Compositions for preventing or treating heart failure (HF)

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating heart failure, comprising a compound represented by formula I, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof as an active ingredient, a method for preventing or treating heart failure using the compound, use of the compound for preventing or treating heart failure, and use of the compound in the preparation of a medicament for preventing or treating heart failure.

Description

[Technical field]

[0001] The present disclosure relates to a pharmaceutical composition for preventing or treating heart failure comprising a compound represented by formula I, its optical isomer, or a pharma- ceutically acceptable salt thereof as an active ingredient, a method for preventing or treating heart failure using the compound, its optical isomer, or a pharma- ceutically acceptable salt thereof, use of the compound, its optical isomer, or a pharma- ceutically acceptable salt thereof for preventing or treating heart failure, and use of the compound, its optical isomer, or a pharma- ceutically acceptable salt thereof in the preparation of a medicament for preventing or treating heart failure. [Background technology]

[0002] "Heart failure (HF)" refers to diseases in which cardiovascular and coronary artery disease, hypertension, and various genetic factors impair the heart's function and thus prevent it from supplying oxygen- and nutrient-filled blood to the rest of the body.

[0003] HF is divided into heart failure with preserved ejection fraction (HFpEF), heart failure with mildly reduced ejection fraction (HFmrEF), and heart failure with reduced ejection fraction (HFrEF) (Theresa AM et al,.Eur Heart J.2021;42(36):3599-3726). To date, HF is a severe chronic disease that manifests as an eventual complication of coronary artery disease, hypertension, cardiomyopathy, etc., with long hospital stays and high rehospitalization rates due to frequent dysfunction of other organs such as the kidneys. HF has the worst prognosis among cardiovascular diseases and therefore has a higher mortality rate than most solid tumors, with a 1-year mortality rate of 37% and a 5-year mortality rate of 78% (Braunwald E et al,.Lancet.2015;385(9970):812-24).

[0004] Drug and surgical treatments have been considered as methods for treating HF. However, most methods are aimed at reducing cardiac function and pain, rather than treating the underlying cause to improve myocardial cell damage. Even if cardiac function is restored by treating HF, it has been shown that 4 out of 10 patients will experience a recurrence of HF within 6 months after discontinuing drug treatment (Brian PH et al,.Lancet.2019;393(10166):61-73).

[0005] Therefore, there is an urgent need to develop drugs that can effectively treat HF.

[0006] [See related art] Patent Literature (Patent Document 1) Korean Patent Application Publication No. 2017-0017792

[0007] Non-patent literature (Non-patent document 1) Theresa AM et al., Eur Heart J 2021;42(36):3599-3726 (Non-patent document 1) Braunwald E. et al., Lancet 2015;385(9970):812-24 (Non-patent document 1) Yao TP et al., Mol. Cell 2005;18,601-607 (Non-patent document 1) Brundel B etal., Nat Rev Cardiol 2017;14(11):637-653 (Non-patent document 1) Pareyson et al., (2011) 10(4):3205 (Non-patent document 1) Brian PH et al,.Lancet.2019;393(10166):61-73) Summary of the Invention [Problem to be solved by the invention]

[0008] The present disclosure may provide a pharmaceutical composition for preventing or treating heart failure, comprising a compound represented by formula I, an optical isomer thereof, or a pharma- ceutical acceptable salt thereof as an active ingredient.

[0009] The present disclosure may provide a method for preventing or treating heart failure, comprising administering to an individual a compound represented by formula I above, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof.

[0010] The present disclosure may provide use of a compound represented by the above formula I, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof for preventing or treating heart failure.

[0011] The present disclosure may provide the use of a compound represented by the above formula I, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof in the preparation of a medicament for preventing or treating heart failure. [Means for solving the problem]

[0012] This will be described in detail below. Note that each description and embodiment disclosed in the present invention can be applied to other descriptions and embodiments. In other words, all combinations of various elements disclosed in the present invention are included in the scope of the present invention. Also, it cannot be seen that the scope of the present invention is limited to the specific description described below.

[0013] The present disclosure provides a pharmaceutical composition for preventing or treating heart failure, comprising a compound represented by the following formula I, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof as an active ingredient. [ka] (In formula I, L1, L2, and L3 each independently represent a bond or -(C1-C2 alkylene)-; R1 is -CX2H or -CX3; R2 is -NR A R B , -OR C , [ka] and { [ka] At least one H is -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 (at least one H of -aryl, -heteroaryl, -(C1-C4 alkyl)-aryl or -(C1-C4 alkyl)-heteroaryl may be substituted with -X, -OH, -CF3 or -CF2H), R3 is -H, -(C1-C4 alkyl), -(C1-C4 alkyl)-O(C1-C4 alkyl), -(C1-C4 alkyl)-C(=O)-O(C1-C4 alkyl), -(C3-C7 cycloalkyl), -(C2-C6 cycloheteroalkyl), -aryl, -heteroaryl, -adamantyl, [ka] and At least one H in the --(C1-C4 alkyl) may be replaced with --X or --OH; At least one H in -aryl or -heteroaryl is independently -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] At least one H is -X, -(C1-C4 alkyl), -NR D R E , -CF3 or -CF2H], -(C3-C7 cycloalkyl), -(C2-C6 cycloheteroalkyl), adamantyl, [ka] at least one H may be independently substituted with -X, -OH or -(C1-C4 alkyl); 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 At least three of Z1 to Z4 may not be N 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-, 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 aryl)-heteroaryl, -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl) or [ka] and {-(C1-C4 alkyl), -(C1-C4 alkyl)-OH or -(C1-C4 alkyl)-NR D R E At least one H may be replaced by -X; At least one H of -aryl, -(C1-C4 alkyl)-aryl, -heteroaryl, -(C1-C4 alkyl)-heteroaryl, -(C3-C7 cycloalkyl) or -(C2-C6 heterocycloalkyl) may be replaced by -X, -OH, -O(C1-C4 alkyl), -(C1-C4 alkyl), -CF3, -CF2H or -CN; [ka] at least one H may be substituted with -X, -OH, -O(C1-C4 alkyl), -(C1-C4 alkyl), -CF3, -CF2H, -CN, -(C2-C6 heterocycloalkyl), -aryl, -(C1-C4 alkyl)-aryl, -heteroaryl or -heteroaryl-(C1-C4 alkyl); R C is -(C1-C4 alkyl), -aryl, -(C1-C4 alkyl)-aryl, -heteroaryl, or -(C1-C4 alkyl)-heteroaryl {at least one H of -(C1-C4 alkyl) may be substituted with -X or -OH, and at least one H of -aryl, -(C1-C4 alkyl)-aryl, -heteroaryl, or -(C1-C4 alkyl)-heteroaryl may be substituted with -X, -OH, -CF3, or -CF2H}, R D and R E are each independently -H, -(C1-C4 alkyl), -aryl, or -(C1-C4 alkyl)-aryl {at least one H of -(C1-C4 alkyl) may be substituted with -X or -OH, and at least one H of -aryl or -(C1-C4 alkyl)-aryl may be substituted with -X, -OH, -CF3, or -CF2H}, R Fis -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). {-(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 at least one H of -S(=O)2-(C1-C4 alkyl) may be substituted with -X; at least one 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 substituted with -X, -OH, -CF3 or -CF2H; R G is -H or -(C1-C4 alkyl), Q is -O- or a bond; [ka] is a single bond or a double bond {wherein [ka] is a double bond, then Y1 is ═CH—; a to e each independently represent an integer of 0, 1, 2, 3, or 4 {provided that a and b do not have to be 0 at the same time, and c and d do not have to be 0 at the same time}; Each X is independently F, Cl, Br or I.

[0014] In a pharmaceutical composition according to the present disclosure, the compound of formula I can be: L1, L2, and L3 each independently represent a bond or -(C1-C2 alkylene)-; R1 is -CX2H or -CX3; R2 is -NR A R B , -OR C , [ka] and { [ka] At least one of the H's is -X, -OH, or -NR D R E , optionally substituted with -(C1-C4 alkyl)}, R3 is -(C1-C4 alkyl), -(C3-C7 cycloalkyl), -aryl, -heteroaryl, -adamantyl, [ka] and At least one H in -aryl or -heteroaryl is 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] At least one H in is -NR D R E or -(C1-C4 alkyl), [ka] at least one H may be independently substituted with -(C1-C4 alkyl); 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 At least three of Z1 to Z4 may not be N 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-, 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 { [ka] at least one H may be substituted with -X, -(C1-C4 alkyl), -CF3, -(C2-C6 heterocycloalkyl), -(C1-C4 alkyl)-aryl, -heteroaryl, or heteroaryl-(C1-C4 alkyl); R C is -(C1-C4 alkyl) or -aryl; R D and R E are each independently -H, -(C1-C4 alkyl) or -(C1-C4 alkyl)-aryl; R F is -H, -(C1~C6 alkyl), -(C1~C4 alkyl)-OH, -(C1~C4 alkyl)-O-(C1~C4 alkyl), -C(=O)-(C1~C4 alkyl), -C(=O)-O(C1~C4 alkyl), -(C1~C4 alkyl)-C(=O)-O(C1~C4 alkyl), -(C1~C4 alkyl)-NR D R E , -S(=O)2-(C1-C4 alkyl), -aryl, -(C1-C4 alkyl)-aryl, -(C2-C4 alkenyl)-aryl, -heteroaryl, -(C1-C4 alkyl)-heteroaryl, -C(=O)-(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl) or -(C1-C4 alkyl)-C(=O)-(C2-C6 heterocycloalkyl). At least one H of —(C1-C4 alkyl) or —C(═O)—O(C1-C4 alkyl) may be substituted with —X; -at least one H of the aryl may be replaced by -X; R G is -(C1-C4 alkyl), Q is -O- or a bond; [ka] is a single bond or a double bond {wherein [ka] is a double bond, then Y1 is -CH-; a to e each independently represent an integer of 0, 1, 2, 3, or 4 {provided that a and b do not have to be 0 at the same time, and c and d do not have to be 0 at the same time}; Each X is independently F, Cl, Br or I.

[0015] In the pharmaceutical composition according to the present disclosure, the compound of formula I may be a compound of formula Ia. [ka] (In formula Ia, R2 is [ka] and R3 is -aryl {at least one H of -aryl may be independently replaced by -X}; Y1 is -O- or -S(=O)2-; Z1 is N or CR Z and {R Z is -X}, a and b are each independently an integer of 0, 1, 2, 3, or 4 {a and b may not be 0 at the same time}; Each X is independently F, Cl, Br or I.

[0016] In a pharmaceutical composition according to the present disclosure, the compound represented by formula Ia may be: R2 is [ka] and R3 is -phenyl {at least one H of -phenyl may be independently replaced by -F or -Cl}; Y1 is -O- or -S(=O)2-; Z1 is N or CF.

[0017] In the pharmaceutical compositions according to the present disclosure, the compounds represented by Formula I may be as shown in Table A below.

[0018] [Table 1]

[0019] [Table 2]

[0020] [Table 3]

[0021] [Table 4]

[0022] [Table 5]

[0023] [Table 6]

[0024] [Table 7]

[0025] [Table 8]

[0026] [Table 9]

[0027] [Table 10]

[0028]

Table 11

[0029]

Table 12

[0030]

Table 13

[0031]

Table 14

[0032]

Table 15

[0033]

Table 16

[0034]

Table 17

[0035]

Table 18

[0036]

Table 19

[0037]

Table 20

[0038] [Table 21]

[0039] [Table 22]

[0040] [Table 23]

[0041] [Table 24]

[0042] [Table 25]

[0043] [Table 26]

[0044] [Table 27]

[0045] [Table 28]

[0046] [Table 29]

[0047] In an exemplary embodiment of the invention, a pharmaceutical composition comprising a compound of Table A, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof as an active ingredient can prevent or treat heart failure.

[0048] In the pharmaceutical compositions according to the present disclosure, the compounds represented by Formula I may be as shown in Table B below.

[0049] [Table 30]

[0050] In an exemplary embodiment of the invention, a pharmaceutical composition comprising a compound of Table B, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof as an active ingredient can prevent or treat heart failure.

[0051] In the present disclosure, the compound represented by the above formula I can be prepared by, but is not limited to, the method disclosed in Korean Patent Application Publication No. 10-2017-0017792.

[0052] In the pharmaceutical composition according to the present disclosure, the compound represented by formula I above may contain at least one asymmetric carbon and therefore may exist as a racemic mixture, a single enantiomer, a mixture of diastereomers, and a single diastereomer. Such isomers can be separated by resolution according to prior art techniques, such as column chromatography, HPLC, etc. Alternatively, isomers may be stereospecifically synthesized using a set of known optically pure starting materials and / or reagents. In particular, said isomers may be optical isomers.

[0053] In the present disclosure, the term "pharmaceutical acceptable" may refer to something that is physiologically tolerable and does not traditionally cause allergic reactions, such as gastrointestinal upset, dizziness, or other similar reactions, when administered to an individual.

[0054] Pharmaceutically acceptable salts according to embodiments of the invention may be prepared by conventional methods known to those of skill in the art.

[0055] Pharmaceutically acceptable salts according to embodiments of the present invention may include, but are not limited to, inorganic ion salts prepared from calcium, potassium, sodium, magnesium, and the like; inorganic acid salts prepared from hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, sulfuric acid, hydroiodic acid, and the like; organic acid salts prepared from acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, and the like; sulfonate salts prepared from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, and the like; amino acid salts prepared from glycine, arginine, lysine, and the like; amine salts prepared from trimethylamine, triethylamine, ammonia, pyridine, picoline, and the like. In an embodiment of the invention, the salts may include hydrochloric acid, trifluoroacetic acid, citric acid, bromic acid, maleic acid, phosphoric acid, sulfuric acid, tartaric acid, or mixtures thereof.

[0056] In this disclosure, the term "heart failure (HF)" may refer to diseases in which the function of the heart is impaired and prevents the heart from supplying oxygen- and nutrient-filled blood to the rest of the body, such as due to cardiovascular and coronary artery disease, hypertension, and various genetic factors, such as due to cardiomyopathy due to dysfunction or death of cardiomyocytes, and / or cardiac fibrosis.

[0057] In an embodiment of the present invention, heart failure may include any cardiac function damage caused by myocardial cell dysfunction and / or death due to various causes, or cardiac fibrosis, etc. For example, heart failure may be related to, but is not limited to, cardiovascular disease, metabolic disease, or genetic factors, or at least two thereof.

[0058] In an embodiment of the present invention, the heart failure may be at least one selected from the group consisting of heart failure with preserved ejection fraction (HFpEF), heart failure with mildly reduced ejection fraction (HFmrEF), and heart failure with reduced ejection fraction (HFrEF), but is not limited thereto.

[0059] In an embodiment of the present invention, the heart failure may include cardiomyopathy, which may be at least one selected from the group consisting of, but not limited to, hypertrophic cardiomyopathy (HCMP), restrictive cardiomyopathy, and dilated cardiomyopathy (DCMP).

[0060] In an embodiment of the present invention, cardiomyopathy may be caused by a genetic abnormality, in which case the cause of the genetic abnormality may be at least one selected from the group consisting of TTN, LMNA, MYH7, MYH6, MYPN, DSP, RBM20, TNNT2, SCN5A and TPM1 gene alterations, but is not limited thereto.

[0061] As used herein, the term "prevention" may refer to any act of inhibiting or delaying the onset of a disease by administering a compound of formula I of the present invention, its optical isomer, or a pharma- ceutically acceptable salt thereof.

[0062] In an embodiment of the present invention, "prevention" may include all actions of preventing, inhibiting, or delaying cardiac function damage caused by cardiomyopathy caused by cardiomyocyte injury, dysfunction or death of cardiomyocytes, and / or cardiac fibrosis, etc. Alternatively, in an embodiment of the present invention, prevention may include cases where symptoms of heart failure are expressed less due to cardiac function damage caused by cardiomyopathy caused by cardiomyocyte injury, dysfunction or death of cardiomyocytes, and / or cardiac fibrosis, etc., compared to a subject not administered the compound of formula I, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof.

[0063] In an embodiment of the present invention, the term "treatment" may refer to any action that improves or favorably changes the symptoms of a suspected individual who is likely to develop a disease or the symptoms of an individual who is suffering from a disease by administering the compound of formula I of the present disclosure, its optical isomer, or its pharma- ceutically acceptable salt. In an embodiment of the present invention, "treatment" may include any action that restores, alleviates, stops, or slows the progression of heart failure, such as cardiac function damage caused by cardiomyocyte damage, cardiomyopathy caused by dysfunction or death of cardiomyocytes, and / or cardiac fibrosis. The pharmaceutical composition comprising the compound of formula I of the present disclosure, its optical isomer, or its pharma- ceutically acceptable salt may have a significantly excellent effect on the prevention and treatment of heart failure.

[0064] The pharmaceutical compositions comprising the compound of formula I, its optical isomer or its pharma- ceutically acceptable salt according to the present disclosure may exhibit excellent efficacy for the prevention and treatment of heart failure with preserved ejection fraction (HFpEF), heart failure with mildly reduced ejection fraction (HFmrEF), heart failure with reduced ejection fraction (HFrEF), or any combination thereof.

[0065] A pharmaceutical composition comprising the compound of formula I according to the present disclosure, its optical isomer or a pharma- ceutically acceptable salt thereof may have a significantly excellent effect on the prevention or treatment of cardiomyopathy.

[0066] The pharmaceutical composition comprising the compound of formula I, its optical isomer or its pharma- ceutically acceptable salt according to the present disclosure may have a significantly excellent effect on the prevention and treatment of at least one cardiomyopathies selected from the group consisting of hypertrophic cardiomyopathy (HCMP), restrictive cardiomyopathy, and dilated cardiomyopathy (DCMP).

[0067] A pharmaceutical composition comprising the compound of formula I according to the present disclosure, an optical isomer thereof, or a pharma- ceutical acceptable salt thereof may have a significantly excellent effect on the prevention and treatment of cardiomyopathy caused by genetic abnormalities.

[0068] The pharmaceutical composition comprising the compound of formula I, its optical isomer or its pharma- ceutically acceptable salt according to the present disclosure can effectively prevent or treat cardiac damage caused by heart failure.For example, the pharmaceutical composition according to the present disclosure can restore the electrocardiogram (ECG) and RR interval to normal in subjects who have cardiac damage caused by heart failure.

[0069] The pharmaceutical composition comprising the compound of formula I, its optical isomer or its pharma- ceutically acceptable salt according to the present disclosure may have significantly reduced side effects.For example, the pharmaceutical composition of the present disclosure may exhibit excellent therapeutic effects without affecting the QT interval of ECG.

[0070] The pharmaceutical composition comprising the compound of formula I, its optical isomer, or its pharma- ceutically acceptable salt according to the present disclosure effectively inhibits and ameliorates cardiac cell fibrosis in subjects with heart failure, and reduces Ca in cardiomyocytes of subjects with heart failure. 2+ It may stabilize the transients, reduce the expression of a-SMA and TGF-β, and restore the expression of acetylated tubulin to normal levels in subjects with cardiac damage due to heart failure.

[0071] In addition, the pharmaceutical composition comprising the compound of formula I, its optical isomer, or its pharma- ceutical acceptable salt according to the present disclosure may have excellent therapeutic effects on heart failure while having excellent safety with little or no side effects. For example, the pharmaceutical composition may have little or no side effects such as induction of ventricular bradycardia.

[0072] A pharmaceutical composition comprising a compound of formula I, its optical isomer or a pharma- ceutically acceptable salt thereof according to the present disclosure can restore the cardiac function of rabbits in a state mimicking cardiac injury (tachycardia pacing) to the level of a normal group of rabbits in which a state mimicking cardiac injury (tachycardia pacing) is not induced.

[0073] The pharmaceutical composition comprising the compound of formula I, its optical isomer or its pharma- ceutical acceptable salt according to the present disclosure may have superior therapeutic effects and significantly less or no side effects compared to conventional drugs.For example, administration of the pharmaceutical composition according to the present disclosure may not result in an increase in the QT interval in electrocardiogram (ECG).

[0074] A pharmaceutical composition comprising a compound of formula I, its optical isomer, or a pharma- ceutically acceptable salt thereof according to the present disclosure can effectively treat, inhibit, or delay cardiac tissue fibrosis in beagle dogs with induced heart failure, for example, can significantly reduce the expression of α-SMA and TGF-β in beagle dogs with induced heart failure.

[0075] A pharmaceutical composition comprising a compound of formula I, its optical isomer, or a pharma- ceutically acceptable salt thereof according to the present disclosure is useful for suppressing Ca2+ accumulation in iPSC-CM cardiomyocytes derived from patients with dilated cardiomyopathy (DCMP) heart failure. 2+ Ca transients in iPSC-CM cardiomyocytes obtained from normal subjects 2+ It may be stabilized to the transient level.

[0076] A pharmaceutical composition comprising the compound of formula I, its optical isomer or a pharma- ceutically acceptable salt thereof according to the present disclosure can stabilize the expression level of acetylated tubulin in tissues obtained from the atria and ventricles of rabbits in a state mimicking cardiac injury (tachycardia pacing) to the level of a normal group of rabbits in which a state mimicking cardiac injury (tachycardia pacing) is not induced.

[0077] A pharmaceutical composition comprising a compound of formula I, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof according to the present disclosure can inhibit the decrease in ejection fraction and the increase in lung and heart weights due to heart failure in rats with heart failure (TAC model).

[0078] The pharmaceutical composition of the present disclosure may further comprise at least one pharma- ceutically acceptable carrier in addition to the compound represented by formula I, its optical isomer or its pharma- ceutically acceptable salt.The pharma-ceutically acceptable carrier may be one that is conventionally used in the art, and specifically includes, but is not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidine, cellulose, water, syrup, methylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral or oil.The pharmaceutical composition of the present invention may further comprise, in addition to the above-mentioned components, lubricant, moisturizer, sweetener, flavoring, emulsifier, suspending agent, preservative, dispersing agent, stabilizer, etc. The pharmaceutical composition of the present invention may be formulated into oral dosage forms such as tablets, powders, granules, pills, capsules, suspensions, emulsions, oral liquids, oils, syrups, etc., as well as external preparations, suppositories, or sterile liquids for injection, using pharma- ceutically acceptable carriers and excipients, and may therefore be prepared in unit dosage forms or in multi-dose containers. Such preparations may be prepared by conventional methods used in the art for formulation, or by methods described in Remington's Pharmaceutical Science (1999). th The composition can be prepared according to the methods disclosed in "The Ingredients and Methods of Preparation of Pharmaceuticals and Medical Devices" (Ed., 1995), and can be formulated into various preparations depending on the disease or ingredient.

[0079] Non-limiting examples of formulations for oral administration using the pharmaceutical composition of the present invention include tablets, troches, lozenges, aqueous suspensions, oil suspensions, prepared powders, granules, emulsions, hard capsules, soft capsules, syrups, elixirs, etc. To formulate the pharmaceutical composition according to the embodiment of the present invention into a formulation for oral administration, the following can be used: binders such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose, gelatin, etc.; excipients such as dicalcium phosphate, etc.; disintegrants such as corn starch, sweet potato starch, etc.; lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate, polyethylene glycol wax, etc.; sweeteners, flavorings, syrups, etc. can also be used. In addition, in the case of capsules, in addition to the above materials, liquid carriers such as fatty oils may also be used.

[0080] Non-limiting examples of parenteral formulations using pharmaceutical compositions according to embodiments of the present invention may include injectable solutions, suppositories, powders for respiratory inhalation, aerosols for spraying, ointments, powders for application, oils, creams, etc. To formulate pharmaceutical compositions according to embodiments of the present invention into preparations for parenteral administration, sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, topical preparations, etc. may be used. As the non-aqueous solvents and suspensions, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, etc. may be used, but are not limited thereto.

[0081] The pharmaceutical compositions according to embodiments of the present invention may be administered orally or parenterally, such as intravenously, subcutaneously, intraperitoneally or topically, in accordance with a targeted method, in particular, but not limited to, oral administration.

[0082] The daily dose of the compound represented by formula I according to the present disclosure, its optical isomer, or a pharma- ceutically acceptable salt thereof may be, but is not limited to, about 0.1 to about 10,000 mg / kg, about 1 to about 8,000 mg / kg, about 5 to about 6,000 mg / kg, or about 10 to about 4,000 mg / kg, and more particularly about 50 to about 2,000 mg / kg, once a day or the daily dose of the compound may be divided and administered several times a day.

[0083] The pharma- ceutical effective amount and effective dosage of the pharmaceutical composition according to the embodiment of the present invention may vary depending on the formulation method, mode of administration, administration time, administration route, etc. of the pharmaceutical composition, and may vary depending on various factors including the type and degree of response achieved by administration of the pharmaceutical composition, the type of individual for administration, the individual's age, weight, general health condition, disease symptoms or severity, sex, diet and excretion, components of other drug compositions used simultaneously or at different times by the corresponding individual, etc., as well as other similar factors well known in the pharmaceutical art, and a person skilled in the art can easily determine and prescribe the effective dosage for the intended treatment.

[0084] Pharmaceutical compositions according to embodiments of the present invention may be administered once a day or in divided doses several times a day.

[0085] The pharmaceutical composition of the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with conventional therapeutic agents. Considering all of the above factors, the pharmaceutical composition of the present invention can be administered in an amount that can achieve maximum effect without side effects at a minimum amount, and such an amount can be easily determined by a person skilled in the art to which the present invention belongs.

[0086] Pharmaceutical compositions comprising a compound of formula I, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof according to embodiments of the invention may be administered in combination with one or more other therapeutic agents.

[0087] The pharmaceutical composition comprising the compound of formula I, its optical isomer or its pharma- ceutical acceptable salt according to the embodiment of the present invention can show excellent effects when used alone, but can also be used in combination with various methods such as hormone therapy, drug treatment, etc. to improve the treatment efficiency.

[0088] The present disclosure may provide a method for preventing or treating heart failure, comprising administering to an individual a compound represented by formula I above, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof.

[0089] The present disclosure may provide a method for preventing or treating heart failure, comprising administering to an individual a compound of Table A above, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof.

[0090] The present disclosure may provide a method for preventing or treating heart failure, comprising administering to an individual a compound of Table B above, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof.

[0091] The terms "heart failure", "prevention" and "treatment" may be the same as above.

[0092] In this disclosure, the term "administration" may refer to the introduction of a given substance into an individual by any suitable method.

[0093] In the present disclosure, the term "individual" may refer to any animal, such as a rat, mouse, livestock, including humans, that has or may develop heart failure, and may in particular be a mammal, including humans, but is not limited to these.

[0094] A method for preventing or treating heart failure according to an embodiment of the present invention may comprise administering a therapeutically effective amount of a compound represented by Formula I above, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof.

[0095] In the present disclosure, the term "therapeutically effective amount" may refer to an amount sufficient to treat a disease with a reasonable risk / benefit ratio applicable to medical treatment and without causing side effects, and may be determined by a person skilled in the art according to factors including the sex, age, weight and health of the patient, the type and severity of the disease, the activity of the drug, sensitivity to the drug, the method of administration, the time of administration, the route of administration, the rate of excretion, the duration of treatment, drugs used in combination or simultaneously, and other factors well known in the pharmaceutical arts. It is preferable that a specific therapeutically effective amount for a specific patient is applied differently depending on various factors including the type and degree of response achieved therefrom, the specific composition, including the presence of other preparations used in some cases, the age, weight, general health, sex and diet of the patient, the time of administration, the route of administration, the rate of excretion of the composition, the duration of treatment and drugs used with or simultaneously with the specific composition, and other similar factors well known in the pharmaceutical arts.

[0096] The method for preventing or treating heart failure of the present disclosure may include not only addressing the disease itself before the onset of symptoms, but also inhibiting or avoiding such symptoms by administering the compound represented by the above formula I, its isomer or its pharma- ceutically acceptable salt. In managing disease, the prophylactic or therapeutic dose of a particular active ingredient may 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 its frequency may vary depending on the age, weight and response of an individual patient. The appropriate dose and method of use may be easily selected by those skilled in the art, naturally taking into account such factors.

[0097] In addition, the method for preventing or treating heart failure of the present disclosure may further include administering a therapeutically effective amount of an additional active agent useful for preventing or treating the disease together with the compound represented by the above formula I, its optical isomer, or a pharma- ceutically acceptable salt thereof, and the additional active agent may exhibit a synergistic or additive effect with the compound represented by the above formula I, its optical isomer, or a pharma- ceutically acceptable salt thereof.

[0098] The present disclosure may provide use of a compound represented by the above formula I, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof for preventing or treating heart failure.

[0099] The present disclosure may provide the use of a compound of Table A above, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof, for preventing or treating heart failure.

[0100] The present disclosure may provide the use of a compound of Table B above, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof, for preventing or treating heart failure.

[0101] The present disclosure may provide the use of a compound represented by the above formula I, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof in the preparation of a medicament for preventing or treating heart failure.

[0102] The present disclosure may provide the use of a compound of Table A above, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof, in the preparation of a medicament for preventing or treating heart failure.

[0103] The present disclosure may provide the use of a compound of Table B above, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof, in the preparation of a medicament for preventing or treating heart failure.

[0104] The terms "heart failure", "prevention" and "treatment" may be the same as above.

[0105] For the preparation of medicines, the compound represented by the above formula I, its optical isomer or its pharma- ceutically acceptable salt may be mixed with a pharma- ceutically acceptable adjuvant, diluent, carrier, etc., and prepared into a combined preparation together with other active agents, thus providing a synergistic effect.

[0106] All references to the pharmaceutical compositions, methods of treatment and uses of the present disclosure apply equally unless they contradict each other. Effect of the Invention

[0107] The compound represented by formula I according to the present disclosure, its optical isomer or a pharma- ceutically acceptable salt thereof, and pharmaceutical compositions containing them as active ingredients can be advantageously used in the prevention or treatment of heart failure. [Brief description of the drawings]

[0108] [Figure 1] FIG. 1 shows the effect of compounds according to the present disclosure on H9c2 cells. [Diagram 2] FIG. 1 shows the effect of compounds according to the present disclosure on H9c2 cells. [Diagram 3] FIG. 2 is an electrocardiogram showing the effect of compounds according to the present disclosure on the treatment and prevention of heart failure in conditions mimicking cardiac damage (tachycardia pacing). [Figure 4] FIG. 1 shows the effect of compounds according to the present disclosure on the treatment and prevention of heart failure in conditions mimicking cardiac damage (tachycardia pacing). [Diagram 5] FIG. 2 is an electrocardiogram showing the safety of compounds according to the present disclosure. [Figure 6] FIG. 2 is an electrocardiogram showing the safety of compounds according to the present disclosure. [Figure 7] FIG. 1 shows the effect of compounds according to the present disclosure on the treatment and prevention of heart failure in a cardiac disease model. [Figure 8] FIG. 1 shows the effect of compounds according to the present disclosure on stabilizing Ca2+ transients in iPSC-CM cardiomyocytes derived from normal individuals. [Figure 9] FIG. 1 shows the effect of compounds according to the present disclosure on stabilizing Ca2+ transients in iPSC-CM cardiomyocytes derived from patients with heart failure. [Figure 10] FIG. 1 shows the effect of compounds according to the present disclosure on the treatment and prevention of heart failure in conditions mimicking cardiac damage (tachycardia pacing). [Figure 11] FIG. 1 shows the effect of compounds according to the present disclosure on the treatment and prevention of heart failure in conditions mimicking cardiac damage (tachycardia pacing). [Figure 12]FIG. 1 shows the effect of compounds according to the present disclosure on the treatment and prevention of heart failure in an animal model of heart failure (TAC model). [Figure 13] FIG. 1 shows the effect of compounds according to the present disclosure on the treatment and prevention of heart failure in an animal model of heart failure (TAC model). [Figure 14] FIG. 1 shows the effect of compounds according to the present disclosure on the treatment and prevention of heart failure in an animal model of heart failure (TAC model). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0109] In the present disclosure, the present disclosure will be described in detail with reference to the following examples. However, it is obvious to those skilled in the art that the examples are merely for illustrating the present invention, and the scope of the present invention is not limited to the examples disclosed below.

[0110] Synthesis 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 [Step 1] N-Phenylthiomorpholine-4-carboxamide 1,1-dioxide [ka] To a solution of aniline (3.000 g, 32,213 mmol) and N,N-diisopropylethylamine (33.439 mL, 193.278 mmol) in dichloromethane (100 mL) was added triphosgene (4.780 g, 16.107 mmol) at 0° C. and stirred at the same temperature. Thiomorpholine 1,1-dioxide (4.790 g, 35.434 mmol) was added to the reaction mixture and stirred at room temperature for another 16 h. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried (anhydrous MgSO4), filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 40 g cartridge; methanol / dichloromethane=2%) and concentrated to give the title compound as a yellow solid (1.325 g, 16.2%).

[0111] [Step 2] Synthesis of methyl 6-((1,1-dioxido-N-phenylthiomorpholine-4-carboxamido)methyl)nicotinate [ka] 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 and mixed with methyl 4-(bromomethyl)-3-fluorobenzoate (0.905 g, 3.932 mmol). The reaction mixture was stirred at room temperature for another 2 h. The reaction mixture was concentrated under reduced pressure to remove the solvent, and water was added to the concentrate, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried (anhydrous MgSO4), filtered, and concentrated under reduced pressure. The crude product was crystallized at room temperature using methanol (20 mL). The resulting precipitate obtained by filtration was washed with methanol and dried to give the title compound as a brown solid (0.816 g, 51.4%).

[0112] [Step 3] Synthesis of N-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide [ka] Methyl 6-((1,1-dioxido-N-phenylthiomorpholine-4-carboxamido)methyl)nicotinate (0.816 g, 2.023 mmol) prepared in step 2 and hydrazine monohydrate (1.910 mL, 40.451 mmol) were mixed in ethanol (10 mL) at room temperature, then heated at 100° C. for 1 h under microwave and cooled to room temperature to quench the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent. The crude product was crystallized from dichloromethane (20 mL) at room temperature. The resulting precipitate obtained by filtration was washed with dichloromethane and dried to give the title compound as a light brown solid (0.560 g, 68.6%).

[0113] [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] A solution of N-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (0.260 g, 0.644 mmol) and triethylamine (0.178 mL, 1.289 mmol) in dichloromethane (2 mL) prepared in step 3 was mixed with difluoroacetic anhydride (0.087 mL, 0.580 mmol) at room temperature. The reaction mixture was stirred at the same temperature for 16 hours. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The mixture was passed through a plastic frit to remove the solid residue and the aqueous layer, and the collected organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane=0%-5%) and concentrated to give the title compound as a white foam (0.156 g, 50.3%).

[0114] [Step 5] Synthesis of compound 43 [ka] A mixture of N-((5-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (0.156 g, 0.324 mmol) prepared in step 4 and 1-methoxy-N-triethylammoniosulfonyl-methanimidate (Burgess Reagent, 0.116 g, 0.486 mmol) in tetrahydrofuran (2 mL) was heated at 150° C. for 30 min in a microwave and cooled to room temperature to quench the reaction. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The biphasic mixture was passed through a plastic frit to remove solid residues and the aqueous layer, and the collected organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane=3%) and concentrated to give the title compound as a colorless oil (0.078 g, 51.9%). 1 H NMR(400MHz,CDCl3)δ 9.23(d,1H,J=2.2Hz),8.38(dd,1H,J=8.2,2.2Hz),7.54(d,1H,J=8.2Hz),7.41-7.31(m,2H),7.19(ddd,3H, LRMS(ES)m / z 464.2(M + +1).

[0115] Synthesis Example 2: Synthesis of Compound 40, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide [Step 1] Methyl 4-((1,1-dioxide-N-phenylthiomorpholine-4-carboxamido)methyl)-3-fluorobenzoate [ka] A solution of N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (1.000 g, 3.932 mmol) and sodium hydride (60.00%, 0.189 g, 4.719 mmol) in N,N-dimethylformamide (30 mL) was mixed with methyl 4-(bromomethyl)-3-fluorobenzoate (1.020 g, 4.129 mmol) at 0° C. and stirred at room temperature for 18 hours. The reaction mixture was then added with saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried (anhydrous MgSO4), filtered, and concentrated in vacuo. The concentrate was purified by column chromatography (SiO2, 40 g cartridge; ethyl acetate / hexane = 0% to 50%) and concentrated to give the title compound methyl 4-((1,1-dioxido-N-phenylthiomorpholine-4-carboxamido)methyl)-3-fluorobenzoate as a white solid (1.240 g, 75.0%).

[0116] [Step 2] N-(2-fluoro-4-(hydrazinecarbonyl)benzyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide [ka] A solution of methyl 4-((1,1-dioxide-N-phenylthiomorpholine-4-carboxamide)methyl)-3-fluorobenzoate (1.240 g, 2.949 mmol) prepared in step 1 and hydrazine monohydrate (2.786 mL, 58.983 mmol) in ethanol (15 mL) was stirred at 120° C. for 1 h and cooled to room temperature to quench the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent, and saturated aqueous sodium bicarbonate was added to the concentrate, followed by extraction with dichloromethane. The biphasic mixture was passed through a plastic frit to remove solid residues and the aqueous layer, and the collected organic layer was concentrated in vacuo. The crude title compound N-(2-fluoro-4-(hydrazinecarbonyl)benzyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide was used without further purification (1.240 g, 100.0%, white solid).

[0117] [Step 3] N-(4-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)-2-fluorobenzyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide [ka] A solution of N-(2-fluoro-4-(hydrazinecarbonyl)benzyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (0.615 g, 1.463 mmol) prepared in step 2, triethylamine (0.304 mL, 2.194 mmol) and difluoroacetic anhydride (0.164 mL, 1.316 mmol) in dichloromethane (10 mL) was stirred at room temperature for 18 hours. Saturated aqueous sodium bicarbonate was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried (anhydrous MgSO4), filtered and concentrated in vacuo. The concentrate was purified by column chromatography (SiO2, 24 g cartridge; methanol / dichloromethane=0%-3%) and concentrated to give the title compound N-(4-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)-2-fluorobenzyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide as a white solid (0.462 g, 63.4%).

[0118] [Step 4] Synthesis of compound 40 [ka] A mixture of N-(4-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)-2-fluorobenzyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (0.462 g, 0.927 mmol) prepared in step 3 and 1-methoxy-N-triethylammoniosulfonyl-methanimidate (Burgess Reagent, 0.331 g, 1.390 mmol) in tetrahydrofuran (10 mL) was heated at 150° C. for 30 min in a microwave and cooled to room temperature to quench the reaction. The reaction mixture was then added with saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The biphasic mixture was passed through a plastic frit to remove solid residues and the aqueous layer, and the collected organic layer was concentrated in vacuo. The concentrate was purified by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 50%) and concentrated to give the title compound N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide as a white solid (0.337 g, 75.7%). 1 H NMR(400MHz,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),7.1 3-7.10(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).

[0119] Synthesis Example 3: Synthesis of Compound 239, N-(3-chlorophenyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)thiomorpholine-4-carboxamide 1,1-dioxide [Step 1] Synthesis of N-(3-chlorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide [ka] 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 precipitate was filtered, washed with diethyl ether and dried to give the title compound as a white solid (1.811 g, 96.3%).

[0120] [Step 2] Synthesis of methyl 6-((N-(3-chlorophenyl)-1,1-dioxidethiomorpholine-4-carboxamido)methyl)nicotinate [ka] 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) was added sodium hydride (60.00%, 0.028 g, 0.693 mmol) at 0° C. The reaction mixture was stirred at the same temperature for 1 hour, and methyl 6-(bromomethyl)nicotinate (0.159 g, 0.693 mmol) was added at the same temperature and stirred for another 2 hours. Water was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried (anhydrous MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, 12 g cartridge; methanol / dichloromethane=0%-5%) and concentrated to give the title compound as a brown oil (0.261 g, 86.0%).

[0121] [Step 3] Synthesis of N-(3-chlorophenyl)-N-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)thiomorpholine-4-carboxamide 1,1-dioxide [ka] Methyl 6-((N-(3-chlorophenyl)-1,1-dioxidothiomorpholine-4-carboxamido)methyl)nicotinate (0.261 g, 0.596 mmol) prepared in step 2 and hydrazine monohydrate (0.290 mL, 5.958 mmol) were mixed in ethanol (2 mL) at room temperature, then stirred at 110° C. for 18 hours, and cooled to room temperature to quench the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent. Water was then added to the resulting concentrate, followed by extraction with dichloromethane. The biphasic mixture was passed through a plastic frit to remove the solid residue and the aqueous layer, and the collected organic layer was concentrated under reduced pressure. The residue was purified by chromatography (SiO2, 4 g cartridge; methanol / dichloromethane=5%-15%) and concentrated to give the title compound as a brown oil (0.261 g, 100.0%).

[0122] [Step 4] Synthesis of compound 239 [ka] N-(3-chlorophenyl)-N-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.261 g, 0.596 mmol) prepared in step 3, triethylamine (0.415 mL, 2.980 mmol) and 2,2-difluoroacetic anhydride (0.195 mL, 1.788 mmol) were mixed in tetrahydrofuran (2 mL) at room temperature, and the resulting solution was then stirred at 80° C. for 18 hours and cooled to room temperature to quench the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent. Water was then added to the resulting concentrate, followed by extraction with dichloromethane. The biphasic mixture was passed through a plastic frit to remove the solid residue and the aqueous layer, and the collected organic layer was concentrated under reduced pressure. The residue was purified and concentrated by chromatography (SiO2, 4 g cartridge; methanol / dichloromethane=0%-3%) to give the title compound as a yellow foam (0.087 g, 29.3%). 1H NMR(400MHz,CDCl3)δ 9.27(dd,1H,J=2.2,0.8Hz),8.43(dd,1H,J=8.2,2.2Hz),7.55(dd,1H,J=8.2,0.9Hz),7.31(t,1H,J=8.0Hz),7.23(t ,1H,J=2.1Hz),7.21-7.10(m,2H),7.10(t,1H),5.12(s,2H),3.75(t,4H,J=5.3Hz),3.06-2.99(m,4H);LRMS(ES)m / z 498.3(M + +1).

[0123] Synthesis 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 [Step 1] N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide [ka] A solution of 1-fluoro-4-isocyanatobenzene (0.500 g, 3.647 mmol) in diethyl ether (10 mL) was mixed with thiomorpholine 1,1-dioxide (0.493 g, 3.647 mmol) at 0° C. and stirred at the same temperature for 1 h. The reaction mixture was stirred at room temperature for another 4 h. The precipitate was collected by filtration, washed with diethyl ether, and dried to give N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide as a white solid (0.920 g, 92.7%).

[0124] [Step 2] Methyl 3-fluoro-4-((N-(4-fluorophenyl)-1,1-dioxidethiomorpholine-4-carboxamido)methyl)benzoate [ka] 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 mixed with methyl 4-(bromomethyl)-3-fluorobenzoate (0.299 g, 1.212 mmol). The reaction mixture was stirred at room temperature for another 17 h and quenched at room temperature by the addition of water (2 mL, stirred for 10 min). Water was then added to the reaction mixture, followed by extraction with dichloromethane. The biphasic mixture was passed through a plastic frit to remove solid residues and the aqueous layer, and the collected organic layer was concentrated in vacuo. The crude product was crystallized at room temperature using dichloromethane (3 mL). The resulting precipitate was filtered, washed with dichloromethane and dried to give methyl 3-fluoro-4-((N-(4-fluorophenyl)-1,1-dioxidothiomorpholine-4-carboxamido)methyl)benzoate as a white solid (0.212 g, 43.9%).

[0125] [Step 3] N-(2-fluoro-4-(hydrazinecarbonyl)benzyl)-N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide [ka] Methyl 3-fluoro-4-((N-(4-fluorophenyl)-1,1-dioxidothiomorpholine-4-carboxamido)methyl)benzoate (0.212 g, 0.484 mmol) prepared in step 2 and hydrazine monohydrate (0.470 mL, 9.670 mmol) were mixed in ethanol (4 mL) at room temperature, then heated at 120° C. for 1 h under microwave and cooled to room temperature to quench the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The biphasic mixture was passed through a plastic frit to remove solid residues and the aqueous layer, and the collected organic layer was concentrated in vacuo. The residue was diluted with diethyl ether (5 mL) and ethyl acetate (1 mL) and stirred at ambient temperature. The resulting precipitate was collected by filtration, washed with hexanes, and dried to give N-(2-fluoro-4-(hydrazinecarbonyl)benzyl)-N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide as a white solid (0.179 g, 84.4%).

[0126] [Step 4] Synthesis of compound 285 [ka] A solution of N-(2-fluoro-4-(hydrazinecarbonyl)benzyl)-N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.100 g, 0.228 mmol) and triethylamine (0.095 mL, 0.684 mmol) prepared in step 3 in dichloromethane (4 mL) was mixed with 2,2-difluoroacetic anhydride (0.028 mL, 0.228 mmol) at room temperature and stirred at the same temperature for 17 hours. Then, saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The biphasic mixture was passed through a plastic frit to remove solid residues and the aqueous layer, and the collected organic layer was concentrated in vacuo. The residue was chromatographed (SiO2, 4 g cartridge; ethyl acetate / hexanes = 20% to 50%) to give N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide as a white solid (0.053 g, 46.6%). 1 H NMR(400MHz,CDCl3)δ 7.90(dd,1H,J=8.0,1.6Hz),7.77(dd,1H,J=10.1,1.6Hz),7.69(t,1H,J=7.6Hz),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).

[0127] Synthesis Example 5. Synthesis of Compound 295, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide [Step 1] Methyl 6-((N-(4-fluorophenyl)-1,1-dioxidethiomorpholine-4-carboxamido)methyl)nicotinate [ka] A solution of N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.500 g, 1.836 mmol) prepared in step 1 of Synthesis 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 mixed with methyl 6-(bromomethyl)nicotinate (0.465 g, 2.020 mmol). The reaction mixture was stirred at room temperature for another 5 hours and quenched at room temperature by the addition of water (5 mL, stirred for 10 minutes). Water was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried (anhydrous MgSO4), filtered, and concentrated in vacuo. Methyl 6-((N-(4-fluorophenyl)-1,1-dioxidothiomorpholine-4-carboxamido)methyl)nicotinate was used without further purification (0.450 g, 58.1%, brown solid).

[0128] [Step 2] N-(4-fluorophenyl)-N-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)thiomorpholine-4-carboxamide 1,1-dioxide [ka] Methyl 6-((N-(4-fluorophenyl)-1,1-dioxidethiomorpholine-4-carboxamide)methyl)nicotinate (0.150 g, 0.356 mmol) prepared in step 1 and hydrazine monohydrate (0.346 mL, 7.118 mmol) were mixed in ethanol (5 mL) at room temperature, then stirred at 100° C. for 17 hours and cooled to room temperature. The precipitate was collected by filtration, washed with ethanol, and dried to give N-(4-fluorophenyl)-N-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)thiomorpholine-4-carboxamide 1,1-dioxide as a pale yellow solid (0.111 g, 74.0%).

[0129] [Step 3] N-((5-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)pyridin-2-yl)methyl)-N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide [ka] A solution of N-(4-fluorophenyl)-N-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.111 g, 0.263 mmol) and triethylamine (0.110 mL, 0.790 mmol) prepared in step 2 in dichloromethane (5 mL) was mixed with 2,2-difluoroacetic anhydride (0.065 mL, 0.527 mmol) at room temperature and stirred at the same temperature for 1 h. Water was then added to the reaction mixture, followed by extraction with dichloromethane. The biphasic mixture was passed through a plastic frit to remove the solid residue and the aqueous layer, and the collected organic layer was concentrated in vacuo. The crude product was used without further purification (0.082 g, 62.3%, yellow solid).

[0130] [Step 4] Synthesis of compound 295 [ka] 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) were mixed in tetrahydrofuran (5 mL) at room temperature, then stirred at 70° C. for 5 hours, cooled to room temperature, filtered to remove solids, and concentrated under reduced pressure. The residue was chromatographed (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) to give N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide as a white solid (0.015 g, 19.0%). 1 H NMR(400MHz,CDCl3)δ 9.27(d,1H,J=1.6Hz),8.43(dd,1H,J=8.2,2.2Hz),7.58(d,2H,J=8.2Hz),7.25-7.21(m,2H) ,7.10-6.84(m,3H),5.08(s,2H),3.73(t,4H,J=5.1Hz),2.98(t,4H,J=5.2Hz);LRMS(ES)m / z 482.1(M + +1).

[0131] Synthesis Example 6: Synthesis of Compound 296, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-(3-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide [Step 1] Methyl 6-((N-(3-fluorophenyl)-1,1-dioxidethiomorpholine-4-carboxamido)methyl)nicotinate [ka] A solution of 1-fluoro-3-isocyanatobenzene (0.500 g, 3.647 mmol) in diethyl ether (10 mL) was mixed with thiomorpholine 1,1-dioxide (0.493 g, 3.647 mmol) at 0° C. and stirred at the same temperature for 1 h. The reaction mixture was stirred at room temperature for another 4 h. The precipitate was collected by filtration, washed with diethyl ether, and dried to give N-(3-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide as a white solid (0.870 g, 87.6%).

[0132] A solution of N-(3-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.500 g, 1.836 mmol) and sodium hydride (60.00%, 0.081 g, 2.020 mmol) prepared above in N,N-dimethylformamide (10 mL) was stirred at 0° C. for 30 min and mixed with methyl 6-(bromomethyl)nicotinate (0.465 g, 2.020 mmol). The reaction mixture was stirred at room temperature for an additional 5 h and quenched at room temperature by the addition of water (5 mL, stirred for 10 min). Water was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried (anhydrous MgSO4), filtered, and concentrated in vacuo. Methyl 6-((N-(3-fluorophenyl)-1,1-dioxidothiomorpholine-4-carboxamido)methyl)nicotinate was used without further purification (0.450 g, 58.1%, brown solid).

[0133] [Step 2] N-(3-fluorophenyl)-N-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)thiomorpholine-4-carboxamide 1,1-dioxide [ka] Methyl 6-((N-(3-fluorophenyl)-1,1-dioxidethiomorpholine-4-carboxamide)methyl)nicotinate (0.150 g, 0.356 mmol) prepared in step 1 and hydrazine monohydrate (0.346 mL, 7.118 mmol) were mixed in ethanol (5 mL) at room temperature, then stirred at 100° C. for 17 hours and cooled to room temperature. The precipitate was collected by filtration, washed with ethanol, and dried to give N-(3-fluorophenyl)-N-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)thiomorpholine-4-carboxamide 1,1-dioxide as a pale yellow solid (0.113 g, 75.3%).

[0134] [Step 3] N-((5-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)pyridin-2-yl)methyl)-N-(3-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide [ka] 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) was mixed with 2,2-difluoroacetic anhydride (0.067 mL, 0.536 mmol) at room temperature and stirred at the same temperature for 1 h. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The biphasic mixture was passed through a plastic frit to remove the solid residue and the aqueous layer, and the collected organic layer was concentrated in vacuo. N-((5-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)pyridin-2-yl)methyl)-N-(3-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide was used without further purification (0.090 g, 67.2%, yellow solid).

[0135] [Step 4] Synthesis of compound 296 [ka] 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) were mixed in tetrahydrofuran (5 mL) at room temperature, then stirred at 70° C. for 5 hours, cooled to room temperature, filtered to remove solids, and concentrated under reduced pressure. The residue was chromatographed (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) to give N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-(3-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide as a white solid (0.044 g, 50.7%). 1 H NMR(400MHz,CDCl3)δ 9.28(d,1H,J=1.6Hz),8.46(dd,1H,J=8.2,2.2Hz),7.58(d,1H,J=8.2Hz),7.37-7.32(m,1H) ,7.10-6.92(m,4H),5.14(s,2H),3.76(t,4H,J=5.1Hz),3.03(t,4H,J=5.2Hz);LRMS(ES)m / z 482.3(M + +1).

[0136] Example 1: Confirmation of effects on H9c2 cells H9c2(2.0×10 5(cells / well, rat, cardiac, myoblast) cells were seeded in a 6-well plate and treated with drugs (compounds 43, 295, 296, 40, 239, and 285) for each concentration. After 4 hours at 37°C, proteins were extracted with lysis buffer and quantified by Bradford method. 5 μg of protein was dissolved in sample buffer, electrophoresed on a 4-12% gradient gel, transferred to a nitrocellulose membrane for 7 minutes, and blocked with 3% BSA solution for 1 hour. After adding anti-acetyl tubulin (1:1,000) and GAPDH (1:2,000) to 3% BSA solution, the membrane was immersed and reacted at 4°C for 10 hours, and then washed three times with 1×TBST for 10 minutes each. After adding IgG-HRP antibody (1:5,000) to 5% BSA, the membrane was immersed and reacted at room temperature for 1 hour, and then washed three times with 1×TBST for 10 minutes each. The protein expression level was confirmed using ECL solution, and the results are shown in FIG. 1 and FIG.

[0137] As seen above in Figures 1 and 2, compounds 43, 295, 296, 40, 239 and 285 of the present disclosure were found to increase the concentration of acetyl tubulin in H9c2 cells in a concentration-related manner.

[0138] <Example 2> Confirmation of therapeutic effect against cardiac damage The effect of the compound of formula 1 (compound 43: compound of Synthesis Example 1) on the treatment of cardiac injury was confirmed by administering the compound of formula 1 (compound 43: compound of Synthesis Example 1) to an animal model.

[0139] 1) Preparation of test method and animal model The Langendorff test method was used to evaluate the therapeutic effect of compound on heart damage.The Langendorff test method is known as a test method that is useful for determining the direct effect of compound on heart in terms of efficacy and safety.In particular, this method has the advantage that it is easy to measure the actual cardiac contractility and heart rate by removing peripheral hemodynamic variables that may interfere with the heart in experimental animals, and it can use various doses of compounds to intensively investigate the correlation between chemical structure and pharmacological action.

[0140] In this example, we attempted to confirm the improving effect of the compound of formula 1 (compound 43: the compound of Synthesis Example 1) and its distinction from existing drugs in the cardiac injury condition induced by tachycardia pacing.

[0141] Male rabbits having the following conditions were prepared:

[0142] [Table 31]

[0143] Tachycardia pacing-induced cardiac injury was produced in the male rabbits.

[0144] Rabbits were supplied by Orient Bio and fed a standard diet (Central Lab Animal, Inc.), housed under constant temperature (20±2°C), humidity (40±10%) and lighting (12-h light / dark cycle) conditions, and allowed free access to water. All experimental procedures were approved and performed in accordance with the Institutional Animal Care and Use Committee (IACUC) of the external testing facility (IACUC animal study protocol approval number: BnH2015-9E).

[0145] The rabbits were divided into a normal group (control or sham), a drug-untreated group (comparison group, vehicle), and a drug-treated group (compound), with 5 rabbits in each group.

[0146] 2) Test method 2-1) Langendorff Experiment Male rabbits were anesthetized by respiration, and the hearts were excised. After removing connective tissue, the hearts were perfused at constant pressure with physiological solution (modified Krebs-Henseleit bicarbonate buffer; composition: 116 mM / L NaCl, 4.7 mM / L KCl, 1.1 mM / L MgSO4, 1.17 mM / L KH2PO4, 24.9 mM / L NaHCO3, 2.52 mM / L CaCl2, 8.32 mM / L glucose) saturated with 95% O2 / 5% CO2. Electrodes were connected to the atrium and ventricle, and the electrocardiogram was measured for 1 hour to confirm the stable state.

[0147] 2-2) Evaluation method of ventricular function using the Langendorff experiment After confirming that the heart was stable for 1 hour by electrocardiogram, cardiac injury stimulation was given by 50Hz tachycardia pacing for 30 minutes. After measuring the electrocardiograms of the atria and ventricles, the test target compound (compound 43: compound of Preparation Example 1) was administered to the physiological fluid, and the electrocardiogram was measured after 1 hour. In order to confirm whether the drug effect was maintained even after removing the compound from the physiological fluid, the physiological fluid containing the compound in which the rabbit heart was immersed was washed out, and physiological fluid containing no compound was administered, and the electrocardiogram was measured after 1 hour.

[0148] 2-3) Evaluation method for cardiac safety using the Langendorff experiment After confirming cardiac stability by electrocardiogram for 1 hour, the compounds were administered into the physiological fluid, and electrocardiograms were taken 30 minutes later to analyze the QT interval.

[0149] 3) Test results 3-1) Verification of compound efficacy under ex vivo conditions The effect of the compound on improving ventricular function was analyzed in an ex vivo cardiac injury mimicking condition (tachycardia pacing), and the results are shown in Figures 3 and 4 and Table 1. In Figure 4 above, ** on the graph may refer to P<0.01 when compared with normal group (sham), and ## may mean P<0.01 when compared with tachycardia pacing (comparison group, vehicle).

[0150] [Table 32]

[0151] As can be seen from FIG. 3, it was confirmed that the electrocardiogram was improved to the same level as the normal group (control) without the irregular ventricular function induced by treatment with 1 μM compound 43, and it was also found that the cardioversion effect was maintained for at least 1 hour after the compound was removed.

[0152] Furthermore, as seen in FIG. 4 and Table 1, when treated with 1 μM of the compound and when the compound was removed, the RR interval improved to the same extent as in the normal group (sham).

[0153] 3-2) Ensuring cardiac safety compared to existing drugs Using dofetilide as a control drug, the effect of the compound according to the present disclosure (Compound 43: the compound of Synthesis Example 1) on the QT interval of ECG was confirmed in normal rabbits.

[0154] Rabbits were prepared under the same conditions as in 1) and divided into a normal group, a dofetilide-treated group, and a compound 43-treated group, and then the hearts of the rabbits were excised according to the Langendorff experimental method in 2-2) and the QT intervals were analyzed according to 2-3), and the results are shown in Figures 5 and 6 and the following Tables 2 and 3. In the above Figures 5 and 6 and Tables 2 and 3, the control can refer to the normal group, and all data values ​​in Tables 2 and 3 are expressed as the mean ± standard error.

[0155] [Table 33]

[0156] As can be seen in Table 2 above and FIG. 5, when treated with dofetilide, the QT interval increased at both 0.3 μM and 1 μM compared to the QT interval of normal EGG.

[0157] [Table 34]

[0158] As seen in FIG. 6 and Table 3, the QT interval of normal ECG was not affected in the normal group when treated with Compound 43.

[0159] Therefore, the compounds of formula I according to the present disclosure are found to be safe drugs that do not cause any adverse effects on the heart.

[0160] Example 3: Confirmation of anti-fibrotic activity 1) Creation of cardiac disease models and preparation of experimental animals The anti-fibrotic activity effect of the compound of the present disclosure in heart failure was confirmed using beagle dogs having the following conditions.

[0161] [Table 35]

[0162] Beagle dogs were supplied by Orient Bio and fed a standard diet (Central Lab Animal, Inc.), housed under constant temperature (23±3°C), humidity (55±15%) and lighting (12-h light / dark cycle) conditions, and allowed free access to water. All experimental procedures were approved and performed in accordance with the Institutional Animal Care and Use Committee (IACUC) of the external testing facility (IACUC animal study protocol approval number: KNOTUS IACUC 18-KE-268).

[0163] To induce anesthesia in beagle dogs (male, 11 months old), pentobarbital (25 mg / kg) was administered intravenously, and anesthesia was maintained with isoflurane. Using a C-arm (ARCADIS Varic, SIEMENS Co.) device and angiographic contrast, an in vivo implantable electrode of a pacemaker (bipolar pacing lead, Medtronic, IRE) was placed in the right atrial appendage, and then the correct insertion was confirmed from the angiogram, and the pacemaker lead was then fixed in the right atrial appendage. After stabilization for one week after surgery, the pacemaker was operated at 400 bpm, and normal induction was confirmed by electrocardiography, and then tachycardia pacing was induced. Hemodynamic parameters of each group were measured.

[0164] In order to confirm the effect of drug administration of the compound according to the present disclosure, beagle dogs with induced heart disease were divided into groups of two, and each group was classified according to the substance administered [vehicle (Veh), compound], route of administration [oral administration (PO)], and administration interval [daily (Bid)] as shown in Table 4 below.

[0165] [Table 36]

[0166] In Table 4 above, the normal group is a group in which tachycardia pacing was not induced, the drug-untreated group is a group in which tachycardia pacing was induced but no drug was administered, and the drug-treated group is a group in which tachycardia pacing was induced and compound 43 (Synthesis Example 1) was administered.

[0167] In order to confirm the effect of the compound according to the present disclosure on the prevention or treatment of heart failure, the expression of α-SMA and TGF-β, which are directly related to fibrosis in cardiac tissue, was analyzed. After isolating the hearts of each group, proteins were isolated from each cardiac tissue. The expression of α-SMA and TGF-β was analyzed for each protein by Western blot, and the degree of cardiac fibrosis between groups was compared, and the results are shown in Figure 7.

[0168] As a result, as shown in Figure 7, the group administered with compound 43 according to the present disclosure showed a decrease in the expression of α-SMA and TGF-β, respectively, compared with the group not administered with the drug under a cardiac damage mimicking condition (tachycardia pacing). Therefore, it can be seen that the compound according to the present disclosure exhibits an anti-fibrotic effect and is therefore advantageously used in the prevention or treatment of heart failure disease.

[0169] Example 4: Ca in DCMP iPSC-CMs with TPM1 mutations 2+ Checking the effect on transient activity To confirm the effect of the compounds according to the present disclosure on the prevention or treatment of heart failure disease, Ca in iPSC-CM cardiomyocytes derived from patients with dilated cardiomyopathy (DCMP) heart failure was measured. 2+ The transient phenomenon was analyzed.

[0170] Cardiomyocytes derived from patients with heart failure were treated with Compound 43 (Synthesis Example 1) at various concentrations for 24 hours. Then, both iPSC-CM cardiomyocytes derived from healthy subjects (normal group, normal) and iPSC-CM cardiomyocytes derived from patients with dilated cardiomyopathy (DCMP) heart failure were stimulated at 3 Hz for 24 hours under conditions mimicking cardiac injury (tachycardia pacing). Each group was treated with the cell permeable calcium dye Fluo-4 (AM, cell permeant-Thermo Fisher Scientific), and then the Ca 2+ Images were taken in real time using a confocal microscope to measure intergroup Ca 2+ The transients were compared and analyzed. The results of cells obtained from normal subjects are shown in FIG. 8, and the results of cells obtained from patients with DCMP heart failure are shown in FIG. 9. Normal in FIG. 8 may refer to cardiomyocytes not treated with tachycardia pacing, and 0, 0.1, 1, and 3 in FIG. 8 and FIG. 9 may represent the concentration of compound 43 (compound of Synthesis Example 1) in cells treated with tachycardia pacing. In addition, in FIG. 8 and FIG. 9, *** may mean P<0.001 when compared with non-tachycardia pacing (normal), and #, ##, and ### may represent P<0.05, P<less than 0.01, and P<0.001, respectively, when compared with the tachycardia pacing group.

[0171] As can be seen in FIG. 9, Ca in cardiomyocytes from patients with DCMP heart failure 2+ Comparative analysis of transients revealed that Ca 2+ It was observed that the Ca transient was reduced in the group administered with compound 43 according to the present disclosure. 2+ The transient phenomenon was restored, and compound 43 was observed to be effective when administered at various concentrations (0.1 to 3 μM). Thus, the compounds according to the present disclosure have 2+ Since the compound exhibits a transient phenomenon stabilizing effect, it can be advantageously used in the prevention or treatment of heart failure, and it has been confirmed that the compound can exert a sufficient therapeutic effect even in severe heart failure.

[0172] <Example 5> Confirmation of the effect on acetylated tubulin in atrial and ventricular tissues in a state mimicking cardiac damage (tachycardia pacing) To confirm the effect of compounds according to the present disclosure on the prevention or treatment of heart failure, the expression of acetylated tubulin was analyzed.

[0173] Male rabbits were prepared in the same manner as in Example 1, and divided into a normal group (sham), a drug-untreated group (vehicle), and a drug-treated group (compound).

[0174] Thereafter, the heart was evaluated by the Langendorff experiment in the same manner as in 2-1) of 2) of Example 2. For the drug treatment group, the heart was treated with a drug by administering Compound 43 (the compound of Synthesis Example 1) to the physiological fluid in the same manner as in 2-2) of 2) of Example 2.

[0175] Then, the atria and ventricles were separated, and proteins were isolated from each tissue. The expression of acetylated tubulin was analyzed for each protein by Western blot, and the expression levels between groups were compared, and the results are shown in Figure 10 and Figure 11. * may mean P<0.05, ** may refer to P<0.01, and *** may represent P<0.001 or less.

[0176] As can be seen in Figures 10 and 11, in the group administered compound 43 according to the present disclosure, the expression of acetylated tubulin was restored to that of the normal group (sham) compared to the vehicle group in which no drug was administered under cardiac injury mimicking conditions (tachycardia pacing).

[0177] Thus, it has been determined that the compounds according to the present disclosure exhibit tubulin stabilizing effects and are therefore advantageously used in the prevention or treatment of heart failure diseases.

[0178] <Example 6> Confirmation of the effect of improving cardiac function in an animal model of heart failure In order to confirm the effect of the compound of the present disclosure (compound 43: compound of Synthesis Example 1) on improving cardiac function, the compound of the present disclosure (compound 43: compound of Synthesis Example 1) was administered to a TAC (transverse aortic constriction) model of heart failure using Sprague-Dawley rats, and the results were analyzed.

[0179] 1) Preparation of animal models and group classification Sprague-Dawley rats were prepared with the following conditions:

[0180] [Table 37]

[0181] Rats were supplied by Koatech and fed a standard diet (Central Lab Animal, Inc.), housed under constant temperature (23±3°C), humidity (55±15%) and lighting (12-h light / dark cycle) conditions, and allowed free access to water. All experimental procedures were approved and performed in accordance with the Institutional Animal Care and Use Committee (IACUC) of the external testing facility (IACUC animal study protocol approval number: KNOTUS IACUC 22-KE-0333).

[0182] After the acclimation period, the animals were weighed and randomly divided into groups so that the average weight of each group was distributed as evenly as possible according to the ranked weights. As a result, the rats were divided into a normal group (control; ctrl), a comparison group (vehicle), and a drug-treated group (compound 43).

[0183] 2) Preparation of the TAC model of heart failure After general anesthesia of Sprague-Dawley rats, the second to third intercostal space on the left side was incised while observing the electrocardiogram, and the transverse aorta in the left and right carotid arteries was isolated and constricted to a 22-gauge needle using a suture.The needle was then removed, and the chest cavity and skin were sutured to prepare an animal model of heart failure.

[0184] 3) Drug Administration According to the method of 2), heart failure was induced in the comparison group (vehicle) and the drug administration group (compound 43). Vehicle (0.5% methylcellulose, 5 mL / kg) was orally administered to the normal group (ctrl) and the comparison group (vehicle), and compound 43 was orally administered to the drug administration group for 6 weeks from the day of induction of heart failure.

[0185] [Table 38]

[0186] 4) Ultrasonic measurement TAC was induced in the animal model, and at 6 weeks after drug administration, cardiac changes according to ejection fraction were measured using an ultrasound device (S-Sharp ProspectT1, Taiwan). All data are presented as ± standard error, and statistical significance was analyzed using one-way ANOVA (multiple comparisons) for comparison of the vehicle-treated control group with other groups. * may represent P<0.05, **** may represent P<0.0001.

[0187] 5) Autopsy of Animal Models TAC was induced in the animal model, and 6 weeks after administration of the drug, the chest was opened, and the heart and lungs were removed and weighed. All data are presented as ± standard error, and statistical significance was analyzed using one-way ANOVA (multiple comparisons) for comparison of the vehicle-treated control group with other groups. * may represent P<0.05, ** may represent P<0.01.

[0188] 6) Confirmation of pharmacological effects by measuring ejection fraction As shown in FIG. 12, compounds according to the present disclosure increased ejection fraction in an animal model of heart failure where ejection fraction was reduced due to heart failure as a result of inducing TAC.

[0189] Thus, it has been confirmed that the compounds according to the present disclosure can be advantageously used in the prevention or treatment of heart failure diseases.

[0190] 7) Confirmation of pharmacological effects by analyzing the weight of the heart and lungs As shown in FIG. 13, compounds according to the present disclosure reduced heart weight in an animal model of heart failure where increased heart weight was due to heart failure as a result of TAC induction.

[0191] Thus, it has been confirmed that the compounds according to the present disclosure can be advantageously used in the prevention or treatment of heart failure diseases.

[0192] As shown in FIG. 14, compounds according to the present disclosure reduced lung weight in an animal model of heart failure where increased lung weight was due to heart failure as a result of TAC induction.

[0193] Thus, it has been confirmed that the compounds according to the present disclosure can be advantageously used in the prevention or treatment of heart failure diseases.

[0194] The present disclosure provides pharmaceutical compositions, methods and uses as follows: Item 1. A pharmaceutical composition for preventing or treating heart failure, comprising a compound represented by the above formula I, an optical isomer thereof, or a pharma- ceutical acceptable salt thereof as an active ingredient.

[0195] Item 2. The pharmaceutical composition according to Item 1, wherein the compound represented by formula I is at least one selected from the group consisting of compounds 1 to 450 listed in Table A above.

[0196] Item 3. The pharmaceutical composition according to item 1 or 2, wherein the compound represented by 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.

[0197] Item 4. A method for preventing or treating heart failure, comprising administering to an individual the compound represented by formula I, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof according to any one of items 1 to 3.

[0198] Item 5. Use of a compound represented by the above formula I according to any one of Items 1 to 3, an optical isomer thereof or a pharma- ceutically acceptable salt thereof for preventing or treating heart failure.

[0199] Item 6. Use of a compound represented by the above formula I, an optical isomer thereof or a pharma- ceutically acceptable salt thereof according to any one of Items 1 to 3 in the preparation of a medicament for preventing or treating heart failure.

[0200] Item 7. The pharmaceutical composition according to any one of Items 1 to 3, the method according to Item 4, or the use according to Item 5 or 6, wherein the heart failure is at least one selected from the group consisting of heart failure with preserved ejection fraction (HFpEF), heart failure with mildly reduced ejection fraction (HFmrEF), and heart failure with reduced ejection fraction (HFrEF).

[0201] Item 8. The pharmaceutical composition according to any one of Items 1 to 3, the method according to Item 4, or the use according to Item 5 or 6, wherein the heart failure includes cardiomyopathy.

[0202] Item 9. The pharmaceutical composition according to any one of Items 1 to 3, the method according to Item 4, or the use according to Item 5 or 6, wherein the cardiomyopathy is at least one selected from the group consisting of hypertrophic cardiomyopathy (HCMP), restrictive cardiomyopathy, and dilated cardiomyopathy (DCMP).

[0203] Item 10. The pharmaceutical composition according to any one of Items 1 to 3, 7, 8 and 9, wherein the pharmaceutical composition is administered orally.

[0204] Item 11. The method according to any one of items 4, 7, 8 and 9, or the use according to any one of items 5 to 9, wherein the compound represented by the above formula I, its optical isomer or its pharma- ceutically acceptable salt according to items 1 to 3 is orally administered.

[0205] Although certain portions of the present invention have been described in detail above, it will be apparent to those skilled in the art that such detailed description is provided merely to illustrate exemplary embodiments and is not to be construed as limiting the scope of the present invention. Therefore, it should be understood that the true scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A pharmaceutical composition for preventing or treating heart failure, comprising as an active ingredient a compound represented by the following formula I, an optical isomer thereof, or a pharma- ceutical acceptable salt thereof: 【Chemistry 1】 (In formula I, L １ , L ２ Or L ３ each independently represents a bond or -(C １ ~C ２ alkylene)-, R １ Ha-CX ２ H or -CX ３ and R ２ Ha-NR Ａ R Ｂ , -OR Ｃ , 【Chemistry 2】 and ｛ 【Chemistry 3】 At least one H is -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 [0036] The above-mentioned -aryl, -heteroaryl, -(C １ ~C ４ alkyl)-aryl or -(C １ ~C ４ At least one H of the alkyl-heteroaryl is -X, -OH, -CF ３ Or -CF ２ H may be substituted. 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 {-(C １ ~C ４ At least one H of -aryl or -heteroaryl may be replaced by -X, -OH, or -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)-O(C １ ~C ４ alkyl), -C(=O)-NR Ｄ R Ｅ , -S(=O) ２ - (C １ ~C ４ alkyl), aryl, heteroaryl, 【Chemistry 5】 may be substituted with [ 【Chemistry 6】 At least one H in is -X, -(C １ ~C ４ alkyl), -NR Ｄ R Ｅ , -CF ３ Or -CF ２ H, - (C ３ ~C ７ Cycloalkyl), -(C ２ ~C ６ cycloheteroalkyl), adamantyl, 【Chemistry 7】 At least one H is 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 and {Z １ ~Z ４ At least three of the above may not be N 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 aryl)-heteroaryl, -(C ３ ~C ７ Cycloalkyl), -(C ２ ~C ６ Heterocycloalkyl) or 【Chemistry 8】 and {Above-(C １ ~C ４ alkyl), -(C １ ~C ４ alkyl)-OH or -(C １ ~C ４ alkyl)-NR Ｄ R Ｅ At least one H may be replaced by -X; The -aryl, -(C １ ~C ４ alkyl)-aryl, -heteroaryl, -(C １ ~C ４ alkyl)-heteroaryl, -(C ３ ~C ７ cycloalkyl) or -(C ２ ~C ６ At least one H of the heterocycloalkyl is -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】 At least one H is -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; １ ~C ４ At least one H of -(alkyl) may be replaced by -X or -OH, -aryl, -(C １ ~C ４ alkyl)-aryl, -heteroaryl or -(C １ ~C ４ At least one H of the alkyl-heteroaryl is -X, -OH, -CF ３ Or -CF ２ and optionally 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; １ ~C ４ At least one H of -(C alkyl) may be replaced by -X or -OH, -aryl or -(C １ ~C ４ At least one H of the alkyl-aryl is -X, -OH, -CF ３ Or -CF ２ optionally 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) {-(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 At least one 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 At least one H of the heterocycloalkyl is -X, -OH, -CF ３ Or -CF ２ optionally 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 {wherein 【Chemistry 11】 When Y is a double bond, １ is =CH-}, a to e each independently represent an integer of 0, 1, 2, 3, or 4 (provided that a and b do not have to be 0 at the same time, and c and d do not have to be 0 at the same time); Each X is independently F, Cl, Br or I.

2. In the compound of formula I, L １ , L ２ Or L ３ are each independently a bond or -(C １ ~C ２ alkylene)-, R １ But, -CX ２ H or -CX ３ and R ２ But -NR Ａ R Ｂ , -OR Ｃ , 【Chemistry 12】 and ｛ 【Chemistry 13】 At least one of H is -X, -OH, -NR Ｄ R Ｅ , -(C １ ~C ４ alkyl)}, R ３ But -(C １ ~C ４ alkyl), -(C ３ ~C ７ -cycloalkyl), -aryl, -heteroaryl, -adamantyl, 【Chemistry 14】 and At least one H of -aryl or -heteroaryl is 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】 At least one H is -NR Ｄ R Ｅ Or - (C １ ~C ４ alkyl), 【Chemistry 17】 At least one H is independently -(C １ ~C ４ alkyl)}, Y １ , Y ２ and Y ４ each independently represents -CH ２ --, --NR Ｆ -, -O-, -C(=O)- or -S(=O) ２ - and Y ３ is —CH— or —N—, Z １ ~Z ４ each independently represents N or CR Ｚ and {Z １ ~Z ４ At least three of the above may not be N at the same time, and R Ｚ is -H, -X or -O(C １ ~C ４ alkyl)}, Z ５ and Z ６ each independently represents -CH ２ - or -O-, Z ７ and Z ８ are each independently ═CH— or ═N—; Z ９ But -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 ｛ 【Chemistry 19】 At least one H in is -X, -(C 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 But -(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) {-(C １ ~C ４ alkyl) or -C(=O)-O(C １ ~C ４ At least one H of the alkyl group may be replaced by —X; -at least one H of the aryl may be replaced by -X; R Ｇ But-(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 to e each independently represent an integer of 0, 1, 2, 3, or 4 (provided that a and b do not have to be 0 at the same time, and c and d do not have to be 0 at the same time); X is each independently F, Cl, Br or I; The pharmaceutical composition of claim 1.

3. The compound of formula I is a compound of formula Ia 【Chemistry 22】 (In formula Ia, R ２ teeth 【Chemistry 23】 and R ３ is -aryl {at least one H of -aryl may be independently replaced by -X}, Y １ is -O- or -S(=O) ２ - and Z １ is N or CR Ｚ and {R Ｚ is -X}, a and b are each independently an integer of 0, 1, 2, 3, or 4 (a and b may not be 0 at the same time); Each X is independently F, Cl, Br or I. The pharmaceutical composition of claim 1 ,

4. In the compound of formula Ia, R ２ but 【Chemistry 24】 and R ３ is -phenyl {at least one H of -phenyl is independently replaced with -F or -Cl}; Y １ is -O- or -S(=O) ２ - and Z １ is N or CF; The pharmaceutical composition according to claim 3.

5. A pharmaceutical composition for preventing or treating heart failure, comprising as an active ingredient a compound, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof, wherein said compound has the following structure: 【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 or treating heart failure, comprising as an active ingredient a compound, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof, wherein said compound has the following structure: 【Table 30】

7. 7. The pharmaceutical composition of claim 1, 5 or 6, wherein the heart failure is at least one selected from the group consisting of heart failure with preserved ejection fraction (HFpEF), heart failure with mildly reduced ejection fraction (HFmrEF) and heart failure with reduced ejection fraction (HFrEF).

8. The pharmaceutical composition of claim 1 , 5 or 6, wherein the heart failure comprises a cardiomyopathy.

9. The pharmaceutical composition according to claim 8, wherein the cardiomyopathy is at least one selected from the group consisting of hypertrophic cardiomyopathy (HCMP), restrictive cardiomyopathy and dilated cardiomyopathy (DCMP).

10. The pharmaceutical composition of claim 1 , 5 or 6, wherein the pharmaceutical composition is administered orally.

11. A method for preventing or treating heart failure, comprising administering to an individual a compound represented by formula I, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof, wherein said formula I is as in claim 1.

12. 1. A method for preventing or treating heart failure, comprising administering to an individual a compound, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof, wherein said compound has the structure: 【Table 31】

13. 2. Use of a compound of formula I, its optical isomer or a pharma- ceutically acceptable salt thereof for preventing or treating heart failure, wherein said formula I is the same as in claim 1.

14. 1. Use of a compound, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof, for preventing or treating heart failure, wherein said compound has the structure: 【Table 32】

15. 2. Use of a compound of formula I, its optical isomer or a pharma- ceutically acceptable salt thereof, in the preparation of a medicament for preventing or treating heart failure, wherein said formula I is the same as that of claim 1.

16. 13. Use of a compound, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof, in the preparation of a medicament for preventing or treating heart failure, wherein said compound has the structure: 【Table 33】

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