed with tetrahydrofuran (2 mL) and heated to 150 °C for 30 minutes using microwave irradiation. The temperature was then lowered to room temperature to complete the reaction. The reaction mixture was poured into water, extracted with methylene chloride, filtered through a plastic frit, and the solid residue and aqueous layer were removed. The extract was then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / methylene chloride = 3%) and concentrated to give the title compound (0.078 g, 51.9%) as a colorless oil.

[0146] 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, LRMS(ES)m / z 464.2(M) + +1).

[0147] Preparation 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

[0148] [Step 1] Synthesis of methyl 4-((1,1-dioxide-N-phenylthiomorpholine-4-carboxamido)methyl)-3-fluorobenzoate [ka]

[0149] To 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) at 0 °C, methyl 4-(bromomethyl)-3-fluorobenzoate (1.020 g, 4.129 mmol) was added and stirred at room temperature for 18 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 40 g cartridge; ethyl acetate / hexane = 0% to 50%) and concentrated to give the title compound (1.240 g, 75.0%) as a white solid.

[0150] [Step 2] Synthesis of N-(2-fluoro-4-(hydrazinecarbonyl)benzyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide [ka]

[0151] A solution of methyl 4-((1,1-dioxide-N-phenylthiomorpholine-4-carboxamido)methyl)-3-fluorobenzoate (1.240 g, 2.949 mmol) prepared in Step 1 and hydrazine hydrate (2.786 mL, 58.983 mmol) in ethanol (15 mL) was stirred at 120 °C for 1 hour at the same temperature, and then the temperature was lowered to room temperature to terminate the reaction. The solvent was removed from the reaction mixture under reduced pressure, and the concentrate obtained was poured into saturated aqueous sodium bicarbonate solution. The mixture was extracted with methylene chloride and then filtered through a plastic frit to remove the solid residue and aqueous layer, followed by concentration under reduced pressure. The title compound was used as is without further purification (1.240 g, 100.0%, white solid).

[0152] [Step 3] Synthesis of N-(4-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)-2-fluorobenzyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide [ka]

[0153] 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 methylene chloride (10 mL) was stirred at room temperature for 18 hours. Saturated aqueous sodium bicarbonate was poured into the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, then filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 24 g cartridge; methanol / methylene chloride = 0% → 3%) and concentrated to give the title compound (0.462 g, 63.4%) as a white solid.

[0154] [Step 4] Synthesis of compound 40 [ka]

[0155] N-(4-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)-2-fluorobenzyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (0.462 g, 0.927 mmol) prepared in Step 3 and 1-methoxy-N-triethylammoniosulfonyl-methaneimidate (Burgess reagent, 0.331 g, 1.390 mmol) were mixed in tetrahydrofuran (10 mL) and heated at 150 °C for 30 minutes using microwave irradiation. The temperature was then lowered to room temperature to complete the reaction. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, which was extracted with methylene chloride and then filtered through a plastic frit. The solid residue and aqueous layer were removed, and the mixture was concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 50%) and concentrated to give the title compound (0.337 g, 75.7%) as a white solid.

[0156] 1 H 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).

[0157] Preparation 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

[0158] [Step 1] Synthesis of N-(3-chlorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide [ka]

[0159] 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 hours. The precipitated solid was filtered, washed with diethyl ether, and dried to give the title compound (1.811 g, 96.3%) as a white solid.

[0160] [Step 2] Synthesis of methyl 6-((N-(3-chlorophenyl)-1,1-dioxidethiomorpholine-4-carboxamido)methyl)nicotinate [ka]

[0161] 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, sodium hydride (60.00%, 0.028 g, 0.693 mmol) was added and stirred at the same temperature for 1 hour. Methyl 6-(bromomethyl)nicotinate (0.159 g, 0.693 mmol) was added to the reaction mixture, and the mixture was stirred at the same temperature for an additional 2 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g cartridge, methanol / dichloromethane = 0% to 5%) and concentrated to give the title compound (0.261 g, 86.0%) as a brown oil.

[0162] [Step 3] Synthesis of N-(3-chlorophenyl)-N-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)thiomorpholine-4-carboxamide 1,1-dioxide [ka]

[0163] A solution of methyl 6-((N-(3-chlorophenyl)-1,1-dioxidethiomorpholine-4-carboxamido)methyl)nicotinate (0.261 g, 0.596 mmol) prepared in Step 2 and hydrazine monohydrate (0.290 mL, 5.958 mmol) in ethanol (2 mL) at room temperature was stirred at 110 °C for 18 hours, then the temperature was lowered to room temperature to complete the reaction. The solvent was removed from the reaction mixture under reduced pressure, and the resulting concentrate was poured into water. The concentrate was extracted with dichloromethane and filtered through a plastic frit to remove the solid residue and aqueous layer, followed by concentration under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge, methanol / dichloromethane = 5% → 15%) and concentrated to give the title compound (0.261 g, 100.0%) as a brown oil.

[0164] [Step 4] Synthesis of compound 239 [ka]

[0165] A solution of 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) in tetrahydrofuran (2 mL) was stirred at 80 °C for 18 hours, and then the temperature was lowered to room temperature to complete the reaction. The solvent was removed from the reaction mixture under reduced pressure, and the resulting concentrate was poured into water. It was extracted with dichloromethane and then filtered through a plastic frit. The solid residue and aqueous layer were removed, and the mixture was concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 3%) and concentrated to give the title compound (0.087 g, 29.3%) as a yellow foam.

[0166] 1 H 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).

[0167] Preparation Example 4: Synthesis of Compound 285, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide

[0168] [Step 1] Synthesis of N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide [ka]

[0169] 1-Fluoro-4-isocyanate benzene (0.500 g, 3.647 mmol) was dissolved in diethyl ether (10 mL), and thiomorpholine 1,1-dioxide (0.493 g, 3.647 mmol) was added at 0°C. The mixture was stirred at the same temperature for 1 hour and then at room temperature for another 4 hours. The precipitated solid was filtered, washed with diethyl ether, and dried to obtain the title compound. (0.920 g, 92.7%) was obtained as a white solid.

[0170] [Step 2] Synthesis of methyl 3-fluoro-4-((N-(4-fluorophenyl)-1,1-dioxidethiomorpholine-4-carboxamido)methyl)benzoate [ka]

[0171] A solution of N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.300 g, 1.102 mmol) prepared in Step 1 and sodium hydride (60.00%, 0.048 g, 1.212 mmol) in N,N-dimethylformamide (5 mL) was stirred at 0 °C for 2 h, and methyl 4-(bromomethyl)-3-fluorobenzoate (0.299 g, 1.212 mmol) was added. The mixture was stirred at room temperature for an additional 17 h. Water (2 mL) was added to the reaction mixture at room temperature and stirred for 10 min to terminate the reaction. The reaction mixture was poured into water, extracted with dichloromethane, filtered through a plastic frit, and the solid residue and aqueous layer were removed. The mixture was then concentrated under reduced pressure. The concentrate was crystallized with dichloromethane (3 mL) at room temperature, filtered, and the resulting solid was washed with dichloromethane and dried to give the title compound (0.212 g, 43.9%) as a white solid.

[0172] [Step 3] Synthesis of N-(2-fluoro-4-(hydrazinecarbonyl)benzyl)-N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide [ka]

[0173] A mixture of methyl 3-fluoro-4-((N-(4-fluorophenyl)-1,1-dioxidethiomorpholine-4-carboxamido)methyl)benzoate (0.212 g, 0.484 mmol) prepared in Step 2 and hydrazine monohydrate (0.470 mL, 9.670 mmol) in ethanol (4 mL) at room temperature was heated at 120 °C for 1 hour using microwave irradiation, and then the temperature was lowered to room temperature to complete the reaction. The solvent was removed from the reaction mixture under reduced pressure, and the resulting concentrate was poured into water. The concentrate was extracted with dichloromethane and filtered through a plastic frit to remove the solid residue and aqueous layer, followed by concentration under reduced pressure. Diethyl ether (5 mL) and ethyl acetate (1 mL) were added to the concentrate and stirred. The precipitated solid was filtered, washed with hexane, and dried to give the title compound (0.179 g, 84.4%) as a white solid.

[0174] [Step 4] Synthesis of compound 285 [ka]

[0175] To a solution of N-(2-fluoro-4-(hydrazinecarbonyl)benzyl)-N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.100 g, 0.228 mmol) prepared in Step 3 and triethylamine (0.095 mL, 0.684 mmol) in dichloromethane (4 mL) at room temperature, 2,2-difluoroacetic anhydride (0.028 mL, 0.228 mmol) was added and stirred at the same temperature for 17 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, filtered through a plastic frit, and the solid residue and aqueous layer were removed. The concentrate was then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 20% to 50%) and concentrated to afford the title compound (0.053 g, 46.6%) as a white solid.

[0176] 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).

[0177] Preparation 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

[0178] [Step 1] Synthesis of methyl 6-((N-(4-fluorophenyl)-1,1-dioxidethiomorpholine-4-carboxamido)methyl)nicotinate [ka]

[0179] A solution of N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.500 g, 1.836 mmol) prepared in Step 1 of Preparation Example 4 (Compound 285) and sodium hydride (60.00%, 0.081 g, 2.020 mmol) in N,N-dimethylformamide (10 mL) was stirred at 0°C for 30 minutes, and methyl 6-(bromomethyl)nicotinate (0.465 g, 2.020 mmol) was added. The mixture was stirred at room temperature for an additional 5 hours. Water (5 mL) was then added to the reaction mixture at room temperature and stirred for 10 minutes to terminate the reaction. Water was poured into the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Concentrated. The title compound was used as is without further purification (0.450 g, 58.1%, brown solid).

[0180] [Step 2] Synthesis of N-(4-fluorophenyl)-N-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)thiomorpholine-4-carboxamide 1,1-dioxide [ka]

[0181] A solution of methyl 6-((N-(4-fluorophenyl)-1,1-dioxidethiomorpholine-4-carboxamido)methyl)nicotinate (0.150 g, 0.356 mmol) prepared in Step 1 and hydrazine monohydrate (0.346 mL, 7.118 mmol) in ethanol (5 mL) at room temperature was stirred at 100°C for 17 hours, and then the temperature was lowered to room temperature to complete the reaction. The precipitated solid was filtered, washed with ethanol, and dried to obtain the title compound (0.111 g, 74.0%) as a pale yellow solid.

[0182] [Step 3] Synthesis of N-((5-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)pyridin-2-yl)methyl)-N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide [ka]

[0183] To 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) prepared in Step 2 and triethylamine (0.110 mL, 0.790 mmol) in dichloromethane (5 mL) at room temperature, 2,2-difluoroacetic anhydride (0.065 mL, 0.527 mmol) was added and stirred at the same temperature for 1 hour. The reaction mixture was poured into water, extracted with dichloromethane, filtered through a plastic frit, and the solid residue and aqueous layer were removed. The mixture was then concentrated under reduced pressure. The title compound was used as is without further purification (0.082 g, 62.3%, yellow solid).

[0184] [Step 4] Synthesis of compound 295 [ka]

[0185] A solution of 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-triethylammoniosulfonyl-methanimidate (Burgess reagent, 0.117 g, 0.493 mmol) in tetrahydrofuran (5 mL) was stirred at 70 °C for 5 h, and then the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was filtered through a paper filter to remove solids. The filtrate was then evaporated under reduced pressure, and the concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to give the title compound (0.015 g, 19.0%) as a white solid.

[0186] 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).

[0187] Preparation 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

[0188] [Step 1] Synthesis of methyl 6-((N-(3-fluorophenyl)-1,1-dioxidethiomorpholine-4-carboxamido)methyl)nicotinate [ka]

[0189] 1-Fluoro-3-isocyanatebenzene (0.500 g, 3.647 mmol) was dissolved in diethyl ether (10 mL), and thiomorpholine 1,1-dioxide (0.493 g, 3.647 mmol) was added at 0°C. The mixture was stirred at the same temperature for 1 hour and then at room temperature for an additional 4 hours. The precipitated solid was filtered, washed with diethyl ether, and dried to obtain the title compound (0.870 g, 87.6%) as a white solid.

[0190] A solution of the previously prepared 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. Methyl 6-(bromomethyl)nicotinate (0.465 g, 2.020 mmol) was added and stirred at room temperature for an additional 5 h. Water (5 mL) was then added to the reaction mixture at room temperature and stirred for 10 min to terminate the reaction. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The title compound was used as is without further purification (0.450 g, 58.1%, brown solid).

[0191] [Step 2] Synthesis of N-(3-fluorophenyl)-N-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)thiomorpholine-4-carboxamide 1,1-dioxide [ka]

[0192] A solution of methyl 6-((N-(3-fluorophenyl)-1,1-dioxidethiomorpholine-4-carboxamido)methyl)nicotinate (0.150 g, 0.356 mmol) prepared in Step 1 and hydrazine monohydrate (0.346 mL, 7.118 mmol) in ethanol (5 mL) at room temperature was stirred at 100°C for 17 hours, and then the temperature was lowered to room temperature to complete the reaction. The precipitated solid was filtered, washed with ethanol, and dried to obtain the title compound (0.113 g, 75.3%) as a pale yellow solid.

[0193] [Step 3] Synthesis of N-((5-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)pyridin-2-yl)methyl)-N-(3-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide [ka]

[0194] To 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) prepared in Step 2 and triethylamine (0.112 mL, 0.804 mmol) in dichloromethane (5 mL) at room temperature, 2,2-difluoroacetic anhydride (0.067 mL, 0.536 mmol) was added and stirred at the same temperature for 1 hour. The reaction mixture was poured into water, extracted with dichloromethane, filtered through a plastic frit, and the solid residue and aqueous layer were removed. The mixture was then concentrated under reduced pressure. The title compound was used as is without further purification (0.090 g, 67.2%, yellow solid).

[0195] [Step 4] Synthesis of compound 296 [ka]

[0196] A solution of 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, 0.180 mmol) prepared in Step 3 and 1-methoxy-N-triethylammoniosulfonyl-methanimidate (Burgess reagent, 0.129 g, 0.541 mmol) in tetrahydrofuran (5 mL) was stirred at 70 °C for 5 h, and then the temperature was lowered to room temperature to complete the reaction. The reaction mixture was filtered through a paper filter to remove solids. The filtrate was then evaporated under reduced pressure, and the concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to give the title compound (0.044 g, 50.7%) as a white solid.

[0197] 1 H 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).

[0198] <Example 1> Confirmation of preventive or therapeutic effect of renal failure 1 Through this experiment, we attempted to confirm the effect of the compounds of the present invention on renal function in renal fibrosis and glomerulosclerosis.

[0199] A chronic renal failure animal model was created by feeding 6-week-old C57BL / 6J mice a 0.2% adenine diet for two weeks. The mice with adenine-induced chronic renal failure were orally administered Preparation 1 (compound 43) twice daily for two weeks (experimental group, compound 43). Meanwhile, in the induced group (Vehicle), the mice with adenine-induced chronic renal failure were orally administered a vehicle twice daily, and the normal group (Ctrl) mice were orally administered a vehicle twice daily.

[0200] The animals were fed a standard diet (Central Lab Animal, Inc.), a 0.2% adenine diet (ENVIGO), and water ad libitum. They were housed in a controlled environment with temperature (22 ± 2°C), humidity (44-56%), and a 12-hour dark / light cycle. All experimental procedures were approved and performed in accordance with the Institutional Animal Care and Use Committee (IACUC) of the Korea CKD Laboratory Animal Center (IACUC animal study protocol approval number: S-21-037). Each group was classified as shown in Table 1 below.

[0201] [Table 31]

[0202] In an adenine-induced chronic renal failure animal model, the experimental group was administered 0.2% adenine in the diet and the compound of formula I (compound 43 of Preparation Example 1) twice daily for two weeks. After two weeks of administration, the mice were sacrificed to obtain kidneys.

[0203] To measure the degree of intrarenal fibrosis, mouse kidneys were fixed in 10% neutral buffered formalin (NBF), infiltrated with paraffin, and embedded. Sagittal sections of the relevant blocks were cut at 4 μm thickness and stained with Masson's trichrome. Images were then taken using an Image Analyzer (NIS-Elements BR 5.11.01, Nikon). The relative fibrotic area was calculated by averaging the total area versus the positive area. Tubulointerstitial fibrosis score was assigned as follows: normal (0 points), 1 point for 10% or less, 2 points for >10% to 25% (2 points), 3 points for >25% to 75% (3 points), and 4 points for 75% or more.

[0204] To measure glomerular sclerosis in the kidney, mouse kidneys were fixed in 10% neutral buffered formalin (NBF), infiltrated with paraffin, and embedded. Sagittal sections of the affected kidneys were cut at 4 μm thickness and stained with periodic acid Schiff (PAS). Images were then taken using an Image Analyzer (NIS-Elements BR 5.11.01, Nikon). The glomerulosclerosis (GS) index was scored based on the number of affected glomeruli: normal (0 points), less than 25% (1 point), 25% to less than 50% (2 points), 50% to less than 75% (3 points), and total lesions (4 points).

[0205] All results are shown as mean ± SEM and were analyzed using GraphPad Prism 5 (GraphPad Software, Inc., USA). Statistical analysis was performed by one-way ANOVA (multiple comparison).

[0206] The results of the analysis of the relative fibrotic area, tubulointerstitial fibrosis score, and glomerulosclerosis score are shown in Figures 1 and 2. In Figures 1 and 2, the error bars indicate ±SEM (standard error of the mean) (vehicle vs. each group). oup), **p<0.01, **** p<0.0001).

[0207] As shown in Figures 1 and 2 above, Compound 43 (Preparation Example 1) was found to reduce renal fibrosis and alleviate nephrosclerosis in an animal model of renal failure. This demonstrates that the compounds of the present invention can be effectively used for the prevention and treatment of renal failure diseases.

[0208] <Example 2> Confirmation of preventive or therapeutic effect of renal failure 2 In this experiment, in order to confirm the preventive and therapeutic effects of the compound of the present invention on renal failure, the administration of the compound of the present invention was performed to determine the effect of acetyl-alpha tubulin (acetyl-alpha The changes in the levels of tubulin and Ace-tub were measured.

[0209] An animal model of chronic renal failure was created by feeding 6-week-old C57BL / 6J mice a 0.2% adenine diet for two weeks. The mice with adenine-induced chronic renal failure were orally administered Preparation 1 (compound 43) twice daily for two weeks (experimental group, compound 43). Meanwhile, in the induced group (Vehicle), the mice with adenine-induced chronic renal failure were orally administered a vehicle twice daily, and the normal group (Ctrl) mice were orally administered a vehicle twice daily. The animals were fed a standard diet (Central Lab Animal, Inc.), a 0.2% adenine diet (ENVIGO), and water ad libitum. They were housed in a controlled environment with temperature (22 ± 2°C), humidity (44-56%), and a 12-hour dark / light cycle. All experimental procedures were approved and performed in accordance with the Institutional Animal Care and Use Committee (IACUC) of the Korea CKD Laboratory Animal Center (IACUC animal study protocol approval number: S-21-037). Each group was classified as shown in Table 2 below.

[0210] [Table 32]

[0211] In order to confirm the preventive and therapeutic effects of the compound of formula I according to the present invention on renal failure, the expression of acetyl-alpha tubulin in the above-mentioned adenine-induced chronic renal failure mice was analyzed, and the results are shown in Figure 3.

[0212] In an animal model of adenine-induced chronic renal failure, the experimental group received 0.2% adenine in the diet and the product of formula I (compound 43 of Preparation Example 1) administered once daily for two weeks. After two weeks of administration, the mouse kidneys were homogenized in RIPA buffer and centrifuged at 13,000 rpm and 4°C for 20 minutes. 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 then loaded onto a NuPAGE Bis-Tris gel (Invitrogen). After loading the gel onto a nitrocellulose membrane, the proteins in the gel were transferred to a nitrocellulose membrane using an iBlot2 Gel Transfer device. Then, acetylated alpha-tubulin (Ace-tub) and alpha-tubulin (α-tub) antibodies were added to a 3% BSA (Bovine Serum Albumin) solution and incubated with the nitrocellulose membrane at 4°C. After the incubation, a detection reagent (Thermo Protein expression was measured using a BioRad Scientific and ChemiDoc™ MP (BIO-RAD, 12003154) instrument, and analyzed using BIO-RAD's Image Lab Software (version 5.0). All results are shown as mean ± SEM and were analyzed using GraphPad Prism 5 (GraphPad Software, Inc., USA). Statistical analysis was performed by one-way ANOVA (multiple comparison).

[0213] The results of the analysis of Ace-tub and α-tub are shown in Figure 3. In Figure 3, error bars indicate ±SEM (standard error of the mean) (vehicle vs. each group, **p<0.05, ****p<0.0001). As shown in Figure 3 above, it was confirmed that Compound 43 (Preparation Example 1) increases tubulin acetylation in an animal model of renal failure. This demonstrates that the compounds of the present invention can be effectively used for the prevention and treatment of renal failure diseases.

[0214] <Example 3> Confirmation of preventive or therapeutic effect of renal failure 3 In this experiment, in order to confirm the preventive and therapeutic effects of the compound of the present invention on renal failure, the degree of change in the expression of collagen type I alpha 1 (COL1A1), which is associated with fibrosis, due to the administration of the compound of the present invention was confirmed.

[0215] An animal model of chronic renal failure was created by feeding 6-week-old C57BL / 6J mice a 0.2% adenine diet for two weeks. The mice with adenine-induced chronic renal failure were orally administered Preparation 1 (compound 43) twice daily for two weeks (experimental group, compound 43). Meanwhile, in the induced group, the mice with adenine-induced chronic renal failure were orally administered a vehicle twice daily, and the normal (Ctrl) mice were orally administered a vehicle twice daily. The animals were fed a standard diet (Central Lab Animal, Inc.), a 0.2% adenine diet (ENVIGO), and water ad libitum. They were housed in a controlled environment with temperature (22 ± 2°C), humidity (44-56%), and a 12-hour dark / light cycle. All experimental procedures were approved and performed in accordance with the Institutional Animal Care and Use Committee (IACUC) of the Korea CKD Laboratory Animal Center (IACUC animal study protocol approval number: S-21-037). Each group was classified as shown in Table 3 below.

[0216] [Table 33]

[0217] To confirm the preventive and therapeutic effects of the compound of formula I according to the present invention on renal failure, the expression of collagen type I alpha 1 (COL1A1), which is associated with intrarenal fibrosis, was analyzed. In an adenine-induced chronic renal failure animal model, the experimental group received 0.2% adenine in the diet and repeated daily administration of the compound of Formula I (Compound 43 of Preparation 1) for two weeks. After two weeks of administration, mouse kidneys were homogenized in RIPA buffer and centrifuged at 13,000 rpm at 4°C for 20 minutes. 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 the protein in the gel was transferred to a nitrocellulose membrane using an iBlot2 Gel Transfer system. COL1A1 and GAPDH antibodies were then added to a 3% BSA (bovine serum albumin) solution and incubated with the nitrocellulose membrane at 4°C. After the incubation, protein expression was measured using a detection reagent (Thermo Scientific) and a ChemiDoc™ MP (BIO-RAD, 12003154) instrument, and analyzed using BIO-RAD's Image Lab Software (version 5.0). All results are shown as mean ± SEM and were analyzed using GraphPad Prism 5 (GraphPad Software, Inc., USA). Statistical analysis was performed by one-way ANOVA (multiple comparison). The expression of COL1A1 was analyzed to compare the degree of renal fibrosis in each group, and the results are shown in Figure 4. In Figure 4, the error bars indicate ±SEM (standard error of the mean) (vehicle vs. each group, **p<0.01, ****p<0.0001).

[0218] As shown in FIG. 4, compound 43 (Preparation Example 1) was observed to reduce the expression of COL1A1 in mice with chronic renal failure. Therefore, it was found that the compound according to the present invention exhibits an effect of suppressing renal fibrosis in patients with renal failure, and can therefore be effectively used for the prevention and treatment of renal failure diseases.

[0219] <Example 4> Confirmation of preventive or therapeutic effect of renal failure 4 Through this experiment, we aimed to confirm the effect of the compounds of the present invention on renal function in renal failure. An animal model of chronic renal failure was created by feeding 6-week-old C57BL / 6J mice a 0.2% adenine diet for 2 weeks. Mice were orally administered Preparation 1 (Compound 43) twice daily for two weeks (experimental group, Compound 43). On the other hand, in the induced group (Vehicle), adenine-induced chronic renal failure mice were orally administered a vehicle twice daily, and normal group (Ctrl) mice were orally administered a vehicle twice daily. The animals were fed a standard diet (Central Lab Animal, Inc.), a 0.2% adenine diet (ENVIGO), and water ad libitum. They were housed in a controlled environment with temperature (22 ± 2°C), humidity (44-56%), and a 12-hour dark / light cycle. All experimental procedures were approved and performed in accordance with the Institutional Animal Care and Use Committee (IACUC) of the Korea CKD Laboratory Animal Center (IACUC animal study protocol approval number: S-21-037). Each group was classified as shown in Table 3 below.

[0220] [Table 34]

[0221] In an adenine-induced chronic renal failure animal model, the experimental group received 0.2% adenine in the diet and the compound of formula I (compound 43 of Preparation 1) twice daily for two weeks. Two weeks after administration, the blood of the mice was centrifuged in EDTA-treated tubes to measure the blood urea nitrogen (BUN) levels. The supernatant plasma was transferred to a new tube. The plasma was placed in a sample cup using a biochemical analyzer (HITACHI-7020), and the BUN levels were measured using BUN (Blood Urea Nitrogen) reagent (WAKO, 416-55192, 416-55292). All results are shown as mean ± SEM and were analyzed using GraphPad Prism 5 (GraphPad Software, Inc., USA). Statistical analysis was performed by one-way ANOVA (multiple comparison).

[0222] The results of the BUN concentration measurements are shown in FIG. 5, and the error bars in FIG. 5 represent ±SEM (standard error of the mean) (vehicle vs. each group, ****p<0.0001). As shown in FIG. 5 above, it was found that Compound 43 (Production Example 1) reduced the BUN concentration in mice with chronic renal failure. Therefore, it was found that the compound according to the present invention exhibits the effect of improving renal function in patients with renal failure, and can therefore be effectively used for the prevention and treatment of renal failure diseases.

[0223] The present disclosure provides the following pharmaceutical compositions, prophylactic and therapeutic methods, and prophylactic and therapeutic uses. Appendix 1. A pharmaceutical composition for preventing and treating renal failure, comprising as an active ingredient a compound represented by the above formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. Appendix 2: The pharmaceutical composition according to Appendix 1, wherein the compound represented by the formula I is at least one selected from the group consisting of compounds 1 to 450 listed in Table A above. Appendix 3. The pharmaceutical composition according to Appendix 1 or 2, wherein the compound represented by the formula I is at least one selected from the group consisting of compound 40, compound 43, compound 239, compound 285, compound 295, and compound 296 listed in Table B above. Appendix 4. A method for preventing and treating renal failure, which comprises administering to a subject a compound represented by the above formula I described in any one of Appendixes 1 to 3, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. Appendix 5. Use of the compound represented by the above formula I according to any one of Appendixes 1 to 3, an optical isomer thereof or a pharmaceutically acceptable salt thereof for the prevention and treatment of renal failure. Appendix 6. Use of a compound represented by the above formula I according to any one of Appendixes 1 to 3, an optical isomer thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention and treatment of renal failure. Appendix 7. The pharmaceutical composition according to any one of Appendixes 1 to 3, the method according to Appendix 4, and the use according to Appendix 5 or 6, wherein the renal failure is at least one selected from the group consisting of acute renal failure and chronic renal failure. Appendix 8. The pharmaceutical composition according to any one of appendices 1 to 3, wherein the pharmaceutical composition is for oral administration. Appendix 9. The method according to Appendix 4, and the use according to Appendix 5 or 6, wherein the compound represented by formula I, its optical isomer, or a pharmaceutically acceptable salt thereof according to any one of Appendixes 1 to 3 is for oral administration.

[0224] Although certain parts of the present invention have been described in detail above, it will be apparent to those skilled in the art that such specific descriptions are merely preferred embodiments and do not limit the scope of the present invention. Therefore, the true scope of the present invention should be defined by the appended claims and their equivalents.

Claims

1. A compound of formula I: 【Chemistry 1】 In the formula I, L １ , L ２ , or L ３ are each independently a single bond or -(C １ -C ２ alkylene)-; R １ is -CX ２ H or -CX ３ and R ２ is -NR Ａ R Ｂ , -OR Ｃ , 【Chemistry 2】 and {where, 【Transformation 3】 One or more H's are -X, -OH, -O(C １ -C ４ alkyl), -NR Ｄ R Ｅ , -(C １ -C ４ alkyl), -CF ３ , -CF ２ H, —CN, -aryl, -heteroaryl, -(C １ -C ４ alkyl)-aryl, or -(C １ -C ４ and optionally substituted with -aryl, -heteroaryl, -(C alkyl)-heteroaryl. １ -C ４ alkyl)-aryl, or -(C １ -C ４ One or more H of the alkyl-heteroaryl may be —X, —OH, —CF ３ , or -CF ２ optionally substituted with H]}; R ３ is -H, -(C １ -C ４ alkyl), -(C １ -C ４ alkyl)-O(C １ -C ４ alkyl), -(C １ -C ４ alkyl)-C(=O)-O(C １ -C ４ alkyl), -(C ３ -C ７ cycloalkyl), -(C ２ -C ６ cycloheteroalkyl), -aryl, -heteroaryl, -adamantyl, 【Chemistry 4】 and {where -(C １ -C ４ one or more H of the alkyl group may be replaced by —X or —OH; One or more H in -aryl or -heteroaryl are each independently -X, -OH, -O(C １ -C ４ alkyl), -OCF ３ , —O-aryl, —NR Ｄ R Ｅ , -(C １ -C ４ alkyl), -CF ３ , -CF ２ H, -C(=O)-(C １ -C ４ alkyl), -C(=O)-0(C １ -C ４ alkyl), C(═O)—NR Ｄ R Ｅ , -S(=O) ２ -(C １ -C ４ alkyl), aryl, heteroaryl, 【Transformation 5】 may be substituted with, 【Transformation 6】 One or more H's in １ -C ４ alkyl), -NR Ｄ R Ｅ , -CF ３ , or -CF ２ may be substituted with H; -(C ３ -C ７ cycloalkyl), -(C ２ -C ６ cycloheteroalkyl), adamantyl, 【Transformation 7】 One or more H's are each independently -X, -OH, or -(C １ -C ４ alkyl)}; Y １ , Y ２ , and Y ４ are each independently —CH ２ -, -NR Ｆ -, -O-, -C(=O)-, or -S(=O) ２ - and; Y ３ is —CH— or —N—; Z １ ~Z ４ are each independently N or CR Ｚ where Z １ ~Z ４ can not be more than two Ns at the same time, and R Ｚ is —H, —X, or —O(C １ -C ４ alkyl)}; Z ５ and Z ６ are each independently —CH ２ - or -O-; Z ７ and Z ８ are each independently ═CH— or ═N—; Z ９ is -NR Ｇ - or -S-; R Ａ and R Ｂ are each independently -H, -(C １ -C ４ alkyl), -(C １ -C ４ alkyl)-OH, -(C １ -C ４ alkyl)-NR Ｄ R Ｅ , -aryl, -(C １ -C ４ alkyl)-aryl, -heteroaryl, -(C １ -C ４ alkyl)-heteroaryl, -(C ３ -C ７ cycloalkyl), -(C ２ -C ６ heterocycloalkyl), or 【Transformation 8】 and {where -(C １ -C ４ alkyl), -(C １ -C ４ alkyl)-OH, or -(C １ -C ４ alkyl)-NR Ｄ R Ｅ one or more H may be replaced by —X; -aryl, -(C １ -C ４ alkyl)-aryl, -heteroaryl, -(C １ -C ４ alkyl)-heteroaryl, -(C ３ -C ７ cycloalkyl), or -(C ２ -C ６ One or more H of the heterocycloalkyl) may be -X, -OH, -O(C １ -C ４ alkyl), -(C １ -C ４ alkyl), -CF ３ , -CF ２ may be substituted with H or —CN; 【Chemistry 9】 One or more H's are -X, -OH, -O(C １ -C ４ alkyl), -(C １ -C ４ alkyl), -CF ３ , -CF ２ H, -CN, -(C ２ -C ６ heterocycloalkyl), -aryl, -(C １ -C ４ alkyl)-aryl, -heteroaryl or -heteroaryl-(C １ -C ４ alkyl)}; R Ｃ is -(C １ -C ４ alkyl), -aryl, -(C １ -C ４ alkyl)-aryl, -heteroaryl, or -(C １ -C ４ alkyl)-heteroaryl {wherein -(C １ -C ４ One or more H of -(C alkyl) may be replaced by -X or -OH, -aryl, -(C １ -C ４ alkyl)-aryl, -heteroaryl or -(C １ -C ４ One or more H of the alkyl-heteroaryl may be —X, —OH, —CF ３ or -CF ２ may be substituted with H}; R Ｄ and R Ｅ are each independently -H, -(C １ -C ４ alkyl), -aryl or -(C １ -C ４ alkyl)-aryl {wherein -(C １ -C ４ alkyl) One or more H may be replaced by —X or —OH, and -aryl or —(C １ -C ４ One or more H of the alkyl-aryl may be -X, -OH, -CF ３ or -CF ２ may be substituted with H}; R Ｆ is -H, -(C １ -C ６ alkyl), -(C １ -C ４ alkyl)-OH, -(C １ -C ４ alkyl)-O-(C １ -C ４ alkyl), -C(=O)-(C １ -C ４ alkyl), -C(=O)-O(C １ -C ４ -alkyl), -(C １ -C ４ alkyl)-C(=O)-O(C １ -C ４ alkyl), -(C １ -C ４ alkyl)-NR Ｄ R Ｅ , -S(=O) ２ -(C １ -C ４ alkyl), -aryl, -(C １ -C ４ alkyl)-aryl, -(C ２ -C ４ alkenyl)-aryl, -heteroaryl, -(C １ -C ４ alkyl)-heteroaryl, —C(═O)—(C ３ -C ７ cycloalkyl), -(C ２ -C ６ heterocycloalkyl) or -(C １ -C ４ alkyl)-C(=O)-(C ２ -C ６ heterocycloalkyl) {where -(C １ -C ４ alkyl), -(C １ -C ４ alkyl)-OH, -(C １ -C ４ alkyl)-O-(C １ -C ４ alkyl), -C(=O)-(C １ -C ４ alkyl), -C(=O)-O(C １ -C ４ alkyl), -(C １ -C ４ alkyl)-C(=O)-O(C １ -C ４ alkyl), -(C １ -C ４ alkyl)-NR Ｄ R Ｅ or -S(=O) ２ -(C １ -C ４ one or more H of the alkyl group may be replaced by —X; -aryl, -(C １ -C ４ alkyl)-aryl, -(C ２ -C ４ alkenyl)-aryl, -heteroaryl, -(C １ -C ４ alkyl)-heteroaryl, —C(═O)—(C ３ -C ７ cycloalkyl), -C ２ -C ６ Heterocycloalkyl or -(C １ -C ４ alkyl)-C(=O)-(C ２ -C ６ One or more H of the heterocycloalkyl may be —X, —OH, —CF ３ or -CF ２ may be substituted with H}; R Ｇ is -H or -(C １ -C ４ alkyl); Q is —O— or a bond; 【Chemistry 10】 is a single bond or a double bond {provided that 【Chemistry 11】 is a double bond, Y １ is ═CH—}; a-e are each independently an integer of 0, 1, 2, 3, or 4 (with the proviso that a and b cannot both be zero, and c and d cannot both be zero); Each X is independently F, Cl, Br, or I; A pharmaceutical composition for preventing and treating renal failure, comprising as an active ingredient a compound represented by formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

2. In the compound represented by formula I, L １ , L ２ or L ３ are each independently a single bond or -(C １ -C ２ alkylene)-; R １ is -CX ２ H or -CX ３ and R ２ is -NR Ａ R Ｂ , -OR Ｃ , 【Chemistry 12】 and {where, 【Chemistry 13】 One or more H's in the formula (I) are selected from -X, -OH, -NR Ｄ R Ｅ , -(C １ -C ４ alkyl)}; R ３ is -(C １ -C ４ alkyl), -(C ３ -C ７ cycloalkyl), -aryl, -heteroaryl, -adamantyl, 【Chemistry 14】 and {wherein one or more H of -aryl or -heteroaryl are each independently -X, -O(C １ -C ４ alkyl), -OCF ３ , —O-aryl, —NR Ｄ R Ｅ , -(C １ -C ４ alkyl), -CF ３ , -S(=O) ２ -(C １ -C ４ alkyl), -aryl, -heteroaryl, 【Chemistry 15】 may be substituted with, 【Chemistry 16】 One or more H in is —NR Ｄ R Ｅ or -(C １ -C ４ alkyl), 【Chemistry 17】 One or more H's are each independently -(C １ -C ４ alkyl)}; Y １ , Y ２ and Y ４ are each independently —CH ２ -, -NR Ｆ -, -O-, -C(=O)- or -S(=O) ２ - and; Y ３ is —CH— or —N—; Z １ ~Z ４ are each independently N or CR Ｚ where Z １ ~Z ４ can not be more than two Ns at the same time, and R Ｚ is —H, —X or —O(C １ -C ４ alkyl)}; Z ５ and Z ６ are each independently —CH ２ - or -O-; Z ７ and Z ８ are each independently ═CH— or ═N—; Z ９ is -NR Ｇ - or -S-; R Ａ and R Ｂ are each independently -H, -(C １ -C ４ alkyl), -(C １ -C ４ alkyl)-OH, -(C １ -C ４ alkyl)-NR Ｄ R Ｅ , -aryl, -(C １ -C ４ alkyl)-aryl, -(C ３ -C ７ cycloalkyl), or [Chemistry 18] and {where, 【Chemistry 19】 One or more H's in １ -C ４ alkyl), -CF ３ , -(C ２ -C ６ heterocycloalkyl), -(C １ -C ４ alkyl)-aryl, -heteroaryl or heteroaryl-(C １ -C ４ alkyl)}; R Ｃ is -(C １ -C ４ alkyl) or -aryl; R Ｄ and R Ｅ are each independently -H, -(C １ -C ４ alkyl) or -(C １ -C ４ alkyl)-aryl; R Ｆ is -H, -(C １ -C ６ alkyl), -(C １ -C ４ alkyl)-OH, -(C １ -C ４ alkyl)-O-(C １ -C ４ alkyl), -C(=O)-(C １ -C ４ alkyl), -C(=O)-O(C １ -C ４ -alkyl), -(C １ -C ４ alkyl)-C(=O)-O(C １ -C ４ alkyl), -(C １ -C ４ alkyl)-NR Ｄ R Ｅ , -S(=O) ２ -(C １ -C ４ alkyl), -aryl, -(C １ -C ４ alkyl)-aryl, -(C ２ -C ４ alkenyl)-aryl, -heteroaryl, -(C １ -C ４ alkyl)-heteroaryl, —C(═O)—(C ３ -C ７ cycloalkyl), -(C ２ -C ６ heterocycloalkyl) or -(C １ -C ４ alkyl)-C(=O)-(C ２ -C ６ heterocycloalkyl) {where -(C １ -C ４ alkyl) or —C(═O)—O(C １ -C ４ one or more H of the alkyl group may be replaced by —X; -one or more H of the aryl may be replaced by -X; R Ｇ is -(C １ -C ４ alkyl); Q is —O— or a bond; 【Chemistry 20】 is a single bond or a double bond {provided that 【Chemistry 21】 is a double bond, Y １ is —CH—}; a-e are each independently an integer of 0, 1, 2, 3, or 4 (with the proviso that a and b cannot both be zero, and c and d cannot both be zero); 2. The pharmaceutical composition of claim 1, wherein each X is independently F, Cl, Br, or I.

3. The compound represented by formula I is a compound represented by the following formula Ia: 【Chemistry 22】 In the formula Ia, R ２ teeth 【Chemistry 23】 and R ３ is -aryl {wherein one or more H of -aryl may each independently be replaced with -X}; Y １ is -O- or -S(=O) ２ - and; Z １ is N or CR Ｚ where R Ｚ is −X}; a and b are each independently an integer of 0, 1, 2, 3, or 4 (provided that a and b cannot both be zero); 2. The pharmaceutical composition of claim 1, wherein each X is independently F, Cl, Br, or I.

4. In the compound represented by formula Ia, R ２ teeth 【Chemistry 24】 and R ３ is -phenyl {wherein one or more H of -phenyl may each independently be replaced with -F or -Cl}; Y １ is -O- or -S(=O) ２ - and; Z １ The pharmaceutical composition of claim 1 , wherein is N or CF.

5. A pharmaceutical composition for preventing and treating renal failure, comprising as an active ingredient a compound having the following structure in Table A, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. Table 1 Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 Table 15 Table 16 Table 17 Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 Table 24 Table 25 Table 26 Table 27 Table 28 Table 29

6. A pharmaceutical composition for preventing and treating renal failure, comprising as an active ingredient a compound having the following structure in Table B, an optical isomer thereof, or a pharmaceutically acceptable salt thereof: Table 30

7. The pharmaceutical composition according to claim 6, wherein the renal failure is at least one selected from the group consisting of acute renal failure and chronic renal failure.

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

9. A method for the prevention and treatment of renal failure, comprising administering to an individual a compound represented by formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula I is the same as that described in claim 1.

10. 10. A method for preventing and treating renal failure, comprising administering to an individual a compound having the structure of Table A of claim 5, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

11. A method for preventing and treating renal failure comprising administering to an individual a compound having the following structure in Table B, an optical isomer thereof, or a pharmaceutically acceptable salt thereof: Table 31

12. The method according to claim 11, wherein the renal failure is at least one selected from the group consisting of acute renal failure and chronic renal failure.

13. Use of a compound of formula I, an optical isomer thereof or a pharmaceutically acceptable salt thereof for the prevention and treatment of renal failure, wherein the compound of formula I is the same as that described in claim 1.

14. 10. Use of a compound having the structure of Table A according to claim 5, an optical isomer thereof or a pharmaceutically acceptable salt thereof for the prevention and treatment of renal failure.

15. Use of a compound having the following structure in Table B, an optical isomer thereof, or a pharmaceutically acceptable salt thereof for the prevention and treatment of renal failure. Table 32

16. The use according to claim 15, wherein the renal failure is at least one selected from the group consisting of acute renal failure and chronic renal failure.

17. Use of a compound of formula I, an optical isomer thereof or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention and treatment of renal failure, wherein the compound of formula I is the same as that described in claim 1.

18. 10. Use of a compound having the following structure in Table A of claim 5, its optical isomer or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention and treatment of renal failure.

19. 10. Use of a compound having the following structure in Table B, an optical isomer thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention and treatment of renal failure. Table 33

20. 20. The use according to claim 19, wherein the renal failure is at least one selected from the group consisting of acute renal failure and chronic renal failure.

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