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 a compound represented by formula I, an optical isomer thereof, 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 said compounds for the prevention or treatment of idiopathic pulmonary fibrosis; the invention also discloses application of the compound in preparation of medicines 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 formula I, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient; a method for preventing or treating idiopathic pulmonary fibrosis using the compound; use of the compound for preventing or treating idiopathic pulmonary fibrosis; and use of the compound in preparing a medicament for preventing or treating idiopathic pulmonary fibrosis. Background Art

[0002] Idiopathic pulmonary fibrosis (IPF) is a disease in which the lung parenchyma becomes fibrous due to abnormal tissue repair mechanisms after the alveolar epithelial cells are damaged for unknown reasons. IPF shows symptoms such as chronic dry cough, shortness of breath and is a disease with a poor prognosis, with a survival period of only about 3-5 years after diagnosis due to the onset of symptoms. It is known that the incidence is higher in men over 50 years of age.

[0003] Currently, two drugs, nintedanib and pirfenidone, are mainly used to treat idiopathic pulmonary fibrosis, but these drugs only slow down the progression of the disease without improving the survival rate. Therefore, there is an urgent need to develop drugs that can effectively treat idiopathic pulmonary fibrosis.

[0004] [Related technical references]

[0005] [Patent Document]

[0006] (Patent Document 1) Korean Unexamined Patent Application Publication No. 10-2017-0017792 DETAILED DESCRIPTION OF THE INVENTION

[0008] Technical issues

[0009] The present disclosure provides a pharmaceutical composition for preventing or treating idiopathic pulmonary fibrosis, comprising a compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an effective ingredient.

[0010] The present disclosure provides a method for preventing or treating idiopathic pulmonary fibrosis, which comprises administering a compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof to an individual.

[0011] The present disclosure provides use of a compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof for preventing or treating idiopathic pulmonary fibrosis.

[0012] The present disclosure provides use of a compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating idiopathic pulmonary fibrosis.

[0013] Technical Solution

[0014] This is described in detail below. At the same time, each description and embodiment disclosed in this disclosure can also be applied to other descriptions and embodiments respectively. In other words, all combinations of various elements disclosed in this disclosure fall within the scope of this disclosure. In addition, it can be found that the scope of this disclosure is not limited to the specific description described below.

[0015] The present disclosure provides a pharmaceutical composition for preventing or treating idiopathic pulmonary fibrosis, comprising a compound represented by the following Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an effective ingredient.

[0016] [Formula I]

[0017]

[0018] In Formula I,

[0019] Where L 1 , L 2 and L 3 are each independently a bond or -(C 1 -C 2 Alkylene)-;

[0020] R 1 For-CX 2 H or -CX 3 ;

[0021] R 2 For-NR A R B 、-OR C ,

[0022] {in At least one H in each of the above may be independently substituted by: -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, [wherein the -aryl, -heteroaryl, -(C 1 -C 4 alkyl)-aryl or -(C 1 -C4 At least one H in the heteroaryl group may be independently replaced by -X, -OH, -CF 3 or -CF 2 H replaces]};

[0023] R 3 -H, -(C 1 -C 4 Alkyl), -(C 1 -C 4 Alkyl)-O(C 1 -C 4 Alkyl), -(C 1 -C 4 alkyl)-C(=O)-O(C 1 -C 4 Alkyl), -(C 3 -C 7 Cycloalkyl), -(C 2 -C 6 cycloheteroalkyl), -aryl, -heteroaryl, -adamantyl,

[0024] {where -(C 1 -C 4 At least one H in the alkyl) may be independently substituted by -X or -OH,

[0025] At least one H in the -aryl or -heteroaryl group may be independently substituted by: -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, [in At least one H in can be independently -X, -(C 1 -C 4 Alkyl), -NR D RE , -CF 3 or -CF 2 H substituted],

[0026] -(C 3 -C 7 Cycloalkyl), -(C 2 -C 6 Cycloheteroalkyl), adamantyl, At least one H in each of the above may be independently -X, -OH or -(C 1 -C 4 alkyl) substituted};

[0027] Y 1 , Y 2 and Y 4 Each is independently -CH 2 -、-NR F -, -O-, -C(=O)- or -S(=O) 2 -;

[0028] Y 3 is -CH- or -N-;

[0029] Z 1 To Z 4 Each independently is N or CR Z , {where Z 1 To Z 4 At least three of them cannot be N at the same time, and R Z is -H, -X or -O(C 1 -C 4 alkyl)};

[0030] Z 5 and Z 6 Each is independently -CH 2 -or-O-;

[0031] Z 7 and Z 8 Each is independently =CH- or =N-;

[0032] Z 9 For-NR G -or-S-;

[0033] R A and R B are independently -H, -(C 1 -C 4 Alkyl), -(C 1 -C 4 Alkyl)-OH, -(C 1 -C 4 Alkyl)-NRD 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

[0034] {wherein the-(C 1 -C 4 Alkyl), -(C 1 -C 4 Alkyl)-OH or -(C 1 -C 4 Alkyl)-NR D R E At least one H in each of the above may be independently substituted by -X,

[0035] The -aryl, -(C 1 -C 4 alkyl)-aryl, -heteroaryl, -(C 1 -C 4 alkyl)-heteroaryl, -(C 3 -C 7 Cycloalkyl) or -(C 2 -C 6 At least one H in the heterocycloalkyl group may be independently substituted by -X, -OH, -O(C 1 -C 4 Alkyl), -(C 1 -C 4 Alkyl), -CF 3 , -CF 2 H or -CN substitution,

[0036] At least one H in each of the above may be independently substituted by: -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)};

[0037] R C For-(C 1 -C 4 alkyl), -aryl, -(C 1 -C 4 alkyl)-aryl, -heteroaryl or -(C 1 -C 4 alkyl)-heteroaryl {wherein -(C 1 -C 4 At least one H in the alkyl) may be independently substituted by -X or -OH, -aryl, -(C 1 -C 4 alkyl)-aryl, -heteroaryl or -(C 1 -C 4 At least one H in the heteroaryl group may be independently replaced by -X, -OH, -CF 3 or -CF 2 H substitution};

[0038] R D and R E are independently -H, -(C 1 -C 4 alkyl), -aryl or -(C 1 -C 4 Alkyl)-aryl {wherein -(C 1 -C 4 At least one H in the alkyl) may be independently substituted by -X or -OH, -aryl or -(C 1 -C 4 At least one H in the alkyl)-aryl group can be independently replaced by -X, -OH, -CF 3 or -CF 2 H substitution};

[0039] R F -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 -C4 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)

[0040] {where -(C 1 -C 4 Alkyl), -(C 1 -C 4 Alkyl)-OH, -(C 1 -C 4 alkyl)-O-(C 1 -C 4 alkyl), -C(=O)-(C 1 -C 4 alkyl), -C(=O)-O(C 1 -C 4 Alkyl), -(C 1 -C 4 alkyl)-C(=O)-O(C 1 -C 4 Alkyl), -(C 1 -C 4 Alkyl)-NR D R E or -S(=O) 2 -(C 1 -C 4 At least one H in the alkyl) may be independently substituted by -X,

[0041] -aryl, -(C 1 -C 4 alkyl)-aryl, -(C 2 -C 4 alkenyl)-aryl, -heteroaryl, -(C1 -C 4 alkyl)-heteroaryl, -C(=O)-(C 3 -C 7 Cycloalkyl), -C 2 -C 6 Heterocycloalkyl or -(C 1 -C 4 alkyl)-C(=O)-(C 2 -C 6 At least one H in the heterocycloalkyl group may be independently substituted by -X, -OH, -CF 3 or -CF 2 H substitution};

[0042] R G -H or -(C 1 -C 4 alkyl);

[0043] Q is -O- or a bond;

[0044] is a single bond or a double bond {the restriction condition is that when When it is a double bond, Y 1 =CH-};

[0045] a to e are each independently an integer of 0, 1, 2, 3 or 4 {with the restriction that a and b cannot be 0 at the same time, and c and d cannot be 0 at the same time};

[0046] Each X is independently F, Cl, Br or I.

[0047] In the present disclosure, in the compound represented by the above formula I, wherein

[0048] L 1 , L 2 and L 3 are each independently a bond or -(C 1 -C 2 Alkylene)-;

[0049] R 1 For-CX 2 H or -CX 3 ;

[0050] R 2 For-NR A R B 、-OR C ,

[0051] {in At least one of the H's can be independently substituted by -X, -OH, -NR D RE or -(C 1 -C 4 alkyl) substituted};

[0052] R 3 For-(C 1 -C 4 Alkyl), -(C 3 -C 7 cycloalkyl), -aryl, -heteroaryl, -adamantyl,

[0053]

[0054] {wherein at least one H in -aryl or -heteroaryl may be independently substituted by: -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, [in At least one H in each of the above may be independently -NR D R E or -(C 1 -C 4 alkyl) substituted],

[0055] At least one H in can be independently -(C 1 -C 4 alkyl) substituted};

[0056] Y 1 , Y 2 and Y 4 Each is independently -CH 2 -、-NR F -, -O-, -C(=O)- or -S(=O) 2 -;

[0057] Y 3 is -CH- or -N-;

[0058] Z 1 To Z 4 Each independently is N or CR Z {where Z 1 To Z 4At least three of them cannot be N at the same time, and R Z is -H or -X or -O(C 1 -C 4 alkyl)};

[0059] Z 5 and Z 6 Each is independently -CH 2 -or-O-;

[0060] Z 7 and Z 8 Each is independently =CH- or =N-;

[0061] Z 9 For-NR G -or-S-;

[0062] R A and R B are 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

[0063] {in At least one H in each of the above may be independently substituted by: -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)};

[0064] R C For-(C 1 -C 4 -alkyl) or -aryl;

[0065] R D and R E are independently -H, -(C 1 -C 4 alkyl) or -(C1 -C 4 alkyl)-aryl;

[0066] R F -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)

[0067] {where -(C 1 -C 4 alkyl) or -C(=O)-O(C 1 -C 4 At least one H in the alkyl) may be independently substituted by -X,

[0068] -At least one H in the aryl group may be substituted by -X};

[0069] R G For-(C 1-C 4 alkyl);

[0070] Q is -O- or a bond;

[0071] is a single bond or a double bond {the restriction condition is that when When it is a double bond, Y 1 for -CH-};

[0072] a to e are each independently an integer of 0, 1, 2, 3 or 4 {with the restriction that a and b cannot be 0 at the same time, and c and d cannot be 0 at the same time};

[0073] Each X is independently F, Cl, Br or I.

[0074] In the present disclosure, the compound represented by the above formula I may be a compound represented by the following formula Ia:

[0075] [Formula Ia]

[0076]

[0077] In Formula Ia,

[0078] R 2 for

[0079] R 3 is -aryl {wherein at least one H in -aryl may be independently substituted by -X};

[0080] Y 1 -S(=O) 2 -;

[0081] Z 1 N or CR Z {where R Z for -X};

[0082] a and b are each independently an integer of 0, 1, 2, 3 or 4 {wherein a and b cannot be 0 at the same time};

[0083] Each X is independently F, Cl, Br or I.

[0084] In the present disclosure, in the compound represented by Formula Ia, wherein

[0085] R 2 for

[0086] R 3 is -phenyl {wherein at least one H in -phenyl may be independently substituted by -F or -Cl};

[0087] Y1 -S(=O) 2 -;

[0088] Z 1 N or CF.

[0089] In the present disclosure, the compound represented by the above Formula I may be a compound described in the following table.

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118] In an exemplary embodiment of the present disclosure, a pharmaceutical composition comprising the compound of the above table, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an effective ingredient can prevent or treat idiopathic pulmonary fibrosis.

[0119] In the present disclosure, the compound represented by the above Formula I may be a compound described in the following table.

[0120]

[0121] In an exemplary embodiment of the present disclosure, a pharmaceutical composition comprising the compound of the above table, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an effective ingredient can prevent or treat idiopathic pulmonary fibrosis.

[0122] In the present disclosure, the compound represented by the above Formula I may be prepared by the method disclosed in Korean Unexamined Patent Application Publication No. 10-2017-0017792, but is not limited thereto.

[0123] In the present disclosure, the compound represented by the above formula I may contain at least one asymmetric carbon, and therefore may exist in the form of a mixture of enantiomers, including a racemic mixture, a single enantiomer (optical isomer), a mixture of diastereomers and a single diastereomer. Such isomers can be separated by splitting according to relevant techniques (e.g., column chromatography, HPLC, etc.). Alternatively, the isomers can be synthesized stereospecifically using a series of known optically pure starting materials and / or reagents. In particular, the isomers can be optical isomers (enantiomers).

[0124] In the present disclosure, the term "pharmaceutically acceptable" may refer to being physiologically acceptable when administered to an individual and generally not causing gastrointestinal disturbances, allergic reactions (eg, dizziness, or other reactions similar thereto).

[0125] The pharmaceutically acceptable salts according to embodiments of the present disclosure can be prepared by conventional methods known to those skilled in the art.

[0126] Pharmaceutically acceptable salts according to embodiments of the present disclosure may 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, carbonic acid, vanillic acid, etc.; sulfonates prepared from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, etc.; amino acid salts prepared from glycine, arginine, lysine, etc.; amine salts prepared from trimethylamine, triethylamine, ammonia, pyridine, picoline, etc.; and the like, 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, or tartaric acid, or mixtures thereof.

[0127] In the present disclosure, the term "idiopathic pulmonary fibrosis (IPF)" may refer to a disease in which the lung parenchyma becomes fibrotic due to abnormal tissue repair mechanisms after alveolar epithelial cells are damaged for unknown reasons.

[0128] In the present disclosure, the term "prevention" may refer to all actions of inhibiting or delaying the occurrence of a disease by administering the compound of formula I of the present disclosure, its optical isomer or a pharmaceutically acceptable salt thereof.

[0129] In the present disclosure, the term "treatment" may refer to all actions to improve or ameliorate the symptoms of an individual who may develop or suffer from a disease by administering the compound of formula I of the present disclosure, its optical isomer or a pharmaceutically acceptable salt thereof.

[0130] The compound represented by Formula I of the present disclosure, its optical isomer or a pharmaceutically acceptable salt thereof can be advantageously used for preventing or treating idiopathic pulmonary fibrosis.

[0131] The compound represented by Formula I of the present disclosure, its optical isomer or a pharmaceutically acceptable salt thereof as an effective ingredient can be advantageously used for preventing or treating idiopathic pulmonary fibrosis.

[0132] In this regard, in a specific embodiment of the present disclosure, it has been confirmed that the compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof of the present disclosure inhibits the expression of TGF-β1-induced fibrotic protein FN-EDA and type I collagen α1 chain precursor (proCOL1A1) ( Figure 1 ).

[0133] In addition, it has been confirmed that the compound represented by Formula I of the present disclosure, its optical isomer or a pharmaceutically acceptable salt thereof inhibits the expression of fibrotic proteins COL1A1 and αSMA, both of which are increased in mice with BLM-induced pulmonary fibrosis ( Figure 2 In addition, it has been confirmed that the compound represented by Formula I of the present disclosure, its optical isomer or a pharmaceutically acceptable salt thereof reduces the increased Ashcroft score and improves the decreased physical activity in mice with BLM-induced pulmonary fibrosis ( Figure 3 ).

[0134] The compounds represented by Formula I, their optical isomers or pharmaceutically acceptable salts thereof disclosed herein can show efficacy in preventing or treating idiopathic pulmonary fibrosis, and the extent of their effect is similar to, or substantially equivalent to, or superior to conventionally known drugs for preventing or treating idiopathic pulmonary fibrosis.

[0135] The pharmaceutical composition comprising the compound represented by Formula I of the present disclosure, its optical isomer or a pharmaceutically acceptable salt thereof as an active ingredient can show efficacy in preventing or treating idiopathic pulmonary fibrosis, and the degree of action thereof is similar to, or substantially equivalent to, or superior to conventionally known drugs for preventing or treating idiopathic pulmonary fibrosis.

[0136] In addition to the compound represented by the above formula I, its optical isomer or its pharmaceutically acceptable salt, the pharmaceutical composition according to the embodiment of the present disclosure may further include at least one pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers can be conventionally used in the art. Carriers, especially including (but not limited to) lactose, glucose (dextrose), sucrose, sorbitol, mannitol, starch, gum arabic (acacia rubber), calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, water, syrup, methylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate or mineral oil. In addition to the above ingredients, the pharmaceutical composition according to the embodiment of the present disclosure may further include lubricants, humectants, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, dispersants, stabilizers, etc. In addition, the pharmaceutical composition according to the embodiment of the present disclosure can be formulated into oral dosage forms, such as tablets, powders, granules, pills, capsules, suspensions, emulsions, internal liquids, oils, syrups, etc., and external forms, suppositories or sterile solutions for injection by using pharmaceutically acceptable carriers and excipients, and thus can be prepared in unit dosage forms or prepared by inserting into multi-dose containers. Such preparations can be prepared according to conventional methods for preparation in the art or methods disclosed in Remington's Pharmaceutical Science (19th edition, 1995), and can be formulated into a variety of preparations according to each disease or component.

[0137] Non-limiting examples of formulations for oral administration using the pharmaceutical composition of the present disclosure may include tablets, troches, lozenges, water-soluble suspensions, oil suspensions, prepared powders, granules, emulsions, hard capsules, soft capsules, syrups, elixirs, etc. In order to formulate the pharmaceutical composition according to the embodiment of the present disclosure into a formulation for oral administration, the following may be used: binders, such as lactose, sucrose, sorbitol, mannitol, starch, pullulan, cellulose, gelatin, etc.; excipients, such as dicalcium phosphate, etc.; disintegrants, such as corn starch, sweet potato starch, etc.; lubricants, such as magnesium stearate, calcium stearate, sodium stearyl fumarate, polyethylene glycol wax, etc.; etc., wherein sweeteners, flavorings, syrups, etc. may also be used. In addition, in the case of capsules, in addition to the materials mentioned above, liquid carriers, such as fatty oils, etc. may be further used.

[0138] Non-limiting examples of parenteral preparations using the pharmaceutical composition according to the embodiments of the present disclosure may include injectable solutions, suppositories, powders for respiratory inhalation, sprays for nebulization, ointments, powders for coating, oils, creams, etc. In order to formulate the pharmaceutical composition according to the embodiments of the present disclosure into a preparation for parenteral administration, the following may be used: sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, external preparations, etc. As for the non-aqueous solvents and suspensions, the following may be used (but are not limited to): propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), injectable esters (e.g., ethyl oleate), etc.

[0139] The pharmaceutical composition according to an embodiment of the present disclosure may be subjected to oral administration or parenteral administration according to the target method, preferably oral administration, but is not limited thereto.

[0140] The daily dose of the compound represented by Formula I of the present disclosure, its optical isomer or a pharmaceutically acceptable salt thereof may be specifically about 0.1 mg / kg to about 10000 mg / kg, about 1 mg / kg to about 8000 mg / kg, about 5 mg / kg to about 6000 mg / kg or about 10 mg / kg to about 4000 mg / kg, and more specifically about 50 mg / kg to about 2000 mg / kg, but is not limited thereto, and may also be administered once a day or may be administered several times a day by dividing the daily dose of the compound.

[0141] The pharmaceutically effective dose and effective dose of the pharmaceutical composition according to the embodiments of the present disclosure may vary according to the method of formulating the pharmaceutical composition, the mode of administration, the time of administration, the route of administration and / or other factors, and may be diversified according to various factors, including the type and degree of response achieved by administering the pharmaceutical composition, the type of individual to be administered, the age, weight, general health, disease symptoms or severity, sex, diet and excretion of the individual, the ingredients of other pharmaceutical compositions used for the corresponding individual at the same time or at different times, etc., as well as other similar factors well known in the pharmaceutical field, and those skilled in the art can easily determine and prescribe effective doses for the intended treatment.

[0142] The pharmaceutical composition according to the embodiment of the present disclosure can be administered once a day or several times a day. The pharmaceutical composition according to the embodiment of the present disclosure can be administered as a single therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with conventional therapeutic agents. Taking all of the above factors into account, the pharmaceutical composition according to the embodiment of the present disclosure can be administered in the following amounts: the maximum effect can be achieved with the minimum amount without side effects, and such amounts can be easily determined by a person skilled in the art of the present disclosure.

[0143] The pharmaceutical composition according to an embodiment of the present disclosure can still show excellent effects even when used alone, but can be further used in combination with various methods (eg, hormone therapy, drug therapy, etc.) to improve the treatment efficiency.

[0144] The present disclosure may provide a method for preventing or treating idiopathic pulmonary fibrosis, comprising administering to an individual a compound represented by the above Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0145] The terms "idiopathic pulmonary fibrosis", "prevention" and "treatment" may be the same as described above.

[0146] In the present disclosure, the term "administering" may refer to introducing a predetermined substance into an individual by an appropriate method.

[0147] In the present disclosure, the term "subject" may refer to all animals that have developed or may develop idiopathic pulmonary fibrosis, such as, but not limited to, rats, mice, livestock, etc., including humans, and may particularly be mammals, including humans.

[0148] The method for preventing or treating idiopathic pulmonary fibrosis according to an embodiment of the present disclosure may include administering a therapeutically effective amount of a compound represented by the above Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0149] In the present disclosure, the term "therapeutically effective amount" may refer to an amount sufficient to treat a disease at a reasonable risk / benefit ratio applicable to medical treatment without causing side effects, and may be determined by a person skilled in the art based on factors including the patient's sex, age, weight, health status, disease type, severity, drug activity, sensitivity to drugs, administration method, administration time, administration route, excretion rate, treatment period, drugs used in combination or simultaneously, and other factors well known in the pharmaceutical field. It is preferred to administer a specific therapeutically effective amount to a certain patient differently depending on various factors, including: the type and degree of response achieved thereby; a specific composition including the presence of other preparations used in some cases; the patient's age, weight, general health status, sex and diet; administration time; administration route; secretion rate of the composition; treatment period and drugs used with or simultaneously with a specific composition; and other similar factors well known in the pharmaceutical field.

[0150] The method for preventing or treating idiopathic pulmonary fibrosis according to the embodiment of the present disclosure may include not only treating the disease itself before its symptoms manifest, but also inhibiting or avoiding such symptoms by administering a compound represented by the above formula I, an isomer thereof, or a pharmaceutically acceptable salt thereof. When managing a disease, the preventive dose or therapeutic dose of a certain active ingredient may vary depending on the characteristics and severity of the disease or condition, and the route of administration of the active ingredient. Its dosage and frequency may vary depending on the age, weight, and response of individual patients. Suitable dosages and usage may be easily selected by those skilled in the art by taking such factors into consideration. In addition, the method for preventing or treating idiopathic pulmonary fibrosis according to the embodiment of the present disclosure may further include administering a therapeutically effective amount of an additional active agent (which helps prevent or treat the disease) together with a compound represented by the above formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, and the additional active agent may show a synergistic or cumulative effect together with the compound represented by the above formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0151] The present disclosure may provide use of a compound represented by the above Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof for preventing or treating idiopathic pulmonary fibrosis.

[0152] The present disclosure may provide use of a compound represented by the above formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating idiopathic pulmonary fibrosis.

[0153] The terms "idiopathic pulmonary fibrosis", "prevention" and "treatment" may be the same as described above.

[0154] For the preparation of medicaments, the compound represented by the above formula I, its optical isomer or a pharmaceutically acceptable salt thereof can be mixed with a pharmaceutically acceptable adjuvant, diluent, carrier, etc., and can be prepared into a composite preparation together with other active agents, thereby providing a synergistic effect.

[0155] If not contradictory to each other, the substances mentioned in the pharmaceutical compositions, methods of treatment and uses of the present disclosure are equally applicable.

[0156] Beneficial Effects

[0157] The compound represented by Formula I, its optical isomer or its pharmaceutically acceptable salt and the pharmaceutical composition comprising the compound represented by Formula I, its optical isomer or its pharmaceutically acceptable salt as an effective ingredient of the present disclosure can be advantageously used for preventing or treating idiopathic pulmonary fibrosis. BRIEF DESCRIPTION OF THE DRAWINGS

[0158] Figure 1 The graph shows the expression levels of fibrosis proteins (FN-EDA and proCOL1A1) in each group. (*p<0.05, **p<0.01, ***p<0.001)

[0159] Figure 2 The graph shows the expression levels of fibrosis proteins (COL1A1 and α-SMA) in each group. (**p<0.01, ***p<0.001)

[0160] Figure 3 A graph showing the Ashcroft score and treadmill test assessment results (physical activity) in each group. (###p<0.001, *p<0.05) DETAILED DESCRIPTION

[0161] The present disclosure will be described in detail with reference to the following embodiments. However, the purpose of the embodiments is only to illustrate the present disclosure, and it is obvious to those skilled in the art that the scope of the present disclosure is not limited to the embodiments disclosed below.

[0162] Synthesis Example 1. Compound 40, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)- Synthesis of N-phenylthiomorpholine-4-carboxamide 1,1-dioxide

[0163] [Step 1] Synthesis of N-phenylthiomorpholine-4-carboxamide 1,1-dioxide

[0164]

[0165] Triphosgene (4.780 g, 16.107 mmol) was added to a solution of aniline (3.000 g, 32.213 mmol) and N,N-diisopropylethylamine (33.439 mL, 193.278 mmol) dissolved in dichloromethane (100 mL) at 0°C and stirred at the same temperature. Thiomorpholine 1,1-dioxide (4.790 g, 35.434 mmol) was added to the reaction mixture and stirred for another 16 hours at room temperature. Subsequently, water was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried (anhydrous MgSO 4 ), filtered and concentrated in vacuo. The concentrate was purified by column chromatography (SiO 2 , 40 g cartridge; methanol / dichloromethane = 2%) and concentrated to give the title compound (1.325 g, 16.2%) as a yellow solid.

[0166] [Step 2] Synthesis of methyl 4-((1,1-dioxy-N-phenylthiomorpholine-4-carboxamide)methyl)-3-fluorobenzoate

[0167]

[0168] Methyl 4-(bromomethyl)-3-fluorobenzoate (1.020 g, 4.129 mmol) was added to a solution of N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (1.000 g, 3.932 mmol) prepared in step 1 and sodium hydride (60.00%, 0.189 g, 4.719 mmol) dissolved in N,N-dimethylformamide (30 mL) at 0°C, and stirred at room temperature for 18 hours. Subsequently, a saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried (anhydrous MgSO 4 ), filtered and concentrated in vacuo. The concentrate was purified by column chromatography (SiO 2 , 40 g cartridge; ethyl acetate / hexanes=0% to 50%) and concentrated to give the title compound (1.240 g, 75.0%) as a white solid.

[0169] [Step 3] Synthesis of N-(2-fluoro-4-(hydrazinecarbonyl)benzyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide

[0170]

[0171] A solution of methyl 4-((1,1-dioxido-N-phenylthiomorpholine-4-carboxamide)methyl)-3-fluorobenzoate (1.240 g, 2.949 mmol) prepared in step 2 and hydrazine monohydrate (2.786 mL, 58.983 mmol) dissolved in ethanol (15 mL) was stirred at 120° C. for 1 hour and cooled to room temperature to terminate the reaction. The reaction mixture was concentrated in vacuo to remove the solvent, and saturated aqueous sodium bicarbonate solution was poured into the concentrate, followed by extraction with dichloromethane. The biphasic mixture was passed through a plastic filter to remove the solid residue and the aqueous layer, and the collected organic layer was concentrated in vacuo. The crude title compound (1.240 g, 100.0%, white solid) was used without further purification.

[0172] [Step 4] Synthesis of N-(4-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)-2-fluorobenzyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide

[0173]

[0174] 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) prepared in step 3 dissolved in dichloromethane (10 mL) was stirred at the same temperature for 18 hours. Subsequently, a saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried (anhydrous MgSO 4 ), filtered and concentrated in vacuo. The concentrate was purified by column chromatography (SiO 2 , 24 g cartridge; methanol / dichloromethane = 0% to 3%) and concentrated to give the title compound (0.462 g, 63.4%) as a white solid.

[0175] [Step 5] Synthesis of Compound 40

[0176]

[0177] 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-triethylammoniumsulfonyl-carboximidate (Burgess reagent, 0.331 g, 1.390 mmol) were mixed in tetrahydrofuran (10 mL) and heated at 150 ° C. for 30 minutes under microwave, and then cooled to room temperature to terminate the reaction. Subsequently, saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The biphasic mixture was passed through a plastic filter to remove the solid residue and the aqueous layer, and the collected organic layer was concentrated in vacuo. The concentrate was purified by column chromatography (SiO 2 , 12 g cartridge; ethyl acetate / hexanes = 0% to 50%) and concentrated to give the title compound (0.337 g, 75.7%) as a white solid.

[0178] 1 H NMR (400 MHz, CDCl 3 )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,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).

[0179] Synthesis Example 2. Compound 43, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl Synthesis of (4-(2-(2-phenylthiomorpholine)-4-carboxamide 1,1-dioxide

[0180] [Step 1] Synthesis of 6-((1,1-dioxido-N-phenylthiomorpholine-4-carboxamido)methyl)nicotinate

[0181]

[0182] A solution of N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (1.000 g, 3.932 mmol) prepared in Step 1 of Synthesis Example 1 and sodium hydride (60.00%, 0.157 g, 3.932 mmol) dissolved 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 to the solution and stirred for another 2 hours at room temperature. The reaction mixture was concentrated in vacuo to remove the solvent, and water was poured into the concentrate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried (anhydrous MgSO 4 ), filtered and concentrated in vacuo. The crude product was crystallized using methanol (20 mL) at room temperature and filtered. The resulting precipitate was washed with methanol and dried to give the title compound (0.816 g, 51.4%) as a brown solid.

[0183] [Step 2] Synthesis of N-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide

[0184]

[0185] The 6-((1,1-dioxido-N-phenylthiomorpholine-4-carboxamido)methyl)nicotinate (0.816 g, 2.023 mmol) prepared in step 1 and hydrazine monohydrate (1.910 mL, 40.451 mmol) were mixed in ethanol (10 mL) at room temperature and heated at 100 ° C. for 1 hour under microwave and then cooled to room temperature to terminate the reaction. The reaction mixture was concentrated in vacuo to remove the solvent. The crude product was crystallized and filtered using dichloromethane (20 mL) at room temperature. The resulting precipitate was washed with dichloromethane and dried to give the title compound (0.560 g, 68.6%) as a light brown solid.

[0186] [Step 3] Synthesis of N-((5-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide

[0187]

[0188] Difluoroacetic anhydride (0.087 mL, 0.580 mmol) was added to a solution of N-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (0.260 g, 0.644 mmol) and triethylamine (0.178 mL, 1.289 mmol) prepared in step 2 in dichloromethane (2 mL) at room temperature and stirred for 16 hours at the same temperature. Subsequently, water was poured into the reaction mixture, followed by extraction with dichloromethane. The biphasic mixture was passed through a plastic filter to remove the solid residue and the aqueous layer, and the collected organic layer was concentrated in vacuo. The concentrate was purified by column chromatography (SiO 2 , 4 g cartridge; methanol / dichloromethane = 0% to 5%) and concentrated to give the title compound (0.156 g, 50.3%) as a white foam.

[0189] [Step 4] Synthesis of compound 43

[0190]

[0191] 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-triethylammoniumsulfonyl-carboximidate (Burgess reagent, 0.116 g, 0.486 mmol) were mixed in tetrahydrofuran (2 mL) and heated at 150 ° C. for 30 minutes under microwave, and then cooled to room temperature to terminate the reaction. Subsequently, water was poured into the reaction mixture, followed by extraction with dichloromethane. The biphasic mixture was passed through a plastic filter to remove the solid residue and the aqueous layer, and the collected organic layer was concentrated in vacuo. The concentrate was purified by column chromatography (SiO 2 , 4 g cartridge; methanol / dichloromethane = 3%) and concentrated to give the title compound (0.078 g, 51.9%) as a colorless oil.

[0192] 1 H NMR (400 MHz, CDCl 3 )δ9.23(d,1H,J=2.2Hz),8.38(dd,1H,J=8.2,2.2Hz),7.54(d,1H,J=8.2Hz),7.41-7.31(m,2H),7.19(ddd,3H ,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 / z 464.2(M + +1).

[0193] Synthesis Example 3. Compound 232, N-(3-chloro-4-fluorophenyl)-N-((5-(5-difluoromethyl)-1,3,4-oxadiazole Synthesis of (4-(2-oxazol-2-yl)pyridin-2-yl)methyl)morpholine-4-carboxamide

[0194] [Step 1] Synthesis of N-(3-chloro-4-fluorophenyl)morpholine-4-carboxamide

[0195]

[0196] Morpholine (0.311 mL, 3.607 mmol) was added to a solution of 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) dissolved in acetonitrile (10 mL) at room temperature, and stirred at the same temperature for 18 hours. Subsequently, water was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried (anhydrous MgSO 4 ), filtered and concentrated in vacuo. The concentrate was purified by column chromatography (SiO 2 , 12 g cartridge; methanol / dichloromethane = 0% to 5%) and concentrated to give the title compound (0.200 g, 22.5%) as a purple solid.

[0197] [Step 2] Synthesis of 6-((N-(3-chloro-4-fluorophenyl)morpholine-4-carboxamido)methyl)nicotinate

[0198]

[0199] Sodium hydride (60.00%, 0.037 g, 0.928 mmol) was added to a solution of N-(3-chloro-4-fluorophenyl)morpholine-4-carboxamide (0.200 g, 0.773 mmol) prepared in step 1 dissolved in N,N-dimethylacrylamide (5 mL) at 0°C and stirred at the same temperature. Methyl 6-(bromomethyl)nicotinate (0.196 g, 0.850 mmol) was added to the reaction mixture and stirred for another 3 hours at room temperature. Subsequently, water was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried (anhydrous MgSO 4 ), filtered and concentrated in vacuo. The concentrate was purified by column chromatography (SiO 2 , 4 g cartridge; ethyl acetate / hexanes=0% to 70%) and concentrated to give the title compound (0.110 g, 34.9%) as a brown solid.

[0200] [Step 3] Synthesis of N-(3-chloro-4-fluorophenyl)-N-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)morpholine-4-carboxamide

[0201]

[0202] The 6-((N-(3-chloro-4-fluorophenyl)morpholine-4-carboxamido)methyl)nicotinate (0.110 g, 0.270 mmol) prepared in step 2 and hydrazine monohydrate (0.262 mL, 5.394 mmol) were mixed in ethanol (5 mL) at room temperature and heated under reflux for 18 hours, and then cooled to room temperature. Subsequently, water was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried (anhydrous MgSO 4 ), filtered and concentrated in vacuo. The crude title compound (0.110 g, 100.0%, light yellow solid) was used without further purification.

[0203] [Step 4] Synthesis of compound 232

[0204]

[0205] 2,2-Difluoroacetic anhydride (0.059 mL, 0.539 mmol) was added to a solution of 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) prepared in step 3 in dichloromethane (3 mL) at 0 ° C. and stirred at room temperature for 16 hours. Subsequently, saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The biphasic mixture was passed through a plastic filter to remove the solid residue and the aqueous layer, and the collected organic layer was concentrated in vacuo. The concentrate was purified by column chromatography (SiO 2 , 4 g cartridge; methanol / dichloromethane = 0% to 5%) and concentrated to give the title compound (0.057 g, 45.2%) as a yellow solid.

[0206] 1 H NMR (400 MHz, CDCl 3 )δ9.24-9.24(m,1H),8.36(dd,1H,J=8.2,2.2Hz),7.59(dd,1H,J=8.2,0.8Hz),7.30-7.28(m,1H),7.10 -7.08(m,2H),6.93(t,1H,J=51.6Hz),5.05(s,2H),3.54-3.52(m,4H),3.27-3.26(m,4H).;LRMS(ES)m / z 468.2(M + +1).

[0207] Synthesis Example 4. Compound 285, N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzyl)- Synthesis of N-(4-Fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide

[0208] [Step 1] Synthesis of N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide

[0209]

[0210] A solution of 1-fluoro-4-phenylisocyanate (0.500 g, 3.647 mmol) dissolved in diethyl ether (10 mL) was mixed with thiomorpholine 1,1-dioxide (0.493 g, 3.647 mmol) at 0°C and stirred at the same temperature for 1 hour. The reaction mixture was stirred at room temperature for another 4 hours. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound (0.920 g, 92.7%) as a white solid.

[0211] [Step 2] Synthesis of methyl 3-fluoro-4-((N-(4-fluorophenyl)-1,1-dioxythiomorpholine-4-carboxamido)methyl)benzoate

[0212]

[0213] A solution of 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) prepared in step 1 was dissolved in N,N-dimethylformamide (5 mL) at 0 ° C for 2 hours. Methyl 4-(bromomethyl)-3-fluorobenzoate (0.299 g, 1.212 mmol) was added to the solution and stirred for another 17 hours at room temperature. The reaction was terminated by adding water (2 mL) to the reaction mixture and stirring for 10 minutes at room temperature. Subsequently, water was poured into the reaction mixture and then extracted with dichloromethane. The biphasic mixture was passed through a plastic filter to remove the solid residue and the water layer, and the collected organic layer was concentrated in vacuo. The crude product was crystallized and filtered using dichloromethane (3 mL) at room temperature. The resulting precipitate was washed by dichloromethane and dried to give the title compound (0.212 g, 43.9%) as a white solid.

[0214] [Step 3] Synthesis of N-(2-fluoro-4-(hydrazinecarbonyl)benzyl)-N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide

[0215]

[0216] The 3-fluoro-4-((N-(4-fluorophenyl)-1,1-dioxidothiomorpholine-4-carboxamido)methyl)benzoic acid methyl ester (0.212 g, 0.484 mmol) prepared in step 2 was mixed with hydrazine monohydrate (0.470 mL, 9.670 mmol) in ethanol (4 mL) at room temperature and heated at 120 ° C for 1 hour under microwave, and then cooled to room temperature to terminate the reaction. The reaction mixture was concentrated in vacuo to remove the solvent. Subsequently, water was poured into the reaction mixture and then extracted with dichloromethane. The biphasic mixture was passed through a plastic filter to remove the solid residue and the aqueous layer, and the collected organic layer was concentrated in vacuo. Diethyl ether (5 mL) and ethyl acetate (1 mL) were added to the concentrate and stirred. The precipitate was collected by filtration, washed with hexane and dried to give the title compound (0.179 g, 84.4%) as a white solid.

[0217] [Step 4] Synthesis of compound 285

[0218]

[0219] 2,2-Difluoroacetic anhydride (0.028mL, 0.228mmol) was added to a solution of N-(2-fluoro-4-(hydrazinecarbonyl)benzyl)-N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.100g, 0.228mmol) and triethylamine (0.095mL, 0.684mmol) prepared in step 3 in dichloromethane (4mL) at room temperature and stirred for 17 hours at the same temperature. Subsequently, saturated aqueous sodium bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The biphasic mixture was passed through a plastic filter to remove the solid residue and the aqueous layer, and the collected organic layer was concentrated in vacuo. The concentrate was purified by column chromatography (SiO 2 , 4 g cartridge; ethyl acetate / hexanes = 20% to 50%) and concentrated to give the title compound (0.053 g, 46.6%) as a white solid.

[0220] 1 H NMR (400 MHz, CDCl 3 )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 / z 499.3(M + +1).

[0221] Synthesis Example 5. Compound 295, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl) Synthesis of (4-(4-fluorophenyl)thiomorpholinecarboxamide 1,1-dioxide

[0222] [Step 1] Synthesis of 6-((N-(4-fluorophenyl)-1,1-dioxythiomorpholine-4-carboxamido)methyl)nicotinate

[0223]

[0224] 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. 6-(Bromomethyl)nicotinate (0.465 g, 2.020 mmol) was added to the solution and stirred for another 5 hours at room temperature. The reaction was terminated by adding water (5 mL) to the reaction mixture and stirring for 10 minutes at room temperature. Subsequently, water was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried (anhydrous MgSO 4 ), filtered and concentrated in vacuo. The crude title compound (0.450 g, 58.1%, brown solid) was used without further purification.

[0225] [Step 2] Synthesis of N-(4-fluorophenyl)-N-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)thiomorpholine-4-carboxamide 1,1-dioxide

[0226]

[0227] A solution of methyl 6-((N-(4-fluorophenyl)-1,1-dioxythiomorpholine-4-carboxamido)methyl)nicotinate (0.150 g, 0.356 mmol) and hydrazine monohydrate (0.346 mL, 7.118 mmol) prepared in step 1 in ethanol (5 mL) was stirred at 100° C. for 17 hours, and then cooled to room temperature to terminate the reaction. The precipitate was collected by filtration, washed with ethanol and dried to give the title compound (0.111 g, 74.0%) as a pale yellow solid.

[0228] [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

[0229]

[0230] 2,2-Difluoroacetic anhydride (0.065 mL, 0.527 mmol) was added 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) and triethylamine (0.110 mL, 0.790 mmol) prepared in step 2 in dichloromethane (5 mL) at room temperature and stirred at the same temperature for 1 hour. Subsequently, water was poured into the reaction mixture, followed by extraction with dichloromethane. The biphasic mixture was passed through a plastic filter to remove the solid residue and the aqueous layer, and the collected organic layer was concentrated in vacuo. The crude title compound (0.082 g, 62.3%, yellow solid) was used without further purification.

[0231] [Step 4] Synthesis of compound 295

[0232]

[0233] A solution of N-((5-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)pyridin-2-yl)methyl)-N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.082 g, 0.164 mmol) and 1-methoxy-triethylammoniumsulfonyl-carboximidate (Burgess reagent, 0.117 g, 0.493 mmol) prepared in step 3 dissolved in tetrahydrofuran (5 mL) was stirred at 70° C. for 5 hours, and then cooled to room temperature to terminate the reaction. The reaction mixture was passed through a paper filter to remove solids, and the filtrate was concentrated in vacuo to remove the solvent. The concentrate was purified by column chromatography (SiO 2 , 4 g cartridge; methanol / dichloromethane / = 0% to 10%) and concentrated to give the title compound (0.015 g, 19.0%) as a white solid.

[0234] 1 H NMR (400 MHz, CDCl 3 )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).

[0235] Synthesis Example 6. Compound 296, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl) Synthesis of (4-(3-fluorophenyl)thiomorpholinecarboxamide)-1,1-dioxide

[0236] [Step 1] Synthesis of N-(3-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide

[0237]

[0238] Thiomorpholine 1,1-dioxide (0.493 g, 3.647 mmol) was added to a solution of 1-fluoro-3-phenylisocyanate (0.500 g. 3.647 mmol) dissolved in diethyl ether (10 mL) at 0°C and stirred at the same temperature for 1 hour. The reaction mixture was stirred at room temperature for another 4 hours. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound (0.870 g, 87.6%) as a white solid.

[0239] [Step 2] Synthesis of 6-((N-(3-fluorophenyl)-1,1-dioxythiomorpholine-4-carboxamido)methyl)nicotinate

[0240]

[0241] A 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. 6-(bromomethyl)nicotinate (0.465 g, 2.020 mmol) was added to the solution and stirred for another 5 hours at room temperature. The reaction was terminated by adding water (5 mL) to the reaction mixture at room temperature and stirring for 10 minutes. Subsequently, water was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried (anhydrous MgSO 4 ), filtered and concentrated in vacuo. The crude title compound (0.450 g, 58.1%, brown solid) was used without further purification.

[0242] [Step 3] Synthesis of N-(3-fluorophenyl)-N-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)thiomorpholine-4-carboxamide 1,1-dioxide

[0243]

[0244] A solution of methyl 6-((N-(3-fluorophenyl)-1,1-dioxythiomorpholine-4-carboxamido)methyl)nicotinate (0.150 g, 0.356 mmol) and hydrazine monohydrate (0.346 mL, 7.118 mmol) prepared in step 2 was dissolved in ethanol (5 mL) and stirred for 17 hours at 100° C., and then cooled to room temperature to terminate the reaction. The precipitate was collected by filtration, washed with ethanol and dried to give the title compound (0.113 g, 75.3%) as a pale yellow solid.

[0245] [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

[0246]

[0247] 2,2-Difluoroacetic anhydride (0.067 mL, 0.536 mmol) was added to a solution of N-(3-fluorophenyl)-N-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.113 g, 0.268 mmol) and triethylamine (0.112 mL, 0.804 mmol) prepared in step 3 in dichloromethane (5 mL) at room temperature and stirred at the same temperature for 1 hour. Subsequently, water was poured into the reaction mixture, followed by extraction with dichloromethane. The biphasic mixture was passed through a plastic filter to remove the solid residue and the aqueous layer, and the collected organic layer was concentrated in vacuo. The crude title compound (0.090 g, 67.2%, yellow solid) was used without further purification.

[0248] [Step 5] Synthesis of Compound 296

[0249]

[0250] A solution of N-((5-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)pyridin-2-yl)methyl)-N-(3-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.090 g, 0.180 mmol) prepared in step 4 and 1-methoxy-triethylammoniumsulfonyl-carboximidate (Burgess reagent, 0.129 g, 0.541 mmol) dissolved in tetrahydrofuran (5 mL) was stirred at 70° C. for 5 hours and then cooled to room temperature to terminate the reaction. The reaction mixture was passed through a paper filter to remove solids, and the filtrate was concentrated in vacuo to remove the solvent. The concentrate was purified by column chromatography (SiO 2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to give the title compound (0.044 g, 50.7%) as a white solid.

[0251] 1 H NMR (400 MHz, CDCl 3 )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).

[0252] <Example 1> Effect of inhibiting the expression of fibrosis proteins

[0253] In order to confirm the effect of the compounds according to the present disclosure in preventing or treating idiopathic pulmonary fibrosis, the expression of fibrosis proteins was analyzed.

[0254] A549 cells (alveolar epithelial cell line) were plated in 6-well plates at 1×10 5 Cells / well were seeded and incubated in CO 2 Incubator (37°C, 5% CO 2 ) for 24 hours. Then, for serum starvation, the medium was replaced with RPMI1690 (1% FBS, 1% P / S) medium and incubated at 4 °C for 24 hours. 2 Incubator (37°C, 5% CO 2 ) for 24 hours. After serum starvation, 10 μM test substances (compounds 40, 43, 239, 285, 295, and 296) were treated with 5 ng / mL of TGF-β1 and cultured in CO 2 Incubator (37°C, 5% CO 2 ) for 48 hours. A medium containing 0.1% DMSO was added to the control group. The expression of fibrotic proteins (FN-EDA, proCOL1A1) in the fully cultured cells was compared by western blot.

[0255] The cells were lysed in 100 μL RIPA buffer (containing protease and phosphatase inhibitors) and incubated on ice for 30 minutes. The resulting product was centrifuged at 13,000 g, 4 ° C for 20 minutes. The supernatant was separated and quantified using a BCA protein analysis kit. Subsequently, NuPAGE sample reducing agent and NuPAGE LDS sample buffer (4 ×) were added to prepare a sample with a concentration of 0.5 μg / μL. The prepared sample was boiled at 100 ° C for five minutes to denature the protein. After loading onto NuPAGE Novex 4% to 12% Bis-Tris gel, 5 μg of protein was separated at 120V and transferred to nitrocellulose (NC) membrane by iBlot 2 dry blotting system. Subsequently, the membrane was blocked for 30 minutes at room temperature with a blocking solution (EzBlock Chemi: distilled water = 1: 4). The membrane was reacted with a primary antibody at 4 ° C overnight, and then washed three times with 1 × TBST, each time for 10 minutes. Subsequently, the resulting product was reacted with a secondary antibody linked to horseradish peroxidase (HRP) at room temperature for one hour and washed three times with 1×TBST for 10 minutes each. The primary and secondary antibodies were diluted in a solution of blocking solution and 1×TBST mixed at a ratio of 1:4. Subsequently, the primary and secondary antibodies were washed with Amersham TM ECL select TM Western blotting detection reagents and ChemiDoc TM Proteins were visualized using the MP imaging system. The observed proteins were quantified using Image Lab 5.0 software and subsequently corrected using β-actin levels.

[0256] 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 P < 0.05 was considered statistically significant.

[0257] Therefore, if Figure 1 As shown in , it was demonstrated that the expression of FN-EDA and proCOL1A1 induced by TGF-β1 was significantly inhibited upon treatment with the compounds of the present disclosure.

[0258] Therefore, it can be found that the compounds of the present disclosure show an effect of inhibiting the expression of fibrotic proteins, and thus can be advantageously used for preventing or treating idiopathic pulmonary fibrosis.

[0259] <Example 2> Preventive or therapeutic effects in an animal model of BLM-induced pulmonary fibrosis

[0260] To confirm the effects of the compounds according to the present disclosure in preventing or treating idiopathic pulmonary fibrosis, the expression of fibrotic proteins was analyzed in an animal model with BLM-induced pulmonary fibrosis.

[0261] Pulmonary fibrosis was induced in 8-week-old C57BL / 6 mice by a single intratracheal administration of bleomycin (BLM, 0.3 U / mouse). In the case of the prevention model, the test substance was administered from the day after BLM administration and repeated twice a day for three weeks, while in the case of the treatment model, the test substance was administered from the 7th day of BLM administration and repeated twice a day for two weeks. Mice with BLM-induced pulmonary fibrosis were grouped according to the administered substance [vehicle (Veh) or compound 43 (43)], administration route [oral administration (PO)] and administration interval [twice a day (BID)] as shown in Table 1 below.

[0262] [Table 1]

[0263]

[0264] On the 21st day, the treadmill test was used to compare the motor capacity of the animals. For the treadmill test, the assessment was performed on the 3rd day after the two-day training period. On the first day of training, each animal was trained at 5rpm for 0 to 1 minute and at 10rpm for 1 to 2 minutes, for a total of 2 minutes. On the second day of training, each animal was trained at 5rpm for 0 to 1 minute, at 10rpm for 1 to 2 minutes, and at 15rpm for 2 to 3 minutes, for a total of 3 minutes. On the third day, the treadmill was set at 5rpm for 0 to 1 minute, at 10rpm for 1 to 2 minutes, at 15rpm for 2 to 3 minutes, and at 20rpm for 3 to 4 minutes, for a total of 4 minutes, and was assessed. During the assessment, if the animal exited the treadmill 10 or more times due to decreased vitality, it was determined that it could not be assessed and was therefore excluded.

[0265] On day 21, animals were anesthetized and bled, lungs were removed, and the expression of fibrotic proteins (COL1A1, α-SMA) was compared using western blot and histological analysis.

[0266] For Western blot, lung tissue was lysed in RIPA buffer (containing protease and phosphatase inhibitors) and incubated on ice for 30 minutes. The resulting product was centrifuged at 13000g, 4°C for 20 minutes. The supernatant was separated and quantified using a BCA protein assay kit. Subsequently, NuPAGE sample reducing agent and NuPAGE LDS sample buffer (4X) were added to prepare a sample with a concentration of 0.5 μg / μL. The prepared sample was boiled at 100°C for five minutes to denature the protein. After loading onto NuPAGE Novex 4% to 12% Bis-Tris gel, 5 μg of protein was separated at 120V and transferred to a nitrocellulose (NC) membrane by an iBlot 2 dry blotting system. Subsequently, the membrane was blocked for 30 minutes at room temperature with a blocking solution (EzBlock Chemi: distilled water = 1:4). The membrane was reacted with a primary antibody at 4°C overnight, and then washed three times with 1×TBST for 10 minutes each. Subsequently, the resulting product was reacted with a secondary antibody linked to horseradish peroxidase (HRP) at room temperature for one hour and washed three times with 1×TBST for 10 minutes each. The primary and secondary antibodies were diluted in a solution of blocking solution and 1×TBST mixed at a ratio of 1:4. Subsequently, the primary and secondary antibodies were washed with Amersham TM ECL select TM Western blotting detection reagents and ChemiDoc TM Proteins were visualized using the MP imaging system. The observed proteins were quantified using Image Lab 5.0 software and subsequently corrected using β-actin levels.

[0267] For histological analysis, lung tissue fixed in 10% neutral buffered formalin solution was cut, dehydrated and paraffin infiltrated, and then transversely embedded in paraffin to form blocks. Paraffin blocks were cut into 3 μm to prepare tissue sections, and hematoxylin and eosin (H&E) staining was performed for morphological evaluation of tissues. The degree of fibrosis in lung tissue was semi-quantitatively determined based on the modified Ashcroft scale system (Biotechniques. 2008; 44 (4): 507-11, 514-7. Table 2).

[0268] One-tailed unpaired t-test (post hoc: Mann-Whitney) or one-way ANOVA (post hoc: Dunnett's multiple comparison test) was performed by using GraphPad Prism 9.3.0 software. All data are expressed as mean ± SEM, and P < 0.05 was considered statistically significant.

[0269] Therefore, if Figure 2As shown, it was confirmed that when treated with the compounds of the present disclosure, the expression of COL1A1 and α-SMA in the lung tissue of mice was significantly inhibited in the case of the prevention model of BLM-induced pulmonary fibrosis.

[0270] In addition, if Figure 3 As shown, it has been demonstrated that Ashcroft scores were significantly reduced and physical activity was improved in mice in the treatment model of BLM-induced pulmonary fibrosis when treated with the compounds of the present disclosure.

[0271] Therefore, it can be seen that the compounds of the present disclosure show the effects of inhibiting the expression of fibrotic proteins, reducing lung fibrosis, and improving exercise capacity, and thus can be advantageously used for preventing or treating idiopathic pulmonary fibrosis.

[0272] The present disclosure provides the following pharmaceutical compositions, methods and uses:

[0273] Item 1. A pharmaceutical composition for preventing or treating idiopathic pulmonary fibrosis, comprising as an effective ingredient a compound represented by the above-mentioned formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0274] Item 2. The pharmaceutical composition according to Item 1, wherein the compound represented by the above-mentioned Formula I is at least one selected from the above-mentioned Compounds 1 to 450 described in the above-mentioned Table.

[0275] Item 3. The pharmaceutical composition according to Item 1 or Item 2, wherein the compound represented by Formula I mentioned above is at least one selected from Compound 40, Compound 43, Compound 239, Compound 285, Compound 295 and Compound 296, which are described in the table mentioned above.

[0276] Item 4. A method for preventing or treating idiopathic pulmonary fibrosis, comprising administering to an individual a compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as described in any one of Items 1 to 3.

[0277] Item 5. Use of the compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as described in any one of Items 1 to 3 for preventing or treating idiopathic pulmonary fibrosis.

[0278] Item 6. Use of the compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as described in any one of Items 1 to 3 in the preparation of a medicament for preventing or treating idiopathic pulmonary fibrosis.

[0279] Item 7. The pharmaceutical composition according to any one of Items 1 to 3, wherein the pharmaceutical composition is for oral administration.

[0280] Item 8. The method according to Item 4 or the use according to Item 5 or Item 6, wherein the compound represented by Formula I as described in any one of Items 1 to 3, its optical isomer or a pharmaceutically acceptable salt thereof is administered orally.

[0281] Although specific parts of the present disclosure have been described in detail above, it is obvious to those skilled in the art that such detailed description is only for illustrating exemplary embodiments and should not be interpreted as limiting the scope of the present disclosure. Therefore, it should be understood that the essential scope of the present disclosure is defined by the appended claims and their equivalents.

Claims

1. A pharmaceutical composition for preventing or treating idiopathic pulmonary fibrosis, comprising as an active ingredient a compound represented by the following formula I, an optical isomer thereof or a pharmaceutically acceptable salt thereof: [Formula I] In Formula I, wherein L1, L2 and L3 are each independently a bond or -(C1-C2 alkylene)-; R1 is -CX2H or -CX3; R2 is -NR A R B 、-OR C , {in At least one H in each of the above may be independently substituted by: -X, -OH, -O(C1-C4 alkyl), -NR D R E , -(C1-C4 alkyl), -CF3, -CF2H, -CN, -aryl, -heteroaryl, -(C1-C4 alkyl)-aryl or -(C1-C4 alkyl)-heteroaryl, [wherein at least one H in 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 cycloheteroalkyl), -aryl, -heteroaryl, -adamantyl, {wherein at least one H in -(C1-C4 alkyl) may be independently substituted by -X or -OH, At least one H in the -aryl or -heteroaryl group may be independently substituted by -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, [in At least one H in can be independently -X, -(C1-C4 alkyl), -NR D R E , -CF3 or -CF2H substituted], -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl), adamantyl, At least one H in each of the above may be independently substituted by -X, -OH or -(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 at least three of Z1 to Z4 cannot be N at the same time, and R Z is -H or -X or -O(C1-C4 alkyl)}; Z5 and Z6 are each independently -CH2- or -O-; Z7 and Z8 are each independently =CH- or =N-; Z9-NR G -or-S-; R A and R B Each is independently -H, -(C1-C4 alkyl), -(C1-C4 alkyl)-OH, -(C1-C4 alkyl)-NR D R E , -aryl, -(C1-C4 alkyl)-aryl, -heteroaryl, -(C1-C4 alkyl)-heteroaryl, -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl) or {wherein the -(C1-C4 alkyl), -(C1-C4 alkyl)-OH or -(C1-C4 alkyl)-NR D R E At least one H in each of the above may be independently substituted by -X, At least one H in the -aryl, -(C1-C4 alkyl)-aryl, -heteroaryl, -(C1-C4 alkyl)-heteroaryl, -(C3-C7 cycloalkyl) or -(C2-C6 heterocycloalkyl) group may be independently substituted by -X, -OH, -O(C1-C4 alkyl), -(C1-C4 alkyl), -CF3, -CF2H or -CN. At least one H in each of the above may be independently substituted by: -X, -OH, -O(C1-C4 alkyl), -(C1-C4 alkyl), -CF3, -CF2H, -CN, -(C2-C6 heterocycloalkyl), -aryl, -(C1-C4 alkyl)-aryl, -heteroaryl or -heteroaryl-(C1-C4 alkyl)}; R C is -(C1-C4 alkyl), -aryl, -(C1-C4 alkyl)-aryl, -heteroaryl or -(C1-C4 alkyl)-heteroaryl {wherein at least one H in -(C1-C4 alkyl) may be independently substituted by -X or -OH, and at least one H in -aryl, -(C1-C4 alkyl)-aryl, -heteroaryl or -(C1-C4 alkyl)-heteroaryl may be independently substituted by -X, -OH, -CF3 or -CF2H}; R D and R E Each is independently -H, -(C1-C4 alkyl), -aryl or -(C1-C4 alkyl)-aryl {wherein at least one H in -(C1-C4 alkyl) may be independently substituted by -X or -OH, and at least one H in -aryl or -(C1-C4 alkyl)-aryl may be independently substituted by -X, -OH, -CF3 or -CF2H}; R F -H, -(C1-C6 alkyl), -(C1-C4 alkyl)-OH, -(C1-C4 alkyl)-O-(C1-C4 alkyl), -C(=O)-(C1-C4 alkyl), -C(=O)-O(C1-C4 alkyl), -(C1-C4 alkyl)-C(=O)-O(C1-C4 alkyl), -(C1-C4 alkyl)-NR D R E , -S(=O)2-(C1-C4 alkyl), -aryl, -(C1-C4 alkyl)-aryl, -(C2-C4 alkenyl)-aryl, -heteroaryl, -(C1-C4 alkyl)-heteroaryl, -C(=O)-(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl) or -(C1-C4 alkyl)-C(=O)-(C2-C6 heterocycloalkyl) {wherein -(C1-C4 alkyl), -(C1-C4 alkyl)-OH, -(C1-C4 alkyl)-O-(C1-C4 alkyl), -C(=O)-(C1-C4 alkyl), -C(=O)-O(C1-C4 alkyl), -(C1-C4 alkyl)-C(=O)-O(C1-C4 alkyl), -(C1-C4 alkyl)-NR D R E or at least one H in -S(=O)2-(C1-C4 alkyl) may be independently substituted by -X, -aryl, -(C1-C4 alkyl)-aryl, -(C2-C4 alkenyl)-aryl, -heteroaryl, -(C1-C4 alkyl)-heteroaryl, -C(═O)-(C3-C7 cycloalkyl), -C2-C6 heterocycloalkyl or -(C1-C4 alkyl)-C(═O)-(C2-C6 heterocycloalkyl), at least one H in each of which may be independently substituted by -X, -OH, -CF3 or -CF2H}; R G is -H or -(C1-C4 alkyl); Q is -O- or a bond; is a single bond or a double bond {the restriction condition is that when When it is a double bond, Y1 is =CH-}; a to e are each independently an integer of 0, 1, 2, 3 or 4 {with the restriction that a and b cannot be 0 at the same time, and c and d cannot be 0 at the same time}; Each X is independently F, Cl, Br or I.

2. The pharmaceutical composition according to claim 1, wherein in the compound represented by the above formula I, L1, L2 and L3 are each independently a bond or -(C1-C2 alkylene)-; R1 is -CX2H or -CX3; R2 is -NR A R B 、-OR C , {in At least one of the H can be independently -X, -OH, -NR D R E or -(C1-C4 alkyl) substituted}; R3 is -(C1-C4 alkyl), -(C3-C7 cycloalkyl), -aryl, -heteroaryl, -adamantyl, {wherein at least one H in -aryl or -heteroaryl may be independently substituted by: -X, -O(C1-C4 alkyl), -OCF3, -O-aryl, -NR D R E , -(C1-C4 alkyl), -CF3, -S(=O)2-(C1-C4 alkyl), -aryl, -heteroaryl, [in At least one H in each of the above may be independently -NR D R E or -(C1-C4 alkyl) substituted], At least one H in each of the above may be independently substituted by -(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 {At least three of Z1 to Z4 cannot be N at the same time, and R Z is -H, -X or -O(C1-C4 alkyl)}; Z5 and Z6 are each independently -CH2- or -O-; Z7 and Z8 are each independently =CH- or =N-; Z9-NR G -or-S-; R A and R B Each independently represents H, -(C1-C4 alkyl), -(C1-C4 alkyl)-OH, -(C1-C4 alkyl)-NR D R E , -aryl, -(C1-C4alkyl)-aryl, -(C3-C7cycloalkyl) or {in At least one H in each of the above may be independently substituted by: -X, -(C1-C4 alkyl), -CF3, -(C2-C6 heterocycloalkyl), -(C1-C4 alkyl)-aryl, -heteroaryl or -heteroaryl-(C1-C4 alkyl)}; R C is -(C1-C4 alkyl) or -aryl; R D and R E Each is independently -H, -(C1-C4 alkyl) or -(C1-C4 alkyl)-aryl; R F -H, -(C1-C6 alkyl), -(C1-C4 alkyl)-OH, -(C1-C4 alkyl)-O-(C1-C4 alkyl), -C(=O)-(C1-C4 alkyl), -C(=O)-O(C1-C4 alkyl), -(C1-C4 alkyl)-C(=O)-O(C1-C4 alkyl), -(C1-C4 alkyl)-NR D R E , -S(=O)2-(C1-C4 alkyl), -aryl, -(C1-C4 alkyl)-aryl, -(C2-C4 alkenyl)-aryl, -heteroaryl, -(C1-C4 alkyl)-heteroaryl, -C(=O)-(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl) or -(C1-C4 alkyl)-C(=O)-(C2-C6 heterocycloalkyl) {wherein at least one H in -(C1-C4 alkyl) or -C(=O)-O(C1-C4 alkyl) may be independently substituted by -X, - at least one H in the aryl group may be independently substituted by -X}; R G is -(C1-C4 alkyl); Q is -O- or a bond; is a single bond or a double bond {the restriction condition is that when When it is a double bond, Y1 is -CH-}; a to e are each independently an integer of 0, 1, 2, 3 or 4 {with the restriction that a and b cannot be 0 at the same time, and c and d cannot be 0 at the same time}; Each X is independently F, Cl, Br or I.

3. The pharmaceutical composition according to claim 1, wherein the compound represented by the above formula I is a compound represented by the following formula Ia: [Formula Ia] In Formula Ia, R2 is R3 is an aryl group {wherein at least one H in the -aryl group may be independently substituted by -X}; Y1 is -S(=O)2-; Z1 is N or CR Z {where R Z for -X}; a and b are each independently an integer of 0, 1, 2, 3 or 4 {wherein a and b cannot be 0 at the same time}; Each X is independently F, Cl, Br or I.

4. The pharmaceutical composition according to claim 3, wherein in the compound represented by the above formula Ia, R2 is R3 is phenyl {wherein at least one H in the -phenyl group may be independently substituted by -F or -Cl}; Y1 is -S(=O)2-; Z1 is N or CF.

5. The pharmaceutical composition according to claim 1, wherein the compound represented by the above formula I is a compound described in the following table:

6. The pharmaceutical composition according to claim 1, wherein the compound represented by the above formula I is a compound described in the following table: 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 formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula I is the same as defined in claim 1.

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

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

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

12. Use of a compound represented by formula I, an optical isomer thereof or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating idiopathic pulmonary fibrosis, wherein the compound represented by formula I is the same as defined in claim 1.

13. The use according to claim 12, wherein the compound represented by formula I is a compound described in the following table:

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