Composition for preventing or treating 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 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.

Background Art

[0002] Idiopathic pulmonary fibrosis (IPF) is a disease in which the alveolar epithelial cells are damaged for unknown reasons, and then the lung parenchyma is fibrosed by an abnormal tissue repair mechanism. Symptoms such as chronic dry cough and shortness of breath appear. 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. However, since these only slow down 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] The present disclosure provides 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.

[0006] The present 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] The present disclosure provides the use of a compound represented by Chemical Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof for preventing or treating idiopathic pulmonary fibrosis.

[0008] The present disclosure provides the use of a compound represented by Chemical Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for preventing or treating idiopathic pulmonary fibrosis.

Means for Solving the Problems

[0009] Specifically, it is 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 various elements disclosed in the present invention belong to the scope of the present invention. Also, it cannot be said that the scope of the present invention is limited by the specific descriptions described below.

[0010] The present disclosure provides a pharmaceutical composition for preventing or treating idiopathic pulmonary fibrosis, comprising, as an active ingredient, a compound represented by the following Chemical Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof: Composition: [Chemical Formula I]

Chemical Formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chemical formula

Chemical formula

[0011] In the present disclosure, the compound represented by the chemical formula I is L1, L2, and L3 are each independently a single bond or -(C1-C2 alkylene); R1 is -CX2H or -CX3; R2 is -NR A R B , -OR C , [Chemical formula] , or [Chemical formula] and {where [Chemical formula] or [Chemical formula] one or more H of are each independently optionally substituted with -X, -OH, -NR D R E , or -(C1-C4 alkyl)}; R3 is -(C1-C4 alkyl), -(C3-C7 cycloalkyl), -aryl, -heteroaryl, -adamantyl, [Chemistry] or [Chemistry] and {wherein one or more H of -aryl or -heteroaryl are each independently -X, -O(C1-C4 alkyl), -OCF3, -O-aryl, -NR D R E , -(C1-C4 alkyl), -CF3, -S(=O)2-(C1-C4 alkyl), -aryl, -heteroaryl, [Chemistry] , [Chemistry] , or [Chemistry] may be substituted [at this time, [Chemistry] one or more H of D R E may each independently be substituted with -NR [Chemistry] or [Chemistry] one or more H may each independently be substituted with -(C1-C4 alkyl)}; Y1, Y2, and Y4 are each independently -CH2-, -NR F -, -O-, -C(=O)-, or -S(=O)2-; Y3 is -CH- or -N-; Z1 to Z4 are each independently N or CR Z wherein, Z1 to Z4 are not N simultaneously for three or more, and R Z is -H, -X, or -O(C1-C4 alkyl)}; Z5 and Z6 are each independently -CH2- or -O-; Z7 and Z8 are each independently =CH- or =N-; Z9 is -NR G - or -S-; R A and R B are each independently -H, -(C1-C4 alkyl), -(C1-C4 alkyl)-OH, -(C1-C4 alkyl)-NR D R E , -aryl, -(C1-C4 alkyl)-aryl, -(C3-C7 cycloalkyl), or

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0012] In the present disclosure, the compound represented by the chemical formula I may be a compound represented by the following chemical formula Ia: [Chemical formula Ia]

Chemical formula

Chemical formula

[0013] In the present disclosure, the compound represented by the chemical formula Ia is R2 is

Chemical formula

[0014] In the present disclosure, the compound represented by the chemical formula I may be a compound described in the following table.

[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 an embodiment of the present disclosure, a pharmaceutical composition containing the compound in the table, its optical isomer or its pharmaceutically acceptable salt as an active ingredient can prevent or treat idiopathic pulmonary fibrosis.

[0045] In the present disclosure, the compound represented by the chemical formula I may be a compound described in the following table.

[0046]

Table 2

[0047] In an embodiment of the present disclosure, a pharmaceutical composition containing, as an active ingredient, the compound in the table, its optical isomer, or its pharmaceutically acceptable salt can prevent or treat idiopathic pulmonary fibrosis.

[0048] In the present disclosure, the compound represented by the chemical formula I can be produced by the method disclosed in Korean Patent Publication No. 10-2 017-0017792, but is not limited thereto.

[0049] In the present disclosure, the compound represented by the chemical formula I may contain one or more asymmetric carbons, whereby it can 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, for example, by resolution such as column chromatography or HPLC. Alternatively, they can be stereospecifically synthesized using optically pure starting materials and / or reagents of known sequences. Specifically, the isomers may be optical isomers.

[0050] In the present disclosure, the term "pharmaceutically acceptable" may mean being physiologically acceptable and not causing allergic reactions such as gastrointestinal disorders, dizziness, or similar reactions when administered to an individual.

[0051] The pharmaceutically acceptable salts according to the embodiments of the present disclosure can be produced by conventional methods known to those of ordinary skill in the art.

[0052] Pharmaceutically acceptable salts according to embodiments of the present disclosure include, for example, inorganic ion salts prepared from calcium, potassium, sodium, magnesium, etc., inorganic acid salts prepared from hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, sulfuric acid, hydroiodic acid, etc., organic acid salts prepared from acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carboxylic acid, vanillic acid, etc., sulfonate salts prepared from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, etc., amino acid salts prepared from glycine, arginine, lysine, etc., and amine salts prepared from trimethylamine, triethylamine, ammonia, pyridine, picoline, etc., but are not limited thereto. In embodiments of the present disclosure, the salt may include hydrochloric acid, trifluoroacetic acid, citric acid, bromic acid, maleic acid, phosphoric acid, sulfuric acid, tartaric acid, or a mixture thereof.

[0053] In the present disclosure, the term "idiopathic pulmonary fibrosis; IPF)" means a disease in which the alveolar epithelial cells are damaged due to some cause and then the lung parenchyma is fibrosed by an abnormal tissue repair mechanism.

[0054] In the present disclosure, the term "prevention" means any act of suppressing or delaying the onset of a disease by administration of a compound of Formula I of the present disclosure, its optical isomers, or its pharmaceutically acceptable salts.

[0055] In the present disclosure, the term "treatment" means any act of improving or beneficially changing the suspicion of a disease and the symptoms of an affected individual by administration of a compound of Formula I of the present disclosure, its optical isomers, or its pharmaceutically acceptable salts.

[0056] The compound represented by Chemical Formula I of the present disclosure, its optical isomers, or its pharmaceutically acceptable salts 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 the present disclosure, its optical isomers, or its pharmaceutically acceptable salts as an active ingredient can be usefully used for the prevention or treatment of idiopathic pulmonary fibrosis.

[0058] In this regard, in a specific embodiment of the present disclosure, it was confirmed that the compound represented by Chemical Formula I of the present disclosure, its optical isomers, or its pharmaceutically acceptable salts suppress the expression of fibrosis proteins, FN-EDA and proCOL1A1, induced by TGF-β1 (Figure 1).

[0059] It was also confirmed that the compound represented by Chemical Formula I of the present disclosure, its optical isomers, or its pharmaceutically acceptable salts suppress the expression of increased fibrosis proteins, COL1A1 and αSMA, in mice with pulmonary fibrosis induced by BLM (Figure 2). Furthermore, the compound represented by Chemical Formula I of the present disclosure, its optical isomers, or its pharmaceutically acceptable salts decrease the increased Ashcroft score and improve the decreased activity in mice with pulmonary fibrosis induced by BLM (Figure 3).

[0060] The compound represented by Chemical Formula I of the present disclosure, its optical isomers, or its pharmaceutically acceptable salts can exhibit a preventive or therapeutic effect on idiopathic pulmonary fibrosis at a level considered to be similar or substantially the same as or superior to that of conventionally known drugs for the prevention or treatment of idiopathic pulmonary fibrosis. A pharmaceutical composition containing the compound represented by Chemical Formula I of the present disclosure, its optical isomers, or its pharmaceutically acceptable salts as an active ingredient can exhibit a preventive or therapeutic effect on idiopathic pulmonary fibrosis at a level considered to be similar or substantially the same as or superior to that of conventionally known drugs for the prevention or treatment of idiopathic pulmonary fibrosis.

[0061] According to an embodiment of the present disclosure, the pharmaceutical composition may further contain one or more pharmaceutically acceptable carriers in addition to the compound represented by the chemical formula I, its optical isomers, or its pharmaceutically acceptable salts. Pharmaceutically acceptable carriers are those commonly used in the art, and specifically may be, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, or mineral oil. The pharmaceutical composition according to an embodiment of the present disclosure may further contain lubricants, wetting agents, sweeteners, flavoring agents, emulsifying agents, suspending agents, preservatives, dispersing agents, stabilizers, etc. in addition to the above components. Further, the pharmaceutical composition according to an embodiment of the present disclosure may be formulated into oral dosage forms such as tablets, powders, granules, pills, capsules, suspensions, emulsions, oral solutions, emulsions, syrups, etc., external preparations, suppositories, or sterile injection solutions using pharmaceutically acceptable carriers and excipients, and manufactured in unit dosage form, or may be manufactured by placing them in multi-dose containers. The formulation may be manufactured by the usual methods used for formulation in the art, or by the methods disclosed in Remington’s Pharmaceutical Science (19 th th ed., 1995), and may be formulated into various formulations according to each disease or component.

[0062] Non-limiting examples of oral dosage forms using the pharmaceutical composition of the present disclosure include tablets, troches, lozenges, aqueous suspensions, oily suspensions, prepared powders, granules, emulsions, hard capsules, soft capsules, syrups or elixirs. To formulate the pharmaceutical composition according to an embodiment of the present disclosure for oral administration, binders such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch or sweet potato starch; lubricating oils such as magnesium stearate, calcium stearate, sodium stearyl fumarate or polyethylene glycol wax may be used, as well as sweeteners, flavors, syrups, etc. may also be used. In the case of capsules, in addition to the above substances, a liquid carrier such as fatty oil may further be used.

[0063] Non-limiting examples of parenteral dosage forms using the pharmaceutical composition according to an embodiment of the present disclosure include injection solutions, suppositories, powders for respiratory inhalation, aerosol agents for spraying, ointments, powders for application, oils, creams, etc. To formulate the pharmaceutical composition according to an embodiment of the present disclosure for parenteral administration, sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, external preparations, etc. may be used, and 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.

[0064] The pharmaceutical composition according to an embodiment of the present disclosure can be administered orally or parenterally according to the intended method, preferably orally, but is not limited thereto.

[0065] The daily dosage of the compound represented by Chemical Formula I of the present disclosure, its optical isomers, or its pharmaceutically acceptable salts 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 may be about 50 to 2,000 mg / kg, but is not limited thereto, and may be administered once or several times a day.

[0066] The pharmaceutically effective amount and effective dosage of the pharmaceutical composition according to the embodiments of the present disclosure can vary depending on the formulation method, administration method, administration time, and / or administration route of the pharmaceutical composition, etc., and can also vary according to the type and degree of the reaction to be achieved by the administration of the pharmaceutical composition, the type of the individual to be administered, age, body weight, general health status, symptoms and degree of the disease, gender, diet content, excretion, drugs used together with the individual simultaneously or at different times, and other components of the composition, etc., as well as various factors such as similar factors well-known in the pharmaceutical field. Those with ordinary knowledge in the art can easily determine and formulate the dosage effective for the intended treatment. The pharmaceutical composition according to the embodiments of the present disclosure may be administered once a day or divided into several times for administration. The pharmaceutical composition according to the embodiments of the present disclosure may be administered as a single therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. Considering all the above elements, the pharmaceutical composition according to the embodiments of the present disclosure may be administered in an amount that has no side effects and can obtain the maximum effect with the minimum amount, which can be easily determined by an ordinary technician in the technical field to which the present disclosure belongs.

[0067] The pharmaceutical composition according to the embodiments of the present disclosure can exhibit excellent effects even when used alone, but in order to further improve the treatment efficiency, it may also be used in combination with various methods such as hormone therapy and drug therapy.

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

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

[0070] In the present disclosure, the term "administration" means introducing a predetermined substance into an individual by an appropriate method.

[0071] In the present disclosure, the term "individual" means all animals such as humans, rats, mice, livestock, etc. in which idiopathic pulmonary fibrosis has developed or may develop, and specifically may be a mammal including a human, but is not limited thereto.

[0072] The method for preventing or treating idiopathic pulmonary fibrosis according to an embodiment of the present disclosure may be administering a compound represented by the above chemical formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof in a therapeutically effective amount.

[0073] In the present disclosure, the term "therapeutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment and that does not cause side effects, which may be determined by those skilled in the art according to factors including the patient's gender, age, weight, health status, type of disease, severity, activity of the drug, sensitivity to the drug, administration method, administration time, administration route, excretion rate, treatment period, ingredients including the formulation or drugs used simultaneously, and other factors well-known in the medical field. The specific therapeutically effective amount for a particular patient may vary depending on the type and degree of response to be achieved, and in some cases, whether other formulations are being used, including the specific composition, the patient's age, weight, general health status, gender and diet content, administration time, administration route and excretion rate of the composition, treatment period, whether used in combination with or simultaneously with the specific composition, and various factors such as drugs, and similar factors well-known in the pharmaceutical field, and it is desirable to apply them differently.

[0074] The method for preventing or treating idiopathic pulmonary fibrosis according to an embodiment of the present disclosure involves administering the compound represented by the chemical formula I, its optical isomer, or a pharmaceutically acceptable salt thereof, not only to address the disease itself before the onset of symptoms, but also to inhibit or avoid its symptoms. In disease management, the prophylactic or therapeutic dosage of a specific active ingredient varies depending on the characteristics and severity of the disease or condition, and the route by which the active ingredient is administered. Dosage and dosing frequency vary depending on the age, weight, and response of the individual patient. Suitable dosages and administration methods can be easily selected by those with ordinary knowledge in the art who naturally consider such factors. Further, the method for preventing or treating idiopathic pulmonary fibrosis according to an embodiment of the present disclosure may further include administering a therapeutically effective amount of a further active formulation useful for preventing or treating the disease together with the compound represented by the chemical formula I, its optical isomer, or a pharmaceutically acceptable salt thereof. By using a further active formulation together with the compound represented by the chemical formula I, its optical isomer, or a pharmaceutically acceptable salt thereof, a synergistic effect or an additive effect can be obtained.

[0075] The present disclosure provides the use of the compound represented by the chemical formula I, its optical isomer, or a pharmaceutically acceptable salt thereof for the prevention or treatment of idiopathic pulmonary fibrosis.

[0076] The present disclosure provides the use of the compound represented by the chemical formula I, its optical isomer, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention or treatment of idiopathic pulmonary fibrosis.

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

[0078] For manufacturing a medicament, the compound represented by the chemical formula I, its optical isomer, or a pharmaceutically acceptable salt thereof may be mixed with pharmaceutically acceptable adjuvants, diluents, carriers, etc., and manufactured as a combined preparation together with other active formulations, so as to have a synergistic effect.

[0079] The matters described in the pharmaceutical compositions, treatment methods, and uses of the present disclosure are equally applicable as long as they do not conflict with each other.

Advantages of the Invention

[0080] The compound represented by Chemical Formula I of the present disclosure, its optical isomers, or its pharmaceutically acceptable salts, and the pharmaceutical composition containing the same as an active ingredient can be usefully used for the prevention or treatment of idiopathic pulmonary fibrosis.

Brief Description of the Drawings

[0081]

Figure 1

Figure 2

Figure 3

Modes for Carrying Out the Invention

[0082] Hereinafter, the present disclosure will be described in more detail by way of examples. However, it will be apparent to those having ordinary knowledge in the art that these examples are merely illustrative of the present disclosure and should not be construed as limiting the scope of the present disclosure thereto.

Examples

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

[0084] [Step 1] Synthesis of N-Phenylthiomorpholine-4-carboxamide 1,1-dioxide [Chemical formula] 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, and triphosgene (4.780 g, 16.107 mmol) was added thereto, followed by stirring at the same temperature. Thiomorpholine 1,1-dioxide (4.790 g, 35.434 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for 16 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride 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-carboxamido)methyl)-3-fluorobenzoate [Chemical formula] The N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (1.000 g, 3.932 mmol) produced in Step 1 and sodium hydride (60.00%, 0.189 g, 4.719 mmol) were dissolved in N,N-dimethylformamide (30 mL) at 0 °C, and methyl 4-(bromomethyl)-3-fluorobenzoate (1.020 g, 4.129 mmol) was added thereto. The mixture was stirred at room temperature for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride 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% to 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 [Chemical formula] A solution of methyl 4-((1,1-dioxide-N-phenylthiomorpholine-4-carboxamide)methyl)-3-fluorobenzoate (1.240 g, 2.949 mmol) produced in Step 2 and hydrazine hydrate (2.786 mL, 58.983 mmol) dissolved in ethanol (15 mL) at 120 °C was stirred for 1 hour, and then the temperature was lowered to room temperature to terminate the reaction. The solvent of the reaction mixture was removed under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was poured into the obtained concentrate, and the mixture was extracted with methylene chloride. After filtration through a plastic filter to remove the solid residue and the aqueous layer, the mixture was concentrated under reduced pressure. The title compound was used as it was 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 [Chemical formula] A solution of N-(2-fluoro-4-(hydrazinecarbonyl)benzyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (0.615 g, 1.463 mmol), triethylamine (0.304 mL, 2.194 mmol), and difluoroacetic anhydride (0.164 mL, 1.316 mmol) in methylene chloride (10 mL) at room temperature was stirred at the same temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried (anhydrous MgSO4), filtered, and concentrated under reduced pressure. The 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 [Chemical formula] 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 4 and 1-methoxy-N-triethylammonio sulfonyl-methanimidate (Burgess reagent, 0.331 g, 1.390 mmol) were mixed in tetrahydrofuran (10 mL), irradiated with microwave, heated at 150 °C for 30 minutes, and then the temperature was lowered to room temperature to terminate the reaction. Saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, and after extraction with methylene chloride, the mixture was filtered through a plastic filter to remove the solid residue and the aqueous layer, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% - 50%) to obtain the title compound (0.337 g, 75.7%) as a white solid. 1 1H NMR (400 MHz, CDCl3) δ 7.87 - 7.85 (m, 1H), 7.75 - 7.72 (m, 1H), 7.67 - 7.64 (m, 1H), 7.38 - 7.34 (m, 2H), 7.25 - 7.20 (m, 1H), 7.13 - 7.10 (m, 2H), 7.03 - 6.77 (m, 1H), 4.92 (s, 2H), 3.71 - 3.67 (m, 4H), 2.77 - 2.74 (m, 4H); LRMS (ES) m / z 481.1 (M + + 1).

[0089] Synthesis Example 2. 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

[0090] [Step 1] Synthesis of Methyl 6 - ((1,1 - dioxide - N - phenylthiomorpholine - 4 - carboxamide) methyl) nicotinate

Chemical Structure

[0091] [Step 2] Synthesis of N-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide

Chem.

[0092] [Step 3] Synthesis of N-((5-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide

Chem.

[0093] [Step 4] Synthesis of Compound 43 [Chem.] 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 3 and 1-methoxy-N-triethylammonio sulfonyl-methanimidate (Burgess reagent, 0.116 g, 0.486 mmol) were mixed in tetrahydrofuran (2 mL), irradiated with microwave and heated at 150 °C for 30 minutes, then the temperature was lowered to room temperature to terminate the reaction. Water was poured into the reaction mixture, extracted with methylene chloride, filtered through a plastic filter to remove the solid residue and the aqueous solution layer, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2, 4 g cartridge; methanol / methylene chloride = 3%) to obtain the title compound (0.078 g, 51.9%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 9.23 (d, 1H, J = 2.2 Hz), 8.38 (dd, 1H, J = 8.2, 2.2 Hz), 7.54 (d, 1H, J = 8.2 H z), 7.41 - 7.31 (m, 2H), 7.19 (ddd, 3H, J = 6.4, 3.0, 1.6 Hz), 6.94 (m, 1H), 5.10 (s, 2H), 3.72 (dd, 4H, J = 6.9, 3.7 Hz), 2.97 - 2.90 (m, 4H); LRMS (ES) m / z 464.2 (M + + 1).

[0094] Synthesis Example 3. Synthesis of Compound 232, N-(3-Chloro-4-fluorophenyl)-N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)morpholine-4-carboxamide

[0095] [Step 1] Synthesis of N-(3-chloro-4-fluorophenyl)morpholine-4-carboxamide

Chem.

[0096] [Step 2] Synthesis of methyl 6-((N-(3-chloro-4-fluorophenyl)morpholine-4-carboxamido)methyl)nicotinate

Chem.

[0097] [Step 3] Synthesis of N-(3-chloro-4-fluorophenyl)-N-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)morpholine-4-carboxamide

Chemical Structure

[0098] [Step 4] Synthesis of Compound 232

Chemical Structure

[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-dioxidothiomorpholine-4-carboxamido)methyl)benzoate

Chemical formula

[0102] [Step 3] Synthesis of N-(2-fluoro-4-(hydrazinecarbonyl)benzyl)-N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide

Chemical formula

[0103] [Step 4] Synthesis of Compound 285 [Chemical formula] N-(2-Fluoro-4-(hydrazinecarbonyl)benzyl)-N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.100 g, 0.228 mmol) prepared in Step 3 and triethylamine (0.095 mL, 0.684 mmol) were dissolved in dichloromethane (4 mL) at room temperature, and 2,2-difluoroacetic anhydride (0.028 mL, 0.228 mmol) was added thereto. The mixture was stirred at the same temperature for 17 hours. A saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the mixture was extracted with dichloromethane. After filtration through a plastic filter to remove the solid residue and the aqueous solution 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. 11H NMR (400 MHz, CDCl3) δ 7.90 (dd, 1H, J = 8.0, 1.6 Hz), 7.77 (dd, 1H, J = 10.1, 1.6 Hz), 7.69 (t, 1H, J = 7.6 Hz), 7.14 - 6.81 (m, 5H), 4.90 (s, 2H), 3.74 - 3.71 (m, 4H), 2.85 - 2.82 (m, 4H); LRMS (ES) m / z 499.3 (M + + 1).

[0104] 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

[0105] [Step 1] Synthesis of Methyl 6-((N-(4-fluorophenyl)-1,1-dioxidothiomorpholine-4-carboxamide)methyl)nicotinate [Chemical Structure Diagram] A solution of N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.500 g, 1.836 mmol) 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 further stirred at room temperature for 5 hours. Then, water (5 mL) was added to the reaction mixture at room temperature and stirred for 10 minutes to terminate the reaction. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried (anhydrous MgSO4), filtered, and concentrated under reduced pressure. The title compound was used as it was without further purification (0.450 g, 58.1%, brown solid).

[0106] [Step 2] Synthesis of N-(4-fluorophenyl)-N-((5-(hydrazinecarbonyl)pyridin-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] To a solution of N-(4-fluorophenyl)-N-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.111 g, 0.263 mmol) prepared in Step 2 and triethylamine (0.110 mL, 0.790 mmol) dissolved in dichloromethane (5 mL) at room temperature was added 2,2-difluoroacetic anhydride (0.065 mL, 0.527 mmol), and the mixture was stirred at the same temperature for 1 hour. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane, then 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] 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) and 1-methoxy-N-triethylammonio sulfonyl-methanimidate (Burgess reagent, 0.117 g, 0.493 mmol) were dissolved in tetrahydrofuran (5 mL) at room temperature, and the solution was stirred at 70 °C for 5 hours. Then, the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was filtered through a paper filter to remove solids, and the solvent was removed from the filtrate under reduced pressure. The concentrate was 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 1H NMR (400 MHz, CDCl3) δ 9.27 (d, 1H, J = 1.6 Hz), 8.43 (dd, 1H, J = 8.2, 2.2 Hz), 7.58 (d, 2H, J = 8.2 Hz), 7.25 - 7.21 (m, 2H), 7.10 - 6.84 (m, 3H), 5.08 (s, 2H), 3.73 (t, 4H, J = 5.1 Hz), 2.98 (t, 4H, J = 5.2 Hz); LRMS (ES) m / z 482.1 (M + + 1).

[0109] 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

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

[0111] [Step 2] Synthesis of methyl 6-((N-(3-fluorophenyl)-1,1-dioxidothiomorpholine-4-carboxamido)methyl)nicotinate

Chemical formula

[0112] [Step 3] Synthesis of N-(3-fluorophenyl)-N-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)thiomorpholine-4-carboxamide 1,1-dioxide

Chemical formula

[0113] [Step 4] Synthesis of N-((5-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)pyridin-2-yl)methyl)-N-(3-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide

Chemical formula

[0114] [Step 5] Synthesis of Compound 296

Chemical formula

[0115] <Example 1> Inhibitory effect on the expression of fibrotic proteins To confirm the prophylactic or therapeutic effect of the compounds according to the present disclosure on idiopathic pulmonary fibrosis, the expression of fibrotic proteins was analyzed. A549 cells, an alveolar epithelial cell line, were seeded in a 6-well plate at 1×10 5Cells were seeded at cells / well and cultured in a CO2 incubator (37 °C, 5% CO2) for 24 hours. Subsequently, the culture medium was replaced with RPMI1690 (1% FBS, 1% P / S) medium to induce serum starvation, and the cells were cultured in a CO2 incubator (37 °C, 5% CO2) for 24 hours. After serum starvation, the cells were treated with 10 μM of test substances (compounds 40, 43, 239, 285, 295, and 296) and 5 ng / mL of TGF-β1, and cultured in a CO2 incubator (37 °C, 5% CO2) for 48 hours. The control group was treated with a culture medium containing 0.1% DMSO. The expression of fibrotic proteins (FN-EDA, proCOL1A1) in the cultured cells was compared by western blot. The cells were lysed in 100 μL of RIPA buffer [containing proteinase and phosphatase inhibitors] and incubated on ice for 30 minutes. This was centrifuged at 13,000 g for 20 minutes at 4 °C. The supernatant was separated, and the protein concentration was measured using a BCA protein assay It was quantified using a kit). Subsequently, NuPAGE sample reducing agent and NuPAGE LDS sample buffer (4X) were added to prepare the sample at a concentration of 0.5 μg / μL. The prepared sample was boiled at 100 °C for 5 minutes to denature the protein. After loading 5 μg of protein onto a NuPAGE Novex 4-12% Bis-Tris gel, it was separated at 120 V and transferred to a nitrocellulose membrane (NC) using the iBlot2 Dry Blotting System. Subsequently, the membrane was blocked at room temperature for 30 minutes with a blocking solution (EzBlock Chemi: distilled water = 1:4). After reacting the membrane with the primary antibody overnight at 4 °C, it was washed 3 times with 1X TBST for 10 minutes each. Subsequently, it was reacted with an HRP (Horseradish peroxidase)-linked secondary antibody at room temperature for 1 hour and washed 3 times with 1X TBST for 10 minutes each. The primary and secondary antibodies were diluted in a solution prepared by mixing the blocking solution and 1X TBST at a ratio of 1:4. Subsequently, Amersham TM ECL select TM western blotting detection reagent) and ChemiDoc TM MP imaging system were used to visualize the protein. The observed protein was quantified using Image Lab 5.0 software and then corrected using the β-actin numerical value. One-way ANOVA (post hoc: Dunnett’s multiple comparison test) was performed using GraphPad Prism 9.3.0 software. All data were expressed as mean ± SEM, and P < 0.05 was considered statistically significant. As a result, as shown in Fig. 1, it was confirmed that when the compound of the present disclosure was treated, the expression of FN-EDA and proCOL1A1 induced by TGF-β1 was significantly suppressed. Therefore, it was found that the compound of the present disclosure exhibits an effect of suppressing the expression of fibrotic proteins, and thus is useful for the prevention or treatment of idiopathic pulmonary fibrosis.

[0116] <Example 2> Preventive or therapeutic effect in a BLM-induced pulmonary fibrosis animal model To confirm the preventive or therapeutic effect of the compound according to the present disclosure on idiopathic pulmonary fibrosis, the expression of fibrotic proteins in a BLM-induced pulmonary fibrosis animal model was analyzed. 8-week-old C57BL / 6 mice were administered bleomycin (BLM, 0.3 U / mouse) once intratracheally to induce pulmonary fibrosis. The test substance was administered starting from the day after BLM administration in the prevention model and repeated 3 times a day, twice a day, for 3 weeks. In the treatment model, administration was started on the 7th day after BLM administration and repeated twice a day for 2 weeks. BLM-induced pulmonary fibrosis mice were grouped as shown in Table 1 below according to the administered substance [vehicle (Veh) or compound 43], administration route [oral administration (PO)], and administration period [twice a day (BID)].

Table 3

[0117] The present disclosure provides the following pharmaceutical compositions, methods, and uses: Item 1. A pharmaceutical composition for the prevention or treatment of idiopathic pulmonary fibrosis, containing as an active ingredient a compound represented by the following Chemical Formula I, its optical isomer, or a pharmaceutically acceptable salt thereof. Item 2. The pharmaceutical composition according to Item 1, wherein the compound represented by the Chemical Formula I is at least one selected from the group consisting of the compounds 1 to 450 described in the above table. Item 3. The pharmaceutical composition according to Item 1 or 2, wherein the compound represented by the 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 described in the above table. Item 4. A method for the prevention or treatment of idiopathic pulmonary fibrosis, including administering to an individual a compound represented by the Chemical Formula I according to any one of Items 1 to 3, its optical isomer, or a pharmaceutically acceptable salt thereof. Item 5. Use of a compound represented by the Chemical Formula I according to any one of Items 1 to 3, its optical isomer, or a pharmaceutically acceptable salt thereof for the prevention or treatment of idiopathic pulmonary fibrosis. Item 6. Use of a compound represented by the Chemical Formula I according to any one of Items 1 to 3, its optical isomer, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention or treatment of idiopathic pulmonary fibrosis. Item 7. The pharmaceutical composition according to any one of Items 1 to 3, wherein the pharmaceutical composition is for oral administration. Item 8. The compound represented by the Chemical Formula I according to any one of Items 1 to 3, its optical isomer, or a pharmaceutically acceptable salt thereof is for oral administration, and is used in the method according to Item 4, or the use according to Item 5 or 6.

[0118] As described in detail above for specific parts of the present disclosure, it is clear to those with ordinary knowledge in the art that such specific descriptions are merely preferred embodiments and do not limit the scope of the present disclosure. Therefore, the substantial scope of the present disclosure is defined by the appended claims and their equivalents.

Claims

1. A pharmaceutical composition for the prevention or treatment of idiopathic pulmonary fibrosis, containing, as an active ingredient, a compound represented by the following chemical formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical formula I] 【Chemical formula 1】 In chemical formula I, L １ 、L ２ 、and L ３ are each independently a single bond (a bond) or -(C 1 - C ２ alkylene)-; R １ is -CX ２ H or -CX ３ ; R ２ is -NR Ａ R Ｂ 、-OR Ｃ 、 【Chemical formula 2】 、or 【Chemical formula 3】 and {where 【Chemical formula 4】 or 【Chemical formula 5】 one or more Hs of are each independently -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 alkyl)-heteroaryl may be substituted [at this time, -aryl, -heteroaryl, -(C １ - C ４-(alkyl)-aryl, or -(C １ -C ４ One or more Hs of -(alkyl)-heteroaryl may each independently be -X, -OH, -CF ３ , or -CF ２ H and may be substituted]; R ３ is -H, -(C １ -C ４ alkyl), -(C １ -C ４ alkyl)-O(C １ -C ４ alkyl), -(C １ -C ４ alkyl)-C(=O)-O(C １ -C ４ alkyl), -(C ３ -C ７ cycloalkyl), -(C ２ -C ６ heterocycloalkyl), -aryl, -heteroaryl, -adamantyl, [Chemical Formula 6] , or [Chemical Formula 7] and {wherein one or more Hs of -(C １ -C ４ alkyl) may each independently be -X or may be substituted with -OH, one or more Hs of -aryl or -heteroaryl may each independently be -X, -OH, -O(C １ -C ４ alkyl), -OCF ３ , -O-aryl, -NR Ｄ R Ｅ , -(C １ -C ４ alkyl), -CF ３ , -CF ２ H, -C(=O)-(C １ -C ４ alkyl), -C(=O)-O(C １ -C ４ alkyl), -C(=O)-NR Ｄ R Ｅ 、 -S(=O) ２ -(C １ -C ４ alkyl), aryl, heteroaryl, 【Chemical Formula 8】 、 【Chemical Formula 9】 、 or 【Chemical Formula 10】 may be substituted [at this time, 【Chemical Formula 11】 one or more Hs of are each independently -X, -(C １ -C ４ alkyl), -NR Ｄ R Ｅ 、 -CF ３ 、 or -CF ２ H may be substituted], -(C ３ -C ７ cycloalkyl), -(C ２ -C ６ heterocycloalkyl), adamantyl, 【Chemical Formula 12】 、 or 【Chemical Formula 13】 one or more Hs of are each independently -X, -OH, or -(C １ -C ４ alkyl) may be substituted}; Y １ 、 Y ２ 、 and Y ４ are each independently -CH ２ -, -NR Ｆ -, -O-, - C(=O)-, or -S(=O) ２ -; Y ３ is -CH- or -N-; Z １ ~Z ４ are each independently N or CR Ｚ ; where Z １~Z ４ is such that three or more of them are not N but R Ｚ is -H, -X, or -O(C １ -C ４ alkyl); Z ５ and Z ６ are each independently -CH ２ - or -O-; Z ７ and Z ８ are each independently =CH- or =N-; Z ９ is -NR Ｇ - or -S-; R Ａ and R Ｂ are each independently -H, -(C １ -C ４ alkyl), -(C １ -C ４ alkyl)-OH, -(C １ -C ４ alkyl)-NR Ｄ R Ｅ -aryl, -(C １ -C ４ alkyl)-aryl, -heteroaryl, -(C １ -C ４ alkyl)-heteroaryl, -(C ３ -C ７ cycloalkyl), -(C ２ -C ６ heterocycloalkyl), or 【Chemical Formula 14】 and {wherein, -(C １ -C ４ alkyl), -(C １ -C ４ alkyl)-OH, or also -(C １ -C ４ alkyl)-NR Ｄ R Ｅ one or more H of which may each independently be replaced by -X, -aryl, -(C １ -C ４ alkyl)-aryl, -heteroaryl, -(C １ -C ４ alkyl)-heteroaryl, -(C ３ -C ７ cycloalkyl), or -(C ２ -C ６ heterocycloalkyl) one or more of the H's are each independently optionally substituted with -X, -OH, -O(C １ -C ４ alkyl), -(C １ -C ４ alkyl), -CF ３ , -CF ２ H, or -CN; 【Chemical Formula 15】 one or more of the H's are each independently optionally substituted with -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{where here, one or more of the H's of -(C １ -C ４ alkyl) are each independently optionally substituted with -X or -OH, -aryl, -(C １ -C ４ alkyl)-aryl, -heteroaryl, or -(C １-C ４ One or more H's of (C-C-alkyl)-heteroaryl are each independently -X, -OH, -CF ３ , or -CF ２ H and may be substituted; R Ｄ and R Ｅ are each independently -H, -(C １ -C ４ -alkyl), -aryl, or -(C １ -C ４ -alkyl)-aryl, where one or more H's of -(C １ -C ４ -alkyl may each independently be substituted with -X or -OH, and one or more H's of -aryl or -(C １ -C ４ -alkyl)-aryl are each independently -X, -OH, -CF ３ , or -CF ２ H and may be substituted; 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), and {wherein, -(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 -alkyl) one or more H's may each independently be replaced by -X, -aryl, -(C １ -C ４ -alkyl)-aryl, -(C ２ -C ４ -alkenyl)-aryl, -heteroaryl, -(C １ -C ４ -alkyl)-heteroaryl, -C(=O)-(C ３ -C ７(cycloalkyl), -C ２ -C ６ heterocycloalkyl, or -(C １ -C ４ alkyl)-C(=O)-(C ２ -C ６ One or more H's of heterocycloalkyl) may each independently be -X, -OH, -CF ３ or -CF ２ H and may be substituted;} R Ｇ is -H or -(C １ -C ４ alkyl); Q is -O- or a single bond; [Chemical Formula 16] is a single bond or a double bond {provided that [Chemical Formula 17] When 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 are not both 0, and c and d are not both 0}; X is each independently F, Cl, Br, or I.

2. The compound represented by the chemical formula I is L １ L ２ and L ３ are each independently a single bond or -(C 1 -C ２ alkylene)-; R １ is -CX ２ H or -CX ３ ; R ２ is -NR Ａ R Ｂ -OR Ｃ [Chemical Formula 18] or 【Chemical Formula 19】 and {where 【Chemical Formula 20】 or 【Chemical Formula 21】 one or more of the Hs are each independently -X, -OH, -NR Ｄ R Ｅ or -(C １ -C ４ alkyl) and may be substituted}; R ３ is -(C １ -C ４ alkyl), -(C ３ -C ７ cycloalkyl), -aryl, -heteroaryl, -adamantyl, 【Chemical Formula 22】 or 【Chemical Formula 23】 and {where one or more of the Hs of -aryl or -heteroaryl are each independently -X, -O(C １ -C ４ alkyl), -OCF ３ , -O-aryl, -NR Ｄ R Ｅ , -(C １ -C ４ alkyl), -CF ３ , -S(=O) ２ -(C １ -C ４ alkyl), -aryl, -heteroaryl, 【Chemical Formula 24】 , 【Chemical Formula 25】 or 【Chemical Formula 26】 and may be substituted [at this time, 【Chemical Formula 27】 One or more of H are each independently, -NR Ｄ R Ｅ or -(C １ -C ４ alkyl) and may be substituted]; 【Chemical formula 28】 or 【Chemical formula 29】 One or more of H are each independently, -(C １ -C ４ alkyl) and may be substituted}; Y １ Y ２ and Y ４ are each independently, -CH ２ -, -NR Ｆ -, -O-, -C(=O)-, or -S(=O) ２ -; Y ３ is -CH- or -N-; Z １ to Z ４ are each independently, N or CR Ｚ wherein Z １ to Z ４ are not more than 3 are simultaneously N, and R Ｚ is -H, -X, or -O(C １ -C ４ alkyl)}; Z ５ and Z ６ are each independently, -CH ２ - or -O-; Z ７ and Z ８ are each independently, =CH- or =N-; Z ９ is -NR Ｇ - or -S-; R Ａ and R Ｂ are each independently, -H, -(C １ -C ４ alkyl), -(C １ -C ４-(alkyl)-OH, -(C １ -C ４ -(alkyl)-NR Ｄ R Ｅ , -aryl, -(C １ -C ４ -(alkyl)-aryl, -(C ３ -C ７ -cycloalkyl), or 【Chemical formula 30】 and is {where 【Chemical formula 31】 one or more Hs of are each independently -X, -(C １ -C ４ -alkyl), -CF ３ , -(C ２ -C ６ -heterocycloalkyl), -(C １ -C ４ -(alkyl)-aryl, -heteroaryl, or -heteroaryl-(C １ -C ４ -(alkyl) may be substituted}; ; R Ｃ is -(C １ -C ４ -alkyl) or -aryl; R Ｄ and R Ｅ are each independently -H, -(C １ -C ４ -alkyl) or -(C １ -C ４ -alkyl)-aryl; R Ｆ is -H, -(C １ -C ６ -alkyl), -(C １ -C ４ -alkyl)-OH, -(C １ -C ４ -alkyl)-O-(C １ -C ４ -alkyl), -C(=O)-(C １ -C ４ -alkyl), -C(=O)-O(C １ -C ４ alkyl), -(C １ -C ４ alkyl)-C(=O)-O(C １ -C ４ alkyl), -(C １ -C ４ alkyl)-NR Ｄ R Ｅ , -S(=O) ２ -(C １ -C ４ alkyl), -aryl, -(C １ -C ４ alkyl)-aryl, -(C ２ -C ４ alkenyl)-aryl, -heteroaryl, -(C １ -C ４ alkyl)-heteroaryl, -C(=O)-(C ３ -C ７ cycloalkyl), -(C ２ -C ６ heterocycloalkyl), or -(C １ -C ４ alkyl)-C(=O)-(C ２ -C ６ heterocycloalkyl); where one or more Hs of -(C {wherein one or more Hs of -(C １ -C ４ alkyl), or -C(=O)-O(C １ -C ４ alkyl ), may each independently be replaced by -X; one or more Hs of -aryl may each independently be replaced by -X}; R Ｇ is -(C １ -C ４ alkyl); Q is -O- or a single bond; [Chemical formula 32] is a single bond or a double bond {provided that [Chemical formula 33] when 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 are not both 0, and c and d are not both 0}; X is each independently F, Cl, Br, or I, The pharmaceutical composition according to claim 1.

3. The compound represented by the chemical formula I is the compound represented by the following chemical formula Ia, and the pharmaceutical composition according to claim 1: [Chemical formula Ia] 【Chemical formula 34】 In the chemical formula Ia, R ２ is 【Chemical formula 35】 and; R ３ is -aryl, {where one or more H of -aryl are each independently optionally substituted with -X}; Y １ is -S(=O) ２ -; Z １ is N or CR Ｚ where R Ｚ is -X; a and b are each independently an integer of 0, 1, 2, 3, or 4 {provided that a and b are not both 0}; X is each independently F, Cl, Br, or I.

4. The compound represented by the chemical formula Ia is R ２ is 【Chemical formula 36】 and; R ３ is -phenyl, {where one or more H of -phenyl are each independently optionally substituted with -F or -Cl}; Y １ is -S(=O)- ２ ; Z １ is N or CF, The pharmaceutical composition according to claim 3.

5. The compound represented by the chemical formula I is the compound described in the following table, and the pharmaceutical composition according to claim 1: 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】 【Table 1-10】 【Table 1-11】 【Table 1-12】 【Table 1-13】 【Table 1-14】 【Table 1-15】 【Table 1-16】 【Table 1-17】 【Table 1-18】 【Table 1-19】 【Table 1-20】 【Table 1-21】 【Table 1-22】 【Table 1-23】 【Table 1-24】 [Table 1-25] [Table 1-26] [Table 1-27] [Table 1-28] [Table 1-29]

6. The pharmaceutical composition according to claim 1, wherein the compound represented by the chemical formula I is a compound described in the following table: [Table 2]

7. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is for oral administration.

8. 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, wherein the compound represented by the chemical formula 1 is the same as that defined in claim 1.

9. The method according to claim 8, wherein the compound represented by the chemical formula I is a compound described in the following table: [Table 3]

10. Use of a compound represented by the chemical formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof for the prevention or treatment of idiopathic pulmonary fibrosis, wherein the compound represented by the chemical formula 1 is the same as that defined in claim 1.

11. The use according to claim 10, wherein the compound represented by the chemical formula I is a compound described in the following table: [Table 4]

12. Use of a compound represented by Chemical Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention or treatment of idiopathic pulmonary fibrosis, wherein the compound represented by Chemical Formula 1 is the same as that defined in Claim 1.

13. The use according to Claim 12, wherein the compound represented by Chemical Formula I is a compound described in the following table: 【Table 5】

Images