Novel febuxostat derivatives and composition for preventing or treating inflammatory diseases containing same

Abstract

The present invention relates to a novel febuxostat derivative compound and a composition comprising same as an active ingredient for preventing or treating inflammatory or autoimmune diseases. The compounds of the present invention significantly reduce the expression of inflammatory cytokines in macrophages even at low doses, thereby effectively suppressing excessive inflammatory responses, and can thus be advantageously used for long-term administration in the treatment of inflammatory diseases, which are, for the most part, chronic.

Description

Novel febuxostat derivatives and compositions containing the same for preventing or treating inflammatory diseases

[0001] The present invention relates to a novel febuxostat derivative compound and a composition for preventing or treating inflammatory or autoimmune diseases comprising the same as an active ingredient.

[0002]

[0003] Inflammation is an immune response that involves immune cells, blood vessels, and inflammatory mediators in response to harmful stimuli such as pathogens, autoantigens, and viral infections. The inflammatory response is induced by substances produced to protect the body. It suppresses cellular damage in its early stages, removes damaged or necrotic tissue, and promotes tissue regeneration. However, despite these protective functions, inflammation can also lead to tissue damage or disease.

[0004] Gout, known to induce an inflammatory response, is a representative metabolic disease caused by hyperuricemia, in which the blood concentration of uric acid, the final product of purine metabolism, increases. As uric acid between the blood and joints is deposited in the form of urate crystals in the tissues around the joints and subcutaneous tissues, it is accompanied by an excessive inflammatory response and pain.

[0005] Febuxostat, developed as a gout treatment, is a xanthine oxidase inhibitor that suppresses the formation of uric acid, a metabolic byproduct of purines consumed through food. However, febuxostat has been reported to cause adverse effects such as cardiovascular damage, impaired liver function, chest pain, and shortness of breath. Furthermore, its high dosage of 80 mg for adults has raised concerns about side effects. Therefore, there is a pressing need for alternative medications that exhibit significant pharmacological effects even at low doses.

[0006] Meanwhile, inflammatory responses caused by various factors in vivo, such as tumorigenesis, autoimmune diseases, and pathogens, are particularly related to the secretion of inflammatory cytokines by the activation of macrophages present throughout tissues. The secretion of inflammatory cytokines such as IL-1β causes neutrophils to accumulate as inflammatory cells, which further induces excessive inflammatory responses in surrounding tissues, resulting in chronic inflammation. IL-1β, a representative inflammatory cytokine, is synthesized in an inactive state and is activated through the formation of a complex with various proteins called inflammasomes. When macrophages are exposed to inflammatory factors, NLRP3 (NLR Family Pyrin Domain Containing 3), a type of inflammasome, activates caspase-1 to produce active IL-1β and IL-18, thereby inducing inflammation. Therefore, inhibiting the production of inflammatory cytokines such as IL-1β and IL-18 is a very important mechanism for suppressing inflammation.

[0007] Accordingly, the inventors of the present invention sought to explore various febuxostat-based derivatives with anti-inflammatory activity by suppressing IL-1β expression in macrophages stimulated with an inflammatory factor.

[0008]

[0009] Numerous papers and patents are referenced and cited throughout this specification. The disclosures of these cited papers and patents are incorporated herein by reference in their entirety to provide a clearer understanding of the state of the art and the scope of the present invention.

[0010] The present inventors have diligently researched and developed novel small-molecule therapeutics that achieve superior therapeutic effects for various diseases caused by excessive or unwanted immune or inflammatory responses. As a result, we discovered that the febuxostat derivative compound of Chemical Formula 1, described below, can be used as an effective therapeutic composition to significantly suppress or alleviate the symptoms of various inflammatory or autoimmune diseases by significantly suppressing the expression of inflammatory cytokines.

[0011] The present invention provides a novel derivative compound of febuxostat and a composition for preventing or treating inflammatory or autoimmune diseases, including the same as an active ingredient.

[0012]

[0013] Other objects and advantages of the present invention will become more apparent from the detailed description, claims and drawings below.

[0014] According to one aspect of the present invention, the present invention provides a compound represented by the following chemical formula 1:

[0015] Chemical Formula 1

[0016]

[0017] In the above chemical formula, R1 is C1-C6 alkoxy, halogen, or 5-membered-6-membered heterocycloalkyl; L1 is a direct bond, -NH-, or -C(O)NH-; A is unsubstituted or substituted 5-membered-9-membered heteroaryl selected from the group consisting of C1-C5 alkyl, C1-C5 hydroxyalkyl, NR3R4 (R3 and R4 are each independently hydrogen or C1-C7 alkyl), and -COOR2 (R2 is hydrogen or C1-C3 alkyl).

[0018] The present inventors have diligently researched and developed novel small-molecule therapeutics that achieve superior therapeutic effects for various diseases caused by excessive or unwanted immune or inflammatory responses. As a result, the present inventors have discovered that the febuxostat derivative compound of Chemical Formula 1 significantly suppresses the expression of inflammatory cytokines in macrophages, thereby significantly suppressing or alleviating the symptoms of various inflammatory or autoimmune diseases. This discovery led to the completion of the present invention.

[0019] In this specification, the term "alkoxy" means a radical formed by the removal of hydrogen from an alcohol, for example, C1-C6 alkoxy means a radical formed by the removal of hydrogen from an alcohol having 1 to 6 carbon atoms.

[0020] As used herein, the term "halogen" refers to a halogen group element, including, for example, fluoro, chloro, bromo, and iodo. According to a specific embodiment of the present invention, the halogen is fluoro.

[0021] As used herein, the term "heterocycloalkyl" refers to a saturated carbon ring containing oxygen, sulfur, or nitrogen as a heteroatom within the ring. Specifically, the heteroatom is nitrogen or oxygen, and more specifically, nitrogen. The number of heteroatoms is 1-2, and specifically, 1. "Heterocycloalkyl of a 5- or 6-membered ring" refers to a ring in which the sum of the numbers of carbons and heteroatoms forming the ring is 5 or 6.

[0022] According to a specific embodiment of the present invention, the heterocycloalkyl of the five-membered-six-membered ring is selected from the group consisting of piperidine, pyrrolidine, morpholine and piperazine, and more specifically, piperidine.

[0023] As used herein, the term "alkyl" means a straight-chain or branched saturated hydrocarbon group, including, for example, methyl, ethyl, propyl, isopropyl, etc. C1-C5 alkyl means an alkyl group having an alkyl unit having 1 to 5 carbon atoms, and when C1-C5 alkyl is substituted, the carbon number of the substituent is not included.

[0024] As used herein, the term "hydroxyalkyl" refers to a straight-chain or branched saturated hydrocarbon group substituted with a hydroxy group. C1-C5 hydroxyalkyl refers to an alkyl group in which any one hydrogen of the alkyl unit having 1 to 5 carbon atoms is replaced with a hydroxy group.

[0025] As used herein, the term "heteroaryl" refers to a heterocyclic aromatic group containing oxygen, sulfur or nitrogen as a heteroatom within the ring. The number of heteroatoms contained within the ring is 1-3, and specifically 1-2. The term "penta- to non-penta-membered ring heteroaryl" refers to a heteroaryl having 5 to 9 ring atoms including both carbon and heteroatoms, and the ring may be a monocycle or a bicycle.

[0026] According to a specific embodiment of the present invention, the 5-membered-9-membered heteroaryl is selected from the group consisting of triazole, thiazole, benzothiazole, thiophene, furan, pyrrole, indole, imidazopyridine, and benzimidazole.

[0027] According to a specific embodiment of the present invention, A is a heteroaryl of a 5-membered or 9-membered ring, which is unsubstituted or substituted with one or two substituents selected from the group consisting of C1-C3 alkyl, C1-C3 hydroxyalkyl, -COOR2 (R2 is hydrogen or C1-C2 alkyl), and NR3R4 (R3 is hydrogen and R4 is hydrogen or C1-C7 alkyl).

[0028] According to a specific embodiment of the present invention, when A is a heteroaryl of a 5-membered or 9-membered ring substituted with two substituents, A is a triazole, thiazole, benzimidazole or imidazopyridine substituted with two substituents selected from the group consisting of C1-C3 alkyl, C1-C3 hydroxyalkyl, -COOR2 (R2 is hydrogen or C1-C2 alkyl) and NR3R4 (R3 is hydrogen and R4 is hydrogen or C4-C7 alkyl).

[0029] More specifically, when A is a heteroaryl of a 5-membered or 9-membered ring substituted with two substituents, A is a triazole or thiazole substituted with C1-C3 alkyl and C1-C3 hydroxyalkyl; an imidazopyridine substituted with -COOH and NR3R4 (R3 is hydrogen and R4 is hydrogen or C4-C7 alkyl); or a benzimidazole substituted with C1-C4 alkyl and -COOR2 (R2 is C1-C2 alkyl).

[0030] According to a specific embodiment of the present invention, when L1 is -NH- or -C(O)NH-, R1 is C2-C5 alkoxy; and A is a heteroaryl having a nine-membered ring substituted with C1-C3 hydroxyalkyl or -COOR2 (R2 is hydrogen or C1-C3 alkyl).

[0031] According to a specific embodiment of the present invention, when L1 is a direct bond, R1 is C2-C5 alkoxy, halogen, or 6-membered ring heterocycloalkyl; and A is 5-9-membered ring heteroaryl substituted with one or more substituents selected from the group consisting of C1-C5 alkyl, C1-C3 hydroxyalkyl, NR3R4 (R3 and R4 are each independently hydrogen or C1-C7 alkyl), and -COOR2 (R2 is hydrogen or C1-C3 alkyl).

[0032]

[0033] According to a specific embodiment of the present invention, the compound represented by the chemical formula 1 is selected from the group consisting of compounds represented by the following chemical formulas 2 to 16:

[0034] Chemical Formula 2

[0035]

[0036] Chemical Formula 3

[0037]

[0038] Chemical Formula 4

[0039]

[0040] Chemical Formula 5

[0041]

[0042] Chemical Formula 6

[0043]

[0044] Chemical Formula 7

[0045]

[0046] Chemical Formula 8

[0047]

[0048] Chemical Formula 9

[0049]

[0050] Chemical Formula 10

[0051]

[0052] Chemical Formula 11

[0053]

[0054] Chemical Formula 12

[0055]

[0056] Chemical Formula 13

[0057]

[0058] Chemical Formula 14

[0059]

[0060] Chemical Formula 15

[0061]

[0062] Chemical Formula 16

[0063]

[0064]

[0065] According to another aspect of the present invention, the present invention provides a composition for preventing or treating inflammation or autoimmune disease, comprising the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient.

[0066] According to another aspect of the present invention, the present invention provides a method for preventing or treating an inflammatory or autoimmune disease, comprising administering to a subject a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0067] The term “inflammatory or autoimmune disease” as used herein refers to a disease in which an internal normal cell or normal tissue of an individual is damaged by an excessive or unwanted immune response and resulting inflammatory response caused by various genetic and / or environmental factors.

[0068] The inflammatory or autoimmune disease prevented or treated by the composition of the present invention is, for example, one or more diseases selected from the group consisting of rheumatoid arthritis, reactive arthritis, type 1 diabetes, type 2 diabetes, systemic lupus erythematosus, multiple sclerosis, idiopathic fibrosing alveolitis, myasthenia gravis, polymyositis, dermatomyositis, localized scleroderma, systemic scleroderma, colitis, inflammatory bowel disease, Sjorgen's syndrome, Raynaud's phenomenon, Bechet's disease, Kawasaki's disease, primary biliary sclerosis, primary sclerosing cholangitis, ulcerative colitis, Crohn's disease, atopic dermatitis, inflammatory encephalopathy, and gout.

[0069] In this specification, the term "inflammatory brain disease" is a comprehensive term that refers to all neurological diseases caused by inflammatory damage to brain tissue including brain parenchyma, and includes Alzheimer's disease, Parkinson's disease, argyrophilic grain disease (AGD), Lewy body dementia, frontotemporal dementia, progressive supranuclear palsy (PSP), progressive supranuclear palsy-Parkinson syndrome (PSP-P), Richardson syndrome, Pick's disease, Niemann-Pick disease, and Rasmussen's syndrome.

[0070] The term "prevention" as used herein means inhibiting the occurrence of a disease or condition in a subject who has not been diagnosed as having the disease or condition but is susceptible to such disease or condition.

[0071] As used herein, the term "treatment" means (a) suppressing the development of a disease, condition, or symptom; (b) alleviating the disease, condition, or symptom; or (c) eliminating the disease, condition, or symptom. The composition of the present invention suppresses the development of symptoms caused by excessive or unwanted immune responses or inflammation by suppressing the expression of inflammatory cytokines in macrophages, thereby suppressing the development of symptoms, eliminating them, or alleviating them. Therefore, the composition of the present invention may be a composition for treating these diseases on its own, or may be administered together with other pharmacological ingredients having an anti-inflammatory effect and used as an adjuvant treatment for the diseases. Accordingly, the terms "treatment" or "therapeutic agent" as used herein include the meaning of "adjuvant treatment" or "adjuvant treatment agent."

[0072] As used herein, the term “administration” or “administering” refers to directly administering a therapeutically effective amount of the composition of the present invention to a subject so that the same amount is formed in the body of the subject.

[0073] In the present invention, the term "therapeutically effective amount" means the content of a composition containing a pharmacological ingredient in the composition sufficient to provide a therapeutic or preventive effect to a subject to whom the pharmaceutical composition of the present invention is to be administered, and includes a "prophylactically effective amount".

[0074] The term "subject" as used herein includes, without limitation, a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, monkey, chimpanzee, baboon, or rhesus macaque. Specifically, the subject of the present invention is a human.

[0075] As used herein, the term "pharmaceutically acceptable salt" includes salts derived from pharmaceutically acceptable inorganic acids, organic acids, or bases. Examples of suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, trifluoroacetic acid, citric acid, methanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. Salts derived from suitable bases may include alkali metals such as sodium, alkaline earth metals such as magnesium, and ammonium.

[0076] When the composition of the present invention is prepared as a pharmaceutical composition, the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier.

[0077] Pharmaceutically acceptable carriers included in the pharmaceutical composition of the present invention are those commonly used in formulations, and include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition to the above components, the pharmaceutical composition of the present invention may further include lubricants, wetting agents, sweetening agents, flavoring agents, emulsifiers, suspending agents, preservatives, and the like. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington's Pharmaceutical Sciences (19th ed., 1995).

[0078] The pharmaceutical composition of the present invention can be administered orally or parenterally, and specifically can be administered orally, intravenously, or intramuscularly.

[0079] The appropriate dosage of the pharmaceutical composition of the present invention may be prescribed in various ways depending on factors such as the formulation method, administration method, patient age, weight, sex, pathological condition, food, administration time, administration route, excretion rate, and response sensitivity. The preferred dosage of the pharmaceutical composition of the present invention is within the range of 0.001-100 mg / kg for adults.

[0080] The pharmaceutical composition of the present invention can be manufactured in a unit dose form or can be manufactured by inserting it into a multi-dose container by formulating it using a pharmaceutically acceptable carrier and / or excipient according to a method that can be easily performed by a person having ordinary skill in the art to which the present invention pertains, and the like. In this case, the formulation may be in the form of a solution, suspension, syrup or emulsion in an oil or aqueous medium, or in the form of an extract, powder, granule, tablet or capsule, and may additionally include a dispersing agent or stabilizer.

[0081] According to another aspect of the present invention, the present invention provides a functional food composition for improving or preventing inflammation or autoimmune disease, comprising the compound of the present invention or a food-related acceptable salt thereof as an active ingredient.

[0082] The chemical formula 1 compound used in the present invention and the inflammatory or autoimmune disease that can be improved or prevented by using the compound have already been described above, so their description is omitted to avoid excessive duplication.

[0083] In this specification, the term "food-acceptable salt" means a salt in a form that can be used in a food composition, among salts in which cations and anions are bonded by electrostatic attraction, and specific examples thereof include the examples of "pharmaceutically acceptable salts" described above.

[0084] When the composition of the present invention is manufactured as a food composition, it may contain not only the compound of the present invention as an active ingredient, but also carbohydrates, seasonings, and flavoring agents that are commonly added during food manufacturing. Examples of carbohydrates include, but are not limited to, monosaccharides such as glucose and fructose; disaccharides such as maltose and sucrose; polysaccharides such as dextrin and cyclodextrin; and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents, natural flavoring agents [thaumatin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.]) and synthetic flavoring agents (saccharin, aspartame, etc.) can be used. For example, when the food composition of the present invention is manufactured as a drink, in addition to the pine bark extract, which is an active ingredient of the present invention, citric acid, liquid fructose, sugar, glucose, acetic acid, malic acid, fruit juice, Eucommia ulmoides extract, jujube extract, licorice extract, etc. can be additionally included.

[0085]

[0086] The features and advantages of the present invention are summarized as follows:

[0087] (a) The present invention provides a novel derivative compound of Febuxostat and a composition for preventing or treating inflammatory or autoimmune diseases, comprising the same as an active ingredient.

[0088] (b) The compound of the present invention can be effectively used for long-term administration to treat inflammatory diseases, most of which are chronic diseases, by significantly reducing the expression of inflammatory cytokines in macrophages even at low doses, thereby effectively suppressing excessive inflammatory responses.

[0089]

[0090] Figure 1 is a diagram illustrating an experimental process in which the anti-inflammatory effect was evaluated by measuring the expression level of IL-1β after treating macrophages induced with inflammation by LPS and ATP with a febuxostat derivative of the present invention.

[0091] Figure 2 is a drawing showing the results of measuring changes in IL-1β expression by compounds FT003, FT005, FT033, and FT042 (Figure 2a); compounds FT025 and FT064 (Figure 2b); and compounds FT023, FT027, FT036, FT037, FT039, FT041, FT046, FT055, and FT058 (Figure 2c) using ELISA.

[0092] Figure 3 shows the results confirming the neuroprotective effect of the febuxostat derivative of the present invention against inflammatory damage. Figure 3a is a diagram illustrating the experimental process for evaluating the anti-inflammatory effect by pretreating microglial cells with the febuxostat derivatives FT033 and FT037 compounds of the present invention, then inducing inflammation with LPS and ATP and measuring the level of IL-1β expression. Figure 3b is a graph showing the results of measuring the change in IL-1β expression by the FT033 and FT037 compounds through ELISA.

[0093]

[0094] 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.

[0095]

[0096] Example

[0097] Synthetic FT series low molecular weight compounds and synthetic process number (chemical formula) structure IUPAC name FT003(2) 2-Fluoro-5-(5-(hydroxymethyl)-4-methyl-1H-1,2,3-triazol-1-yl)benzonitrileFT005(3) 2-Fluoro-5-(5-(hydroxymethyl)-4-methylthiazol-2-yl)benzonitrile FT023(4) 2-((3-cyano-4-isobutoxyphenyl)amino)benzo[d]thiazole-6-carboxylic acid FT025(5) Ethyl 2-(3-cyano-4-isobutoxybenzamido)benzo[d]thiazole-6-carboxylate FT027(6) 3-Cyano-N-(6-(hydroxymethyl)benzo[d]thiazol-2-yl)-4-isobutoxybenzamide FT033(7) 5-(3-cyano-4-isobutoxyphenyl)thiophene-2-carboxylic acid FT036(8) 5-(3-cyano-4-isobutoxyphenyl)furan-2-carboxylic acid FT037(9) 5-(5-(hydroxymethyl)furan-2-yl)-2-isobutoxybenzonitrile FT039(10) 5-(3-cyano-4-isobutoxyphenyl)-1H-pyrrole-2-carboxylic acid FT041(11) 3-(3-cyano-4-isobutoxyphenyl)-1H-indole-5-carboxylic acid FT042(12) Methyl 2-(3-cyano-4-(piperidin-1-yl)phenyl)benzo[d]thiazole-6-carboxylate FT046(13) 3-(tert-butylamino)-2-(3-cyano-4-isobutoxyphenyl)imidazo[1,2-a]pyridine-6-carboxylic acid FT055(14) 2-(3-cyano-4-isobutoxyphenyl)imidazo[1,2-a]pyridine-6-carboxylic acid FT058(15) 3-Amino-2-(3-cyano-4-isobutoxyphenyl)imidazo[1,2-a]pyridine-6-carboxylic acid FT064(16) Methyl 2-(3-cyano-4-isobutoxyphenyl)-1-isobutyl-1H-benzo[d]imidazole-6-carboxylate

[0098]

[0099]

[0100] Synthetic example

[0101] Synthesis of compound FT003

[0102] [FT003]

[0103]

[0104] (1) Synthesis of compound B

[0105] Compound A 600 mg (3.79 mmol) and ethyl 2-butynoate 622 mg (5.55 mmol) were dissolved in 20 mL of toluene solvent, and the mixture was heated and stirred at 130°C for 16 hours. The reaction mixture was cooled to room temperature and distilled under reduced pressure. The obtained mixture was separated and purified by silica gel column chromatography (Hex: CH2Cl2 = 1: 3 volume ratio) to obtain compound B 352 mg (1.28 mmol, yield 35%).

[0106]

[0107] (2) Synthesis of compound FT003

[0108] Compound B58 mg (0.21 mmol) was dissolved in 3 mL of MeOH solvent, cooled to 0°C, and NaBH416 mg (0.42 mmol) was slowly added. The reaction mixture was stirred at room temperature for 16 hours, and 10 mL of sat. NH4Cl(aq) was added dropwise to the reaction mixture, and extracted twice with 10 mL of EtOAc. The obtained EtOAc layer was dried over MgSO4, and the solid was removed by filtering, and the filtrate was distilled under reduced pressure. The obtained mixture was separated and purified by silica gel column chromatography (Hex:EtOAc = 1:1 volume ratio) to obtain compound FT00332 mg (0.14 mmol, yield 66%).

[0109] 1 H NMR (600 MHz, Methanol-d4) δ8.22(dd,J=5.5, 2.7 Hz, 1H), 8.10 (ddd,J=9.0, 4.6, 2.7 Hz, 1H), 7.63 (t,J=8.8 Hz, 1H), 4.61 (s, 2H), 2.41 (s, 3H).

[0110]

[0111] Synthesis of compound FT005

[0112] [FT005]

[0113]

[0114] (1) Synthesis of compound E

[0115] Compound C 200 mg (1.00 mmol), Compound D 256 mg (1.50 mmol), Pd(OAc) 244.9 mg (0.2 mmol), P(t-Bu) 340.46 mg (0.2 mmol), and K2CO3 276.39 mg (2.0 mmol) were dissolved in 3 mL of toluene solvent, and the mixture was heated and stirred at 130°C for 48 hours. 10 mL of sat. NH4Cl(aq) was added dropwise to the reaction mixture, and extracted twice with 10 mL of EtOAc. The obtained EtOAc layer was dried over MgSO4, and the solid was removed by filtering, and the filtrate was distilled under reduced pressure. The obtained mixture was separated and purified by silica gel column chromatography (Hex:EtOAc = 30:1 volume ratio) to obtain Compound E 113 mg (0.39 mmol, yield 38%).

[0116]

[0117] (2) Synthesis of compound FT005

[0118] Compound E11 mg (0.04 mmol) was dissolved in 1 mL of THF solvent, the temperature was lowered to 0°C, and 1.65 mg (0.08 mmol) of LiBH4 was slowly added. The reaction mixture was stirred at room temperature for 16 hours, and 10 mL of sat. NH4Cl(aq) was added dropwise to the reaction mixture, and extracted twice with 10 mL of EtOAc. The obtained EtOAc layer was dried over MgSO4, the solid was removed by filtering, and the filtrate was distilled under reduced pressure. The obtained mixture was separated and purified by silica gel column chromatography (Hex:EtOAc = 3:1 volume ratio) to obtain compound FT0056 mg (0.02 mmol, yield 63%).

[0119] 1 H NMR (600 MHz, Methanol-d4) δ8.29(dd,J=6.0, 2.3 Hz, 1H), 8.23 ​​(ddd,J=8.9, 5.0, 2.4 Hz, 1H), 7.48 (t,J=8.9 Hz, 1H), 4.76 (s, 2H), 2.43 (s, 3H).

[0120] Synthesis of compound FT023

[0121] [FT023]

[0122]

[0123] (1) Synthesis of compound H

[0124] Compound F40 mg (0.17 mmol) and compound G57 mg (0.21 mmol) were dissolved in 2 mL of DMSO, and then CuBr 0.2 mg (0.002 mmol) and tetrabutyl ammonium bromide 16 mg (0.17 mmol) were added. The reaction mixture was heated and stirred at 40°C for 6 hours. After the reaction mixture was cooled to room temperature, 10 mL of water was added dropwise, and extracted twice with 10 mL of EtOAc. The obtained EtOAc layer was dried over MgSO4, the solid was removed by filtering, and the filtrate was distilled under reduced pressure. The obtained mixture was separated and purified by silica gel column chromatography (Hex:EtOAc = 3:1 volume ratio) to obtain compound H35 mg (0.092 mmol, yield 53%).

[0125]

[0126] (2) Synthesis of compound FT023

[0127] Compound H40 mg (0.10 mmol) was dissolved in MeOH:THF (1 mL, 1.5 mL) solvent, 0.63 mL (1.26 mmol) of 2M NaOH aqueous solution was added, and the mixture was stirred at room temperature for 16 hours. Acidic ion exchange resin was added to the reaction mixture to adjust the pH to 3–4, filtered, and the ion exchange resin was washed with EtOAc. The entire filtrate was collected and distilled under reduced pressure to obtain FT02316 mg (0.05 mmol, yield 43%).

[0128] 1H NMR (600 MHz, DMSO-d6)δ10.83(s,1H),8.42(d,J=1.8 Hz, 1H), 8.21 (d,J=2.8 Hz, 1H), 7.92-7.87 (m, 2H), 7.66 (d,J=8.4 Hz, 1H), 7.30 (d,J=9.2 Hz, 1H), 3.91 (d,J=6.5 Hz, 2H), 2.09-2.04 (m, 1H), 1.01 (d,J=6.7 Hz, 6H).

[0129]

[0130] Synthesis of compound FT025

[0131] [FT025]

[0132]

[0133] (1) Synthesis of compound FT025

[0134] Compound I 200 mg (0.91 mmol) was dissolved in 12 mL of DMF solvent, then compound J 243 mg (1.09 mmol) and HOBt 283 mg (1.82 mmol) were added, the temperature was lowered to 0℃, and EDCI 349 mg (1.82 mmol) was added. After stirring at room temperature for 16 hours, 10 mL of sat. NaHCO3(aq) was added dropwise to the reaction mixture, and extracted twice with 10 mL of EtOAc. The obtained EtOAc layer was dried over MgSO4, and the solid was removed by filtering, and the filtrate was distilled under reduced pressure. The obtained mixture was separated and purified by silica gel column chromatography (CH2Cl2:MeOH=20:1 volume ratio) to obtain compound FT025 145 mg (0.35 mmol, yield 38%).

[0135] 1H NMR (600 MHz, DMSO-d6) δ8.67(d,J=1.8 Hz, 1H), 8.55(d,J=2.4 Hz, 1H), 8.40(dd,J=8.9, 2.3 Hz, 1H), 8.03(dd,J=8.5, 1.8 Hz, 1H), 7.84(d,J=8.4 Hz, 1H), 7.43 (d,J=9.0 Hz, 1H), 4.35(q,J=7.1 Hz, 2H), 4.04(d,J=6.5 Hz, 2H), 2.14-2.06 (m, 1H), 1.35 (t,J=7.1 Hz, 3H), 1.02 (d,J=6.7 Hz, 6H).

[0136]

[0137] Synthesis of compound FT027

[0138] [FT027]

[0139]

[0140] (1) Synthesis of compound FT027

[0141] Compound FT02580 mg (0.19 mmol) was dissolved in 2 mL of THF solvent, the temperature was lowered to 0℃, and 0.76 mL (0.76 mmol) of DIBAL-H 1.0 M in THF was added dropwise. The reaction mixture was stirred at room temperature for 16 hours, and 10 mL of sat. NH4Cl(aq) was added dropwise to the reaction mixture, and extracted twice with 10 mL of EtOAc. The obtained EtOAc layer was dried over MgSO4, and the solid was removed by filtering, and the filtrate was distilled under reduced pressure. The obtained mixture was separated and purified by silica gel column chromatography (Hex: Acetone = 2:1 volume ratio) to obtain FT02742 mg (0.11 mmol, yield 56%).

[0142] 1H NMR (600 MHz, DMSO-d6) δ8.53(d,J= 2.3 Hz, 1H), 8.39 (dd,J= 8.9, 2.3 Hz, 1H), 7.93 (s, 1H), 7.72 (d,J=8.2 Hz, 1H), 7.43 - 7.40 (m, 2H), 5.28 (s, 1H), 4.61 (d,J= 4.6 Hz, 2H), 4.03 (d,J= 6.5 Hz, 2H), 2.14 - 2.06 (m, 1H), 1.02 (d,J= 6.7 Hz, 6H).

[0143]

[0144] Synthesis of compound FT033

[0145] [FT033]

[0146]

[0147] (1) Synthesis of compound M

[0148] Compound K245 mg (0.81 mmol), compound L120 mg (0.54 mmol), Pd(PPh3)463 mg (0.05 mmol), and Na2CO3115 mg (1.09 mmol, 2 M aqueous solution) were dissolved in 5 mL of 1,4-dioxane solvent, and stirred and heated at 90°C for 6 hours. After cooling the reaction mixture to room temperature, 10 mL of sat. NH4Cl(aq) was added dropwise, and extracted twice with 10 mL of EtOAc. The obtained EtOAc layer was dried over MgSO4, and the solid was removed by filtering, and the filtrate was distilled under reduced pressure. The obtained mixture was separated and purified by silica gel column chromatography (Hex:EtOAc = 8:1 volume ratio) to obtain compound M120 mg (0.38 mmol, yield 70%).

[0149]

[0150] (2) Synthesis of compound FT033

[0151] Compound M50 mg (0.16 mmol) was dissolved in THF: MeOH: H2O (1 mL, 2 mL, 1 mL), 0.95 mL (1.90 mmol) of 2M NaOH aqueous solution was added, and the mixture was heated and stirred at 60°C for 10 hours. After cooling the reaction mixture to room temperature, acidic ion exchange resin was added to adjust the pH to 3-4, filtered, and the ion exchange resin was washed with EtOAc. The entire filtrate was collected and distilled under reduced pressure to obtain FT03340 mg (0.13 mmol, yield 84%).

[0152] 1 H NMR (600 MHz, Methanol-d4)δ7.98-7.85(m,2H),7.72(d,J= 3.5 Hz, 1H), 7.41 - 7.35 (m, 1H), 7.20 (d,J= 8.3 Hz, 1H), 3.94 (d,J= 6.2 Hz, 2H), 2.21 - 2.12 (m, 1H), 1.09 (d,J= 6.6 Hz, 6H).

[0153]

[0154] Synthesis of compound FT036

[0155] [FT036]

[0156]

[0157]

[0158] (1) Synthesis of compound O

[0159] Compound K331 mg (1.10 mmol), compound N150 mg (0.73 mmol), Pd(PPh3)485 mg (0.07 mmol), and 0.73 mL (1.46 mmol) of 2M Na2CO3 aqueous solution were dissolved in 5 mL of 1,4-dioxane solvent, and stirred and heated at 85°C for 12 hours. After cooling the reaction mixture to room temperature, 10 mL of sat. NH4Cl(aq) was added dropwise, and extracted twice with 10 mL of EtOAc. The obtained EtOAc layer was dried over MgSO4, and the solid was removed by filtering, and the filtrate was distilled under reduced pressure. The obtained mixture was separated and purified by silica gel column chromatography (Hex:EtOAc = 8:1 volume ratio) to obtain compound O110 mg (0.37 mmol, yield 50%).

[0160]

[0161] (2) Synthesis of compound FT036

[0162] Compound O30 mg (0.10 mmol) was dissolved in THF:MeOH (1 mL, 1 mL) solvent, 0.6 mL (1.20 mmol) of 2 M NaOH aqueous solution was added, and the mixture was heated and stirred at 55°C for 8 hours. After cooling the reaction mixture to room temperature, acidic ion exchange resin was added to adjust the pH to 3–4, filtered, and the ion exchange resin was washed with EtOAc. The entire filtrate was collected and distilled under reduced pressure to obtain FT03623 mg (0.08 mmol, yield 80%).

[0163] 1 H NMR (600 MHz, Chloroform-d / Methanol-d4(4:1)) δ 7.94 - 7.86 (m, 2H), 7.19 (d,J= 3.6 Hz, 1H), 6.95 (d,J= 8.9 Hz, 1H), 6.62 (d,J= 3.6 Hz, 1H), 3.81 (d,J= 6.5 Hz, 2H), 2.16 - 2.09 (m, 1H), 1.06 - 1.00 (m, 6H).

[0164]

[0165] Synthesis of compound FT037

[0166] [FT037]

[0167]

[0168] (1) Synthesis of compound FT037

[0169] To a solution of Compound O30 mg (0.10 mmol) dissolved in 1.5 mL of THF solvent, 10.92 mg (0.50 mmol) of LiBH4 was added, and the mixture was heated and stirred at 55°C for 6 hours. After cooling the reaction mixture to room temperature, 10 mL of sat. NH4Cl(aq) was added dropwise, and extracted twice with 10 mL of EtOAc. The obtained EtOAc layer was dried over MgSO4, the solid was removed by filtering, and the filtrate was distilled under reduced pressure. The obtained mixture was separated and purified by silica gel column chromatography (Hex: EtOAc = 3:1 volume ratio) to obtain FT03716 mg (0.06 mmol, yield 58%).

[0170] 1 H NMR (600 MHz, Chloroform-d / Methanol-d4(4:1)) δ 7.84 (d,J= 2.2 Hz, 1H), 7.79 - 7.77 (m, 1H), 6.96 (d,J= 8.9 Hz, 1H), 6.52 (d,J= 3.3 Hz, 1H), 6.38 (d,J= 3.3 Hz, 1H), 4.66 (s, 2H), 3.86 (d,J= 6.5 Hz, 2H), 2.22 - 2.14 (m, 1H), 1.08 (d,J= 6.7 Hz, 6H).

[0171]

[0172] Synthesis of compound FT039

[0173] [FT039]

[0174]

[0175] (1) Synthesis of compound Q

[0176] Compound K415 mg (1.38 mmol), compound P300 mg (0.99 mmol), Pd(PPh3)4114 mg (0.10 mmol), and Na2CO3209 mg (1.97 mmol, 2 M aqueous solution) were dissolved in 10 mL of 1,4-dioxane solvent, and stirred and heated at 95°C for 15 hours. After cooling the reaction mixture to room temperature, 10 mL of sat. NH4Cl(aq) was added dropwise, and extracted twice with 10 mL of EtOAc. The obtained EtOAc layer was dried over MgSO4, and the solid was removed by filtering, and the filtrate was distilled under reduced pressure. The obtained mixture was separated and purified by silica gel column chromatography (Hex:EtOAc = 5:1 volume ratio) to obtain compound Q200 mg (0.50 mmol, yield 51%).

[0177]

[0178] (2) Synthesis of compound R

[0179] Compound Q200 mg (0.50 mmol) was dissolved in 1 mL of CH2Cl2 solvent, cooled to 0 °C, and 0.5 mL of trifluoroacetic acid was added dropwise. The reaction mixture was stirred at room temperature for 2 hours, and 10 mL of sat. Na2CO3(aq) was added dropwise to the reaction mixture, and extracted twice with 10 mL of EtOAc. The obtained EtOAc layer was dried over MgSO4, and the solid was removed by filtering and distilled under reduced pressure to obtain Compound R120 mg (0.40 mmol, yield 80%).

[0180]

[0181] (3) Synthesis of compound FT039

[0182] Dissolve 40 mg (0.13 mmol) of compound R in THF: H2O (1 mL, 1 mL) solvent and add LiOH .2.5 mg (0.54 mmol) of H2O2 was added and stirred at 50°C for 5 hours. After cooling the reaction mixture to room temperature, an acidic ion exchange resin was added to adjust the pH to 3–4, filtered, and the ion exchange resin was washed with EtOAc. The entire filtrate was collected and distilled under reduced pressure to obtain FT03920 mg (0.07 mmol, yield 52%).

[0183] 1 H NMR (600 MHz, Chloroform-d / Methanol-d4(4:1)) δ 7.71 (d,J= 36.8 Hz, 2H), 6.94 - 6.85 (m, 2H), 6.36 (s, 1H), 3.78 (d,J= 5.2 Hz, 2H), 2.13 - 2.06 (m, 1H), 1.00 (d,J= 6.5 Hz, 6H).

[0184]

[0185] Synthesis of compound FT041

[0186] [FT041]

[0187]

[0188] (1) Synthesis of compound T

[0189] Compound K358 mg (1.19 mmol), Compound S300 mg (0.85 mmol), Pd(PPh3)498 mg (0.09 mmol), and Na2CO3180 mg (1.70 mmol, 2 M aqueous solution) were dissolved in 8 mL of DMF solvent, and stirred with heating at 95°C for 16 hours. After cooling the reaction mixture to room temperature, 10 mL of sat. NH4Cl (aq) was added dropwise, and extracted twice with 10 mL of EtOAc. The obtained EtOAc layer was dried over MgSO4, and the solid was removed by filtering, and the filtrate was distilled under reduced pressure. The obtained mixture was dissolved in 5 mL of CH2Cl2 solvent, and 1 mL of trifluoroacetic acid was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 2 hours, and then 10 mL of sat. NaHCO3 (aq) was added dropwise, and extracted twice with 10 mL of EtOAc. The obtained EtOAc layer was dried over MgSO4, the solid was removed by filtering, and the filtrate was distilled under reduced pressure. The obtained mixture was separated and purified by silica gel column chromatography (Hex: EtOAc = 1:1 volume ratio) to obtain compound T131 mg (0.38 mmol, yield 44%).

[0190]

[0191] (2) Synthesis of compound FT041

[0192] Dissolve 30 mg (0.09 mmol) of compound T in THF:H2O (1 mL, 1 mL) solvent and add LiOH . 15 mg (0.34 mmol) of H2O was added and stirred at 50°C for 5 hours. After cooling the reaction mixture to room temperature, an acidic ion exchange resin was added to adjust the pH to 3–4, filtered, and the ion exchange resin was washed with EtOAc. The entire filtrate was collected and distilled under reduced pressure to obtain FT04122 mg (0.07 mmol, yield 76%).

[0193] 1H NMR (600 MHz, Chloroform-d / Methanol-d4(4:1))δ8.52(d,J=1.0Hz, 1H), 7.88 (dd,J= 8.6, 1.6 Hz, 1H), 7.79 (dd,J= 8.7, 2.3 Hz, 1H), 7.75 (d,J= 2.2 Hz, 1H), 7.41 (d,J= 8.6 Hz, 1H), 7.36 (s, 1H), 7.02 (d,J= 8.7 Hz, 1H), 3.84 (d,J= 6.5 Hz, 2H), 2.18 - 2.11 (m, 1H), 1.04 (d,J=6.7 Hz, 6H).

[0194]

[0195] Synthesis of compound FT042

[0196] [FT042]

[0197]

[0198] (1) Synthesis of compound V

[0199] Compound U600 mg (2.26 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) 632 mg (2.49 mmol), and potassium acetate 444 mg (4.53 mmol) were added to 20 mL of 1,4-dioxane solvent, and 111 mg (0.14 mmol) of Pd(dppf)Cl2 were added, and the gas inside the vessel was replaced with nitrogen for 10 minutes. The reaction mixture was heated and stirred at 100°C for 12 hours. After the reaction mixture was cooled to room temperature, 20 mL of sat. NH4Cl(aq) was added dropwise, and extracted twice with 20 mL of EtOAc. The obtained EtOAc layer was dried over MgSO4, the solid was removed by filtering, and the filtrate was distilled under reduced pressure. The obtained mixture was separated and purified by silica gel column chromatography (Hex:EtOAc = 5:1 volume ratio) to obtain compound V706 mg (2.26 mmol, yield 92%).

[0200]

[0201] (2) Synthesis of compound FT042

[0202] Compound V442 mg (1.42 mmol), compound W289 mg (1.01 mmol), Pd(PPh3)4117 mg (0.10 mmol), and Na2CO3214 mg (2.02 mmol, 2 M aqueous solution) were dissolved in 10 mL of 1,4-dioxane solvent, and stirred and heated at 90°C for 15 hours. After cooling the reaction mixture to room temperature, 10 mL of sat. NH4Cl(aq) was added dropwise, and extracted twice with 10 mL of EtOAc. The obtained EtOAc layer was dried over MgSO4, and the solid was removed by filtering, and the filtrate was distilled under reduced pressure. The obtained mixture was separated and purified by silica gel column chromatography (Hex:EtOAc = 8:1 volume ratio) to obtain compound FT042186 mg (0.48 mmol, yield 47%).

[0203] 1 H NMR (600 MHz, Chloroform-d / Methanol-d4(4:1)) δ 8.60 (d,J= 1.5 Hz, 1H), 8.26 (d,J= 2.2 Hz, 1H), 8.16 (dd,J= 8.5, 1.6 Hz, 1H), 8.13 (dd,J= 8.8, 2.1 Hz, 1H), 8.03 (d,J= 8.5 Hz, 1H), 7.04 (d,J= 8.8 Hz, 1H), 4.43 (q,J= 7.1 Hz, 2H), 3.38 - 3.36 (m, 4H), 1.80 (p,J= 5.8 Hz, 4H), 1.67 (p,J= 5.8 Hz, 2H), 1.43 (t,J= 7.1 Hz, 3H).

[0204]

[0205] Synthesis of compound FT046

[0206] [FT046]

[0207]

[0208] (1) Synthesis of compound X

[0209] Compound I241 mg (1.18 mmol) and compound AA (0.99 mmol) were dissolved in 5 mL of MeOH solvent, and then 90 mg (1.08 mmol) of pivalonitrile and 38 mg (0.20 mmol) of p-toluenesulfonic acid monohydrate were added. The reaction mixture was stirred at room temperature for 16 hours, 10 mL of sat. NaHCO3(aq) was added dropwise, and extracted twice with 10 mL of EtOAc. The obtained EtOAc layer was dried over MgSO4, the solid was removed by filtering, and the filtrate was distilled under reduced pressure. The obtained mixture was separated and purified by silica gel column chromatography (Hex:EtOAc = 2:1 volume ratio) to obtain compound U227 mg (0.54 mmol, yield 55%).

[0210]

[0211] (2) Synthesis of compound FT046

[0212] Compound X30 mg (0.07 mmol) was dissolved in THF:MeOH:H2O (0.5 mL, 1 mL, 0.5 mL) solvent, NaOH 34 mg (0.86 mmol, 2 M aqueous solution) was added, and the mixture was heated and stirred at 60°C for 10 hours. After cooling the reaction mixture to room temperature, acidic ion exchange resin was added to adjust the pH to 3-4, filtered, and the ion exchange resin was washed with EtOAc. The entire filtrate was collected and distilled under reduced pressure to obtain FT04622 mg (0.05 mmol, yield 76%).

[0213] 1H NMR (600 MHz, Chloroform-d / Methanol-d4(4:1)) δ 8.91 (s, 1H), 8.17 (d,J= 2.2 Hz, 1H), 8.08 (dd,J= 8.8, 2.2 Hz, 1H), 7.69 (d,J= 9.3 Hz, 1H), 7.43 (d,J= 9.1 Hz, 1H), 6.97 (d,J= 8.9 Hz, 1H), 3.79 (d,J= 6.4 Hz, 2H), 2.12 - 2.03 (m, 1H), 0.98 (d,J= 6.7 Hz, 6H), 0.97 (s, 9H).

[0214]

[0215] Synthesis of compound FT055

[0216] [FT055]

[0217]

[0218] (1) Synthesis of compound Z

[0219] Compound Y150 mg (0.59 mmol) and compound K247.97 mg (0.82 mmol) were added to 3 mL of DMF solvent, and Pd(dppf)Cl248 mg (0.06 mmol) and Na2CO3 2M aqueous solution 0.59 mL (1.18 mmol) were added, and the gas inside the vessel was replaced with nitrogen for 10 minutes. The reaction mixture was heated and stirred at 90 °C for 14 hours. After the reaction mixture was cooled to room temperature, 20 mL of sat. NH4Cl(aq) was added dropwise, and extracted twice with 20 mL of EtOAc. The obtained EtOAc layer was dried over MgSO4, and the solid was removed by filtering, and the filtrate was distilled under reduced pressure. The obtained mixture was separated and purified by silica gel column chromatography (Hex:EtOAc = 4:1 volume ratio) to obtain compound Z67 mg (0.19 mmol, yield 33%).

[0220]

[0221] (2) Synthesis of compound FT055

[0222] Dissolve 30 mg (0.09 mmol) of compound Z in THF:H2O (1 mL, 1 mL) solvent and add LiOH . 7.21 mg (0.17 mmol) of H2O was added and stirred at 50 °C for 12 hours. After cooling the reaction mixture to room temperature, acidic ion exchange resin was added to adjust the pH to 3–4, filtered, and the ion exchange resin was washed with EtOAc. The entire filtrate was collected and distilled under reduced pressure to obtain FT05520 mg (0.08 mmol, yield 70%).

[0223] 1 H NMR (600 MHz, Chloroform-d / Methanol-d4(4:1)) δ 8.87 (s, 1H), 8.03 - 7.99 (m, 2H), 7.86 (s, 1H), 7.70 (dd,J= 9.4, 1.6 Hz, 1H), 7.49 (d,J= 9.4 Hz, 1H), 6.98 (d,J= 8.7 Hz, 1H), 3.80 (d,J= 6.5 Hz, 2H), 2.14 - 2.06 (m, 1H), 0.99 (d,J= 6.7 Hz, 6H).

[0224]

[0225] Synthesis of compound FT058

[0226] [FT058]

[0227]

[0228] (1) Synthesis of compound AB

[0229] Compound AA500 mg (3.29 mmol) and compound I801 mg (3.94 mmol) were dissolved in 10 mL of methanol, and then 2-isocyano-2-4-4-trimethylpentane503 mg (3.61 mmol) and p-toluenesulfonic acid monohydrate125 mg (0.66 mmol) were added. The reaction mixture was stirred at room temperature for 18 hours, then 10 mL of sat. NaHCO3(aq) was added dropwise, and extracted twice with 10 mL of EtOAc. The obtained EtOAc layer was dried over MgSO4, and the solid was removed by filtering, and the filtrate was distilled under reduced pressure. The obtained mixture was separated and purified by silica gel column chromatography (Hex: EtOAc = 4:1 volume ratio) to obtain compound AB1 g (2.17 mmol, yield 66%).

[0230]

[0231] (2) Synthesis of compound AC

[0232] Compound AB850 mg (1.84 mmol) was dissolved in 5 mL of methanol solvent, 4M HCl in dioxane 5.75 mL (1.84 mmol) was added, and the mixture was heated and stirred at 60°C for 12 hours. After cooling the reaction mixture to room temperature, 10 mL of sat. NaHCO3(aq) was added dropwise to adjust the pH to 8, and extracted twice with 10 mL of CH2Cl2. The obtained CH2Cl2 layer was dried over MgSO4, the solid was removed by filtering, and the filtrate was distilled under reduced pressure. The obtained mixture was separated and purified by silica gel column chromatography (CH2Cl2 / MeOH=10:1 volume ratio) to obtain compound AC550 mg (1.84 mmol, yield 82%).

[0233]

[0234] (3) Synthesis of compound FT058

[0235] Dissolve 20 mg (0.05 mmol) of compound AC in THF:H2O (1 mL, 1 mL) solvent and add LiOH .H2O4.61mg (0.11mmol) was added and stirred at room temperature for 16 hours. Acidic ion exchange resin was added to the reaction mixture to adjust the pH to 3-4, filtered, and the ion exchange resin was washed with CH2Cl2: MeOH (9:1 volume ratio). All filtrates were collected and distilled under reduced pressure to obtain FT0588mg (0.02mmol, yield 41%).

[0236] 1 H NMR (600 MHz, Methanol-d4) δ 8.87 (s, 1H), 8.26 - 8.20 (m, 2H), 7.75 (d,J= 9.3 Hz, 1H), 7.41 (d,J= 9.3 Hz, 1H), 7.23 (d,J= 8.9 Hz, 1H), 3.95 (d,J= 6.1 Hz, 2H), 2.22 - 2.12 (m, 1H), 1.10 (d,J= 6.6 Hz, 6H).

[0237]

[0238] Synthesis of compound FT064

[0239]

[0064]

[0240]

[0241]

[0242] (1) Synthesis of compounds FT064 and FT065

[0243] FT01740 mg (0.11 mmol) was dissolved in 2 mL of DMF solvent, then the temperature was lowered to ℃, and 112 mg (0.34 mmol) of Cs2CO3, 19 mg (0.11 mmol) of potassium iodide, and 0.037 mL (0.34 mmol) of isobutyl bromide were added dropwise. The reaction mixture was heated and stirred at 80 ℃ for 16 hours, and the solvent was removed by distillation under reduced pressure. 10 mL of water was added dropwise to the obtained mixture, and it was extracted twice with 10 mL of CH2Cl2. The obtained CH2Cl2 layer was dried over MgSO4, and the solid was removed by filtering, and the filtrate was distilled under reduced pressure. The obtained mixture was separated and purified by silica gel column chromatography (CHCl3: MeOH = 100: 1 volume ratio) to obtain FT0648 mg (0.02 mmol, yield 17%) and FT06512 mg (0.03 mmol, yield 26%).

[0244] 1 H NMR (600 MHz, Chloroform-d) δ 8.17 (d, J = 1.5 Hz, 1H), 8.04 (dd, J = 8.5, 1.5 Hz, 1H), 8.00 - 7.95 (m, 1H), 7.92 (d, J = 2.2 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 4.14 (d, J = 7.7 Hz, 2H), 3.97 (s, 3H), 3.93 (d, J = 6.5 Hz, 2H), 2.27 - 2.19 (m, 1H), 2.19 - 2.12 (m, 1H), 1.11 (s, 3H), 1.10 (s, 3H), 0.78 (s, 3H), 0.76 (s, 3H).

[0245]

[0246] Synthesis of compound FT065

[0247] [FT065]

[0248] 1H NMR (600 MHz, Chloroform-d) δ 8.50 (d, J=1.2 Hz, 1H), 8.05 (dd, J=8.6, 1.5 Hz, 1H), 7.97-7.88(m, 2H), 7.43(d, J=8.6 Hz, 1H), 7.11(d, J=8.7 Hz, 1H), 4.09(d, J=7.6 Hz, 2H), 3.95(s, 3H), 3.93(d, J=6.5 Hz, 2H), 2.26-2.17(m, 1H), 2.15-2.06(m, 1H), 1.11(s, 3H), 1.10(s, 3H), 0.77(s, 3H), 0.76(s, 3H).

[0249]

[0250] Anti-inflammatory effects of each compound in macrophages stimulated with LPS and ATP

[0251] The DMEM culture medium of macrophages attached to a 96-well cell culture plate was removed, and the cells were washed once with 1 x PBS (phosphate-buffered saline). Then, Opti-MEM (Thermo Fisher Scientific, USA) containing 100 ng / ml LPS was treated to each well, and the cells were incubated in an incubator at 37°C for 4 hours. Then, as specified in Fig. 2, febuxostat (10, 20, 40 μM), as a positive control, and the derivative compound of the present invention (Table 1) were treated to each well, and the cells were incubated for 30 minutes. Additionally, 2 mM ATP (Merck, Germany) was treated, and the cells were incubated in an incubator for 40 minutes, and the cell culture medium was collected. The concentration of IL-1β (Invitrogen, USA) in the collected cell culture medium was measured using an enzyme-linked immunosorbent assay (ELISA).

[0252] As a result, derivatives that reduce the amount of IL-1β expression compared to each concentration treated with febuxostat under inflammatory response induction conditions (LPS + ATP treatment) were selected. As shown in Fig. 2, the febuxostat-based derivatives of the present invention significantly suppress the expression amount of IL-1β, a representative inflammatory cytokine, in macrophages, and in particular, some derivatives (FT033, FT023, FT027, FT037, FT041, FT046) were confirmed to exhibit higher anti-inflammatory efficacy than febuxostat.

[0253]

[0254] Anti-inflammatory effects of each compound in LPS- and ATP-stimulated microglia.

[0255] Mouse-derived microglia cell lines (Professor Shin Chan-young, Konkuk University) are cell lines used to study key functions related to immune responses and are frequently used as models for research on nervous system inflammation or neurotoxicity. Therefore, the inventors of the present invention attempted to evaluate the anti-inflammatory ability of febuxostat derivatives in neurons using microglia cell lines in order to more deeply confirm the neuroprotective effect of the febuxostat derivatives of the present invention.

[0256] Mouse-derived BV2 cell line was seeded at 1 x 10 in a 24-well plate. 5 After attachment to the well, the cells were pretreated with FT033 and FT037, which are febuxostat derivatives, at concentrations of 50 μM and 100 μM, respectively, for 30 minutes. Thereafter, the pretreated cells were stimulated with LPS (10 ng / ml) for 3 hours and treated with ATP (2 mM) for 1 hour to induce an inflammatory response (Fig. 3a).

[0257] In the induced inflammatory response, both FT033 and FT037 showed a concentration-dependent IL-1β reduction effect compared to the control group (LPS (10 ng / ml) + ATP (2 mM), and it was confirmed that they exhibited a significant inflammation-suppressing ability compared to the control group. In addition, both FT033 and FT037 showed a significant IL-1β reduction effect compared to MCC950, which is known as an inflammation inhibitor. As above, it is shown that febuxostat derivatives can be used as an efficient therapeutic composition for inflammatory brain diseases that can protect brain nerve tissue from inflammatory damage by effectively suppressing inflammation occurring in brain tissue and cells.

[0258]

[0259] 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 embodiments 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.

Claims

1. A compound represented by the following chemical formula 1: Chemical Formula 1 In the above chemical formula, R1 is C1-C6 alkoxy, halogen or 5-membered-6-membered heterocycloalkyl; L1 is a direct bond, -NH- or -C(O)NH-; A is unsubstituted or substituted with one or more substituents selected from the group consisting of C1-C5 alkyl, C1-C5 hydroxyalkyl, -COOR2 (R2 is hydrogen or C1-C3 alkyl) and NR3R4 (R3 and R4 are each independently hydrogen or C1-C7 alkyl).

2. A compound characterized in that in the first paragraph, the heterocycloalkyl of the 5-membered-6-membered ring is selected from the group consisting of piperidine, pyrrolidine, morpholine, and piperazine.

3. A compound characterized in that in the first paragraph, the heteroaryl of the 5-membered-9-membered ring is selected from the group consisting of triazole, thiazole, benzothiazole, thiophene, furan, pyrrole, indole, imidazopyridine, and benzimidazole.

4. A compound characterized in that in paragraph 1, A is a heteroaryl of a 5-membered or 9-membered ring, which is unsubstituted or substituted with one or two substituents selected from the group consisting of C1-C3 alkyl, C1-C3 hydroxyalkyl, -COOR2 (R2 is hydrogen or C1-C2 alkyl), and NR3R4 (R3 is hydrogen and R4 is hydrogen or C1-C7 alkyl).

5. In the fourth paragraph, when A is a heteroaryl of a 5-membered or 9-membered ring substituted with two substituents, A is a compound characterized in that A is a triazole, thiazole, benzimidazole or imidazopyridine substituted with two substituents selected from the group consisting of C1-C3 alkyl, C1-C3 hydroxyalkyl, -COOR2 (R2 is hydrogen or C1-C2 alkyl) and NR3R4 (R3 is hydrogen and R4 is hydrogen or C4-C7 alkyl).

6. A compound characterized in that in the 5th paragraph, when A is a heteroaryl of a 5-membered or 9-membered ring substituted with two substituents, A is a triazole or thiazole substituted with C1-C3 alkyl and C1-C3 hydroxyalkyl; an imidazopyridine substituted with -COOH and NR3R4 (R3 is hydrogen and R4 is hydrogen or C4-C7 alkyl); or a benzimidazole substituted with C1-C4 alkyl and -COOR2 (R2 is C1-C2 alkyl).

7. A compound characterized in that in the first paragraph, when L1 is -NH- or -C(O)NH-, R1 is C2-C5 alkoxy; and A is a heteroaryl of a nine-membered ring substituted with C1-C3 hydroxyalkyl or -COOR2 (R2 is hydrogen or C1-C3 alkyl).

8. In the first paragraph, when L1 is a direct bond, R1 is C2-C5 alkoxy, halogen, or 6-membered ring heterocycloalkyl; A compound characterized in that A is a 5-membered-9-membered ring heteroaryl substituted with one or more substituents selected from the group consisting of C1-C5 alkyl, C1-C3 hydroxyalkyl, NR3R4 (R3 and R4 are each independently hydrogen or C1-C7 alkyl), and -COOR2 (R2 is hydrogen or C1-C3 alkyl).

9. In the first paragraph, the compound represented by the chemical formula 1 is a compound characterized in that it is selected from the group consisting of compounds represented by the following chemical formulas 2 to 16: Chemical Formula 2 Chemical Formula 3 Chemical Formula 4 Chemical Formula 5 Chemical Formula 6 Chemical Formula 7 Chemical Formula 8 Chemical Formula 9 Chemical Formula 10 Chemical Formula 11 Chemical Formula 12 Chemical Formula 13 Chemical Formula 14 Chemical Formula 15 Chemical Formula 16 10. In the 9th paragraph, the compound represented by the chemical formula 1 is a compound characterized in that it is selected from the group consisting of compounds represented by the following chemical formulas 7, 9 and 11: Chemical Formula 7 Chemical Formula 9 Chemical Formula 11 11. A composition for preventing or treating inflammation or autoimmune disease, comprising a compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof as an active ingredient.

12. In claim 11, the inflammatory or autoimmune disease is at least one selected from the group consisting of rheumatoid arthritis, reactive arthritis, type 1 diabetes, type 2 diabetes, systemic lupus erythematosus, multiple sclerosis, idiopathic fibrosing alveolitis, myasthenia gravis, polymyositis, dermatomyositis, localized scleroderma, systemic scleroderma, colitis, inflammatory bowel disease, Sjorgen's syndrome, Raynaud's phenomenon, Bechet's disease, Kawasaki's disease, primary biliary sclerosis, primary sclerosing cholangitis, ulcerative colitis, Crohn's disease, atopic dermatitis, inflammatory encephalopathy, and gout. A composition characterized by being a disease.

13. A composition according to claim 12, wherein the inflammatory brain disease is at least one disease selected from the group consisting of Alzheimer's disease, Parkinson's disease, argyrophilic grain disease (AGD), Lewy body dementia, frontotemporal dementia, progressive supranuclear palsy (PSP), progressive supranuclear palsy-Parkinson syndrome (PSP-P), Richardson syndrome, Pick's disease, Niemann-Pick disease, and Rasmussen's syndrome.

14. A functional food composition for improving or preventing inflammation or autoimmune disease, comprising a compound of any one of claims 1 to 10 or a food-related salt thereof as an active ingredient.

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