Prodrug compound activated by fibroblast activation protein

Abstract

The present invention relates to a prodrug compound activated by a fibroblast activation protein (FAP).

Description

Prodrug compounds activated by fibroblast-activating protein

[0001] The present invention relates to a prodrug compound activated by fibroblast activation protein (FAP) and its use as an antifibrotic agent.

[0002] Fibroblast activation protein (FAP) is generally rarely expressed in normal adult tissues, but has been reported to be selectively highly expressed in reactive stromal fibroblasts in more than 90% of examined epithelial malignancies (primary and metastatic) including lung, colorectal, bladder, ovarian, and breast carcinomas, and in malignant mesenchymal cells of bone and soft tissue sarcomas. In addition to tumor or cancer tissue, FAP is known to be involved in tissue remodeling and is highly expressed in activated fibroblasts within scar tissue. Recently, FAP has been found to be highly expressed in fibrotic lesions of tissues such as the liver, lung, and colon.

[0003] Meanwhile, fibroblast activation protein (FAP)-targeting prodrugs have been developed to diagnose or treat FAP-related diseases. However, these prodrugs have limitations in that they are not specific for FAP due to the high homology between FAP and DPP4 around the active site, as well as the significant overlap in the substrate specificity between FAP and PREP. This has led to the problem of drug activation in various unintended human tissues where DPP4 and PREP are expressed. Furthermore, to date, the focus has been solely on prodrugs that utilize FAP as a biomarker for tumor tissue, and no FAP-targeting antifibrotic agents have been developed.

[0004] The purpose of the present invention is to provide a novel prodrug compound having a high selectivity for fibroblast activation protein (FAP), which can specifically release and deliver a drug only in a fibrotic environment where FAP is overexpressed.

[0005] Another object of the present invention is to provide a pharmaceutical composition that can effectively prevent, improve or treat fibrosis-related diseases, including the above-mentioned prodrug.

[0006] However, the technical problems to be solved by the present invention are not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by those skilled in the art from the description below.

[0007] Hereinafter, various embodiments described herein will be described with reference to the drawings. In the following description, various specific details, such as specific configurations, compositions, and processes, are set forth to provide a thorough understanding of the present invention. However, certain embodiments may be practiced without one or more of these specific details, or in conjunction with other known methods and configurations. In other instances, well-known processes and manufacturing techniques have not been described in specific detail so as not to unnecessarily obscure the present invention. Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, configuration, composition, or characteristic described in connection with the embodiment is included in one or more embodiments of the present invention. Thus, the appearances of "in one embodiment" or "an embodiment" in various places throughout this specification do not necessarily refer to the same embodiment of the present invention. Additionally, the particular features, configurations, compositions, or characteristics may be combined in any suitable manner in one or more embodiments.

[0008]

[0009] The present invention provides a prodrug that can be activated by fibroblast activation protein (FAP). The prodrug of the present invention comprises a substrate that can be recognized and cleaved by FAP and an oxindole-based kinase inhibitor drug, wherein the substrate and the drug are linked by a linker having a p-aminobenzyl structure.

[0010] In this specification, "Fibroblast Activation Protein (FAP)" is an enzyme belonging to the serine protease family, which plays a key role primarily in tissue remodeling, wound healing, and certain pathological conditions such as cancer. FAP is rarely expressed in normal adult tissues, but is highly expressed in cancer, fibrosis, and inflammatory diseases.

[0011] As used herein, the term "prodrug" refers to a compound that can be converted to a biologically active compound described herein under physiological conditions or by solvolysis. Thus, the term "prodrug" refers to a pharmaceutically acceptable precursor of a biologically active compound. In some embodiments, a prodrug is inactive when administered to a subject, but is converted to the active compound, for example, by hydrolysis. Prodrug compounds often offer the advantages of solubility, tissue compatibility, or delayed release in mammalian organisms.

[0012] In general, the selection of the substrate, drug, and linker connecting them is crucial in prodrug design. Each component of the prodrug can significantly impact its efficacy, stability, and overall therapeutic effect. In particular, the drug used as the payload in the present invention contains an oxindole ring, the polarity and electronic properties of which can promote linker degradation.

[0013] As a result of extensive efforts, the inventors of the present invention have developed a prodrug compound in which a drug containing an oxindole ring is linked to a FAP substrate via a p-aminobenzyl linker, as represented by the chemical structural formula below. When the substrate is cleaved by FAP, the linker of the prodrug of the present invention is degraded in a chain reaction manner, thereby releasing an oxindole-based kinase inhibitor drug, thereby exerting pharmacological activity. On the other hand, in normal tissues where the substrate is not cleaved by FAP, the structure of the prodrug is stably maintained, such that the linker is not degraded, and the drug can remain in an inactive state. The present invention will be described in detail below.

[0014] According to one embodiment of the present invention, the present invention relates to a prodrug compound selected from the group consisting of a compound represented by the following chemical formula 1, a pharmaceutically acceptable salt thereof, a solvate thereof, and a hydrate thereof:

[0015] [Chemical Formula 1]

[0016]

[0017] In the above chemical formula 1, P 1 is a radical of a kinase inhibitor drug containing an oxindole ring, which is a radical derived from the removal of a hydrogen atom from the NH group of the oxindole ring. Specifically, the P 1 The radical structure of the oxindole-based kinase inhibitor may be selected from the chemical formulas below, but is not limited thereto. In the chemical formulas below, * indicates a portion where a bond is formed.

[0018]

[0019]

[0020]

[0021] Compounds containing an oxindole ring represented by the above chemical formula act as kinase inhibitors (preferably tyrosine kinase inhibitors) and can treat fibrosis (Biomed Pharmacother. 2021 Sep;141:111842.; J. Med. Chem. 58 (2015) 1053e1063; Molecules 2017, 22(11), 1979;). In particular, the fibrosis-improving or therapeutic effect of nintedanib has been confirmed in various papers or clinical trials (J Med Chem. 2015 Feb 12;58(3):1053-63; Expert Opin Pharmacother. 2018 Feb;19(2):167-175.; Eur Respir J. 2015 May;45(5):1434-45).

[0022] However, the prodrug compound represented by the chemical formula 1 provided in the present invention has a novel structure that has not been previously known.

[0023] The compound represented by the above chemical formula 1 may be selected from the group consisting of the following compounds:

[0024]

[0025]

[0026]

[0027] Preferably, the prodrug compound may be a compound represented by the following chemical formula 8, but is not limited thereto:

[0028] [Chemical Formula 8]

[0029]

[0030] In prodrugs, the linker must not only functionally and physically bind the ligand and the drug, but also ensure that the drug is immediately degraded by a chain reaction after the substrate is cleaved, enabling the drug to be active. While various self-removable linkers have been known, there have been cases where the FAP substrate was not properly recognized by FAP due to structural issues, or the linker was not properly removed after the FAP substrate was cleaved, resulting in the drug not being effective. Furthermore, there was a problem where the exposed end of the linker reacted with other parts of the drug or with the cleaved FAP substrate, preventing the drug from working effectively.

[0031] In the prodrug compound of the present invention, the drug binding to the ligand, particularly the oxindole-based kinase inhibitor drug, has a large structure, so when it binds directly to the ligand recognized and cleaved by FAP without connecting a linker, FAP cannot properly recognize the ligand due to steric hindrance, and thus cannot exhibit enzymatic activity.

[0032] However, in the present invention, by connecting an N-(1-(2-carbamoylpyrrolidin-1-yl)-1-oxopropan-2-yl)isonicotinamide moiety as a FAP substrate and an oxindole-based kinase inhibitor drug such as nintedanib through a linker of p-aminobenzoyl structure, the linker can be well inserted into a pocket in the FAP enzyme. Through this, the substrate is selectively cleaved by FAP with high sensitivity, and the linker is subsequently degraded and removed from the drug, thereby enabling P 1 The drug can be active.

[0033] More specifically, in the compounds according to the present invention, oxindole-based kinase inhibitor drugs such as nintedanib, which exhibit an anti-fibrotic effect, do not act in an inactive state in normal tissues where fibroblast activation protein (FAP) is not expressed. However, in an environment where fibroblast activation protein (FAP) is overexpressed, i.e., in fibrotic tissues, the N-(1-(2-carbamoylpyrrolidin-1-yl)-1-oxopropan-2-yl)isonicotinamide moiety is cleaved by FAP as shown in the following reaction schemes 1 and 2. Thereafter, as the linker of the p-aminobenzoyl structure is continuously and spontaneously removed, the drug can be effectively delivered to the fibrotic tissues and exhibit an effective therapeutic effect.

[0034] [Reaction Formula 1]

[0035]

[0036] [Reaction Formula 2]

[0037]

[0038] When the prodrug of the present invention reacts with tyrosine kinase, such as VEGFR2, FGFR1, PDGFRα, FLT1, etc., the prodrug is positioned outside the binding pocket. This causes P 1 The binding affinity between the drug and tyrosine kinase is reduced, preventing effective activity. Therefore, the prodrug of the present invention is less likely to cause side effects, as the drug does not work properly in normal tissues.

[0039] In the present invention, the fibrotic tissue may be a tissue in which a fibrotic condition has occurred in the liver, lungs, heart, blood vessels, joints or interstitial tissue, pancreas, skin, mouth, digestive tract, brain, breast, bone marrow, peritoneum, or kidney, and preferably, may be lung fibrotic tissue, but is not limited thereto.

[0040] The present invention also provides pharmaceutically acceptable salts of the compounds described above. Pharmaceutically acceptable salts are salts generally considered by those skilled in the art to be suitable for medical applications (e.g., because they are not harmful to a subject to be treated with the salt), or salts that cause acceptable side effects within the respective treatment. Typically, pharmaceutically acceptable salts are salts deemed acceptable by regulatory authorities such as the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or the Pharmaceuticals and Medical Devices Agency (PMDA) of the Ministry of Health, Labour and Welfare of Japan. However, the present invention also encompasses salts of the compounds of the present invention that are not pharmaceutically acceptable in themselves, for example, as intermediates in the preparation of the compounds of the present invention or physiologically functional derivatives thereof, or as intermediates in the preparation of pharmaceutically acceptable salts of the compounds of the present invention or physiologically functional derivatives thereof. Such salts include water-insoluble salts, and in particular, water-soluble salts.

[0041] In each case, a person skilled in the art can readily determine whether a particular compound according to the invention or a physiologically functional derivative thereof is capable of forming a salt, i.e. whether the compound according to the invention or a physiologically functional derivative thereof has a group capable of carrying a charge, such as, for example, an amino group, a carboxylic acid group, etc.

[0042] Exemplary salts of the compounds of the present invention are acid addition salts or salts with bases, particularly pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases commonly used in pharmacy, which are water-insoluble or particularly water-soluble acid addition salts. Depending on the substituents of the compounds of the present invention, salts with bases may also be suitable. Acid addition salts can be formed, for example, by mixing a solution of a compound of the present invention with a solution of a pharmaceutically acceptable acid, such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Similarly, pharmaceutically acceptable base addition salts include alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amine cations formed using counter anions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyl sulfonates and aryl sulfonates).Illustrative examples of pharmaceutically acceptable salts include acetate, adipate, alginate, arginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, ethanesulfonate, formate, fumarate, galactate, galacturonate, gluconate, glutamate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrobromide, hydrochloride, hydroiodide, Including but not limited to 2-hydroxy-ethanesulfonate, hydroxynaphthoate, iodide, isobutyrate, isothionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate (mesylate), methyl sulfate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate / diphosphate, phthalate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, suberate, succinate, tannate, tartrate, tosylate, undecanoate, valerate, etc.

[0043] Salts which are not pharmaceutically acceptable and which may be obtained, for example, as process products during the preparation of the compounds according to the invention on an industrial scale, are also encompassed by the present invention and, if desired, can be converted into pharmaceutically acceptable salts by methods known to those skilled in the art.

[0044] In addition, the compounds of the present invention, as well as their salts, may contain varying amounts of solvent, for example when isolated in crystalline form. Accordingly, solvates, particularly hydrates, of the compounds of the present invention, as well as solvates, particularly hydrates, of salts of the compounds of the present invention, may be included within the scope of the present invention. More particularly, the present invention may include hydrates of the compounds, salts, and / or physiologically functional derivatives according to the present invention, which contain one, two, or half water molecules with respect to the stoichiometry.

[0045]

[0046] According to another embodiment of the present invention, the present invention relates to a pharmaceutical composition for preventing, improving or treating a fibrotic disease, comprising a prodrug compound provided by the present invention as an active ingredient.

[0047] In the present invention, the fibrotic diseases include scleroderma, atherosclerosis, cardiac fibrosis, organ transplant fibrosis, muscle fibrosis, pancreatic fibrosis, myelofibrosis, liver fibrosis, splenic fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, idiopathic interstitial fibrosis, diffuse interstitial fibrosis, interstitial lung disease, chronic interstitial lung disease, pneumoconiosis, silicosis, interstitial fibrosis, sarcoidosis, mediastinal fibrosis, cardiac fibrosis, atrial fibrosis, endocardial fibrosis, renal fibrosis, macular degeneration, keloid lesions, hypertrophic scars, renal systemic fibrosis, injection fibrosis, fibrotic complications of surgery, fibrotic chronic allograft angiopathy, fibrosis associated with ischemic reperfusion injury, arthrofibrosis, Dupuytren's disease, fibrotic proliferative lesions of the oral cavity, fibrotic intestinal stenosis, glial scarring, leptomeningeal fibrosis, fibrosis due to radiation exposure, and fibrosis due to breast cystic rupture. It may be, but is not limited to, fibrosis, myelofibrosis, retroperitoneal fibrosis or progressive massive fibrosis, and preferably idiopathic pulmonary fibrosis.

[0048] In the present specification, the "pharmaceutical composition" may be characterized as being in the form of a capsule, tablet, granule, injection, ointment, powder or beverage, and the pharmaceutical composition may be characterized as being intended for animals, specifically humans.

[0049] The pharmaceutical compositions described above are not limited thereto, but may be formulated and used in the form of oral dosage forms such as powders, granules, capsules, tablets, and aqueous suspensions, as well as external preparations, suppositories, and sterile injectable solutions, each according to a conventional method. The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers may include binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, coloring agents, fragrances, etc. for oral administration, and buffers, preservatives, analgesics, solubilizers, isotonic agents, stabilizers, etc. for injections. For topical administration, bases, excipients, lubricants, preservatives, etc. may be used. The formulations of the pharmaceutical composition of the present invention may be prepared in various ways by mixing with the pharmaceutically acceptable carriers described above. For example, for oral administration, it can be manufactured in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and for injections, it can be manufactured in the form of unit dose ampoules or multiple doses. In addition, it can be formulated in the form of solutions, suspensions, tablets, capsules, sustained-release preparations, etc.

[0050] Meanwhile, examples of carriers, excipients, and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, or mineral oil. In addition, fillers, anticoagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives, and the like may be additionally included.

[0051] In the present invention, the pharmaceutical composition may further comprise a radical scavenger in addition to the compound of the present invention or a pharmaceutically acceptable salt thereof. The radical scavenger may be used to prevent radiolysis. Radiolysis is a process in which the ionization of oxygen or water molecules induced by radionuclides forms other reactive species such as superoxide, hydrogen peroxide, hydrogen radicals, ozone, and hydroxyl radicals. These reactive species can also cause damage to DNA and other cellular structures. In some embodiments, the radical scavenger is an antioxidant selected from carnosic acid, green tea extract, apigenin, diosmin, rosmarinic acid, lipoic acid, beta-carotene, L-ascorbic acid (vitamin C), N-acetylcysteine ​​(NAC), δ-tocopherol, rutin, amifostine, resveratrol, gentisic acid, and gallic acid. In some embodiments, the radical scavenger may be an antioxidant selected from, but not limited to, gallic acid, L-ascorbic acid, and N-acetyl cysteine ​​(NAC).

[0052] Routes of administration of the pharmaceutical composition according to the present invention include, but are not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, or rectal. Oral or parenteral administration is preferred, and the term "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques. The pharmaceutical composition of the present invention may also be administered in the form of a suppository for rectal administration.

[0053] In addition, the pharmaceutical composition may vary depending on various factors including the activity of the specific compound used, age, body weight, general health, sex, dosage form, administration time, administration route, excretion rate, drug combination, and severity of the specific disease to be prevented or treated, and the dosage of the pharmaceutical composition may vary depending on the patient's condition, body weight, degree of disease, drug form, administration route, and period, but may be appropriately selected by those skilled in the art, and may be administered at 0.0001 to 50 mg / kg or 0.001 to 50 mg / kg per day. Administration may be administered once a day or divided into several times. The dosage does not limit the scope of the present invention in any way. The pharmaceutical composition according to the present invention may be formulated as a pill, a sugar-coated tablet, a capsule, a liquid, a gel, a syrup, a slurry, or a suspension.

[0054] The pharmaceutical composition of the present invention can be administered alone or in combination with other antifibrotic agents. Herein, the other antifibrotic agent is pirfenidone or a receptor tyrosine kinase inhibitor (RTKI) such as sorafenib and other RTKI, or an angiotensin II (AT1) receptor blocker, or a CTGF inhibitor, or any antifibrotic compound that is likely to interfere with the TGFβ and BMP-activated pathway (including activators of latent TGFβ complexes such as MMP2, MMP9, THBS1 or cell-surface integrins, TGFβ receptor type I (TGFBRI) or type II (TGFBRII) and their ligands such as TGFβ, activin, inhibin, Nodal, anti-Müllerian hormone, GDF or BMP, coreceptors (also known as type III receptors)), or a component of the SMAD-dependent canonical pathway (including respiratory or inhibitory SMAD proteins), or a member of the SMAD-independent or non-canonical pathway (MAPK signaling, TAK1, Rho-like GTPase signaling pathway, These may include, but are not limited to, the phosphatidylinositol-3 kinase / AKT pathway, including various branches of the TGFβ-induced EMT process), or members of the canonical and non-canonical Hedgehog signaling pathways (including Hh ligands or target genes), or the WNT, or Notch pathways (which are susceptible to TGFβ).

[0055]

[0056] According to another embodiment of the present invention, there is provided a method for preventing, improving or treating a fibrotic disease, comprising administering to a subject in need thereof a prodrug compound of the present invention in a pharmaceutically effective amount.

[0057] In the present invention, the subject is an subject that has developed or is suspected of developing a fibrotic disease, and the subject suspected of developing the disease means all animals including humans, monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits or guinea pigs that have developed or can develop the disease, but subjects that can be treated with the effective substance provided in the present invention are included without limitation.

[0058] As used herein, a "pharmaceutically effective amount" is an amount sufficient to stop or alleviate the physiological effects of a subject or patient caused by a fibrosis-related disease. An appropriate effective amount may be determined by a treating physician within the scope of sound medical judgment, and may be administered once or in several divided doses. However, for the purpose of the present invention, it is preferable to apply a specific therapeutically effective amount for a specific patient differently depending on various factors such as the type and degree of response to be achieved, whether other agents are used in some cases, the composition containing the specific effective ingredient, the patient's age, weight, general health condition, sex, and diet, the time of administration, route of administration, number of administrations, and secretion rate of the composition containing the effective ingredient, the treatment period, drugs used together or concurrently with the specific composition, and similar factors well known in the medical field.

[0059] The total effective amount of the composition of the present invention can be administered to a patient as a single dose, or can be administered by a fractionated treatment protocol in which multiple doses are administered over a long period of time. The composition of the present invention may vary in the content of the active ingredient depending on the severity of the disease. Specifically, a preferred total dosage of the composition of the present invention may be about 0.0001 mg to 500 mg per kg of patient body weight per day. However, since the dosage of the composition is determined by taking into consideration various factors such as the route of administration of the pharmaceutical composition and the number of treatments, as well as the patient's age, weight, health status, sex, severity of the disease, diet, and excretion rate, a person having ordinary skill in the art will be able to determine an appropriate effective dosage for a specific use of the composition of the present invention. The pharmaceutical composition according to the present invention is not particularly limited in its formulation, route of administration, or method of administration, as long as it exhibits the effects of the present invention.

[0060] In addition, the method for preventing, improving or treating the fibrotic disease in the present invention may be a combination therapy further comprising administering a compound or substance having therapeutic activity against one or more diseases.

[0061] As used herein, "combined use" should be understood to refer to simultaneous, separate, or sequential administration. If the administration is sequential or separate, the interval between the administration of the secondary components should be such that the beneficial effects of the combination are not lost.

[0062] In the method for preventing, improving or treating the above fibrotic disease, the type of fibrotic disease and the secondary components that can be administered in combination are described above and thus are omitted for detailed description.

[0063] The prodrug compound provided by the present invention can exhibit effective activity in lesion tissues by cleaving the substrate by fibroblast activation protein (FAP) in a fibrotic environment, particularly in lung fibrotic tissue, where FAP is overexpressed, and releasing an oxidol-based drug through a linker chain degradation reaction. The prodrug compound of the present invention has the advantage of not being activated in normal tissues where FAP is not or underexpressed because its structure is stably maintained, and binding to tyrosine kinase is also prevented, thereby reducing the possibility of side effects.

[0064] Figure 1 shows the results of LC-MS analysis performed on FAAP synthesized in an embodiment of the present invention.

[0065] Figure 2 shows the results of NMR analysis performed on FAAP synthesized in an embodiment of the present invention ( 1 H NMR, 400 MHz, CD3OD).

[0066] Figure 3 shows the results of observing the change in fluorescence intensity after treating FAP, PREP, and DPP4 on the AMC-conjugated FAP substrate according to the present invention in Experimental Example 1.

[0067] Figure 4a shows a schematic diagram of FAAP decomposition over time after treating FAP according to the present invention in Experimental Example 2.

[0068] Figure 4b shows the results of analyzing the degree of FAAP decomposition over time using HPLC after treating FAAP according to the present invention in Experimental Example 2.

[0069] Figures 5a to 5c show the results of LC-MS analysis of whether a precursor is generated and whether nintedanib is released as FAAP is decomposed over time after treating FAP to FAAP according to the present invention in Experimental Example 2. Figure 5a shows the results of analyzing the presence or absence of FAAP (①), Figure 5b shows the results of analyzing the presence or absence of a precursor (②), and Figure 5c shows the results of analyzing the presence or absence of nintedanib (③).

[0070] Figure 6a shows a photograph observed using a confocal microscope after treating U87MG cells with nintedanib and FAAP, or a FAP inhibitor (OncoFAP) in Experimental Example 5, and Figures 6b and 6c show a comparison of the fluorescence intensity according to each treatment.

[0071] According to one embodiment of the present invention, the present invention relates to a prodrug compound selected from the group consisting of a compound represented by the following chemical formula 1, a pharmaceutically acceptable salt thereof, a solvate thereof, and a hydrate thereof:

[0072] [Chemical Formula 1]

[0073]

[0074] In the above chemical formula 1, P 1 is a radical of a kinase inhibitor drug containing an oxindole ring, which is a radical derived from the removal of a hydrogen atom from the NH group of the oxindole ring. The P 1 The radical structure of the oxindole-based kinase inhibitor may be selected from the chemical formulas below, but is not limited thereto. In the chemical formulas below, * indicates a portion where a bond is formed.

[0075]

[0076]

[0077]

[0078] The compound represented by the above chemical formula 1 may be selected from the group consisting of the following compounds:

[0079]

[0080]

[0081]

[0082] Preferably, the prodrug compound may be a compound represented by the following chemical formula 8, but is not limited thereto:

[0083] [Chemical Formula 8]

[0084]

[0085] The prodrug according to the present invention can be effectively delivered to fibrotic tissue and exhibit effective efficacy by cleaving the N-(1-(2-carbamoylpyrrolidin-1-yl)-1-oxopropan-2-yl)isonicotinamide moiety by FAP in an environment where fibroblast activation protein (FAP) is overexpressed, i.e., in fibrotic tissue, and continuously and spontaneously removing the linker of the p-aminobenzoyl structure.

[0086] The fibrotic tissue may be a tissue in which a fibrotic condition has occurred in the liver, lungs, heart, vascular system, joints or interstitial tissue, pancreas, skin, mouth, digestive tract, brain, breast, bone marrow, peritoneum, or kidney, and preferably, may be lung fibrotic tissue, but is not limited thereto.

[0087] According to another embodiment of the present invention, the present invention relates to a pharmaceutical composition for preventing, improving or treating a fibrotic disease, comprising a prodrug compound provided by the present invention as an active ingredient.

[0088] According to another embodiment of the present invention, there is provided a method for preventing, improving or treating a fibrotic disease, comprising administering to a subject in need thereof a prodrug compound of the present invention in a pharmaceutically effective amount.

[0089] In the present invention, the fibrotic diseases include scleroderma, atherosclerosis, cardiac fibrosis, organ transplant fibrosis, muscle fibrosis, pancreatic fibrosis, myelofibrosis, liver fibrosis, splenic fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, idiopathic interstitial fibrosis, diffuse interstitial fibrosis, interstitial lung disease, chronic interstitial lung disease, pneumoconiosis, silicosis, interstitial fibrosis, sarcoidosis, mediastinal fibrosis, cardiac fibrosis, atrial fibrosis, endocardial fibrosis, renal fibrosis, macular degeneration, keloid lesions, hypertrophic scars, renal systemic fibrosis, injection fibrosis, fibrotic complications of surgery, fibrotic chronic allograft angiopathy, fibrosis associated with ischemic reperfusion injury, arthrofibrosis, Dupuytren's disease, fibrotic proliferative lesions of the oral cavity, fibrotic intestinal stenosis, glial scarring, leptomeningeal fibrosis, fibrosis due to radiation exposure, and fibrosis due to breast cystic rupture. It may be, but is not limited to, fibrosis, myelofibrosis, retroperitoneal fibrosis or progressive massive fibrosis, and preferably idiopathic pulmonary fibrosis.

[0090] Hereinafter, the present invention will be described in more detail through examples. These examples are intended solely to illustrate the present invention more specifically, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples, in accordance with the gist of the present invention.

[0091]

[0092] Example

[0093]

[0094] [Example 1] Synthesis of FAAP

[0095] According to the following reaction scheme 3, a compound (FAAP) represented by the following chemical formula 8 was synthesized.

[0096] [Reaction Formula 3]

[0097]

[0098] 1. Preparation of (S)-benzyl 1-((R)-2-((tert-butoxycarbonyl)amino)propanoyl)pyrrolidone-2-carboxylate (formula 2)

[0099] To a solution of benzyl L-prolinate hydrochloride (5 g, 20.7 mmol) in 200 mL DCM were added (tert-butoxycarbonyl)-D-alanine (3.62 g, 20.7 mmol), EDCHCl (4.76 g, 24.84 mmol), HOBt (3.36 g, 24.84 mmol), and DIPEA (14.4 ml, 82.8 mmol). The mixture was stirred at 25 °C for 18 h. The mixture was extracted with 0.1 M HCl (100 mL x 3), and the organic layer was extracted again with brine (50 mL x 3). The residue was dried over Na2SO4, concentrated, and purified by flash chromatography (FC) (ethyl acetate (EtOAc) / hexane = 4 / 6) to give 4.78 g of clear oil 2 (yield: 63.7%).

[0100] 1 H NMR (400 MHz, CD3OD) δ 7.41-7.29 (m, 5H), 5.22 (s, 1H), 5.14 (s, 1H), 4.49-4.42 (m, 1H), 4.09-4.05 (m, 1H), 3.84-3.80 (m, 1H), 3.63-3.49(m, 1H), 2.26-1.92(m, 4H), 1.46-1.40(m, 9H), 1.28-1.26(d,J= 8 Hz, 2H), 1.06-1.04(d,J= 8 Hz, 1H). MS (ESI)m / z377.2 (M+H) +

[0101] 2. Preparation of (S)-benzyl 1-((R)-2-aminopropanoyl)pyrrolidone-2-carboxylate 2,2,2-trifluoroacetate (chemical formula 3)

[0102] A solution of 1 (4.78 g, 13.18 mmol) in 100 mL of 20% TFA / DCM was stirred at room temperature for 2 h. The mixture was concentrated, H2O (50 mL) was added, and lyophilized to obtain 5 g of pale yellow oil 3 (yield 99%).

[0103] 1 H NMR (400 MHz, CD3OD) δ 7.40-7.32 (m, 5H), 5.23-5.12 (m, 2H), 4.53-4.50 (m, 1H), 4.32-4.26 (m, 1H), 3.78-3.74 (m, 1H), 3.63-3.56(m, 1H), 2.31-1.98(m, 4H), 1.50-1.22(m, 3H). 1 H NMR (400 MHz, CD3OD) δ 7.40-7.32 (m, 5H), 5.23-5.12 (m, 2H), 4.53-4.50 (m, 1H), 4.32-4.26 (m, 1H), 3.78-3.74 (m, 1H), 3.63-3.56(m, 1H), 2.31-1.98(m, 4H), 1.50-1.22(m, 3H). MS (ESI)m / z277.1 (M+H) +

[0104] 3. Preparation of (S)-benzyl 1-((R)-2-(isonicotinamido)propanoyl)pyrrolidone-2-carboxylate (chemical formula 4)

[0105] To a solution of 2 (1.995 g, 5.11 mmol) in 50 mL of DMF were added isonicotinic acid (0.629 g, 5.11 mmol), HATU (2.9 g, 7.665 mmol), and DIPEA (2.67 mL, 15.33 mmol). The mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated, diluted with 50 mL of DCM, extracted with 0.1 M HCl (50 mL x 3), and the organic layer was extracted again with brine (50 mL x 3). The organic layer was dried over anhydrous sodium sulfate (Na2SO4) and filtered. The filtrate was concentrated, and the residue was purified by flash chromatography (FC) (methanol / dichloromethane = 1 / 9) to give 1.7 g of white foam solid 4 (yield: 87%).

[0106] 1 H NMR (400 MHz, CDCl3) δ 8.72-8.69(m, 2H), 7.91-7.89(d,J= 8 Hz, 1H), 7.71-7.67(m, 2H), 7.3-7.21(m, 5H), 5.22-5.11(m, 2H), 5.04-4.93(m, 1H), 4.67-4.54(m, 1H), 4.12-3.56(m, 2H), 2.30-2.04(m, 4H), 1.49-1.24(m, 3H). MS (ESI)m / z382.1 (M+H) +

[0107] 4. Preparation of (S)-1-((R)-2-(isonicotinamido)propanoyl)pyrrolidine-2-carboxylic acid (chemical formula 5)

[0108] To a solution of 3 (1.7 g, 4.46 mmol) in 100 mL of 20% MeOH / DCM, 10 wt% Pd / C (470.4 mg, 0.46 mmol) was added, and the mixture was stirred at room temperature for 4 h while bubbling hydrogen gas. The mixture was filtered through a Celite filter, and the filtrate was concentrated to obtain 1.13 g of white foam solid 5 (yield 87%).

[0109] 1H NMR (400 MHz, CD3OD) δ 8.69-8.67 (m, 2H), 7.84-7.80 (m, 2H), 4.39-4.33 (m, 1H), 3.77-3.32 (m, 2H), 3.07-2.98 (m, 1H), 2.60-1.81(m, 4H), 1.46-1.29(m, 3H). MS (ESI)m / z292.2 (M+H) +

[0110] 5. Preparation of N-((R)-1-((S)-2-((4-(hydroxymethyl)phenyl)carbamoyl)pyrrolidin-1-yl)-1-oxopropan-2-yl)isonicotinamide (chemical formula 6)

[0111] To a solution of 4 (500 mg, 1.72 mmol) in 50 mL of 20% MeOH / THF were added EEDQ (445.7 mg, 1.80 mmol) and PABOH (221.9 mg, 1.80 mmol). The mixture was stirred at 25 °C for 16 h. After concentrating the reaction mixture, the residue was purified by flash chromatography (FC) (methanol / dichloromethane = 1 / 9) to give 260 mg of beige foam solid 6 (yield: 38%).

[0112] 1 H NMR (400 MHz, cd3od) δ 8.69-8.67(m, 2H), 7.84-7.80(m, 2H), 7.64-7.57(m, 2H), 7.34-7.27(m, 2H), 4.59-4.55(m, 3H), 4.03-3.64(m, 2H), 3.32-3.30(m, 1H), 2.34-2.06(m, 4H), 1.48-1.33(m, 3H). MS (ESI)m / z397.2 (M+H) +

[0113] 6. Preparation of N-((R)-1-((S)-2-((4-(chloromethyl)phenyl)carbamoyl)pyrrolidin-1-yl)-1-oxopropan-2-yl)isonicotinamide hydrochloride (chemical formula 7)

[0114] To a solution of 5 (181 mg, 0.457 mmol) in 10 mL of DCM was added thionyl chloride (331.6 μL, 4.57 mmol). The mixture was stirred at 0 °C for 30 min and then at room temperature for 1 h. After concentrating the reaction mixture, 10 mL of DCM was added, and concentration was repeated twice before proceeding with the next reaction.

[0115] 1 H NMR (400 MHz, CD3OD) δ 9.70-9.68 (m, 2H), 8.73-8.69 (m, 2H), 7.64-7.57 (m, 2H), 7.34-7.27 (m, 2H), 4.47-4.43 (m, 3H), 3.31-2.92(m, 2H), 2.61-2.59(m, 1H), 1.96-1.68(m, 4H), 1.41-1.26(m, 3H). MS (ESI)m / z415.4 (M+H) +

[0116] 7. Preparation of (Z)-methyl 1-(4-((S)-1-((R)-2-(isonicotinamido)propanoyl)pyrrolidine-2-carboxamido)benzyl)-3-(((4-(N-methyl-2-(4-methylpiperazin-1-yl)acetamido)phenyl)amino)phenyl)methylene)-2-oxoindoline-6-carboxylate (Formula 8)

[0117] Compound 7 was dissolved in 10 mL of DCM, and nintedanib (197 mg, 0.3656 mmol) and TEA (239 μL, 1.371 mmol) were added. The mixture was stirred at room temperature for 48 h. After concentrating the reaction mixture, the residue was purified by using a Biotage® Sfδr KP-Amino D Duo 50 μm 5 g column (methanol / dichloromethane = 1 / 19), followed by further purification via HPLC and lyophilization to give 68.1 mg of yellow solid 8 (yield: 16%) (Figs. 1 and 2).

[0118] 1H NMR (400 MHz, CD3OD) δ 8.67(s, 2H), 7.86-7.81(m, 4H), 7.63-7.46(m, 8H), 7.28-7.26(dd,J = 8.2, 1.6 Hz, 1H), 7.12-7.10(d, J = 8.4 Hz, 2H), 6.91-6.89(d, J = 8.4 Hz, 2H), 5.95-5.93(m, 1H), 4.60-4.51(m, 3H), 4.06-3.99(m, 1H), 3.84(s, 3H), 3.79-3.73(m, 1H), 3.65-3.55(m, 1H), 3.40 (m, 2H), 3.20-2.96 (m, 10H), 2.88-2.74 (m, 4H), 2.37-1.98 (m, 4H), 1.49-1.36 (m, 3H). HRMS (FAB)m / z918.4313 (M+H) +

[0119] 8. Purity Analysis

[0120] As a result of confirming the purity by checking the m / z value of the FAAP compound through HPLC and LC / MS analysis, it was confirmed that FAAP was contained in the product at a purity of approximately 60% or more.

[0121]

[0122] [Examples 2 to 52] Synthesis of prodrugs

[0123] In step 7 of Example 1, the drug shown in Table 1 below was added instead of nintedanib to prepare a prodrug compound shown in Table 1 below.

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137] [Experimental Example 1] Evaluation of substrate decomposition by FAP

[0138] To confirm whether the FAP substrate according to the present invention is specifically recognized and cleaved only by FAP, the following experiment was performed. 2.5 μM of the AMC-conjugated isonicotinoyl-D-Ala-Pro moiety represented by the following chemical formula 9 as a substrate, 2.5 μg / mL of FAP, and <1% (v / v) of DMSO were added to a buffer (0.01 M Tris-HCl, pH 7.4, 0.01 M MgCl2, 0.05% Tween-20, distilled water), and the mixture was incubated at 37°C. PREP and DPP4, which are peptidases similar to FAP, were added as controls. The fluorescence intensity according to the incubation time was measured using a microplate device (SYNERGY H1, BioTek), and the results are shown in Fig. 3.

[0139] [Chemical Formula 9]

[0140]

[0141] As shown in Fig. 3, it was confirmed that the substrate according to the present invention was specifically cleaved only by the FAP enzyme and fluorescence was detected, and that it was not cleaved by PREP or DPP4, which have a similar structure to FAP.

[0142]

[0143] [Experimental Example 2] Evaluation of substrate decomposition by FAP

[0144] To evaluate the degree of activation of FAAP synthesized in Example 1 according to FAP, 100 μM FAAP and 4.45 μg / mL FAP were incubated at 37°C in a buffer (0.01 M Tris-HCl, pH 7.4, 0.01 M MgCl2, 0.05% Tween-20, distilled water) and DMSO <2.5% (v / v). Thereafter, samples were collected at regular intervals, and whether FAAP was decomposed to produce nintenanib was confirmed using the mass detector and UV detector (390 nm) of the device using HPLC and LC / MS. The results are shown in Figures 4a and 4b and Figures 5a to 5c. However, the analysis conditions of the HPLC and LC-MS system (Agilent) are as follows:

[0145] Analytical column: X Terra MS C18 column, 25 Å, 3.5 ㎛, 2.1 mm x 100 mm

[0146] HPLC, LC-MS conditions: 0-2 min, 20% A / B; 2-15 min, 20-90% A / B; 15-20 min, 90% A / B; 0.25 ml / min flowrate

[0147] As a buffer, the eluents of acetonitrile (solvent A) and water (solvent B) were mixed with 0.1% formic acid (v / v).

[0148] As shown in Figures 4 and 5, the [M + H] of FAAP compound (①) was determined through LC / MS analysis. + The value is approximately 919, and the [M + H] of the precursor (②) generated by decomposition in the presence of FAP + The value was confirmed to be approximately 645, and [M + H] of Nintedanib (③) +The value was confirmed to be 540. In addition, it was confirmed that 40% of FAAP was degraded within 1.5 hours, 80% within 5 hours, and completely degraded to nintedanib at the later time points, thereby activating the prodrug. Meanwhile, it was confirmed that the compound was very stable for a long period of time in the absence of FAP.

[0149]

[0150] [Experimental Example 3] Evaluation of FAAP's binding affinity to tyrosine kinase

[0151] Nintedanib, a drug included in the FAAP of the present invention, is known to bind to three types of tyrosine kinases (VEGFR2, FGFR1, PDGFRα). Docking simulations of the structures of nintedanib and FAAP were performed in the region corresponding to the receptor pocket using molecular docking simulations (AutoDock Vina). However, the types of receptors used in the experiment were VEGFR-2 crystal (PDB ID: 3C7Q) and PDGFRα (PDB ID: 6JOL). The binding affinity and binding location of nintedanib to tyrosine kinases within the FAAP structure were confirmed, and the results are shown in Table 2.

[0152] Compound VEGFR2 PDGFRα Nintedanib-9.38.2 Example 1 (FAAP)-8.066-6.805

[0153] As a result, as shown in Table 2, it was confirmed that the binding affinity of FAAP according to the present invention to tyrosine kinase was lower than that of the drug nintedanib alone.

[0154]

[0155] [Experimental Example 4] Evaluation of FAAP's binding ability to target kinases

[0156] This experiment was based on a competitive binding assay, which quantitatively measures the ability of a compound to compete with an immobilized active-site-directed ligand. This assay involved combining three components: a DNA-tagged kinase, a ligand immobilized on beads, and a test compound. If the test compound binds to the kinase and directly or indirectly blocks the ATP site, the number of protein molecules (kinase) bound to the ligand immobilized on the beads decreases. If the test compound does not bind to the kinase, the tagged protein (kinase) can bind to the beads. Therefore, the degree of binding is assessed by measuring the amount of fusion protein bound to the beads using quantitative PCR (qPCR). Kinase, liganded beads, and test compounds (nintedanib and FAAP were diluted 3-fold starting from 10 mM as the highest concentration, and a total of 11 points were tested) were placed in the test plate and incubated with agitation at room temperature for 1 hour. After resuspending the beads in elution buffer (1x PBS, 0.05% Tween 20, 0.5 μM non-biotinylated affinity ligand), the beads were incubated with agitation at room temperature for 30 minutes, and the kinase concentration in the eluate was measured by qPCR. The binding ability of FAAP to each kinase was compared with that of nintedanib, and the results are shown in Table 3 below.

[0157] Binding affinity of FAAP compared to target nintedanibFGFR10.8 timesFLT10.2 timesPDGFRα0.47 times

[0158] As shown in Table 3 above, it was confirmed that the binding affinity of FAAP according to the present invention to tyrosine kinase was lower than that of nintedanib. This indicates that the prodrug compound according to the present invention can reduce the possibility of side effects by inhibiting binding to tyrosine kinase expressed in normal organs.

[0159]

[0160] [Experimental Example 5] Evaluation of FAAP degradation depending on the presence or absence of intracellular FAP.

[0161] To confirm whether FAAP was activated by FAP at the cellular level, the normal group with FAP and the group in which FAP was blocked using oncoFAP were treated with nintedanib and FAAP, and the uptake pattern was observed using a confocal microscope. Specifically, 2 X 10 per well in a confocal dish 5 Cells were seeded at 10 cells / mL and treated with drugs after 24 hours of incubation. The normal group with FAP was treated with 2 μL (10 μM) each of FAAP and nintedanib. The FAP-blocked group was first treated with 10 μL (1 mM) of oncoFAP, shaken from side to side, incubated for 30 minutes, and then treated with 2 μL (10 μM) of FAAP. After drug treatment, the cells were shaken at 165 rpm for 5 minutes. After incubation in an incubator for 15 minutes, 2 hours, 6 hours, and 10 hours, they were washed twice with warm DPBS. After incubation for 15 minutes with 1 mL of warm 4% PFA and washing twice, the cells were fixed by refilling the plate with DPBS to prevent drying, and confocal images were taken. The drug images of nintedanib were obtained using a Hoechst 33258 filter. The reason why it was possible to confirm with a confocal microscope is because nintedanib has an inherent fluorescence property (emission 482 nm, excitation 390 nm), whereas FAAP does not show fluorescence.

[0162] As shown in Figures 6a to 6c, nintedanib exhibited fluorescence 15 minutes after treatment, but FAAP did not exhibit fluorescence until 10 hours after FAAP treatment in the cells, when the fluorescence intensity increased. In addition, in the group treated with FAAP after blocking FAP with OncoFAP, a FAP inhibitor, no fluorescence was observed even after 10 hours.

[0163] Through these experiments, it was found that the FAAP of the present invention is specifically activated by nintedanib at the cellular level by FAP.

[0164]

[0165] While specific aspects of the present invention have been described in detail above, it should be apparent to those skilled in the art that these specific descriptions are merely preferred implementation examples and do not limit the scope of the present invention. Therefore, the substantial scope of the present invention is defined by the appended claims and their equivalents.

[0166] The present invention relates to a prodrug compound activated by fibroblast activation protein (FAP) that can be used as an antifibrotic agent, and its application.

[0167]

[0168] [National Research and Development Project Supporting This Invention]

[0169] [Project ID] 1465037025

[0170] [Assignment Number] HN22C0632000022

[0171] [Ministry Name] Ministry of Health and Welfare

[0172] [Name of Project Management (Specialist) Institution] (Foundation) National Drug Development Foundation

[0173] [Research Project Name] National New Drug Development Project (Ministry of Science and ICT, Ministry of Health and Welfare, Ministry of Trade, Industry and Energy)

[0174] [Research Project Name] Research on the Derivation of Effective Substances for Transformative Protein-Targeted Cancer Treatments

[0175] [Name of the project performing organization] Seoul National University Industry-Academic Cooperation Foundation

[0176] Research Period: May 1, 2022 - April 30, 2025

[0177]

[0178] [National Research and Development Project Supporting This Invention]

[0179] [Project ID] 1415180797

[0180] [Assignment Number] 20018522

[0181] Ministry of Trade, Industry and Energy

[0182] [Name of Project Management (Specialist) Agency] Korea Industrial Technology Evaluation and Planning Institute

[0183] [Research Project Name] Development of Advanced Vaccine Raw Materials Production Technology

[0184] [Research Project Name] Development of mRNA Vaccine Product Quality and Efficacy Evaluation Technology

[0185] [Name of Project Performing Organization] Seoul National University

[0186] Research Period: April 1, 2022 - December 31, 2025

[0187]

[0188] [National Research and Development Project Supporting This Invention]

[0189] [Project ID] 1711168268

[0190] [Assignment Number] 2020R1C1C1009000

[0191] [Ministry Name] Ministry of Science and ICT

[0192] [Name of Project Management (Specialist) Institution] National Research Foundation of Korea

[0193] [Research Project Name] Outstanding New Researcher

[0194] [Research Project Title] Development of a Targeted Radionuclide-Photodynamic Combination Cancer Therapy Using a Radioluminescent Liposome Nanoplatform

[0195] [Name of Project Performing Organization] Seoul National University

[0196] Research Period: March 1, 2020 - February 28, 2025

[0197]

[0198] [National Research and Development Project Supporting This Invention]

[0199] [Project ID] 1711158495

[0200] [Assignment Number] 2021M2E8A1039564

[0201] [Ministry Name] Ministry of Science and ICT

[0202] [Name of Project Management (Specialist) Institution] National Research Foundation of Korea

[0203] [Research Project Name] Research on Future Innovation-Based Technology for Radiation Utilization

[0204] [Research Project Title] Development of Radiation-Induced Photoimmunotherapy Using an Antibody-Europium-Photosensitizer Complex

[0205] [Name of Project Performing Organization] Seoul National University

[0206] Research Period: May 1, 2021 - December 31, 2024

[0207]

[0208] [Project ID] RS-2021-NR059015

[0209] [Assignment Number] 2021R1A2C2003301

[0210] [Ministry Name] Ministry of Science and ICT

[0211] [Name of Project Management (Specialist) Institution] National Research Foundation of Korea

[0212] [Research Project Name] Mid-Career Researcher Support Project (R1A2)

[0213] [Research Project Title] Development of pH- and temperature-sensitive nanocomposite-based nanocarriers that enhance the loading capacity, tumor selectivity, and retention of mitochondrial-targeting tumor therapeutic drugs.

[0214] [Name of the project performing organization] Bundang Seoul National University Hospital

[0215] Research Period: March 1, 2021 - February 28, 2026

Claims

1. A prodrug compound selected from the group consisting of a compound represented by the following chemical formula 1, a pharmaceutically acceptable salt thereof, a solvate thereof, and a hydrate thereof: [Chemical Formula 1] In the above chemical formula 1, P 1 is a radical of a kinase inhibitor drug containing an oxindole ring, which is a radical derived from the removal of a hydrogen atom from the NH group of the oxindole ring.

2. In paragraph 1, The above P 1 A prodrug compound selected from the groups represented by the chemical formula below:

3. In paragraph 1, The above prodrug compound is a prodrug compound represented by the following chemical formula 8: [Chemical Formula 8] 4. In paragraph 1, The above prodrug compound is degraded by fibroblast activation protein (FAP) to form P 1 This is a prodrug compound that is activated.

5. A pharmaceutical composition for preventing or treating a fibrotic disease, comprising a prodrug compound of any one of claims 1 to 4 as an active ingredient.

6. In paragraph 5, The above fibrotic diseases are scleroderma, atherosclerosis, cardiac fibrosis, organ transplant fibrosis, muscle fibrosis, pancreatic fibrosis, myelofibrosis, liver fibrosis, splenic fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, idiopathic interstitial fibrosis, diffuse interstitial fibrosis, interstitial lung disease, chronic interstitial lung disease, pneumoconiosis, silicosis, interstitial fibrosis, sarcoidosis, mediastinal fibrosis, cardiac fibrosis, atrial fibrosis, endocardial fibrosis, renal fibrosis, macular degeneration, keloid lesions, hypertrophic scars, renal systemic fibrosis, injection fibrosis, fibrotic complications of surgery, fibrotic chronic allograft angiopathy, fibrosis associated with ischemia-reperfusion injury, arthrofibrosis, Dupuytren's disease, fibrotic proliferative lesions of the oral cavity, fibrotic intestinal stenosis, glial scarring, leptomeningeal fibrosis, fibrosis due to radiation exposure, fibrosis due to breast cystic rupture, A pharmaceutical composition for treating myelofibrosis, retroperitoneal fibrosis or progressive massive fibrosis.

7. A method for preventing or treating a fibrotic disease, comprising administering to a subject in need of administration a pharmaceutically effective amount of a prodrug compound of any one of claims 1 to 4.

8. In paragraph 7, The above fibrotic diseases are scleroderma, atherosclerosis, cardiac fibrosis, organ transplant fibrosis, muscle fibrosis, pancreatic fibrosis, myelofibrosis, liver fibrosis, splenic fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, idiopathic interstitial fibrosis, diffuse interstitial fibrosis, interstitial lung disease, chronic interstitial lung disease, pneumoconiosis, silicosis, interstitial fibrosis, sarcoidosis, mediastinal fibrosis, cardiac fibrosis, atrial fibrosis, endocardial fibrosis, renal fibrosis, macular degeneration, keloid lesions, hypertrophic scars, renal systemic fibrosis, injection fibrosis, fibrotic complications of surgery, fibrotic chronic allograft angiopathy, fibrosis associated with ischemia-reperfusion injury, arthrofibrosis, Dupuytren's disease, fibrotic proliferative lesions of the oral cavity, fibrotic intestinal stenosis, glial scarring, leptomeningeal fibrosis, fibrosis due to radiation exposure, fibrosis due to breast cystic rupture, A method for preventing or treating a fibrotic disease, such as myelofibrosis, retroperitoneal fibrosis or progressive massive fibrosis.

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