Composition for preventing or treating pulmonary arterial hypertension

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating pulmonary arterial hypertension, 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 pulmonary arterial hypertension using the compound, use of the compound for preventing or treating pulmonary arterial hypertension, and use of the compound in the preparation of a medicament for preventing or treating pulmonary arterial hypertension.

Description

[Technical field]

[0001] The present disclosure relates to a pharmaceutical composition for preventing or treating pulmonary arterial hypertension 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 pulmonary arterial hypertension 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 pulmonary arterial hypertension, 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 pulmonary arterial hypertension. [Background technology]

[0002] Pulmonary arterial hypertension (PAH) is a disease in which the blood pressure in the pulmonary arteries that supply blood from the heart to the lungs increases, and is a fatal disease that can lead to early death. The main symptoms are shortness of breath, general weakness, dizziness, chest pain, etc., which may appear frequently in daily life, making early diagnosis difficult. PAH is a rare disease that mainly affects women in their 30s to 50s, and occurs in 15 to 50 cases per million adults (Levine DJ et al., Am J Manag Care. 2021; 27 (3): 35-41).

[0003] It is estimated that there are approximately 100,000 patients worldwide, with approximately 1,500 patients in Korea. Currently, pulmonary arterial hypertension is treated with adjuvant therapy such as diuretics, anticoagulant therapy, and other vasodilator drugs, and surgical procedures (lung transplantation) (Rebecca L et al., US Cardiology Review. 2016; 10(2): 78-84). Although studies have shown that early initiation of combination therapy improves patients' symptoms and improves survival rates, the conditions for combination therapy are strict, and currently there are no drugs targeted to treat patients while targeting the underlying disease mechanism. To date, drugs for the treatment of pulmonary arterial hypertension include bosentan, macitentan, sildenafil, and other drugs that focus on preventing pulmonary vasoconstriction and vascular occlusion due to thrombosis, as well as drugs that prevent inflammatory mechanisms and fibrosis and improve vascular structure remodeling to improve the symptoms of pulmonary arterial hypertension.

[0004] However, the above-mentioned therapeutic drugs are still not sufficiently effective in treating pulmonary arterial hypertension, and are often unable to provide sufficient treatment effects for patients with hereditary pulmonary arterial hypertension caused by genetic factors such as BMPR2 gene mutations (Atkinson C et al., Circulation. 2002; 105: 1672-1678).

[0005] Therefore, there is a great need to develop a therapeutic agent capable of treating various pulmonary arterial hypertension, including hereditary pulmonary arterial hypertension, more fundamentally.

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

[0007] Non-patent literature (Non-patent document 1) Levine DJ et al.,Am J Manag Care.2021;27(3):35-41 (Non-patent document 2) Rebecca L et al., US Cardiol Review.2016;10(2):78-84 (Non-patent document 3) Boucherat O et al., Sci Rep.2017 Jul 3;7(1):4546 (Non-patent document 4) Atkinson C et al.,Circulation.2002;105:1672-1678 (Non-patent document 5) Rabionovitch M., J Clin Invest.2008;118:2372-2379 (Non-patent document 6)Morrell NW.,Proc Am Thorac Soc.2006 Nov;3(8):680-6 Summary of the Invention [Problem to be solved by the invention]

[0008] The present disclosure may provide a pharmaceutical composition for preventing or treating pulmonary arterial hypertension, 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 pulmonary arterial hypertension, 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 pulmonary arterial hypertension.

[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 pulmonary arterial hypertension. [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 pulmonary arterial hypertension, 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 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). {-(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 -NRA 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 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). 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, is capable of preventing or treating pulmonary arterial hypertension.

[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 is capable of preventing or treating pulmonary arterial hypertension.

[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] As used herein, the term "pulmonary arterial hypertension (PAH)" may refer to a disease in which blood pressure is elevated in the blood vessels that supply blood to the lungs.

[0057] In an embodiment of the present invention, pulmonary arterial hypertension may refer to a condition in which the mean pulmonary arterial pressure is elevated to 25 mmHg or more, in particular, the mean pulmonary arterial pressure at rest assessed through right heart catheterization (RHC) is elevated to 25 mmHg or more, but is not limited thereto, and the occurrence of pulmonary arterial hypertension may be determined according to the patient's gender, age, weight, health condition, type of disease, severity of disease, drug activity, drug sensitivity, etc.

[0058] In an embodiment of the invention, pulmonary arterial hypertension may cause endothelial cell dysfunction in the pulmonary arteries, reduced pulmonary vascular compliance, or narrowing of the vessel lumen, or may cause symptoms such as right ventricular failure.

[0059] In embodiments of the invention, symptoms associated with pulmonary arterial hypertension may include dyspnea during exercise, fatigue, angina, fainting, dry cough, vomiting during exercise, cyanosis, peripheral edema, and the like.

[0060] In an embodiment of the invention, the pulmonary arterial hypertension may correspond to any one of the WHO functional classes I to IV.

[0061] In embodiments of the invention, pulmonary arterial hypertension may include idiopathic pulmonary arterial hypertension (IPAH), hereditary pulmonary arterial hypertension, drug- and toxin-induced pulmonary arterial hypertension, disease-related pulmonary arterial hypertension (APAH), pulmonary arterial hypertension showing prolonged response to calcium channel blockers, pulmonary arterial hypertension with clear signs of venous / capillary invasion, persistent pulmonary arterial hypertension in newborns, or combinations thereof.

[0062] In particular, in idiopathic pulmonary arterial hypertension, pulmonary arterial pressure may increase without any particular cause, whereas in hereditary pulmonary arterial hypertension, pulmonary arterial pressure may increase despite the presence of genetic abnormalities such as bone morphogenetic protein receptor 2 (BMPR2) mutations.

[0063] The pharmaceutical composition comprising the compound of formula I according to the present disclosure, its optical isomer or its pharma- ceutically acceptable salt may have significantly excellent preventive and therapeutic effects on pulmonary arterial hypertension.

[0064] 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 excellent prophylactic and therapeutic effects against idiopathic pulmonary arterial hypertension (IPAH), hereditary pulmonary arterial hypertension, drug- and toxin-induced pulmonary arterial hypertension, disease-related pulmonary arterial hypertension (APAH), pulmonary arterial hypertension showing long-term response to calcium channel blockers, pulmonary arterial hypertension with clear signs of venous / capillary invasion, persistent pulmonary arterial hypertension in neonates, or a combination thereof.

[0065] The pharmaceutical composition comprising the compound of formula I, its optical isomer, or a pharma- ceutical acceptable salt thereof according to the present disclosure can have excellent preventive or therapeutic effects on all WHO functional classes 1 to 4 of pulmonary arterial hypertension, and can exhibit excellent therapeutic effects not only in low-risk groups of pulmonary arterial hypertension but also in medium- or high-risk groups thereof, and can delay the progression of the disease, such as preventing the disease from progressing to a severe level at an early stage of the disease, and can significantly extend the survival time of subjects suffering from pulmonary arterial hypertension after diagnosis of the disease.

[0066] As used herein, the term "prevention" may refer to any act of inhibiting or delaying the occurrence of pulmonary arterial hypertension by administering a compound of formula I, its optical isomer, or a pharma- ceutically acceptable salt thereof in accordance with the present disclosure, and may also mean any case in which pulmonary arterial hypertension occurs with a lesser degree of symptoms compared to the case in which the compound of formula I, its optical isomer, or a pharma- ceutically acceptable salt thereof is not administered.

[0067] In embodiments of the invention, prevention can include when pulmonary artery pressure does not increase or when the time point at which pulmonary artery pressure begins to increase is delayed, or when clinical symptoms (e.g., dyspnea during exercise, fatigue, angina, fainting, dry cough, vomiting during exercise, cyanosis, peripheral edema, etc.) do not appear or when the time point at which symptoms begin to appear is delayed. For example, prevention can include when pulmonary artery pressure is maintained at a normal level or when the time point at which pulmonary artery pressure begins to increase is delayed.

[0068] In embodiments of the invention, prevention may include maintenance of normal thickness of the pulmonary arterial duct on histological examination or a delay in the time at which the thickness of the pulmonary arterial duct begins to increase.

[0069] In the present disclosure, the term "treatment" may refer to any action that improves or favorably changes the symptoms of individuals who are likely to develop a disease and the symptoms of individuals who are suffering from a disease by administering the compound of formula I, its optical isomer, or its pharma- ceutically acceptable salt according to the present disclosure. In an embodiment of the present invention, the treatment of the present disclosure may include any case in which pulmonary artery pressure is reduced, clinical symptoms are weakened, WHO functional class is reduced, or risk level is reduced in risk assessment.

[0070] In embodiments of the invention, treatment may include where pulmonary artery pressure is below 20 mmHg or is reduced to normal pulmonary artery pressure, or where clinical symptoms (e.g., dyspnea during exercise, fatigue, angina, faintness, dry cough, vomiting during exercise, cyanosis, peripheral edema, etc.) are eliminated or attenuated.

[0071] In an embodiment of the present invention, it has been confirmed that the compound represented by formula I, its optical isomer, or a pharma- ceutically acceptable salt thereof increases the survival rate and suppresses the lung weight in rats with pulmonary arterial hypertension, thereby exhibiting excellent therapeutic effects against pulmonary arterial hypertension (FIGS. 4 and 5).

[0072] In an embodiment of the present invention, it was confirmed by gravimetric measurement that the compound represented by formula I, its optical isomer, or a pharma- ceutically acceptable salt thereof improves right ventricular hypertrophy in rats with induced pulmonary arterial hypertension (FIG. 6).

[0073] In an embodiment of the present invention, it was confirmed through electrocardiogram that the compound represented by formula I according to the present disclosure, its optical isomer, or a pharma- ceutically acceptable salt thereof improves heart rate, ventricular bradycardia, and right ventricular hypertrophy in rats with pulmonary arterial hypertension (FIGS. 7 to 16).

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] 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.

[0079] 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.

[0080] Pharmaceutical compositions according to embodiments of the present invention may be administered once a day or in divided doses several times a day.

[0081] 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.

[0082] 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.

[0083] The pharmaceutical composition comprising the compound of formula I, its optical isomer or its pharma- ceutically 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.

[0084] The present disclosure may provide a method for preventing or treating pulmonary arterial hypertension, comprising administering to an individual a compound represented by formula I above, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof.

[0085] The present disclosure may provide a method for preventing or treating pulmonary arterial hypertension, comprising administering to an individual a compound of Table A above, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof.

[0086] The present disclosure may provide a method for preventing or treating pulmonary arterial hypertension, comprising administering to an individual a compound of Table B above, an optical isomer thereof, or a pharma- ceutically acceptable salt thereof.

[0087] The terms "pulmonary arterial hypertension", "prevention" and "treatment" may be the same as above.

[0088] In this disclosure, the term "administration" may refer to the introduction of a given substance into an individual by any suitable method.

[0089] 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 pulmonary arterial hypertension, and may in particular be a mammal, including humans, but is not limited to these.

[0090] A method for preventing or treating pulmonary arterial hypertension 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.

[0091] 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.

[0092] The method for preventing or treating pulmonary arterial hypertension 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 the 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.

[0093] In addition, the method for preventing or treating pulmonary arterial hypertension 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 together with the compound represented by the above formula I, its optical isomer, or a pharma- ceutically acceptable salt thereof.

[0094] 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 pulmonary arterial hypertension.

[0095] 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 pulmonary arterial hypertension.

[0096] 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 pulmonary arterial hypertension.

[0097] 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 pulmonary arterial hypertension.

[0098] 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 pulmonary arterial hypertension.

[0099] 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 pulmonary arterial hypertension.

[0100] The terms "pulmonary arterial hypertension", "prevention" and "treatment" may be the same as above.

[0101] 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.

[0102] 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

[0103] 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 for the prevention or treatment of pulmonary arterial hypertension. [Brief description of the drawings]

[0104] [Figure 1] FIG. 1 shows the effect of treatment with compounds of the present disclosure on ameliorating pulmonary arterial hypertension in a cellular model of pulmonary arterial hypertension. [Diagram 2] FIG. 1 shows the effect of treatment with compounds of the present disclosure on ameliorating pulmonary arterial hypertension in a cellular model of pulmonary arterial hypertension. [Diagram 3] FIG. 1 shows the effect of treatment with compounds of the present disclosure on ameliorating pulmonary arterial hypertension in a cellular model of pulmonary arterial hypertension. [Figure 4] FIG. 1 shows 4-week survival of individuals in an animal model of pulmonary arterial hypertension upon administration of a compound of the present disclosure. [Diagram 5] FIG. 1 shows lung weights over 4 weeks for individuals in an animal model of pulmonary arterial hypertension following administration of a compound of the present disclosure. [Figure 6] FIG. 1 shows the ratio of right to left ventricular mass in an animal model of pulmonary arterial hypertension upon administration of a compound of the present disclosure. [Figure 7] FIG. 1 shows the results of ECG measurements in an animal model of pulmonary arterial hypertension upon administration of a compound of the present disclosure. [Figure 8] FIG. 1 shows the results of ECG measurements in an animal model of pulmonary arterial hypertension upon administration of a compound of the present disclosure. [Figure 9] FIG. 1 shows the results of ECG measurements in an animal model of pulmonary arterial hypertension upon administration of a compound of the present disclosure. [Figure 10] FIG. 1 shows the results of ECG measurements in an animal model of pulmonary arterial hypertension upon administration of a compound of the present disclosure. [Figure 11] FIG. 1 shows the results of ECG measurements in an animal model of pulmonary arterial hypertension upon administration of a compound of the present disclosure. [Figure 12] FIG. 1 shows the results of ECG measurements in an animal model of pulmonary arterial hypertension upon administration of a compound of the present disclosure. [Figure 13] FIG. 1 shows the results of ECG measurements in an animal model of pulmonary arterial hypertension upon administration of a compound of the present disclosure. [Figure 14] FIG. 1 shows the results of ECG measurements in an animal model of pulmonary arterial hypertension upon administration of a compound of the present disclosure. [Figure 15] FIG. 1 shows the results of ECG measurements in an animal model of pulmonary arterial hypertension upon administration of a compound of the present disclosure. [Figure 16] FIG. 1 shows the results of ECG measurements in an animal model of pulmonary arterial hypertension upon administration of a compound of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0105] 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.

[0106] 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%).

[0107] [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%).

[0108] [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%).

[0109] [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%).

[0110] [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%). 1H 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).

[0111] 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%).

[0112] [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).

[0113] [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%).

[0114] [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).

[0115] 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%).

[0116] [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%).

[0117] [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%).

[0118] [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).

[0119] 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%).

[0120] [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%).

[0121] [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%).

[0122] [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).

[0123] 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).

[0124] [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%).

[0125] [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).

[0126] [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).

[0127] 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%).

[0128] 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).

[0129] [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%).

[0130] [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).

[0131] [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). EXAMPLES

[0132] Confirmation of the therapeutic effect of the compounds disclosed herein on pulmonary arterial hypertension (PAH) <Example 1> The therapeutic effect of the compounds of the present disclosure on pulmonary arterial hypertension (PAH) was confirmed by cell experiments.

[0133] <Example 1-1> HPAEC(3.0×10 5(cells / well, human pulmonary artery endothelial cells) Pulmonary artery endothelial cells were seeded in a 6-well plate and then treated with each concentration of drug (compounds 43, 295, 296, 40, 239, and 285). 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 expression level of the protein was confirmed using ECL solution, and the results are shown in Figure 1. In Figure 1, the control group shows cells that were not treated with the compound of the synthetic example.

[0134] As shown in Figure 1, compounds 43, 295, 296, 40, 239, and 285 each induced tubulin acetylation at a low concentration of 0.1 μg, confirming that all compounds 43, 295, 296, 40, 239, and 285 exhibited excellent activity even at low concentrations.

[0135] <Example 1-2> The survival rates of HPAEC cells, a model of pulmonary arterial hypertension, stimulated with TGF-β and treated with the compounds of Synthesis Examples 1 to 6 were confirmed by measuring cell survival rates.

[0136] HPAEC(2.0×10 3 Cells (cells / well) were seeded in a 96-well plate and cultured in serum-free medium for 24 hours as starvation. After simultaneously treating 1 μM concentration of drugs (compounds 43, 295, 296, 40, 239, 285) with TGF-β (10 ng / ml) and culturing for 48 hours, cell viability was measured by CCK-8 assay, and the results are shown in Figure 2. In Figure 2 above, the control group indicates cells that were not treated with TGF-β and the compound of the synthesis example, and "-" indicates cells that were treated with TGF-β only.

[0137] As shown in FIG. 2, treatment with compounds 43, 295, 296, 40, 239 and 285 after TGF-β stimulation improved survival rates compared to when no compound was administered after TGF-β stimulation, thus confirming that the compounds disclosed herein have excellent HPAEC cell protective effects.

[0138] <Example 1-3> The inhibition rate of cell proliferation by TGF-β stimulation of HPASMC (human pulmonary artery smooth muscle) cells, a model of pulmonary arterial hypertension, and treatment with the six compounds of Synthesis Examples 1 to 6 was confirmed by measuring cell viability.

[0139] HPASMC (5.0 × 10 3 Cells (cells / well) were seeded in a 96-well plate and cultured in serum-free medium for 24 hours as starvation. After simultaneously treating 1 μM concentration of drugs (compounds 43, 295, 296, 40, 239, 285) with TGF-β (10 ng / ml) and culturing for 24 hours, cell viability was measured by CCK-8 assay, and the results are shown in Figure 3. In Figure 3 above, the control group indicates cells not treated with TGF-β and the compound of the synthesis example, and "-" indicates cells treated with TGF-β only.

[0140] As shown in FIG. 3, when compounds 43, 295, 296, 40, 239 and 285 were treated after TGF-β stimulation, the proliferation rates were all inhibited compared to when no compound was treated after TGF-β stimulation, thus confirming that the compounds disclosed herein have excellent inhibitory effects on excessive HPASMC cell proliferation.

[0141] <Example 2> The efficacy of compounds of the present disclosure for the treatment of pulmonary arterial hypertension (PAH) was confirmed by administering compounds of the present disclosure to an animal model of PAH.

[0142] 1) Preparation of test animals and drug administration SD rats having the following conditions were prepared.

[0143] [Table 31]

[0144] Rats were supplied by Orient Bio and fed a standard diet (Central Lab Animal, Inc.), housed under constant temperature (22 ± 2°C), humidity (44–56%) and lighting (12-h light / dark cycle) conditions, and allowed to drink water ad libitum. All experimental procedures were approved and performed in accordance with the Institutional Animal Care and Use Committee (IACUC) of the Korea CKD Laboratory Animal Center (IACUC animal study protocol approval number: CE22368-1).

[0145] The experimental animals, rats, were divided into the following groups, taking into consideration their body weights on the day before the start of drug administration.

[0146] [Table 32]

[0147] During the study period, the normal group received saline, and the control group (MCT+vehicle) received a single subcutaneous injection of monocrotaline (MCT) aqueous solution at 3ml / Kg, followed by a vehicle consisting of a mixture of Cremophor EL, ethanol and saline in a volume ratio of 1:1:8. The MCT aqueous solution was prepared using a 1N NAOH solution in 1N HCL to reach a concentration of 20mg / mL in a solvent adjusted to pH 7.4. It was then adjusted to 50mg / kg and administered subcutaneously.

[0148] The drug administration group was first subcutaneously administered 3 ml / kg of MCT aqueous solution once, and then orally administered 20 mg / kg of Compound 43 (compound of Synthesis Example 1) twice a day during the test period (4 weeks). Compound 43 was dissolved in a mixture of Cremophor EL, ethanol, and saline in a volume ratio of 1:1:8, and then orally administered.

[0149] 2) Test results All data are expressed as mean ± SEM and each group and the control group were compared using an unpaired T-test (p<0.05) to determine the effect of each experimental group.

[0150] 2-1) Individual survival rate After grouping, the mice were administered with the MCT aqueous solution, and the survival rate was evaluated by checking for deaths during the test period.

[0151] The pulmonary arterial hypertension induced animal model is a model in which the inner diameter of the overall smooth muscle is narrowed due to proliferation and contraction of endothelial cells and smooth muscle cells that constitute the pulmonary artery that delivers blood from the heart to the lungs, and shows problems in the circulation of blood delivered from the heart to the lungs. Such problems in blood circulation reduce the supply of oxygen and nutrients to the entire body, causing abnormalities throughout the body. Therefore, the survival rate is an index that best reflects the overall condition of the animal.

[0152] The survival rates of individuals over the 4-week test period are shown in FIG.

[0153] The survival rate of each group was calculated by reflecting the number of animals surviving in the corresponding week from the first 10 animals enrolled in the experiment. The numbers on the left side of the line graphs indicate the survival rate of each group (surviving animals / total number of animals enrolled in the experiment).

[0154] As seen in Figure 4, no animals died in the normal group over the 4-week period, whereas deaths occurred in the control group administered MCT and vehicle from the 3rd week of the experiment, with a total of 5 animals dying, for an individual survival rate of just 50%. In contrast, in the group administered compound 43, only 1 out of 10 animals died, showing a significant individual survival rate of 90%.

[0155] 2-2) Measurement of lung and ventricle weights After 4 weeks of the test period, the lungs and hearts were excised and the weights of the lungs and the left and right ventricles of each group were measured. The results are shown in FIG. 5 and FIG.

[0156] The heart of an animal model of pulmonary arterial hypertension is overloaded under pressure due to high blood pressure in the blood vessels delivered from the right ventricle to the lungs, and the volume of the right ventricle may increase accordingly, which may lead to an increase in the total heart weight. In other words, in the case of an animal model of pulmonary arterial hypertension caused by MCT, after an increase in the right ventricular volume is first induced, the symptoms may become more severe and the survival rate may increase.

[0157] In Figures 5 and 6, all results are expressed as mean ± SEM, and statistical significance was analyzed using unpaired T-test for comparison of vehicle-treated control group with other groups. **** indicates comparison of normal group with control group with P<0.0001, and #### indicates comparison of control group with drug-treated group with P<0.0001.

[0158] Figure 5 shows the lung weight. As can be seen in Figure 5, the lung weight was significantly increased in the vehicle-administered control group compared to the normal group.

[0159] Figure 6 shows the ratio of right ventricular weight to left ventricular weight, which is the value obtained by dividing the weight of right ventricle by the weight of left ventricle.As confirmed in the above Figure 6, the ratio of right ventricular weight to left ventricular weight in the control group administered with vehicle is significantly increased compared to the normal group.However, the ratio of right ventricular weight to left ventricular weight in the drug administration group administered with compound 43 is significantly decreased compared to the control group.

[0160] This demonstrates that the compound of the present disclosure improves right ventricular hypertrophy caused by pulmonary artery pressure overload.

[0161] 2-3) ECG Examination After the four-week test period, the animals were anesthetized with isoflurane via inhalation and electrodes were attached to the limbs to record the animals' electrocardiograms over 30 seconds. The results were recorded using a BioAmp ECG machine and analyzed using LabChart 8 software.

[0162] The results of ECG measurement are shown in Figures 7 to 16. In Figures 7 to 16, all result values ​​are expressed as mean ± standard error, and statistical significance was analyzed for the control group and each other group using unpaired T-test. * may mean P<0.05, ** may mean P<0.01, *** may mean P<0.001, **** may mean P<0.0001, *, **, ***, and **** may indicate a comparison between the normal group and the control group. # may mean P<0.05, ## may mean P<0.01, ### may mean P<0.001, #### may mean P<0.0001, and #, ##, ###, and #### may indicate a comparison between the control group and the drug-administered group. In Figures 7 to 16, normal may mean the normal group, vehicle may mean the control group, and compound 43 may mean the drug-administered group.

[0163] As seen in Figures 7 to 16 above, the control group administered with the vehicle was confirmed to show significant changes in total heart rate and RR interval compared to the normal group. This phenomenon was considered to be highly related to the prolongation of the QT interval in the electrocardiogram process. It is well known that an increase in the QT interval is highly related to right ventricular hypertrophy, and this was confirmed through a study of clinical patients in which the QT interval significantly increased with right ventricular hypertrophy in actual patients with pulmonary arterial hypertension (Int J Cardiol.QTc prolongation is associated with impaired right ventricular function and predicts mortality in pulmonary hypertension.2013;167(3):669-676).

[0164] On the other hand, in the drug administration group administered with Compound 43, it was confirmed that the QT interval, QTc and JT interval were significantly decreased compared to the control group.

[0165] Therefore, it is evident that the compounds of the present disclosure improve right ventricular hypertrophy, heart rate and ventricular bradycardia caused by pulmonary artery pressure overload.

[0166] The present disclosure provides pharmaceutical compositions, methods and uses as follows:

[0167] Item 1. A pharmaceutical composition for preventing or treating pulmonary arterial hypertension, comprising the compound represented by the above formula I, an optical isomer thereof, or a pharma- ceutical acceptable salt thereof as an active ingredient.

[0168] 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.

[0169] 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.

[0170] Item 4. A method for preventing or treating pulmonary arterial hypertension, 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.

[0171] Item 5. Use of the 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 pulmonary arterial hypertension.

[0172] Item 6. Use of a compound represented by the above formula I, an optical isomer thereof or a pharma- ceutical acceptable salt thereof according to any one of Items 1 to 3 in the preparation of a medicament for preventing or treating pulmonary arterial hypertension.

[0173] 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 pulmonary arterial hypertension is at least one selected from the group consisting of idiopathic pulmonary arterial hypertension (IPAH), hereditary pulmonary arterial hypertension, drug- and toxin-induced pulmonary arterial hypertension, disease-related pulmonary arterial hypertension (APAH), pulmonary arterial hypertension showing long-term response to calcium channel blockers, pulmonary arterial hypertension with clear signs of venous / capillary invasion, and persistent pulmonary arterial hypertension in newborns.

[0174] 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 pulmonary arterial hypertension is a pulmonary arterial pressure of 25 mmHg or more.

[0175] Item 9. The pharmaceutical composition according to any one of Items 1 to 3, 7, and 8, which is orally administered.

[0176] Item 10. The method according to any one of items 4, 7, and 8, or the use according to any one of items 5 to 8, wherein the compound represented by the above formula I, its optical isomer, or its pharma- ceutically acceptable salt is orally administered.

[0177] 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 pulmonary arterial hypertension, comprising as an active ingredient a compound represented by the following formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 (In formula I, L １ , L ２ or L ３ are each independently 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 ｛ 【Transformation 3】 At least one H in 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 and optionally substituted with -aryl, -heteroaryl, -(C alkyl)-heteroaryl. 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 and optionally substituted with H. R ３ is -H, -(C １ ~C ４ alkyl), -(C １ ~C ４ alkyl)-O(C １ ~C ４ alkyl), -(C １ ~C ４ alkyl)-C(=O)-O(C １ ~C ４ alkyl), -(C ３ ~C ７ cycloalkyl), -(C ２ ~C ６ cycloheteroalkyl), -aryl, -heteroaryl, -adamantyl, 【Chemistry 4】 and {-(C １ ~C ４ At least one H in -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, 【Transformation 5】 may be substituted with [ 【Transformation 6】 At least one H in １ ~C ４ alkyl), -NR Ｄ R Ｅ , -CF ３ or -CF ２ optionally substituted with H; -(C ３ ~C ７ cycloalkyl), -(C ２ ~C ６ cycloheteroalkyl), adamantyl, 【Transformation 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 these 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 【Transformation 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 optionally substituted with H or —CN, 【Chemistry 9】 At least one H in 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 and {-(C １ ~C ４ At least one H of -(C 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 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 and {-(C １ ~C ４ At least one H of -(C alkyl) may be replaced by -X or -OH, and -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, or -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 {provided that 【Chemistry 11】 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 may not be 0 at the same time, and c and d may not 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 the H's is -X, -OH, or -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 in -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 in is —NR Ｄ R Ｅ or -(C １ ~C ４ alkyl), 【Chemistry 17】 At least one H in each group is independently -(C １ ~C ４ alkyl)}, Y １ , Y ２ and Y ４ are each independently —CH ２ -, -NR Ｆ -, -O-, -C(=O)- or -S(=O) ２ - and Y ３ is —CH— or —N—, Z １ ~Z ４ are each independently N or CR Ｚ and {Z １ ~Z ４ At least three of these 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 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 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 However, -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 are each independently an integer of 0, 1, 2, 3, or 4 (provided that a and b may not be 0 at the same time, and c and d may not 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 with -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); X is independently F, Cl, Br, or I. The pharmaceutical composition of claim 1, wherein

4. In the compound of formula Ia, R ２ but 【Chemistry 24】 and R ３ is -phenyl {at least one H of -phenyl is each 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. 1. A pharmaceutical composition for preventing or treating pulmonary arterial hypertension, comprising a compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the 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. 1. A pharmaceutical composition for preventing or treating pulmonary arterial hypertension, comprising a compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the compound has the following structure: Table 30

7. 7. The pharmaceutical composition of claim 1, 5 or 6, wherein the pulmonary arterial hypertension is at least one selected from the group consisting of idiopathic pulmonary arterial hypertension (IPAH), hereditary pulmonary arterial hypertension, drug- and toxin-induced pulmonary arterial hypertension, disease-related pulmonary arterial hypertension (APAH), pulmonary arterial hypertension showing long-term response to calcium channel blockers, pulmonary arterial hypertension with clear signs of venous / capillary infiltration, and persistent pulmonary arterial hypertension in newborns.

8. 7. The pharmaceutical composition of claim 1, 5 or 6, wherein the pulmonary arterial hypertension has a pulmonary arterial pressure of 25 mmHg or greater.

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

10. A compound represented by formula I, its optical isomer or a pharmaceutically acceptable salt thereof, for preventing or treating pulmonary arterial hypertension, wherein said formula I is the same as that of claim 1.

11. A compound, its optical isomer, or a pharmaceutically acceptable salt thereof for preventing or treating pulmonary arterial hypertension, wherein the compound has the following structure: Table 32

12. A compound represented by formula I, its optical isomer or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for preventing or treating pulmonary arterial hypertension, wherein said formula I is the same as that of claim 1.

13. 1. A compound, its optical isomer, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating pulmonary arterial hypertension, wherein the compound has the structure: Table 33

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