Pharmaceutical composition for preventing or treating inflammatory disease or autoimmune disease comprising pyridine compound as effective ingredient

Abstract

The present application relates to a pharmaceutical composition for preventing or treating an inflammatory disease or an autoimmune disease, including a pyridine compound as an effective ingredient. The pyridine compound of the present application used as an effective ingredient of the pharmaceutical composition can significantly inhibit innate immune responses and inflammatory responses by very high efficacy in inhibiting the activity of IRAK4, and thus can be effectively used for preventing or treating an inflammatory disease or an autoimmune disease.

Description

[0001] This application claims the benefit of priority based on Korean Patent Application No. 10-2024-0031574, filed on March 5, 2024, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention relates to a pharmaceutical composition comprising a pyridine compound as an active ingredient for the prevention or treatment of inflammatory diseases or autoimmune diseases. Background Technology

[0003] Immunity is one of the body's self-protective systems against all foreign macromolecules (antigens) that invade or are injected into living tissues. The main component of the immune system is lymphocytes, which are white blood cells produced in the bone marrow and circulated through the bloodstream to lymphatic tissues or organs (primarily lymph nodes, spleen, and tonsils). Among the cells involved in the immune response, B cells proliferate rapidly upon stimulation by appropriate antigens, forming clones that produce specific antibodies (immunoglobulins) capable of neutralizing antigens. These antibodies produced by B cells circulate in body fluids for humoral immunity. Additionally, T cells mature in the thymus and migrate to lymphatic tissues, where they are responsible for cell-mediated immunity, directly attacking antigens.

[0004] One of the most important characteristics of a normal individual is the ability to not react harmfully to the antigens that constitute their own body, while simultaneously recognizing, reacting with, and eliminating many non-self antigens. This lack of responsiveness to self-antigens is called immune non-responsiveness or tolerance. When problems arise in inducing or maintaining this self-tolerance, an immune response to self-antigens occurs, leading to the body attacking its own tissues, thus causing autoimmune diseases such as multiple sclerosis, type 1 diabetes, rheumatoid arthritis, and Hashimoto's thyroiditis. The primary cause of autoimmune diseases is believed to be the migration of lymphocytes into tissues, triggering abnormalities in the autoimmune system; however, the exact pathogenic mechanisms of each disease remain unknown.

[0005] Recent research has focused on the development of therapeutics for autoimmune diseases, particularly effective immunosuppression at the cellular and molecular levels. This includes both cellular and molecular immunosuppression, such as steroids, cyclosporine, rapamycin, methotrexate, cyclophosphamide, IV immunoglobulin, azathioprine, and infliximab. However, most cases involve persistent inflammation and frequent relapses, and treatment is often accompanied by numerous systemic side effects. Therefore, there is an urgent need to research and develop therapeutics for autoimmune diseases that demonstrate superior efficacy while causing fewer side effects.

[0006] Against this technical background, the inventors completed the present invention by confirming that the pyridine compounds according to the present invention have potent inhibitory activity against innate immune responses and inflammatory responses, while having low cytotoxicity and therefore low risk of side effects. Summary of the Invention

[0007] [Technical Issues] The present invention aims to provide a pharmaceutical composition that can be used to prevent or treat inflammatory diseases or autoimmune diseases.

[0008] The purpose of this invention is to provide a health food composition that can be used to prevent or improve inflammatory diseases or autoimmune diseases.

[0009] [Technical Solution] To achieve the above objectives, the present invention provides a pharmaceutical composition for the prevention or treatment of inflammatory diseases or autoimmune diseases, the pharmaceutical composition comprising a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof as the active ingredient: [Formula 1]

[0010] (wherein, in the above formula, R) 1 R 2 R 3 R 4 and R 5 As defined in this invention.

[0011] Furthermore, the present invention provides a health food composition for preventing or improving inflammatory diseases or autoimmune diseases, the health food composition comprising a compound represented by the following formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient: [Formula 1]

[0012] (wherein, in the above formula, R)1 R 2 R 3 R 4 and R 5 As defined in this invention.

[0013] [Beneficial Effects] The compounds of Formula 1 according to the present invention possess DYRK1A inhibitory activity, and thus are capable of inhibiting adaptive immune responses (such as T-cell immune responses) and potent inhibitory activity against IRAK4, thereby being equally effective in inhibiting innate immune responses and inflammatory responses; and have been confirmed to exhibit higher efficacy and significantly lower cytotoxicity compared to existing anti-inflammatory or innate immune response suppressants currently undergoing clinical trials. Therefore, the compounds of Formula 1 according to the present invention can be effectively used for the prevention or treatment of inflammatory diseases or autoimmune diseases. Attached Figure Description

[0014] Figure 1 Results confirming the inhibitory effect of compound P1 on the binding of DYRK1A, IRAK4, and IRAK1 substrates and on the inhibition of kinase activity.

[0015] Figure 2 The mechanism of action of compound P1 in its innate immune response-inhibitory activity is shown.

[0016] Figure 3 The results show the comparison of phosphorylation levels of downstream TLR4 kinases after THP-1 cells were treated with LPS and compound P1 or existing IRAK4 or DYRK1A / CLK inhibitors.

[0017] Figure 4a The results show the comparison of inflammatory gene expression patterns after treating THP-1 cells with LPS-induced innate immune responses with the pyridine compound of the present invention (compound P1) and three control drugs, respectively.

[0018] Figure 4b The results show the results of confirming the expression levels of genes related to the innate immune response after treating THP-1 cells with LPS-induced innate immune responses using compound P1.

[0019] Figure 5 The results show the comparison of gene expression patterns after treating THP-1 cells with LPS-induced innate immune responses with compound P1 and the control drug Lorecivivint, respectively.

[0020] Figure 6 The results show the results of comparing the CLK inhibitory activity of compound P1 and the control drug Lorecivivint by measuring the phosphorylation level of SR protein.

[0021] Figure 7 The results show the comparison of luciferase activity and cell viability in cellular systems capable of quantitatively monitoring NF-κB signaling based on luciferase, following concentration-dependent treatment with LPS and either compound P1 or competing drugs such as IRAK4 inhibitors (Zimlovisertib, Emavusertib, KT-474), JAK inhibitors (baricitinib), and DYRK1A / CLK inhibitors (Lorecivivint).

[0022] Figure 8a and Figure 8b The results show the changes in the amount of secreted cytokine proteins after THP-1 cells were treated with LPS and compound P1 or existing IRAK4 inhibitor drugs.

[0023] Figure 9 The results show the comparison of cell viability after treatment of CCD-18Co cells and GM14660 cells with compound P1 or Lorecivivint.

[0024] Figure 10 The results show the comparison of luciferase activity levels, cell viability, and expression levels of NF-κB downstream genes after transfecting THP-1 cells with the NF-κB-luciferase plasmid and treating the cells with LPS and each of the three pyridine compounds of the present invention (compound P1, compound P2, or compound P3), as well as the comparison of cytotoxicity by measuring cell viability after treating HepG2 cells with each compound.

[0025] Figure 11 The results of molecular docking predictions for compounds P1, P2, and P3 with IRAK4 are shown.

[0026] Figure 12 The results of in vitro ADME and in vivo PK evaluations of compound P1 are shown.

[0027] Figure 13 The results of evaluating the cardiotoxicity and genotoxicity of compound P1 are shown.

[0028] Figure 14a and Figure 14b Results of non-GLP-level toxicity assessment after repeated administration of compound P1 to mice are shown.

[0029] Figure 15a and Figure 15b The results show the effect of treating a mouse model of rheumatoid arthritis with various concentrations of compound P1 on improving rheumatoid arthritis symptoms.

[0030] Figure 16a and Figure 16b The results show the efficacy in improving rheumatoid arthritis symptoms after treating a mouse model of rheumatoid arthritis with various concentrations of compound P1 and competing drugs. Detailed Implementation

[0031] The invention will be described in detail below.

[0032] The present invention provides compounds represented by the following Formula 1.

[0033] [Formula 1]

[0034] In Equation 1, R 1 It can be hydrogen or -NR 6 R 7 Here, R 6 and R 7 Each can be independently hydrogen, C1-C5 straight-chain or branched alkyl or benzyl, and specifically, R 6 and R 7 They can all be independently hydrogen or C1-C3 straight-chain or branched alkyl groups.

[0035] In Equation 1, R 2 R 3 and R 4 They can all be independently hydrogen, halogen, C1-C5 straight-chain or branched alkyl, -NR 8 R 9 -OR 8 -CN, -NHC(O)R 8 -SO2R 8 -OS(O)2R 8 , pyrrolidinyl, piperidinyl or morpholinyl; specifically, R 2 R 3 and R 4 They can all be independently hydrogen, -F, -Cl, -Br, -I, C1-C3 straight-chain or branched alkyl, -NR 8 R 9 -OR 8 -CN, -NHC(O)R 8 -SO2R 8 -OS(O)2R 8 pyrroleyl, piperidinyl, or morpholinyl; more specifically, R 2 R 3 and R 4 Each can be independently hydrogen, -F, -Cl, -Br, -I, or a C1-C3 straight-chain or branched alkyl group. Here, R 8 and R9 Each of these can be independently hydrogen, C1-C5 straight-chain or branched alkyl, C1-C5 straight-chain or branched alkynyl, C1-C5 straight-chain or branched alkenyl, or C6-C 12 Aryl groups, halogenated C6-C 12 Aryl or C6-C substituted with trihalomethyl 12 aryl, and specifically, R 8 and R 9 They can all be independently hydrogen or C1-C5 straight-chain or branched alkyl groups.

[0036] In Equation 1, R 5 It can be hydrogen, C1-C5 straight-chain or branched alkyl, unsubstituted 4-piperidinyl or acetyl-substituted 4-piperidinyl, and specifically, R 5 It can be hydrogen, C1-C3 straight-chain or branched alkyl, unsubstituted 4-piperidinyl or acetyl-substituted 4-piperidinyl.

[0037] The compound represented by Formula 1 can be a compound represented by Formula 2, Formula 3 or Formula 4 below.

[0038] [Equation 2]

[0039] [Formula 3]

[0040] [Formula 4]

[0041] The compounds of Formula 1 of the present invention exhibit potent inhibitory effects on innate immune and inflammatory responses. In specific examples of the present invention, it was confirmed that the compounds of Formula 1 reversed gene expression patterns altered by LPS treatment, significantly reducing the expression of innate immune response-related genes CCL2, CCL4, CCL3, CXCL1, PTAFR, CCL8, CXCL11, CCL5, BCL6, CCL20, IL-6, IL-1β, TNF-α, and MyD88, and also significantly reducing the expression of NF-κB downstream genes. Furthermore, it was confirmed that these activities are due to the significant inhibition of IRAK4 by the compounds of Formula 1, which is the main kinase acting at the highest level in the TLR4 downstream signaling pathway. As can be seen from the above results, the compounds of Formula 1 of the present invention can potently inhibit innate immune and inflammatory responses, and therefore can be used as active ingredients in pharmaceutical compositions for the prevention or treatment of inflammatory or autoimmune diseases.

[0042] Therefore, the present invention provides a pharmaceutical composition for the prevention or treatment of inflammatory diseases or autoimmune diseases, the pharmaceutical composition comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0043] Compounds represented by Formula 1 or pharmaceutically acceptable salts thereof may have potent inhibitory activity against IRAK4 (interleukin-1 receptor-associated kinase 4).

[0044] The term "prevention" refers to reducing the risk of contracting a disease or condition, that is, preventing the progression of one or more clinical symptoms of a disease in a subject who is exposed to or susceptible to the disease but has not yet contracted the disease or exhibited its symptoms. The term "treatment" refers to alleviating a disease or condition, that is, stopping or reducing the progression of a disease or one or more clinical symptoms of it.

[0045] Inflammatory diseases are diseases caused by mediators of an inflammatory response, that is, diseases in which inflammation is one of their causes. Examples include, but are not limited to, pulmonary fibrosis, allergic diseases, rhinitis, pneumonia, bronchitis, pharyngitis, chronic obstructive pulmonary disease, esophagitis, gastritis, hepatitis (including non-alcoholic steatohepatitis, alcoholic hepatitis, hepatitis B, and hepatitis C), pancreatitis, nephritis, cystitis, enteritis, dermatitis, myositis, vasculitis, arthritis, inflammatory eye disease, periodontitis, gout, and postoperative trauma inflammation. Autoimmune diseases are diseases caused by a pathological response to self-antigens. Examples include, but are not limited to, inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, Hashimoto's thyroiditis, chronic thyroiditis, ankylosing spondylitis, glomerulonephritis, chronic active infection, Behçet's disease, multiple sclerosis, systemic sclerosis, graft-versus-host disease, asthma, atopic dermatitis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes.

[0046] In specific examples of the present invention, it has been confirmed that the compounds represented by Formula 1 of the present invention have higher efficacy and significantly lower cytotoxicity compared to existing anti-inflammatory or innate immune response suppressing drugs currently undergoing clinical trials, and that the compounds represented by Formula 1 of the present invention can significantly improve symptoms in animal models of rheumatoid arthritis compared to competing drugs. Therefore, it can be seen that the compounds represented by Formula 1 of the present invention can be used as active ingredients in pharmaceutical compositions for the prevention or treatment of inflammatory diseases or autoimmune diseases.

[0047] The term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Such salts can be prepared by conventional methods in the art and include, for example, salts formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, sodium bisulfate, phosphoric acid, nitric acid, and carbonic acid); salts formed with organic acids (such as formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gentian acid, fumaric acid, lactobionic acid, salicylic acid, or acetylsalicylic acid (aspirin)); salts formed with amino acids (such as glycine, alanine, vanillin, isoleucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine, and proline); salts formed with sulfonic acids (such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid); metal salts formed by reaction with alkali metals (such as sodium and potassium); or salts formed with ammonium ions.

[0048] The pharmaceutical compositions according to the invention can be formulated by adding non-toxic, pharmaceutically acceptable carriers, adjuvants, excipients, etc., according to conventional methods, and can be prepared into formulations for oral administration (e.g., tablets, capsules, lozenges, solutions, or suspensions) or into formulations for parenteral administration.

[0049] In addition, excipients that can be used in the pharmaceutical compositions according to the present invention include sweeteners, binders, solvents, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, flavoring agents, etc., and specific examples include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silicon dioxide, talc, stearic acid, sterols, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth gum, alginate, sodium alginate, methylcellulose, sodium carboxymethyl cellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange flavor, strawberry flavor, and vanilla flavor.

[0050] The compounds of the present invention may be included in a concentration level ranging from 0.1% by weight to 95% by weight based on the total weight of the pharmaceutical composition, that is, in an amount sufficient to achieve the desired effect.

[0051] The pharmaceutical compositions of the present invention can be formulated and used in the form of oral formulations (such as powders, granules, tablets, capsules, suspensions, emulsions, syrups or aerosols), topical formulations, suppositories or sterile injectable solutions according to conventional methods.

[0052] Pharmaceutical compositions comprising the compounds of the present invention may further include suitable carriers, excipients, or diluents according to conventional methods. Specifically, when formulated, the compositions may be prepared using commonly used diluents or excipients (such as fillers, expanders, binders, wetting agents, disintegrants, and surfactants). Solid dosage forms for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid dosage forms may be prepared by mixing the compound with at least one excipient (e.g., starch, calcium carbonate, sucrose, lactose, or gelatin). In addition to simple excipients, lubricants (such as magnesium stearate and talc) may also be used. Liquid dosage forms for oral administration include suspensions, oral solutions, emulsions, and syrups, and may include various excipients such as wetting agents, sweeteners, flavoring agents, and preservatives, in addition to water and liquid paraffin, which are commonly used as simple diluents. Dosage forms for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations, and suppositories. As non-aqueous solvents and suspensions, propylene glycol, polyethylene glycol, vegetable oils (such as olive oil), and injectable esters (such as ethyl oleate) can be used. As a matrix for suppositories, Witopsol, polyethylene glycol, Tween 61, cocoa butter, lauryl acetate, glycerin gelatin, etc., can be used.

[0053] The pharmaceutical compositions of the present invention can be administered to mammals (such as rats, mice, livestock, and humans) via various routes. All routes of administration can be performed, for example, by skin, oral, rectal, intravenous, intraperitoneal, intramuscular, subcutaneous, intrauterine, epidural, or intraventricular injection, and the compositions can preferably be administered via oral or intravenous routes, but are not limited thereto.

[0054] The pharmaceutical compositions of the present invention can be administered in pharmaceutically effective amounts. The term "pharmaceutically effective amount" refers to an amount sufficient to treat a disease with a reasonable benefit / risk ratio suitable for medical treatment, and the effective dose level can be determined based on factors including the type and severity of the subject, age, sex, drug activity, drug sensitivity, time of administration, route of administration and excretion rate, duration of treatment, concomitant drugs, and other factors well known in the medical field. For example, the pharmaceutical compositions can be administered at doses from 0.0001 mg / kg to 1000 mg / kg daily (specifically, from 0.01 mg / kg to 100 mg / kg), and can be administered once daily or in divided doses several times daily.

[0055] The pharmaceutical compositions of the present invention can be administered as a single therapeutic agent or in combination with other therapeutic agents for autoimmune diseases, and can be administered sequentially or simultaneously with conventional therapeutic agents for autoimmune diseases. They can also be administered as a single dose or multiple doses. Importantly, taking into account all of the above factors, the dosage is chosen to achieve the maximum effect without side effects, and this can be readily determined by those skilled in the art.

[0056] Furthermore, the present invention provides a health food composition for preventing or improving inflammatory diseases or autoimmune diseases, the health food composition comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0057] In this invention, "food" refers to a natural or processed product containing one or more nutrients, and specifically, to a product that has undergone a certain degree of processing and is ready for direct consumption; in its conventional sense, the term is used to cover various foods, functional foods, beverages, food additives, and beverage additives. Examples of food include various foods, beverages, chewing gum, tea, vitamin complexes, functional foods, etc. Furthermore, the foods of this invention include, but are not limited to, special nutritional foods (such as formula milk, infant food, etc.), processed meat products, processed fish products, tofu products, Korean-style starch jelly (jelly) products, noodle products (such as ramen (instant noodles), noodles, etc.), health supplements, condiments (such as soy sauce, soybean paste, chili sauce, mixed sauces, etc.), sauces, pastries (such as snacks), dairy products (such as fermented milk, cheese, etc.), other processed foods, kimchi, pickled foods (various kimchi, pickled vegetables (jangajji), etc.), beverages (such as fruit and vegetable beverages, soy milk, fermented beverages, ice cream, etc.), natural seasonings (such as ramen soup base, etc.), vitamin complexes, alcoholic beverages, wine, and other health supplements. Functional foods, beverages, food additives, or beverage additives can be prepared using conventional preparation methods.

[0058] As used herein, the term "health functional food" refers to a food manufactured and processed into tablets, capsules, powders, granules, liquids, pills, etc., using raw materials or ingredients that have functional properties beneficial to the human body. Here, the term "function" refers to achieving effects useful for health purposes, such as the regulation of the structure and function of nutrients or physiological functions related to the human body. The health functional food compositions of the present invention can be prepared by methods commonly used in the art, and in such preparation, raw materials and ingredients typically added in the art can be used. Furthermore, formulations of the health functional food compositions can be prepared without limitation, as long as they are considered formulations of health functional foods. The health functional food compositions of the present invention can be prepared into various dosage forms and, unlike general pharmaceuticals, have the advantage of not having the side effects that may occur with long-term drug administration due to their use of food as raw materials, and also have excellent portability. Therefore, the health functional food compositions of the present invention can be taken as supplements for the prevention or improvement of autoimmune diseases.

[0059] In addition, the health functional food composition may include food science-acceptable food additives, and may also include suitable carriers, excipients and diluents commonly used in the manufacture of functional foods.

[0060] In addition to the active ingredient, the health-functional food composition of the present invention may include sweeteners, flavoring agents, physiologically active ingredients, minerals, etc. Sweeteners may be used in an amount that imparts an appropriate sweetness to the food and may be natural or synthetic. Specifically, natural sweeteners may be used, and examples of natural sweeteners include sugar sweeteners (such as corn syrup solids, honey, sucrose, fructose, lactose, and maltose). Flavoring agents may be used to improve taste or aroma, and both natural and synthetic flavoring agents may be used. Specifically, natural flavoring agents may be used. When natural flavoring agents are used, nutritional fortification can be achieved in addition to flavoring. Examples of natural flavoring agents include natural flavoring agents obtained from apples, lemons, citrus fruits, grapes, strawberries, peaches, etc., or from green tea leaves, Solomon's seal rhizome (…). Polygonatum odoratum Natural flavorings can be obtained from bamboo leaves, cinnamon, chrysanthemum leaves, jasmine, etc. Additionally, natural flavorings can be obtained from ginseng (red ginseng), bamboo shoots, aloe vera, ginkgo, etc. Natural flavorings can be liquid concentrates or solid extracts. In some cases, synthetic flavorings can be used, and examples of synthetic flavorings that can be used include esters, alcohols, aldehydes, and terpenes. Examples of physiologically active substances that can be used include catechins (such as catechin, epicatechin, gallocatechin, and epigallocatechin) and vitamins (such as retinol, ascorbic acid, tocopherol, calciferol, thiamine, and riboflavin). Examples of minerals that can be used include calcium, magnesium, chromium, cobalt, copper, fluoride, germanium, iodine, iron, lithium, magnesium, manganese, molybdenum, phosphorus, potassium, selenium, silicon, sodium, sulfur, vanadium, and zinc.

[0061] In addition to the sweeteners mentioned above, the health-functional food composition of the present invention may also include preservatives, emulsifiers, acidifiers, thickeners, etc., as needed. These preservatives, emulsifiers, etc., are preferably added and used in trace amounts, as long as their purpose can be achieved. When expressed numerically, "trace amount" means a range of about 0.0005% by weight to about 0.5% by weight based on the total weight of the food composition. Examples of preservatives that can be used include sodium calcium sorbate, sodium sorbate, potassium sorbate, calcium benzoate, sodium benzoate, potassium benzoate, and EDTA (ethylenediaminetetraacetic acid). Examples of emulsifiers that can be used include gum arabic, carboxymethyl cellulose, xanthan gum, and pectin. Examples of acidifiers that can be used include citric acid, malic acid, fumaric acid, adipic acid, phosphoric acid, gluconic acid, tartaric acid, ascorbic acid, acetic acid, and phosphoric acid. In addition to enhancing flavor, such acidifiers may be added to inhibit microbial growth by adjusting the acidity of the food composition to an appropriate level. Examples of thickeners that can be used include suspending agents, precipitating agents, gelling agents, and swelling agents.

[0062] Furthermore, the present invention provides a method for preventing, improving, or treating inflammatory diseases or autoimmune diseases, the method comprising administering to a subject a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.

[0063] Furthermore, the present invention provides the use of compounds represented by Formula 1 or pharmaceutically acceptable salts thereof for the prevention, improvement or treatment of inflammatory diseases or autoimmune diseases.

[0064] The invention will be described in detail below with reference to the following experimental examples.

[0065] However, the following experimental examples are intended to illustrate the invention only, and the scope of the invention is not limited to the experimental examples.

[0066] [Experimental Example 1] Analysis of the inhibitory effect of pyridine compounds on innate immune response Previous studies have confirmed that the compound represented by Formula 2 (compound P1) potently inhibits DYRK1A, which promotes adaptive immune responses (such as T-cell immune responses). In this invention, experiments were conducted to determine whether compound P1 can also participate in innate immune responses in addition to adaptive immunity.

[0067] First, in vitro kinase assays were performed on compound P1 against 460 kinases. The results showed that, in addition to DYRK1A, IRAK4 and IRAK1 were identified among the top 20 kinases exhibiting high inhibitory activity. Specifically, for IRAK4 and IRAK1, substrate binding was confirmed to be inhibited by 99.6% and 99.1%, respectively, at a concentration of 1 μM, and even at a concentration of 0.1 μM, it was inhibited by 80% and 78%, respectively. A similar trend was observed in the kinase activity assay, with a high IC50 of 27 nM for IRAK4. 50 For IRAK1, there is an IC with a capacity of 153nm. 50 ( Figure 1 Given that IRAK4 and IRAK1 are the kinases that function at the highest levels in the downstream signaling pathway of TLR4, it can be explained that compound P1 can significantly suppress the overall innate immune response by inhibiting IRAK4 and IRAK1. Figure 2 ).

[0068] [Experimental Example 2] Analysis of the mechanism of action of pyridine compounds in inhibiting the innate immune response [2-1] Comparison of the innate immune response-inhibitory activities of pyridine compounds In Experiment Example 1 above, compound P1 was confirmed to have the potential to significantly suppress the overall innate immune response by inhibiting IRAK4 and IRAK1. To confirm the inhibition of IRAK4 and IRAK1 at the cellular level, THP-1 cells were treated with LPS and either compound P1 or existing IRAK4 inhibitors (Emavusertib and Zimlovisertib). After 30 minutes, the phosphorylation levels of downstream kinases of TLR4 were analyzed by Western blotting. The results showed that the phosphorylation level of IRAK4, as well as the phosphorylation levels of p38 and JNK, which are downstream kinases of IRAK4, were inhibited by compound P1 in a concentration-dependent manner. Figure 3 Specifically, compound P1 has a greater inhibitory effect on JNK than Zimlovisertib.

[0069] The above experiments confirmed that the potent inhibitory activity of compound P1 against the innate immune response stems from its inhibition of IRAK4, the main kinase that functions at the highest level in the downstream signaling pathway of TLR4.

[0070] [2-2] Analysis of expression patterns of genes associated with innate immune response and inflammatory response To confirm the inhibitory activity of compound P1 on the innate immune response, human THP-1 mononuclear cells were first treated with 0.1 μg / mL LPS to induce an innate immune response. Subsequently, cells were treated with compound P1 and three control drugs (3 μM each) for 12 hours. RNA was then obtained and RNA-seq was performed to analyze changes in expression patterns of 1499 genes related to innate and inflammatory responses out of a total of 24424 genes. Two DYRK1A / CLK inhibitors (Lorecivivint and B-02) currently undergoing clinical trials for autoimmune and inflammatory diseases, along with Aristolactam BIII, a naturally derived DYRK1A inhibitor, were used as control drugs.

[0071] The analysis confirmed that almost all gene expression patterns altered by LPS treatment were reversed after treatment with compound P1. Figure 4a This can be explained by the fact that compound P1 fundamentally inhibits the LPS-induced TLR4 innate immune response. Conversely, after treatment with Lorecivivint, the gene expression patterns altered by LPS treatment were reversed in some cases; however, for approximately 40% of genes, it was confirmed that the gene expression changes induced by LPS treatment were further aggravated. Meanwhile, in the B-02 treatment group and the Aristolactam BIII treatment group, it was confirmed that it had only a minimal effect on the gene expression patterns altered by LPS treatment.

[0072] Subsequently, highly representative genes were selected from those identified by RNA-seq analysis as described above, and their expression levels were analyzed by RT-PCR. The results confirmed that treatment with compound P1 reduced the expression levels of all genes—CCL2, CCL4, CCL3, CXCL1, PTAFR, CCL8, CXCL11, CCL5, BCL6, CCL20, IL-6, IL-1β, TNF-α, and MyD88—in a concentration-dependent manner. Figure 4b ).

[0073] Meanwhile, Lorecivivint altered the expression of some genes modified by LPS treatment in a direction that further exacerbated the changes, and this pattern was also observed in a group of genes other than those related to inflammation. Figure 5 This can be interpreted as indicating that, in the case of Lorecivivint, it does not merely specifically suppress the innate immune response, but rather induces alterations in gene expression through various mechanisms of action, with anti-inflammatory responses emerging as one of the consequences.

[0074] To analyze the mechanisms of action of compounds P1 and Lorecivivint more specifically, their inhibitory activity against cdc2-like kinase (CLK) was compared by measuring the phosphorylation level of the SR protein. Previous studies have reported that part of the anti-inflammatory effect of Lorecivivint is generated through CLK inhibition. The results confirmed that Lorecivivint exhibited significant CLK inhibitory activity, while compound P1 did not show any CLK inhibitory activity. Figure 6 This suggests that the anti-inflammatory effect of Lorecivivint may be related to its CLK inhibitory activity, and that the potent innate immune response suppressive activity of compound P1 is not derived from CLK inhibitory activity. Furthermore, given that both compound P1 and Lorecivivint possess DYRK1A inhibitory activity, this indicates that the innate immune response suppressive activity of compound P1 is not based on DYRK1A inhibitory activity.

[0075] The experiments described above confirmed that the compound represented by Formula 2 (compound P1) can significantly inhibit the expression of genes related to innate immune and inflammatory responses. Furthermore, it was confirmed that the innate immune response-suppressing activity of compound P1 is significantly superior to that of existing DYRK1A inhibitors, and that compound P1 exhibits this activity through a mechanism of action different from that of existing DYRK1A inhibitors.

[0076] [2-3] Comparison of innate immune response-inhibitory activities between pyridine compounds and competing drugs To compare and evaluate the innate immune response-inhibitory activity of compound P1 relative to competing drugs at the cellular level, a cell system capable of quantitatively monitoring NF-κB signaling based on luciferase (THP1-Lucia) was used. TM NF-κB cells (InvivoGen) are essential for regulating the expression of downstream genes in the innate immune response. After inducing an inflammatory response by treating cells with LPS, the cells were treated for 12 hours with compound P1 or with an IRAK4 inhibitor (Zimlovisertib, Emavusertib, KT-474), a JAK inhibitor (baricitinib), or a DYRK1A / CLK inhibitor (Lorecivivint) as a competing drug. Luciferase activity was then measured for comparative analysis.

[0077] As a result, LPS treatment increased luciferase expression, but it decreased significantly after concentration-dependent treatment with each drug. Specifically, treatment with compound P1 resulted in the largest decrease in luciferase expression. Figure 7 (A in the middle).

[0078] Next, to confirm the cytotoxicity of each drug, THP1-Lucia was treated with each drug. TM NF-κB cells were treated for 12 hours, and cell viability was then measured using Cell-Titer Glo. The results specifically confirmed that treatment with compound P1 resulted in the lowest cytotoxicity relative to a decrease in luciferase expression. Figure 7 (B in the middle).

[0079] The above experiments confirmed that compound P1, which has IRAK4 inhibitory activity, has innate immune response-suppressive activity in immune cells. Specifically, it was confirmed that compound P1 has significantly higher innate immune response-suppressive activity relative to its toxicity compared with competing drugs IRAK4 inhibitors (Zimlovisertib, Emavusertib, KT-474), JAK inhibitors (baricitinib), and DYRK1A / CLK inhibitors (Lorecivivint).

[0080] [Experimental Example 3] Analysis of the expression of secreted cytokines from pyridine compounds To compare the potent innate immune response-suppressive efficacy of compound P1 relative to competing drugs, the levels of cytokine production and secretion were analyzed using the Olink assay (a state-of-the-art proteomics technique). Specifically, after inducing an inflammatory response by treating THP-1 cells with LPS, the cells were treated with compound P1 or with Zimlovisertib, Emavusertib, or Lorecivivint as competing drugs, and then the cell culture medium was collected to analyze changes in the relative amounts of approximately 80 cytokine proteins.

[0081] As a result, LPS treatment significantly increased the levels of approximately 30 cytokine proteins, and the tested drugs exhibited inhibitory effects. Specifically, in the cases of compounds P1, Zimlovisertib, and Emavusertib, which have IRAK4 inhibitory activity, an overall reduction in approximately 30 genes was observed, clearly confirming a pattern completely opposite to that observed with LPS treatment alone. Figure 8a and 8b Of the three drugs, compound P1 was confirmed to exhibit the most concentration-dependent and relatively highest inhibitory efficacy. Conversely, Lorecivivint, which is mechanistically different from compound P1, was found to induce nonspecific changes in cytokine expression levels, confirming a similar trend to the mRNA level results observed above.

[0082] [Experimental Example 4] Analysis of the cytotoxicity of pyridine compounds Through Experiments 1, 2, and 3 described above, it was confirmed that compound P1 not only has the potential to effectively suppress adaptive immune responses by inhibiting DYRK1A, but also to effectively suppress innate immune responses by inhibiting IRAK4. In the following experiments, the cytotoxicity of compound P1 was compared with that of the existing DYRK1A inhibitor Lorecivivint, which is currently undergoing clinical trials.

[0083] As a result of cell viability measurements after treatment of CCD-18Co colonic fibroblasts and GM14660 lymphoblasts with compound P1 or Lorecivivint, it was confirmed that the cytotoxicity of compound P1 was significantly lower than that of Lorecivivint in both cell lines. Figure 9 ).

[0084] The above experiments confirmed that, despite possessing potent innate immune response-suppressive activity and a high probability of adaptive immune (specifically, T-cell immune regulation) activity based on its DYRK1A inhibitory activity, compound P1 exhibits significantly lower cytotoxicity than Lorecivivint, which is currently undergoing a phase 3 clinical trial for inflammatory diseases. Ultimately, due to its excellent anti-inflammatory effects and lower cytotoxicity compared to existing drugs, compound P1 is expected to be highly competitive as a treatment for inflammatory or autoimmune diseases.

[0085] [Experimental Example 5] Comparison of the innate immunosuppressive activities of pyridine compounds Next, innate immune response-inhibitory activity was compared among other pyridine compounds having structures similar to those of the compound represented by Formula 2 (compound P1). Compounds represented by Formula 3 (compound P2) and Formula 4 (compound P3), which have been reported to have inhibitory activity against DYRK1A in previous studies, were used as other pyridine compounds.

[0086] Innate immune response-inhibition activity was compared by transfecting THP-1 cells with the NF-κB-luciferase plasmid (as a reporter gene for expression of downstream genes in the TLR4 signaling pathway), followed by simultaneous treatment of cells with LPS and each drug for 6 hours, and then measuring luciferase activity.

[0087] As a result, LPS treatment increased luciferase expression, but a significant decrease in luciferase expression was observed after treatment with each drug. Specifically, treatment with compound P1 resulted in the largest decrease in luciferase expression. Figure 10 (A in the middle).

[0088] Next, to confirm the cytotoxicity of each drug, cell viability was measured using Cell-Titer Glo after each drug treatment. The results showed no significant changes in cell viability after treatment with any drug. Figure 10 (B in the middle).

[0089] Furthermore, after treating THP-1 cells with LPS and each of the other drugs simultaneously for 6 hours, total RNA was obtained, and the expression of several downstream genes of NF-κB was analyzed by RT-PCR. The results showed that LPS treatment increased the expression of downstream genes of NF-κB, but this expression was significantly reduced after additional treatment with each drug. Specifically, the expression of downstream genes of NF-κB was found to be significantly reduced in the compound P1 treatment group and the compound P2 treatment group. Figure 10 (C in the middle).

[0090] Meanwhile, as a result of cytotoxicity analysis 72 hours after treating hepatocellular carcinoma cells (HepG2) with pyridine drugs instead of immune cells, it was confirmed that compound P1 had relatively lower cytotoxicity than compound P2. Figure 10 (D in the middle).

[0091] Next, to confirm whether the innate immunosuppressive activity of pyridine drugs is generated through interaction with IRAK4, analysis was performed using a molecular docking prediction procedure. The results confirmed that all three pyridine compounds formed hydrogen bonds with amino acid residues around the ATP-binding pocket of IRAK4, thereby inhibiting IRAK4 activity. Figure 11 ).

[0092] The experiments described above confirmed that compounds represented by Formula 2 (compound P1), Formula 3 (compound P2), and Formula 4 (compound P3) (each possessing DYRK1A inhibitory activity) exhibit innate immune response-suppressive activity, which is generated through interaction with IRAK4. Specifically, compound P1 was confirmed to have significantly high innate immune response-suppressive activity, and none of compounds P1 to P3 exhibited significant cytotoxicity.

[0093] [Experimental Example 6] Evaluation of Drug Metabolism and Pharmacokinetics of Pyridine Compounds To evaluate the fundamental pharmaceutical properties of compound P1, which exhibits potent innate immune response-inhibitory activity and low cytotoxicity, various drug metabolism and pharmacokinetic evaluation experiments were performed as follows.

[0094] [6-1] In vitro ADME assessment The following six assessments were performed when in vitro ADME (absorption, distribution, metabolism, excretion) was conducted on compound P1.

[0095] First, as a result of confirming the physicochemical properties of compound P1, it was confirmed that all of the criteria for satisfying Ribinsky's five rules were met. Figure 12 (A in the middle).

[0096] Secondly, a metabolic stability analysis of compound P1 was performed. The metabolic stability of compound P1 was assessed using liver microsomes from mice, rats, dogs, and humans, with buspirone used as a positive control. The results confirmed that even at the longest test time of 60 minutes, over 50% of compound P1 remained in the liver microsomes. Figure 12 (A in the text). This means that the half-life of compound P1 in liver microsomes is 1 hour or longer, indicating that its metabolic stability is acceptable.

[0097] Third, procaine was used as a positive control to assess the plasma stability of compound P1. As a result of the assessment, even at the longest test time of 2 hours, compound P1 remained near 100%, confirming very high plasma stability. Figure 12 (A) In contrast, procaine was found to be almost undetectable in human serum after 2 hours.

[0098] Fourth, plasma protein binding analysis of compound P1 was performed using plasma proteins from humans, mice, rats, and dogs. As a result of the evaluation, the unbound drug fraction (fu) was measured at 25.18% in humans, 20.91% in mice, 22.14% in rats, and 38.85% in dogs. Figure 12 (A) This indicates the possibility that drug portions not bound to plasma proteins can be distributed into tissues, thus demonstrating the efficacy of compound P1.

[0099] Fifth, a Caco-2 assay was performed to analyze and predict the intestinal absorption rate of compound P1. As a result of the evaluation, the efflux ratio (ER) of compound P1 was confirmed to be 1.89 at 1 μM and 1.51 at 10 μM, indicating that normal absorption of the drug occurs in the intestine. Figure 12 (A in the middle).

[0100] Finally, the inhibitory efficacy of compound P1 against seven CYP (cytochrome P450) enzymes (1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4) was evaluated. These enzymes account for more than 90% of drug metabolism among the CYP enzymes important for drug metabolism in the liver. As a result of the evaluation, compound P1 was confirmed to have moderate inhibitory activity (IC50) against CYP 2C9. 50 =1.52μM), and had no inhibitory activity against the other six CYP enzymes ( Figure 12 (A in the middle).

[0101] [6-2] In vivo PK assessment Perform in vivo PK (pharmacokinetic) assessments to evaluate how much of compound P1 is absorbed, distributed, metabolized, and excreted in vivo.

[0102] Compound P1 was dissolved in a solvent containing DMAC, Cremophor EL, and 0.1M citrate buffer in a 1:1:8 ratio, and then administered intravenously or orally to mice and rats. Serum drug concentrations were measured over time. The intravenous dose was 1 mg / kg, and the oral dose was 10 mg / kg.

[0103] As a result of the measurements, intravenous administration resulted in a short half-life and low bioavailability; however, oral administration showed a very good half-life of 1.26 hours and a bioavailability of 6.7% in mice, and a half-life of 5.9 hours and a bioavailability of approximately 40% in rats. Figure 12 (B in the middle).

[0104] [6-3] Acute toxicity assessment To confirm the acute toxicity level of compound P1, cardiotoxicity and genotoxicity assessments were performed.

[0105] Specifically, compound P1 was dissolved in DMSO to prepare the drug, and to confirm the cardiotoxicity of the drug, hERG (human...) was analyzed. ether-à-go-go The inhibitory potential of compound P1 on potassium channels (related genes) was assessed. As a result of the assessment, low toxicity (IC50) of compound P1 to hERG channels was confirmed in hERG manual patch-clamp assays. 50 =265.2 μM), and similarly, in hERG fluorescence polarization assays, the low potential for hERG channel inhibition (IC50) was confirmed. 50 >75μM) Figure 13 ).

[0106] Next, to confirm the genotoxicity of compound P1, the Amethemoglobin assay was performed on mutant strains of Salmonella Typhimurium (TA98, TA100, TA1535, TA1537) and Escherichia coli (uvrA[pKM101]) to determine whether compound P1 induced reversion mutations. The results showed that the potential for compound P1 to induce reversion mutations was very low across all strains within the tested concentration range. Figure 13 ).

[0107] The above experiments confirmed that the compound represented by Formula 2 (compound P1) is a safe drug with very low potential to cause cardiotoxicity and genotoxicity.

[0108] [6-4] Non-GLP Toxicity Assessment Next, to confirm the in vivo toxicity level of compound P1, a non-GLP-level toxicity assessment was performed in mice.

[0109] First, compound P1 was dissolved in distilled water to prepare the drug. To determine the optimal concentration range, mice were orally administered a single dose of the drug at concentrations of 250 mg / kg, 500 mg / kg, or 1000 mg / kg, and survival was observed for one week. Results showed no mortality was observed at concentrations up to 500 mg / kg, while approximately 70% of the animals died at a concentration of 1000 mg / kg, confirming the approximately LD50. 50 The values ​​ranged from 500 mg / kg to 1000 mg / kg.

[0110] Based on the above results, the maximum dosing concentration was set at 500 mg / kg, and additional concentrations of 160 mg / kg and 50 mg / kg, corresponding to one-third of this concentration, were also included. Mice were then administered the drug orally once daily for two weeks, and survival rates were observed. Results showed no mortality at concentrations up to 160 mg / kg, while approximately 60% of the animals died at a concentration of 500 mg / kg.

[0111] Furthermore, during the 2-week repeated-dose experiment, the analysis and evaluation of indicators other than survival rate (body weight change, feed intake, general symptoms, ophthalmic symptoms, hematological examination, blood biochemistry, organ weight, necropsy findings, etc.) revealed that at a concentration of 500 mg / kg, not only did approximately 60% of the animals die, but abnormalities were also confirmed in various in vivo indicators. Meanwhile, at a concentration of 160 mg / kg, statistically significant changes and abnormal necropsy findings were confirmed in some indicators, while at a concentration of 50 mg / kg, no abnormalities were observed in any indicators. Figure 14a and Figure 14b Therefore, the No Observed Adverse Effect Level (NOAEL) is considered to be 50 mg / kg.

[0112] [Experimental Example 7] Confirmation of the therapeutic efficacy of pyridine compounds against autoimmune diseases In Experiment Examples 1 through 3 above, it was confirmed that compound P1 can potently suppress the innate immune response by inhibiting IRAK4, and also has the potential to modulate the adaptive immune response by inhibiting DYRK1A. In the following experiments, an in vivo efficacy assessment was performed to confirm whether compound P1 has therapeutic efficacy against actual autoimmune diseases.

[0113] Rheumatoid arthritis (RA), a representative autoimmune disease, was used as the model for this autoimmune disease. Specifically, a collagen-induced arthritis (CIA) model was established by administering type II collagen and CFA (complete Freund's adjuvant) to mice, followed by a second administration of type II collagen and IFA (incomplete Freund's adjuvant). Starting two days after IFA administration, mice were orally administered compound P1 once daily, and the severity of arthritis symptoms was assessed using the CAI (Clinical Arthritis Index) score. As a positive control, methotrexate, a first-line treatment for autoimmune diseases, was administered.

[0114] As a result of the experiment, clinical rheumatic symptoms began to appear 3 weeks after administration of type II collagen and CFA, and the severity of symptoms was found to worsen over time; however, after administration of compound P1, a 60% reduction in symptom severity (CAI score) was confirmed compared to the solvent-based group (a negative control). This symptom improvement was clearly observed even in the lowest dose group of 1 mg / kg, and the symptom improvement in the compound P1 group was confirmed to be similar to that in the methotrexate group (a positive control). Figure 15a and Figure 15b ).

[0115] Furthermore, as a result of histomorphological evaluation of mouse paws, excellent therapeutic effects were observed in both quantitative indicators of inflammatory activity and the severity of cartilage and bone damage (synovial hyperplasia, pannus formation, cartilage destruction, bone erosion) in arthritic tissues after treatment with compound P1, and quantitative indicators showing cartilage damage in the joint (matrix staining, surface regularity, cartilage thickness). This symptom improvement in the compound P1-treated group was found to be dose-dependent, and the therapeutic activity in the 10 mg / kg compound P1-treated group was confirmed to be similar to that in the methotrexate-treated group (positive control). Figure 15a and Figure 15b ).

[0116] Next, the dosage of compound P1 was reduced, and in vivo comparative efficacy was performed using Zimlovisertib (an IRAK4 inhibitor undergoing clinical trials for rheumatoid arthritis) and Baricitinib (a JAK1 / 2 inhibitor marketed as a treatment for rheumatoid arthritis) as positive control drugs.

[0117] As a result of the experiment, clinical rheumatic symptoms began to appear 3 weeks after administration of type II collagen and CFA, and the severity of symptoms was found to worsen over time; however, after administration of compound P1, the symptom severity (CAI score) was confirmed to be reduced to 60% compared to the solvent-based group, which served as a negative control. This symptom improvement was clearly observed even in the lowest dose group of 0.1 mg / kg, and the symptom improvement effect of the compound P1 group was confirmed to be superior to that of the 10 mg / kg Zimlovisertib group, which has a similar inhibitory mechanism. Conversely, the 5 mg / kg Baricitinib group showed superior symptom improvement compared to the compound P1 group. Figure 16a and Figure 16b Baricitinib has different inhibitory mechanisms.

[0118] Furthermore, as a result of histomorphological evaluation of mouse paws, the treatment with compound P1 confirmed excellent therapeutic effects in both quantitative indicators of inflammatory activity and the severity of cartilage and bone damage in arthritic tissues (synovial hyperplasia, pannus formation, cartilage destruction, bone erosion) and quantitative indicators of cartilage damage in the joint (matrix staining, surface regularity, cartilage thickness). This symptom improvement in the compound P1-treated group was found to be dose-dependent. Figure 16a and Figure 16b ).

[0119] The above experiments confirmed that compound P1, which possesses potent inhibitory activity against both innate and adaptive immune responses, exhibited excellent symptom-improving effects in a disease model of rheumatoid arthritis, a real autoimmune disease. Therefore, compound P1 is expected to be effectively used as a drug for inflammatory or autoimmune diseases.

[0120] Preferred embodiments of the invention have been described above by way of example; however, the scope of the invention is not limited to such specific embodiments, and those skilled in the art will be able to make appropriate modifications within the scope described in the claims of the invention.

Claims

1. A pharmaceutical composition for the prevention or treatment of inflammatory diseases or autoimmune diseases, the pharmaceutical composition comprising a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof as an active ingredient: [Formula 1] in, In Equation 1, R 1 For hydrogen or -NR 6 R 7 , where R 6 and R 7 Each is independently hydrogen, C1-C5 straight-chain or branched alkyl, or benzyl; R 2 R 3 and R 4 All are independently hydrogen, halogen, C1-C5 straight-chain or branched alkyl, -NR 8 R 9 -OR 8 -CN, -NHC(O)R 8 -SO2R 8 -OS(O)2R 8 , pyrrolidinyl, piperidinyl or morpholinyl, wherein R 8 and R 9 Each is independently hydrogen, C1-C5 straight-chain or branched alkyl, C1-C5 straight-chain or branched alkynyl, C1-C5 straight-chain or branched alkenyl, C6-C 12 Aryl groups, halogenated C6-C 12 Aryl or C6-C substituted with trihalomethyl 12 Aryl; and R 5 It is a hydrogen, C1-C5 straight-chain or branched alkyl, unsubstituted 4-piperidinyl or acetyl-substituted 4-piperidinyl.

2. The pharmaceutical composition according to claim 1, wherein, R 1 For hydrogen or -NR 6 R 7 , where R 6 and R 7 Each is independently hydrogen or a C1-C3 straight-chain or branched alkyl group; R 2 R 3 and R 4 All are independently hydrogen, -F, -Cl, -Br, -I, C1-C3 straight-chain or branched alkyl, -NR 8 R 9 -OR 8 -CN, -NHC(O)R 8 -SO2R 8 -OS(O)2R 8 , pyrrolidinyl, piperidinyl or morpholinyl, wherein R 8 and R 9 Each is independently hydrogen or a C1-C5 straight-chain or branched alkyl group; and R 5 It is a hydrogen, C1-C3 straight-chain or branched alkyl, unsubstituted 4-piperidinyl or acetyl-substituted 4-piperidinyl.

3. The pharmaceutical composition according to claim 1, wherein, R 1 For hydrogen or -NR 6 R 7 , where R 6 and R 7 Each is independently hydrogen or a C1-C3 straight-chain or branched alkyl group; R 2 R 3 and R 4 Each can be independently hydrogen, -F, -Cl, -Br, -I, or C. 1- C3 straight-chain or branched alkyl groups; and R 5 It is a hydrogen, C1-C3 straight-chain or branched alkyl, unsubstituted 4-piperidinyl or acetyl-substituted 4-piperidinyl.

4. The pharmaceutical composition according to claim 1, wherein, R 1 It is -NH2; R 2 R 3 and R 4 Both are independently hydrogen; and R 5 It is a hydrogen, C1-C3 straight-chain or branched alkyl, unsubstituted 4-piperidinyl or acetyl-substituted 4-piperidinyl.

5. The pharmaceutical composition according to claim 4, wherein, R 5 It is a hydrogen, C1 alkyl, unsubstituted 4-piperidinyl or acetyl-substituted 4-piperidinyl.

6. The pharmaceutical composition according to claim 1, wherein, Autoimmune diseases are diseases selected from at least one of the following groups: inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, Hashimoto's thyroiditis, chronic thyroiditis, ankylosing spondylitis, glomerulonephritis, chronic active infection, Behçet's disease, multiple sclerosis, systemic sclerosis, graft-versus-host disease, asthma, atopic dermatitis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes.

7. A health food composition for preventing or improving inflammatory diseases or autoimmune diseases, the health food composition comprising a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof as an active ingredient: [Formula 1] in, In Equation 1, R 1 For hydrogen or -NR 6 R 7 , where R 6 and R 7 Each is independently hydrogen, C1-C5 straight-chain or branched alkyl, or benzyl; R 2 R 3 and R 4 All are independently hydrogen, halogen, C1-C5 straight-chain or branched alkyl, -NR 8 R 9 -OR 8 -CN, -NHC(O)R 8 -SO2R 8 -OS(O)2R 8 , pyrrolidinyl, piperidinyl or morpholinyl, wherein R 8 and R 9 Each is independently hydrogen, C1-C5 straight-chain or branched alkyl, C1-C5 straight-chain or branched alkynyl, C1-C5 straight-chain or branched alkenyl, C6-C 12 Aryl groups, halogenated C6-C 12 Aryl or C6-C substituted with trihalomethyl 12 Aryl; and R 5 It is a hydrogen, C1-C5 straight-chain or branched alkyl, unsubstituted 4-piperidinyl or acetyl-substituted 4-piperidinyl.

8. The health functional food composition according to claim 7, wherein, R 1 For hydrogen or -NR 6 R 7 , where R 6 and R 7 Each is independently hydrogen or a C1-C3 straight-chain or branched alkyl group; R 2 R 3 and R 4 All are independently hydrogen, -F, -Cl, -Br, -I, C1-C3 straight-chain or branched alkyl, -NR 8 R 9 -OR 8 -CN, -NHC(O)R 8 -SO2R 8 -OS(O)2R 8 , pyrrolidinyl, piperidinyl or morpholinyl, wherein R 8 and R 9 Each is independently hydrogen or a C1-C5 straight-chain or branched alkyl group; and R 5 It is a hydrogen, C1-C3 straight-chain or branched alkyl, unsubstituted 4-piperidinyl or acetyl-substituted 4-piperidinyl.

9. The health functional food composition according to claim 7, wherein, R 1 For hydrogen or -NR 6 R 7 , where R 6 and R 7 Each is independently hydrogen or a C1-C3 straight-chain or branched alkyl group; R 2 R 3 and R 4 Each can be independently hydrogen, -F, -Cl, -Br, -I, or C. 1- C3 straight-chain or branched alkyl groups; and R 5 It is a hydrogen, C1-C3 straight-chain or branched alkyl, unsubstituted 4-piperidinyl or acetyl-substituted 4-piperidinyl.

10. The health functional food composition according to claim 7, wherein, R 1 It is -NH2; R 2 R 3 and R 4 Both are independently hydrogen; and R 5 It is a hydrogen, C1-C3 straight-chain or branched alkyl, unsubstituted 4-piperidinyl or acetyl-substituted 4-piperidinyl.

11. The health functional food composition according to claim 10, wherein, R 5 It is a hydrogen, C1 alkyl, unsubstituted 4-piperidinyl or acetyl-substituted 4-piperidinyl.

12. The health functional food composition according to claim 7, wherein, Autoimmune diseases are diseases selected from at least one of the following groups: inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, Hashimoto's thyroiditis, chronic thyroiditis, ankylosing spondylitis, glomerulonephritis, chronic active infection, Behçet's disease, multiple sclerosis, systemic sclerosis, graft-versus-host disease, asthma, atopic dermatitis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes.

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