Composition for the prevention or treatment of idiopathic pulmonary fibrosis (IPF)

Abstract

The present disclosure relates to a pharmaceutical composition for preventing or treating idiopathic pulmonary fibrosis, comprising, as an active ingredient, a compound represented by Chemical Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, a method for preventing or treating idiopathic pulmonary fibrosis using the compound, the use of the compound for preventing or treating idiopathic pulmonary fibrosis, and the use of the compound in the manufacture of a medicament for preventing or treating idiopathic pulmonary fibrosis.

Description

Technical Field

[0001] The present disclosure relates to a pharmaceutical composition for preventing or treating idiopathic pulmonary fibrosis, comprising a compound represented by Chemical Formula I, its optical isomers, or a pharmaceutically acceptable salt thereof as an active ingredient, a method for preventing or treating idiopathic pulmonary fibrosis using the compound, the use of the compound for preventing or treating idiopathic pulmonary fibrosis, and the use of the compound in the manufacture of a medicament for preventing or treating idiopathic pulmonary fibrosis.

Background Art

[0002] Idiopathic pulmonary fibrosis (IPF) is a disease in which the lung parenchyma is fibrosed by an abnormal tissue repair mechanism after alveolar epithelial cells are damaged for unknown reasons. Symptoms such as chronic dry cough and shortness of breath appear, and usually, the survival period after the symptoms appear and a diagnosis is made is about 3 to 5 years, and it is a particularly poor prognosis disease. It is known that the incidence rate is high in men over 50 years old.

[0003] Currently, as therapeutic agents for idiopathic pulmonary fibrosis, mainly two drugs, nintedanib and pirfenidone, are used, but since these only delay the progression of the disease and cannot improve the survival rate, the development of effective therapeutic agents is strongly desired.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0005] This disclosure provides a pharmaceutical composition for the prevention or treatment of idiopathic pulmonary fibrosis, comprising a compound represented by chemical formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0006] This disclosure provides a method for preventing or treating idiopathic pulmonary fibrosis, comprising administering to an individual a compound represented by chemical formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0007] This disclosure provides uses for a compound represented by chemical formula I, its optical isomers, or pharmaceutically acceptable salts thereof for the prevention or treatment of idiopathic pulmonary fibrosis.

[0008] This disclosure provides uses of a compound represented by chemical formula I, its optical isomer, or a pharmaceutically acceptable salt thereof in the manufacture of a drug for the prevention or treatment of idiopathic pulmonary fibrosis. [Means for solving the problem]

[0009] This can be explained in detail as follows. On the other hand, each description and embodiment disclosed in the present invention can also be applied to each other description and embodiment. That is, all combinations of the various elements disclosed in the present invention fall within the scope of the present invention. Furthermore, the scope of the present invention cannot be said to be limited by the specific descriptions described below.

[0010] This disclosure relates to a pharmaceutical compound for the prevention or treatment of idiopathic pulmonary fibrosis, comprising as an active ingredient a compound represented by the following chemical formula I, its optical isomer, or a pharmaceutically acceptable salt thereof. To provide finished products: [Chemical formula I] [ka] In chemical formula I, L1, L2, and L3 are each independently a single bond (a bond) or a -(C1-C2 alkylene)-; R1 is either -CX2H or -CX3; R2 is -NR A R B , -OR C , [ka] ,or [ka] And, {Here, [ka] or [ka] One or more H atoms can be independently -X, -OH, -O(C1-C4 alkyl), or -NR. D R E -(C1-C4 alkyl), -CF3, -CF2H, -CN, -aryl, -heteroaryl, -(C1-C4 alkyl)-aryl, or -(C1-C4 alkyl It may be substituted with a -heteroaryl [in this case, one or more H atoms of the -aryl, -heteroaryl, -(C1-C4 alkyl)-aryl, or -(C1-C4 alkyl)-heteroaryl may be independently 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 heterocycloalkyl), -aryl, -heteroaryl, -adamantyl [ka] ,or [ka] and, where one or more H of -(C1-C4 alkyl) may each independently be replaced by -X or -OH, one or more H of -aryl or -heteroaryl may each independently be -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,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0011] In this disclosure, the compound represented by chemical formula I is L1, L2, and L3 are each independently a single bond (a bond) or a -(C1-C2 alkylene)-; R1 is either -CX2H or -CX3; R2 is -NR A R B , -OR C , [ka] ,or [ka] And, {Here, [ka] or [ka] One or more H atoms are, independently of each other, -X, -OH, and -NR. D R E , or may be substituted with -(C1-C4 alkyl); R3 is -(C1-C4 alkyl), -(C3-C7 cycloalkyl), -aryl, -heteroaryl, -adamantyl [ka] ,or [ka] And, {Here, one or more H atoms in an aryl or heteroaryl group are each independently, -X, -O(C1-C4 alkyl), -OCF3, -O-aryl, -NR D R E -(C1-C4 alkyl), -CF3, -S(=O)2-(C1-C4 alkyl), -aryl, -heteroaryl, [ka] , [ka] , or [ka] It may also be replaced with [at this time, [ka] One or more H's are, independently, -NR D R E Or it may be substituted with -(C1-C4 alkyl)], [ka] ,or [ka] One or more of the H atoms may be independently substituted with -(C1-C4 alkyl) atoms. Y1, Y2, and Y4 are independently -CH2- and -NR F -, -O-, -C(=O)-, or -S(=O)2-; Y3 is either -CH- or -N-; Z1-Z4 are each independently N or CR Z And so, {where Z1~Z4 are, Three or more simultaneously are not N, but R Z is -H, -X, or -O(C1-C4 alkyl); Z5 and Z6 are independently -CH2- or -O-; Z7 and Z8 are independently =CH- or =N-; Z9 is -NR G -or -S-; R A and R B These are, independently, -H, -(C1-C4 alkyl), -(C1-C4 alkyl)-OH, and -(C1-C4 alkyl)-NR. D R E -aryl, -(C1-C4 alkyl)-aryl, -(C3-C7 cycloalkyl), or [ka] And, {Here, [ka] One or more H atoms may be independently 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 EEach of these is independently -H, -(C1-C4 alkyl), or -(C1-C4 alkyl)-aryl; R F -H, -(C1-C6alkyl), -(C1-C4alkyl)-OH, -(C1-C4alkyl)-O-(C1-C4alkyl), -C(=O)-(C1-C4alkyl), -C(=O)-O(C1-C4alkyl), -(C1-C4alkyl)-C(=O)-O(C1-C4alkyl), -(C1-C4alkyl)-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), {Here, -(C1-C4 alkyl), or -C(=O)-O(C1-C4 alkyl One or more H values ​​in ) may be independently substituted with -X. -One or more H's in the aryl group may be independently substituted with -X; R G It is -(C1-C4 alkyl); Q is either an O- or a single bond; [ka] It is a single bond or a double bond {however, [ka] If it is a double bond, then Y1 is -CH-; a to e are each independent integers 0, 1, 2, 3, or 4 {where a and e are...} b and c are not both 0, and c and d are not both 0. X is independently F, Cl, Br, or I.

[0012] In this disclosure, the compound represented by chemical formula I may be the compound represented by the following chemical formula Ia: [Chemical formula Ia] [ka] In chemical formula Ia, R2 is [ka] and; R3 is an aryl, where one or more H of the aryl are independent of each other. And it may be replaced with -X. Y1 is -S(=O)2-; Z1 is N or CR Z And {here, R Z is -X; a and b are each independent integers of 0, 1, 2, 3, or 4 {where a is an integer}. Both values ​​b are not 0. X is independently F, Cl, Br, or I.

[0013] In this disclosure, the compound represented by the chemical formula Ia is R2 is [ka] and; R3 is phenyl, where one or more H atoms in phenyl are independently And it may be substituted with -F or -Cl. Y1 is -S(=O)2-; Z1 is either N or CF.

[0014] In this disclosure, the compound represented by chemical formula I may be one of the compounds listed in the table below.

[0015] Table 1-1

[0016] Table 1-2

[0017] Table 1-3

[0018] Table 1-4

[0019] Table 1-5

[0020] Table 1-6

[0021] Table 1-7

[0022] Table 1-8

[0023] Table 1-9

[0024] Table 1-10

[0025] Table 1-11

[0026] Table 1-12

[0027] Table 1-13

[0028] Table 1-14

[0029] Table 1-15

[0030] Table 1-16

[0031] Table 1-17

[0032] Table 1-18

[0033] Table 1-19

[0034] Table 1-20

[0035] Table 1-21

[0036] [Table 1-22]

[0037] [Table 1-23]

[0038] [Table 1-24]

[0039] [Table 1-25]

[0040] [Table 1-26]

[0041] [Table 1-27]

[0042] [Table 1-28]

[0043] [Table 1-29]

[0044] In embodiments of this disclosure, pharmaceutical compositions comprising the compounds listed in the table above, their optical isomers, or pharmaceutically acceptable salts thereof as active ingredients can prevent or treat idiopathic pulmonary fibrosis.

[0045] In this disclosure, the compound represented by chemical formula I may be one of the compounds listed in the table below.

[0046] [Table 2]

[0047] In embodiments of this disclosure, pharmaceutical compositions comprising the compounds listed in the table above, their optical isomers, or pharmaceutically acceptable salts thereof as active ingredients can prevent or treat idiopathic pulmonary fibrosis.

[0048] In this disclosure, the compound represented by chemical formula I is referred to in Published Patent Publication No. 10-2 of the Republic of Korea. It can be manufactured by the method disclosed in Patent No. 017-0017792, but is not limited thereto.

[0049] In this disclosure, the compound represented by chemical formula I may contain one or more chiral carbons, thereby allowing it to exist as an enantiomer mixture including a racemic mixture, a single enantiomer (optical isomer), a diastereomer mixture, and a single diastereomer. These isomers can be separated by conventional techniques, such as column chromatography or HPLC. Alternatively, they can be synthesized stereospecifically using optically pure starting materials and / or reagents of known sequences. Specifically, the isomers may be optical isomers.

[0050] In this disclosure, the term "pharmaceutically acceptable" may mean physiologically acceptable and not typically cause gastrointestinal disturbances, dizziness, or other allergic or similar reactions when administered to an individual.

[0051] The pharmaceutically acceptable salts according to embodiments of this disclosure can be prepared by ordinary methods known to the ordinary technicians of the art.

[0052] Examples of pharmaceutically acceptable salts according to embodiments of this disclosure include, but are not limited to, inorganic ion salts produced from calcium, potassium, sodium, magnesium, etc.; inorganic acid salts produced from hydrochloric acid, nitric acid, phosphoric acid, bromate, iodic acid, perchloric acid, sulfuric acid, hydroiodic acid, etc.; organic acid salts produced 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, carboxylic acid, vanillic acid, etc.; sulfonate salts produced from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, etc.; amino acid salts produced from glycine, arginine, lysine, etc.; and amine salts produced from trimethylamine, triethylamine, ammonia, pyridine, picoline, etc. In embodiments of the present disclosure, the salt may include hydrochloric acid, trifluoroacetic acid, citric acid, bromate, maleic acid, phosphoric acid, sulfuric acid, tartaric acid, or a mixture thereof.

[0053] In this disclosure, the term "idiopathic pulmonary fibrosis" is used. Fibrosis (IPF) refers to a disease in which the alveolar epithelial cells are damaged for some reason, and the lung parenchyma becomes fibrotic due to an abnormal tissue repair mechanism.

[0054] In this disclosure, the term “prevention” means any action that suppresses or delays the onset of a disease by administering a compound of chemical formula I of this disclosure, its optical isomer, or a pharmaceutically acceptable salt thereof.

[0055] In this disclosure, the term “treatment” means any act that improves or beneficially alters the symptoms of an individual suspected of or exhibiting a disease by administering a compound of chemical formula I of this disclosure, its optical isomer, or a pharmaceutically acceptable salt thereof.

[0056] The compound represented by chemical formula I of this disclosure, its optical isomers, or pharmaceutically acceptable salts thereof can be usefully used for the prevention or treatment of idiopathic pulmonary fibrosis.

[0057] A pharmaceutical composition containing the compound represented by chemical formula I of this disclosure, its optical isomer, or a pharmaceutically acceptable salt thereof as an active ingredient can be usefully used for the prevention or treatment of idiopathic pulmonary fibrosis.

[0058] In this regard, in one specific embodiment of the present disclosure, it was confirmed that the compound represented by chemical formula I of the present disclosure, its optical isomer, or a pharmaceutically acceptable salt thereof suppresses the expression of the TGF-β1-induced fibrillation proteins, FN-EDA and proCOL1A1 (Figure 1).

[0059] Furthermore, we confirmed that the compound represented by chemical formula I of this disclosure, its optical isomer, or a pharmaceutically acceptable salt thereof suppressed the expression of the fibrotic proteins COL1A1 and αSMA, which were increased in mice with pulmonary fibrosis induced by BLM (Figure 2). In addition, the compound represented by chemical formula I of this disclosure, its optical isomer, or a pharmaceutically acceptable salt thereof suppressed the expression of Ashcroft, which was increased in mice with pulmonary fibrosis induced by BLM. We confirmed that it reduced the score and improved the reduced activity level (Figure 3).

[0060] The compound represented by chemical formula I of this disclosure, its optical isomers, or pharmaceutically acceptable salts thereof may exhibit prophylactic or therapeutic effects for idiopathic pulmonary fibrosis at a level considered to be similar to or substantially identical to conventionally known drugs for the prophylaxis or treatment of idiopathic pulmonary fibrosis, or at a level superior to such effects. A pharmaceutical composition comprising the compound represented by chemical formula I of this disclosure, its optical isomer, or a pharmaceutically acceptable salt thereof as an active ingredient may exhibit a level of prophylactic or therapeutic effect for idiopathic pulmonary fibrosis that is considered to be similar to or substantially identical to conventionally known drugs for the prophylactic or therapeutic effect of idiopathic pulmonary fibrosis, or even better.

[0061] The pharmaceutical compositions according to embodiments of the present disclosure may further contain, in addition to the compound represented by chemical formula I, its optical isomers, or pharmaceutically acceptable salts thereof, one or more pharmaceutically acceptable carriers. The pharmaceutically acceptable carriers are those commonly used in the industry and may, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidine, cellulose, water, syrup, methylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, or mineral oil. In addition to the above components, the pharmaceutical compositions according to embodiments of the present disclosure may further contain lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, dispersants, stabilizers, and the like. Furthermore, the pharmaceutical compositions according to embodiments of this disclosure may be manufactured in unit dose form by formulating them with pharmaceutically acceptable carriers and excipients in the form of oral preparations such as tablets, powders, granules, pills, capsules, suspensions, emulsions, oral solutions, emulsions, syrups, topical preparations, suppositories, or sterile injection solutions, or in multi-volume containers. The formulations may be manufactured using conventional methods of formulation in the industry, or according to Remington's Pharmaceutical Science (19 th It may be manufactured by the method disclosed in ed., 1995, and may be formulated into various formulations depending on the disease or component.

[0062] Non-limiting examples of oral formulations using the pharmaceutical compositions of this disclosure include tablets, lozenges, water-soluble suspensions, oily suspensions, prepared powders, granules, emulsions, hard capsules, soft capsules, syrups, or elixirs. To formulate the pharmaceutical compositions according to embodiments of this disclosure for oral administration, binders such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose, or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch or sweet potato starch; lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate, or polyethylene glycol wax may be used, along with sweeteners, flavorings, syrups, etc. You may also use [the other substance]. In the case of capsules, in addition to the above substance, you may also use a liquid carrier such as fatty oil.

[0063] Non-limiting examples of parenteral formulations using the pharmaceutical compositions according to embodiments of this disclosure include injections, suppositories, respiratory inhalation powders, spray aerosols, ointments, topical powders, oils, and creams. Sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations, topical preparations, etc., may be used to formulate the pharmaceutical compositions according to embodiments of this disclosure for parenteral administration. The non-aqueous solvents and suspensions may include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.

[0064] The pharmaceutical compositions according to embodiments of this disclosure may be administered orally or parenterally, depending on the intended method, and may preferably be administered orally, but are not limited thereto.

[0065] The daily dose of the compound represented by chemical formula I of this disclosure, its optical isomer, or a pharmaceutically acceptable salt thereof may specifically be about 0.1 to 10,000 mg / kg, about 1 to 8,000 mg / kg, about 5 to 6,000 mg / kg, or about 10 to 4,000 mg / kg, and more specifically, about 50 to 2,000 mg / kg, but is not limited thereto, and may be administered in one to several divided doses per day.

[0066] The pharmaceutically effective amount and effective dose of the pharmaceutical composition according to the embodiments of this disclosure can be varied depending on the formulation method, administration method, administration time and / or route of administration of the pharmaceutical composition, and can be varied according to various factors including the type and degree of reaction to be achieved by the administration of the pharmaceutical composition, the type, age, weight, general health status, symptoms and severity of disease of the individual to be administered, sex, diet, excretion, drugs used simultaneously or at different times with the individual, and other components of the composition, as well as similar factors well known in the pharmaceutical field. A person with ordinary skill in the art can easily determine and prescribe an effective dose for the intended treatment. The pharmaceutical compositions according to embodiments of this disclosure may be administered once daily or in several divided doses. The pharmaceutical compositions according to embodiments of this disclosure may be administered as a monotherapy, in combination with other therapeutics, or sequentially or concurrently with conventional therapeutics. Taking all of the above into consideration, the pharmaceutical compositions according to embodiments of this disclosure may be administered in an amount that provides the greatest effect with the minimum amount without side effects, which can be easily determined by a person of the ordinary skill in the art to which this disclosure belongs.

[0067] The pharmaceutical compositions according to the embodiments of this disclosure can exert excellent effects when used alone, but may also be used in combination with various methods such as hormone therapy and drug therapy to further enhance therapeutic efficiency.

[0068] This disclosure provides a method for preventing or treating idiopathic pulmonary fibrosis, comprising administering to an individual a compound represented by the chemical formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0069] The terms "idiopathic pulmonary fibrosis," "prevention," and "treatment" mentioned above are as previously stated.

[0070] In this disclosure, the term "administration" means introducing a given substance into an individual in an appropriate manner.

[0071] In this disclosure, the term “individual” means all animals, including humans, rats, mice, and livestock, that have or are likely to have idiopathic pulmonary fibrosis, and may specifically include, but are not limited to, mammals, including humans.

[0072] A method for preventing or treating idiopathic pulmonary fibrosis according to embodiments of the present disclosure may involve administering a therapeutically effective amount of the compound represented by chemical formula I, its optical isomer, or a pharmaceutically acceptable salt thereof.

[0073] In this disclosure, the term “therapeutably effective dose” means a dose sufficient to treat a disease with a reasonable benefit-to-risk ratio applicable to medical treatment, without causing adverse effects, which may be determined by a person skilled in the art depending on the patient’s sex, age, weight, health status, type and severity of disease, drug activity, sensitivity to the drug, method of administration, time of administration, route of administration, elimination rate, duration of treatment, drugs used in combination or concurrently with the specific composition, and other factors well known in the medical field. It is desirable that the specific therapeutically effective dose for a particular patient be applied differently depending on various factors, including the type and degree of response to be achieved, and in some cases whether other formulations are being used, as well as similar factors well known in the medical field, including the specific composition, the patient’s age, weight, general health status, sex and diet, time of administration, route of administration and elimination rate of the composition, duration of treatment, drugs used in combination with or concurrently with the specific composition, and other factors well known in the medical field.

[0074] Methods for the prevention or treatment of idiopathic pulmonary fibrosis according to embodiments of the present disclosure include not only treating the disease itself before the onset of symptoms, but also inhibiting or avoiding its signs, by administering the compound represented by chemical formula I, its optical isomers, or pharmaceutically acceptable salts thereof. In the management of the disease, the prophylactic or therapeutic dose of a particular active ingredient varies depending on the characteristics and severity of the disease or condition, and the route through which the active ingredient is administered. The dose and frequency of dose vary depending on the age, weight, and response of the individual patient. A suitable dose and administration method can be easily selected by a person with ordinary knowledge of the art, taking such factors into consideration. Furthermore, methods for the prevention or treatment of idiopathic pulmonary fibrosis according to embodiments of the present disclosure may further include the administration of a therapeutically effective amount of a further active preparation useful for the prevention or treatment of the disease, together with the compound represented by chemical formula I, its optical isomers, or pharmaceutically acceptable salts thereof, and a synergistic or additive effect can be obtained by using the further active preparation together with the compound represented by chemical formula I, its optical isomers, or pharmaceutically acceptable salts thereof.

[0075] This disclosure provides uses for the compound represented by chemical formula I, its optical isomers, or pharmaceutically acceptable salts thereof for the prevention or treatment of idiopathic pulmonary fibrosis.

[0076] This disclosure provides uses for the compound represented by chemical formula I, its optical isomers, or pharmaceutically acceptable salts thereof in the manufacture of agents for the prevention or treatment of idiopathic pulmonary fibrosis.

[0077] The terms "idiopathic pulmonary fibrosis," "prevention," and "treatment" mentioned above are as previously stated.

[0078] To manufacture a drug, the compound represented by chemical formula I, its optical isomer, or a pharmaceutically acceptable salt thereof may be mixed with pharmaceutically acceptable auxiliaries, diluents, carriers, etc., and a synergistic effect can be obtained by manufacturing a complex formulation together with other active agents.

[0079] The provisions described in the pharmaceutical compositions, therapeutic methods, and uses of this disclosure shall apply equally to each other, insofar as they do not contradict each other. [Effects of the Invention]

[0080] The compound represented by chemical formula I of this disclosure, its optical isomers, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing them as active ingredients can be usefully used for the prevention or treatment of idiopathic pulmonary fibrosis. [Brief explanation of the drawing]

[0081] [Figure 1] Figure 1 is a graph showing the expression levels of fibrillation proteins (FN-EDA and proCOL1A1) in each group (*p<0.05, **p<0.01, ***p<0.001). [Figure 2] Figure 2 is a graph showing the expression levels of fibrillation proteins (COL1A1 and α-SMA) in each group (**p<0.01, ***p<0.001). [Figure 3] Figure 3 is a graph showing the Ashcroft score and treadmill test evaluation results (activity) for each group (###p<0.001, *p<0.05). [Modes for carrying out the invention]

[0082] The present disclosure will be described in more detail below with reference to examples. However, it will be obvious to those of ordinary skill in the art that these examples are merely illustrative of the present disclosure and that the scope of the present disclosure should not be limited by these examples. [Examples]

[0083] Synthesis Example 1. Synthesis of Compound 40: N-(4-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)-2-fluorobenzyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide

[0084] [Step 1] Synthesis of N-phenylthiomorpholine-4-carboxamide 1,1-dioxide [ka] Aniline (3.000 g, 32.213 mmol) and N,N-diisopropylethylamine (33.439 mL, 193.278 mmol) were dissolved in methylene chloride (100 mL) at 0°C. Triphosgene (4.780 g, 16.107 mmol) was added to this solution and the mixture was stirred at the same temperature. Thiomorpholine 1,1-dioxide (4.790 g, 35.434 mmol) was added to the reaction mixture and the mixture was stirred at room temperature for a further 16 hours. Water was poured over the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried (anhydrous MgSO4), filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 40 g cartridge; methanol / methylene chloride = 2%) to obtain the title compound (1.325 g, 16.2%) as a yellow solid.

[0085] [Step 2] Synthesis of methyl 4-((1,1-dioxide-N-phenylthiomorpholine-4-carboxamide)methyl)-3-fluorobenzoate [ka] In Step 1, N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (1,000 g, 3,932 mmol) and sodium hydride (60.00%, 0.189 g, 4.719 mmol) were prepared by dissolving them in N,N-dimethylformamide (30 mL) at 0°C. Methyl 4-(bromomethyl)-3-fluorobenzoate (1,020 g, 4.129 mmol) was added to the solution and the mixture was stirred at room temperature for 18 hours. Saturated sodium bicarbonate aqueous solution was poured over the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried (anhydrous MgSO4), filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 40 g cartridge; ethyl acetate / hexane = 0%~50%) to obtain the title compound (1,240 g, 75.0%) as a white solid.

[0086] [Step 3] Synthesis of N-(2-fluoro-4-(hydrazinecarbonyl)benzyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide [ka] The methyl 4-((1,1-dioxide-N-phenylthiomorpholine-4-carboxamide)methyl)-3-fluorobenzoate (1.240 g, 2.949 mmol) prepared in Step 2 and hydrazine hydrate (2.786 mL, 58.983 mmol) were dissolved in ethanol (15 mL) at 120 °C. The solution was stirred for 1 hour, and then the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was removed under reduced pressure to remove the solvent. A saturated sodium bicarbonate aqueous solution was added to the resulting concentrate, and after extraction with methylene chloride, the mixture was filtered through a plastic filter to remove the solid residue and aqueous layer, and concentrated under reduced pressure. The title compound was used as is without further purification (1.240 g, 100.0%, white solid).

[0087] [Step 4] Synthesis of N-(4-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)-2-fluorobenzyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide [ka] The solution prepared in Step 3 by dissolving N-(2-fluoro-4-(hydrazinecarbonyl)benzyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (0.615 g, 1.463 mmol), triethylamine (0.304 mL, 2.194 mmol), and difluoroacetic anhydride (0.164 mL, 1.316 mmol) in methylene chloride (10 mL) at room temperature was stirred for 18 hours at the same temperature. Saturated sodium bicarbonate aqueous solution was poured over the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried (anhydrous MgSO4), filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 24 g cartridge; methanol / methylene chloride = 0%~3%) to obtain the title compound (0.462 g, 63.4%) as a white solid.

[0088] [Step 5] Synthesis of Compound 40 [ka] N-(4-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)-2-fluorobenzyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (0.462 g, 0.927 mmol) and 1-methoxy-N-triethylammoniosulfonyl-methaneimidate (Burgess reagent, 0.331 g, 1.390 mmol) prepared in Step 4 were mixed in tetrahydrofuran (10 mL), heated at 150°C for 30 minutes under microwave irradiation, and then the temperature was lowered to room temperature to terminate the reaction. A saturated sodium bicarbonate aqueous solution was poured over the reaction mixture, extracted with methylene chloride, filtered through a plastic filter to remove solid residue and aqueous layer, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12g cartridge; ethyl acetate / hexane = 0%~50%) to obtain the title compound (0.337g, 75.7%) as a white solid. 1 H NMR(400MHz,CDCl3)δ7.87-7.85(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,1 H),7.13-7.10(m,2H),7.03-6.77(m,1H),4.92(s,2H),3.71-3.67(m,4H),2.77-2.74(m,4H);LRMS(ES)m / z481.1(M + +1).

[0089] Synthesis Example 2. Synthesis of Compound 43, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide

[0090] [Step 1] Synthesis of methyl 6-((1,1-dioxide-N-phenylthiomorpholine-4-carboxamide)methyl)nicotinate [ka] The solution prepared by dissolving N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (1,000 g, 3,932 mmol) and sodium hydride (60.00%, 0.157 g, 3,932 mmol) in N,N-dimethylformamide (10 mL) was stirred at 0°C for 1 hour. Methyl 4-(bromomethyl)-3-fluorobenzoate (0.905 g, 3,932 mmol) was added, and the mixture was stirred at room temperature for a further 2 hours. The solvent was removed from the reaction mixture under reduced pressure, and water was added to the resulting concentrate, which was then extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried (anhydrous MgSO4), filtered, and concentrated under reduced pressure. The concentrate was crystallized with methanol (20 mL) at room temperature, filtered, and the resulting solid was washed with methanol and dried to obtain the title compound (0.816 g, 51.4%) as a brown solid.

[0091] [Step 2] Synthesis of N-((5-(hydrazinecarbonyl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide [ka] The mixture of methyl 6-((1,1-dioxide-N-phenylthiomorpholine-4-carboxamide)methyl)nicotinate (0.816 g, 2.023 mmol) and hydrazine hydrate (1.910 mL, 40.451 mmol) prepared in Step 1 was mixed with ethanol (10 mL) at room temperature. The mixture was irradiated with microwaves and heated at 100 °C for 1 hour, after which the temperature was lowered to room temperature to terminate the reaction. After removing the solvent from the reaction mixture under reduced pressure, the concentrate was crystallized with methylene chloride (20 mL) at room temperature. The resulting solid was filtered, washed with methylene chloride, and dried to obtain the title compound (0.560 g, 68.6%) as a light brown solid.

[0092] [Step 3] Synthesis of N-((5-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide [ka] N-((5-(hydrazinecarbonyl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (0.260 g, 0.644 mmol) and triethylamine (0.178 mL, 1.289 mmol) prepared in Step 2 were dissolved in methylene chloride (2 mL) at room temperature. Difluoroacetic anhydride (0.087 mL, 0.580 mmol) was added to this solution and the mixture was stirred at the same temperature for 16 hours. Water was poured over the reaction mixture, and after extraction with methylene chloride, the solid residue and aqueous layer were removed by filtration through a plastic filter and the mixture was concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; methanol / methylene chloride = 0%~5%) to obtain the title compound (0.156 g, 50.3%) as a white foam.

[0093] [Step 4] Synthesis of Compound 43 [ka] N-((5-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (0.156 g, 0.324 mmol) and 1-methoxy-N-triethylammoniosulfonyl-methaneimidate (Burgess reagent, 0.116 g, 0.486 mmol) prepared in Step 3 were mixed in tetrahydrofuran (2 mL), heated at 150°C for 30 minutes under microwave irradiation, and then the temperature was lowered to room temperature to terminate the reaction. Water was added to the reaction mixture, extracted with methylene chloride, filtered through a plastic filter to remove solid residue and aqueous layer, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4g cartridge; methanol / methylene chloride = 3%) to obtain the title compound (0.078g, 51.9%) as a colorless oil. 1 H NMR(400MHz,CDCl3)δ9.23(d,1H,J=2.2Hz),8.38(dd,1H,J=8.2,2.2Hz),7.54(d,1H,J=8.2H z),7.41-7.31(m,2H),7.19(ddd,3H,J=6.4,3.0,1.6Hz),6.94(m,1H),5.10( s,2H),3.72(dd,4H,J=6.9,3.7Hz),2.97-2.90(m,4H);LRMS(ES)m / z464.2(M + +1).

[0094] Synthesis Example 3. Synthesis of Compound 232: N-(3-chloro-4-fluorophenyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)morpholine-4-carboxamide

[0095] [Step 1] Synthesis of N-(3-chloro-4-fluorophenyl)morpholine-4-carboxamide [ka] 3-chloro-4-fluoroaniline (0.500 g, 3.435 mmol), 1,1'-carbonyldiimidazole (0.613 g, 3.779 mmol), and triethylamine (0.575 mL, 4.122 mmol) were dissolved in acetonitrile (10 mL) at room temperature. Morpholine (0.311 mL, 3.607 mmol) was added to the solution, and the mixture was stirred at the same temperature for 18 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried (anhydrous MgSO4), filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0%~5%) to obtain the title compound (0.200 g, 22.5%) as a purple solid.

[0096] [Step 2] Synthesis of methyl 6-((N-(3-chloro-4-fluorophenyl)morpholine-4-carboxamide)methyl)nicotinate [ka] The solution of N-(3-chloro-4-fluorophenyl)morpholine-4-carboxamide (0.200 g, 0.773 mmol) prepared in Step 1 in N,N-dimethylformamide (5 mL) at 0 °C was added with sodium hydride (60.00%, 0.037 g, 0.928 mmol), and stirred at the same temperature. Methyl 6-(bromomethyl)nicotinate (0.196 g, 0.850 mmol) was added to the reaction mixture, and further stirred at room temperature for 3 hours. Water was poured into the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried (anhydrous MgSO4), filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 0% - 70%) to obtain the title compound (0.110 g, 34.9%) as a brown oil.

[0097] [Step 3] Synthesis of N-(3-chloro-4-fluorophenyl)-N-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)morpholine-4-carboxamide [Chemical formula] A mixture of methyl 6-((N-(3-chloro-4-fluorophenyl)morpholine-4-carboxamide)methyl)nicotinate (0.110 g, 0.270 mmol) prepared in Step 2 and hydrazine monohydrate (0.262 mL, 5.394 mmol) in ethanol (5 mL) at room temperature was heated to reflux for 18 hours, then cooled to room temperature. Water was poured into the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried (anhydrous MgSO4), filtered, and concentrated under reduced pressure. It was used as it was without further purification for the title compound (0.110 g, 100.0%, bright yellow solid).

[0098] [Step 4] Synthesis of Compound 232 [Chemical formula] N-(3-Chloro-4-fluorophenyl)-N-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)morpholine-4-carboxamide (0.110 g, 0.270 mmol) and N,N-diisopropylethylamine (0.070 mL, 0.405 mmol) were dissolved in dichloromethane (3 mL) at 0 °C, and 2,2-difluoroacetic anhydride (0.059 mL, 0.539 mmol) was added thereto. The mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. After filtration through a plastic filter to remove the solid residue and the aqueous layer, the mixture was concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% - 5%) to obtain the title compound (0.057 g, 45.2%) as a yellow solid. 1 1H NMR (400 MHz, CDCl3) δ 9.24 - 9.24 (m, 1H), 8.36 (dd, 1H, J = 8.2, 2.2 Hz), 7.59 (dd, 1H, J = 8.2, 0.8 Hz), 7.30 - 7.28 (m, 1H), 7.10 - 7.08 (m, 2H), 6.93 (t, 1H, J = 51.6 Hz), 5.05 (s, 2H), 3.54 - 3.52 (m, 4H), 3.27 - 3.26 (m, 4H); LRMS (ES) m / z 468.2 (M + +1).

[0099] 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

[0100] [Step 1] Synthesis of N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide

Chemical Structure

[0101] [Step 2] Synthesis of methyl 3-fluoro-4-((N-(4-fluorophenyl)-1,1-dioxide thiomorpholine-4-carboxamide)methyl)benzoate [ka] The solution prepared in Step 1 by dissolving N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.300 g, 1.102 mmol) and sodium hydride (60.00%, 0.048 g, 1.212 mmol) in N,N-dimethylformamide (5 mL) was stirred at 0°C for 2 hours. Methyl 4-(bromomethyl)-3-fluorobenzoate (0.299 g, 1.212 mmol) was added, and the mixture was stirred at room temperature for a further 17 hours. Then, water (2 mL) was added to the reaction mixture at room temperature and stirred for 10 minutes to terminate the reaction. Water was poured over the reaction mixture, extracted with dichloromethane, and then filtered through a plastic filter to remove the solid residue and aqueous layer. The mixture was then concentrated under reduced pressure. The concentrate was crystallized at room temperature with dichloromethane (3 mL), filtered, and the resulting solid was washed with dichloromethane and dried to obtain the title compound (0.212 g, 43.9%) as a white solid.

[0102] [Step 3] Synthesis of N-(2-fluoro-4-(hydrazinecarbonyl)benzyl)-N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide [ka] The mixture of methyl 3-fluoro-4-((N-(4-fluorophenyl)-1,1-dioxidethiomorpholine-4-carboxamide)methyl)benzoate (0.212 g, 0.484 mmol) and hydrazine monohydrate (0.470 mL, 9.670 mmol) prepared in Step 2 was mixed with ethanol (4 mL) at room temperature. The mixture was irradiated with microwaves and heated at 120 °C for 1 hour, after which the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was removed under reduced pressure to remove the solvent, water was added to the resulting concentrate, and it was extracted with dichloromethane. The mixture was then filtered through a plastic filter to remove the solid residue and aqueous layer, and concentrated under reduced pressure. Diethyl ether (5 mL) and ethyl acetate (1 mL) were added to the concentrate and stirred. The precipitated solid was filtered, washed with hexane, and dried to obtain the title compound (0.179 g, 84.4%) as a white solid.

[0103] [Step 4] Synthesis of Compound 285 [ka] 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 were dissolved in dichloromethane (4 mL) at room temperature. 2,2-difluoroacetic anhydride (0.028 mL, 0.228 mmol) was added to this solution, and the mixture was stirred at the same temperature for 17 hours. A saturated aqueous sodium bicarbonate solution was poured over the reaction mixture, extracted with dichloromethane, and then filtered through a plastic filter to remove the solid residue and aqueous layer. The mixture was concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; ethyl acetate / hexane = 20%~50%) to obtain the title compound (0.053 g, 46.6%) as a white solid. 1H NMR(400MHz,CDCl3)δ7.90(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 / z499.3(M + +1).

[0104] Synthesis Example 5. Synthesis of Compound 295: N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide

[0105] [Step 1] Synthesis of methyl 6-((N-(4-fluorophenyl)-1,1-dioxide thiomorpholine-4-carboxamide)methyl)nicotinate [ka] The 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 and sodium hydride (60.00%, 0.081 g, 2.020 mmol) dissolved in N,N-dimethylformamide (10 mL) was stirred at 0°C for 30 minutes. Methyl 6-(bromomethyl)nicotinate (0.465 g, 2.020 mmol) was added, and the mixture was stirred at room temperature for a further 5 hours. Then, water (5 mL) was added to the reaction mixture at room temperature and stirred for 10 minutes to terminate the reaction. Water was poured over the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried (anhydrous MgSO4), filtered, and concentrated under reduced pressure. The title compound was used as is without further purification (0.450 g, 58.1%, brown solid).

[0106] [Step 2] Synthesis of N-(4-fluorophenyl)-N-((5-(hydrazinecarbonyl)pyridine-2-yl)methyl)thiomorpholine-4-carboxamide 1,1-dioxide [Chemical formula] A solution of methyl 6-((N-(4-fluorophenyl)-1,1-dioxidothiomorpholine-4-carboxamide)methyl)nicotinate (0.150 g, 0.356 mmol) prepared in Step 1 and hydrazine monohydrate (0.346 mL, 7.118 mmol) dissolved in ethanol (5 mL) at room temperature was stirred at 100 °C for 17 hours, and then the temperature was lowered to room temperature to terminate the reaction. The precipitated solid was filtered, washed with ethanol and dried to obtain the title compound (0.111 g, 74.0%) as a pale yellow solid.

[0107] [Step 3] Synthesis of N-((5-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)pyridin-2-yl)methyl)-N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide [Chemical formula] A solution of N-(4-fluorophenyl)-N-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.111 g, 0.263 mmol) prepared in Step 2 and triethylamine (0.110 mL, 0.790 mmol) dissolved in dichloromethane (5 mL) at room temperature was added with 2,2-difluoroacetic anhydride (0.065 mL, 0.527 mmol), and stirred at the same temperature for 1 hour. Water was poured into the reaction mixture, and after extraction with dichloromethane, it was filtered through a plastic filter to remove the solid residue and the aqueous solution layer, and concentrated under reduced pressure. The title compound was used as it was without further purification (0.082 g, 62.3%, yellow solid).

[0108] [Step 4] Synthesis of Compound 295 [Chemical formula] The solution, prepared by dissolving N-((5-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)pyridine-2-yl)methyl)-N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.082 g, 0.164 mmol) and 1-methoxy-N-triethylammoniosulfonyl-methaneimidate (Burgess reagent, 0.117 g, 0.493 mmol) in tetrahydrofuran (5 mL) at room temperature, was stirred at 70 °C for 5 hours, after which the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was filtered through a paper filter to remove the solid, and the solvent was removed from the filtrate under reduced pressure. The concentrate was then purified and concentrated by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0%~10%) to obtain the title compound (0.015 g, 19.0%) as a white solid. 1 H NMR(400MHz,CDCl3)δ9.27(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 / z482.1(M + +1).

[0109] Synthesis Example 6. Synthesis of Compound 296: N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-(3-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide

[0110] [Step 1] Synthesis of N-(3-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide [ka] 1-Fluoro-3-isocyanatebenzene (0.500 g, 3.647 mmol) was dissolved in diethyl ether (10 mL), and thiomorpholine 1,1-dioxide (0.493 g, 3.647 mmol) was added at 0°C. The mixture was stirred at the same temperature for 1 hour, and then stirred at room temperature for a further 4 hours. The precipitated solid was filtered, washed with diethyl ether, and dried to obtain the title compound (0.870 g, 87.6%) as a white solid.

[0111] [Step 2] Synthesis of methyl 6-((N-(3-fluorophenyl)-1,1-dioxide thiomorpholine-4-carboxamide)methyl)nicotinate [ka] The solution of N-(3-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.500 g, 1.836 mmol) prepared in Step 1 and sodium hydride (60.00%, 0.081 g, 2.020 mmol) dissolved in N,N-dimethylformamide (10 mL) was stirred at 0°C for 30 minutes. Methyl 6-(bromomethyl)nicotinate (0.465 g, 2.020 mmol) was added, and the mixture was stirred at room temperature for a further 5 hours. Then, water (5 mL) was added to the reaction mixture at room temperature and stirred for 10 minutes to terminate the reaction. Water was poured over the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried (anhydrous MgSO4), filtered, and concentrated under reduced pressure. The title compound was used as is without further purification (0.450 g, 58.1%, brown solid).

[0112] [Step 3] Synthesis of N-(3-fluorophenyl)-N-((5-(hydrazinecarbonyl)pyridine-2-yl)methyl)thiomorpholine-4-carboxamide 1,1-dioxide [ka] The methyl 6-((N-(3-fluorophenyl)-1,1-dioxidethiomorpholine-4-carboxamide)methyl)nicotinate (0.150 g, 0.356 mmol) prepared in Step 2 and hydrazine monohydrate (0.346 mL, 7.118 mmol) were dissolved in ethanol (5 mL) at room temperature. The solution was stirred at 100 °C for 17 hours, after which the temperature was lowered to room temperature to terminate the reaction. The precipitated solid was filtered, washed with ethanol, and dried to obtain the title compound (0.113 g, 75.3%) as a pale yellow solid.

[0113] [Step 4] Synthesis of N-((5-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)pyridine-2-yl)methyl)-N-(3-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide [ka] N-(3-fluorophenyl)-N-((5-(hydrazinecarbonyl)pyridine-2-yl)methyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.113 g, 0.268 mmol) prepared in Step 3 and triethylamine (0.112 mL, 0.804 mmol) were dissolved in dichloromethane (5 mL) at room temperature. 2,2-difluoroacetic anhydride (0.067 mL, 0.536 mmol) was added to this solution and the mixture was stirred at the same temperature for 1 hour. Water was poured over the reaction mixture, and after extraction with dichloromethane, the mixture was filtered through a plastic filter to remove the solid residue and aqueous layer, and concentrated under reduced pressure. The title compound was used without further purification (0.090 g, 67.2%, yellow solid).

[0114] [Step 5] Synthesis of Compound 296 [ka] The solution, prepared by dissolving N-((5-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)pyridine-2-yl)methyl)-N-(3-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.090 g, 0.180 mmol) and 1-methoxy-N-triethylammoniosulfonyl-methaneimidate (Burgess reagent, 0.129 g, 0.541 mmol) in tetrahydrofuran (5 mL) at room temperature, was stirred at 70 °C for 5 hours, and then the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was filtered through a paper filter to remove the solid, and the solvent was removed from the filtrate under reduced pressure. The concentrate was then purified and concentrated by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0%~10%) to obtain the title compound (0.044 g, 50.7%) as a white solid. 1 H NMR(400MHz,CDCl3)δ9.28(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 / z482.3(M + +1).

[0115] <Example 1> Inhibitory effect on the expression of fibrous proteins In order to confirm the preventive or therapeutic effect of the compounds disclosed herein on idiopathic pulmonary fibrosis, Protein expression was analyzed. A549 cells, an alveolar epithelial cell line, were placed in a 6-well plate at a rate of 1 × 10⁶ 5Cells were seeded in a cell / well and cultured in a CO2 incubator (37°C, 5% CO2) for 24 hours. Then, to induce serum starvation, the culture medium was replaced with RPMI1690 (1% FBS, 1% P / S) culture medium and cultured in a CO2 incubator (37°C, 5% CO2) for 24 hours. After serum starvation, 10 μM of test substances (compounds 40, 43, 239, 285, 295, and 296) were treated with 5 ng / mL of TGF-β1 and cultured in a CO2 incubator (37°C, 5% CO2) for 48 hours. The control group was given a culture medium containing 0.1% DMSO. The expression of fibrotic proteins (FN-EDA, proCOL1A1) in the cultured cells was examined by Western blotting. The comparison was performed using blot. Cells were dissolved in 100 μL of RIPA buffer [containing proteinase and phosphatase inhibitors] and incubated on ice for 30 minutes. This was then centrifuged at 13,000 g at 4°C for 20 minutes. The supernatant was separated and tested using a BCA protein assay kit. The protein was quantified using a kit. Then, a sample was prepared at a concentration of 0.5 μg / μL by adding NuPAGE sample reducing agent and NuPAGE LDS sample buffer (4X). The prepared sample was boiled at 100°C for 5 minutes to denature the protein. 5 μg of protein was loaded onto a NuPAGE Novex 4-12% Bis-Tris gel, separated at 120V, and transferred to a nitrocellulose membrane (NC) using the iBlot2 Dry Blotting System. The membrane was then blocked at room temperature for 30 minutes with blocking solution (EzBlock Chemi: distilled water = 1:4). The membrane was reacted with the primary antibody at 4°C overnight, and then washed three times with 1X TBST for 10 minutes each. Subsequently, the primary and secondary antibodies were reacted with an HRP (horseradish peroxidase)-linked secondary antibody at room temperature for 1 hour, and then washed three times with 1X TBST for 10 minutes each. The primary and secondary antibodies were diluted in a solution of blocking solution and 1X TBST in a 1:4 ratio. Then, Amersham TM ECL select TM Western blotting detection reagent detection reagent) and ChemiDoc TM Proteins were visualized using an MP imaging system. The observed proteins were quantified using Image Lab 5.0 software and then corrected using β-actin values. Using GraphPad Prism 9.3.0 software, one-way An ANOVA (post hoc: Dunnett's multiple comparison test) was performed. All data are expressed as mean ± SEM, and a p-value of < 0.05 was considered statistically significant. As a result, as shown in Figure 1, we confirmed that when treated with the compounds of this disclosure, the expression of TGF-β1-induced FN-EDA and proCOL1A1 was significantly suppressed. Therefore, the compounds of this disclosure exhibit an inhibitory effect on the expression of fibrotic proteins, and were found to be useful in the prevention or treatment of idiopathic pulmonary fibrosis.

[0116] <Example 2> Preventive or therapeutic effect in an animal model of BLM-induced pulmonary fibrosis To confirm the preventive or therapeutic effects of the compounds disclosed herein on idiopathic pulmonary fibrosis, the expression of fibrotic proteins in an animal model of BLM-induced pulmonary fibrosis was analyzed. A single intra-airway dose of bleomycin (BLM, 0.3U / mouse) was administered to 8-week-old C57BL / 6 mice to induce pulmonary fibrosis. The test substance was a prophylactic model. In the case of the regular model, administration began the day after BLM administration and was repeated twice daily for 3 weeks. In the treatment model, administration began on the 7th day after BLM administration and was repeated twice daily for 2 weeks. BLM-induced pulmonary fibrosis mice were grouped according to the administered substance [vehicle (Veh) or compound 43], route of administration [oral administration (PO)], and administration cycle [twice daily (BID)] as shown in Table 1 below. [Table 3] On day 21, the animals' athletic abilities were compared using a treadmill test. The treadmill test was evaluated on day 3 after a two-day training period. On day 1 of training, each animal was trained for a total of 2 minutes: 0-1 minute at 5 rpm and 1-2 minutes at 10 rpm. On day 2 of training, each animal was trained for a total of 3 minutes: 0-1 minute at 5 rpm, 1-2 minutes at 10 rpm, and 2-3 minutes at 15 rpm. On day 3, the treadmill was set to 5 rpm for 0-1 minute, 1-2 minutes at 10 rpm, 2-3 minutes at 15 rpm, and 3-4 minutes at 20 rpm, for a total of 4 minutes of evaluation. If an animal dropped off the treadmill more than 10 times due to decreased vitality during evaluation, it was deemed impossible to evaluate and was excluded. On day 21, the animals were anesthetized, bled to death, and their lungs were removed. The expression of fibrotic proteins (COL1A1, α-SMA) was compared using Western blot and histological analysis. For Western blotting, lung tissue was lysed in RIPA buffer (containing proteinase and phosphatase inhibitors) and incubated on ice for 30 minutes. This was then centrifuged at 13,000 g at 4°C for 20 minutes. The supernatant was separated and quantified using the BCA protein assay kit. Subsequently, a sample was prepared at a concentration of 0.5 μg / μL by adding NuPAGE sample reducing agent and NuPAGE LDS sample buffer (4X). The prepared sample was boiled at 100°C for 5 minutes to denature the protein. 5 μg of protein was loaded onto a NuPAGE Novex 4-12% Bis-Tris gel, separated at 120 V, and transferred to a nitrocellulose membrane (NC) using the iBlot2 Dry Blotting System. The membrane was then blocked with blocking solution (EzBlock Chemi: distilled water = 1:4) at room temperature for 30 minutes. After reacting the membrane with the primary antibody overnight at 4°C, it was washed three times for 10 minutes each with 1X TBST. Subsequently, it was reacted with HRP (horseradish peroxidase)-linked secondary antibody at room temperature for 1 hour, and washed three times for 10 minutes each with 1X TBST. The primary and secondary antibodies were diluted in a solution of blocking solution and 1X TBST in a 1:4 ratio. Then, Amersham TM ECL select TM Western blotting detection reagent and ChemiDoc TM Proteins were visualized using an MP imaging system. The observed proteins were quantified using Image Lab 5.0 software and then corrected using β-actin values. For histological analysis, lung tissue fixed in 10% neutral buffered formalin solution was trimmed, dehydrated, and subjected to tissue processing such as paraffin infiltration, then horizontally embedded in paraffin, and blotted. A block was prepared. Paraffin blocks were thinly sectioned to 3 μm to prepare tissue sections, and hematoxylin and eosin (H&E) staining was performed for morphological evaluation of the tissue. The degree of fibrosis in the lung tissue was semi-quantitatively assessed according to the modified Ashcroft scale system criteria (Biotechniques.2008;44(4):507-11,514-7.Table2). One-tail unpaired t-test (post hoc: Mann-Whitney) or one-way ANOVA (post hoc: Dunnett's multiple comparison test) was performed using GraphPad Prism 9.3.0 software. All data are expressed as mean ± SEM, and a P < 0.05 was considered statistically significant. As a result, as shown in Figure 2, we confirmed that treatment with the compounds of this disclosure significantly suppressed the expression of COL1A1 and α-SMA in the lung tissue of BLM-induced pulmonary fibrosis mice, a preventive model. Furthermore, as shown in Figure 3, we confirmed that when treated with the compounds of this disclosure, the Ashcroft score was significantly reduced and physical activity was improved in BLM-induced pulmonary fibrosis mice, a therapeutic model. Therefore, the compounds of this disclosure exhibit inhibitory effects on the expression of fibrotic proteins, effects on reducing pulmonary fibrosis, and effects on improving exercise capacity, and have been found to be useful in the prevention or treatment of idiopathic pulmonary fibrosis.

[0117] This disclosure provides the following pharmaceutical compositions, methods, and uses: Item 1. A pharmaceutical composition for the prevention or treatment of idiopathic pulmonary fibrosis, comprising as an active ingredient a compound represented by the chemical formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. Item 2. The pharmaceutical composition according to Item 1, wherein the compound represented by chemical formula I is at least one selected from the group consisting of compounds 1 to 450 listed in the table. Item 3. The pharmaceutical composition according to Item 1 or 2, wherein the compound represented by chemical 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 as listed in the table. Item 4. A method for the prevention or treatment of idiopathic pulmonary fibrosis, comprising administering to an individual a compound represented by chemical formula I as described in any of items 1 to 3, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. Item 5. Uses of any compound represented by chemical formula I, its optical isomer, or a pharmaceutically acceptable salt thereof, as described in any of Items 1-3, for the prevention or treatment of idiopathic pulmonary fibrosis. Item 6. Uses of a compound represented by chemical formula I, its optical isomer, or a pharmaceutically acceptable salt thereof, as described in any of Items 1-3, in the manufacture of a drug for the prevention or treatment of idiopathic pulmonary fibrosis. Item 7. The pharmaceutical composition described above is an oral pharmaceutical composition as described in any of Items 1 to 3. Item 8. A compound represented by chemical formula I as described in any of Items 1-3, its optical isomer, or a pharmaceutically acceptable salt thereof, which is administered orally, by the method described in Item 4, or for the uses described in Item 5 or 6.

[0118] Although specific parts of this disclosure have been described in detail above, it will be clear to those with ordinary skill in the art that such specific descriptions are merely preferred embodiments and do not limit the scope of this disclosure. Therefore, the substantial scope of this disclosure is defined by the appended claims and their equivalents.

Claims

1. A pharmaceutical composition for the prevention or treatment of idiopathic pulmonary fibrosis, comprising the compounds listed in the table below. Table 1

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is administered orally.

3. The pharmaceutical composition according to claim 1, wherein the compound is represented by the following chemical formula. 【Chemistry 1】

4. Use of a compound, its optical isomer, or a pharmaceutically acceptable salt thereof in the manufacture of a drug for the prevention or treatment of idiopathic pulmonary fibrosis, wherein the compound is one of the compounds listed in the table below. Table 2

5. The use according to claim 4, wherein the compound is represented by the following chemical formula. 【Chemistry 2】

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