3-pyridylisoxazole derivative and pharmaceutical composition containing same as active ingredient for preventing or treating ocular diseases

Abstract

The present invention relates to a 3-phenylisoxazole derivative, a preparation method therefor, and a pharmaceutical composition containing same as an active ingredient for preventing or treating ocular disease. The 3-pyridylisoxazole derivative or a pharmaceutically acceptable salt thereof of the present disclosure enhances autophagy activity, thereby promoting the removal of metabolic waste products such as A2E accumulated in the eye and effectively inhibiting damage or apoptosis of ocular cells caused by blue-light–oxidized A2E. Accordingly, the compound of the present invention can be provided as a first-in-class therapeutic agent based on a novel concept for ocular diseases, such as dry macular degeneration, for which no fundamental treatment currently exists.

Description

3-Pyridylisoxazole derivative and pharmaceutical composition containing the same as an active ingredient for preventing or treating eye diseases

[0001] This application claims priority to Korean Patent Application No. 10-2024-0095893, filed July 19, 2024, the entire disclosure of which is incorporated herein by reference.

[0002] The present invention relates to 3-pyridylisoxazole derivatives, a method for preparing the same, and a pharmaceutical composition containing the same as an active ingredient for preventing or treating ocular diseases. Specifically, the present invention relates to compounds having a specific structure and their pharmaceutical uses. The present invention also relates to methods for preventing or treating ocular diseases using the compounds of the present invention.

[0003] Modern people spend most of their time in front of various digital screens, and this environmental impact is leading to a steady rise in the rate of vision loss. The frequent use of LEDs in smart device screens is exposing eye health to blue light. Blue light, a blue-colored light in the 400-500nm range of the visible spectrum, refers to the light emitted from digital devices and smartphones.

[0004] Long-term exposure to blue light stimulates the optic nerve, causing eye fatigue and various eye diseases. Blue light has high energy and high penetrability, so if it directly enters the eye, it focuses on the retina opaquely, reducing clarity. Chronic exposure can cause retinal aging and degeneration. The known effects of blue light on the human body include dry eyes, eye fatigue, decreased vision, various eye diseases, accelerated retinal aging, macular degeneration, and insomnia due to suppression of melatonin production (Ganka Gakkai Zasshi. 2001 Oct;105(10):687-95; Archives of Ophthalmology 1992;110:99-104; Review of Ophthalmology Oct 15 2003;10(10)).

[0005] Age-related macular degeneration (AMD) comes in two forms: dry and wet. Dry AMD accounts for 90% of AMD cases and progresses through the buildup of debris, such as drusen, on the retina. Wet AMD, on the other hand, occurs in about 10% of cases and involves the development of new blood vessels in the macula, leading to leakage of fluid and blood.

[0006] The retinal tissue, particularly the retinal pigment epithelium (RPE), the layer beneath the central retina where rod photoreceptors are densely packed, is the site where metabolic waste products accumulate most actively. As humans reach a certain age threshold, the body's physiological ability to process these metabolic waste products within the retina declines, leading to the formation of drusen (yellow deposits in the retina) in the RPE layer. These drusen are thought to contribute to age-related macular degeneration (AMD) by interfering with the normal physiological and metabolic processes that allow adequate nutrients to reach photoreceptors and inducing RPE cell death.

[0007] These metabolic waste products are characterized by specific fluorophores. The most important of these is N-retinylidene-N-retinyl-ethanolamine (A2E), a component of lipofuscin. A2E is known to be a major cause of phototoxic retinal diseases, including photooxidation upon exposure to blue light, leading to the production of reactive oxygen species.

[0008] Prevention and treatment methods differ between dry and wet AMD. For wet AMD, prevention is primarily focused on preventing bleeding from abnormal blood vessels, a key risk factor. Treatment typically involves intraocular injections of anti-angiogenic growth factors or photodynamic therapy (PDT) using a specialized laser. Furthermore, treatments for wet AMD primarily focus on suppressing or improving abnormal blood vessels.

[0009] In contrast, there is no standardized treatment for dry macular degeneration. Currently, treatment involves the use of hypolipidemic medications (statins) to reduce the amount of lipids that form waste products like drusen, or the use of powerful antioxidants like flavonoids, such as lutein and zeaxanthin. However, these methods are indirect treatments, and no treatment exists that directly removes the metabolic products accumulated in retinal cells.

[0010] The purpose of the present invention is to provide a compound useful for preventing or treating ocular diseases, particularly dry macular degeneration, for which there is currently no fundamental treatment. In particular, the present invention provides a compound capable of preventing or treating ocular diseases by removing accumulated A2E and directly inhibiting damage or death of retinal cells caused by A2E oxidized by blue light.

[0011] Another object of the present invention is to provide a method for producing the compound.

[0012] Another object of the present invention is to provide a pharmaceutical composition containing the compound as an active ingredient for preventing or treating ocular diseases, particularly dry macular degeneration. That is, another object of the present invention is to provide a method for treating or preventing ocular diseases, particularly dry macular degeneration, comprising administering a compound according to the present invention to a subject in need of such treatment or prevention.

[0013] Another object of the present invention is to provide a health functional food composition that helps improve eye diseases, containing the compound as an active ingredient.

[0014] Another object of the present invention is to provide a health functional food or pharmaceutical composition useful for protecting the retina from damage caused by blue light. That is, another object of the present invention is to provide a method for protecting the retina from damage caused by blue light, comprising administering a compound according to the present invention to a subject in need of retinal protection.

[0015] To achieve the above purpose, the present invention provides a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0016] [Chemical Formula 1]

[0017]

[0018] In the above chemical formula 1,

[0019] X1 and X2 are independently N or CH, and at least one of X1 and X2 is N,

[0020] R1 is hydrogen, C 1-6 Alkyl, or C 3-6 Cycloalkyl, wherein optionally C 1-6 Alkyl or C 3-6 Cycloalkyl is a group in which one or more hydrogens are hydroxyl, C 1-3 substituted with one or more substituents independently selected from the group consisting of alkoxy and halogen (e.g., F),

[0021] R2 is hydrogen, -C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-6 Alkoxy, -C 1-3 Alkylene-ORa, -C 1-3 Alkylene-NRaRb, -C 1-3 Alkylene-heterocycloalkyl (preferably heterocycloalkyl is piperazine, piperidine, morpholine, pyrrolidine, 3,8-diazabicyclo[3.2.1]octane, or 2,5-diazabicyclo[2.2.2]octane), or -C 1-3 Alkylene-heteroaryl (preferably heteroaryl is 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine), where Ra and Rb are independently hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, allyl, benzyl, -C 1-3 Alkylene-NH-C 1-3 Alkyl, -C 1-3 Alkylene-OH, -C 1-3 Alkylene-COOH, -C 1-3 Alkylene-COO-C 1-3 Alkyl, pyrrolidine, -C 1-3 Alkylene-pyrrolidine, aryl, or heteroaryl (e.g., quinazoline, pyridyl, etc.), wherein optionally the -C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-3 One or more hydrogens of alkylene or heterocycloalkyl are =O, -C 1-3 Alkyl, -OH, -COOH, -CO-C 1-3 Alkyl, -CONH2, -SO2-C 1-3 Alkyl, -NH2, -NHCH3, -N(CH3)2, -NHCOCH3, halogen, allyl, phenyl, benzyl, -C 1-3 Alkylene-OH, -C 1-3 Alkylene-COOH, -C 1-3Alkylene-COOC 1-3 substituted with alkyl, methoxycarbonyl, ethoxycarbonyl, or tert-butoxycarbonyl,

[0022] R3 is hydrogen, halogen (preferably Br, F), C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, heterocycloalkyl (preferably morpholine), -CH2-CR4(=CR5R6), -CN, haloC 1-3 Alkyl, -C 1-3 Alkylene-OR4, -C(O)R4, -C 1-3 Alkylene-C(O)R4, -C 1-3 Alkylene-COOH, or -COOH, wherein R4, R5, and R6 are independently hydrogen, methyl, or -NH2.

[0023]

[0024] Against this backdrop, the inventors of the present invention have endeavored to develop a therapeutic agent for ocular diseases, particularly dry macular degeneration, for which there is still no fundamental treatment. In the process, the inventors of the present invention have discovered that the 3-pyridylisoxazole derivative not only exhibits excellent effects in suppressing damage or death of retinal cells in various aspects, but also increases autophagy activity to promote the removal of waste products such as A2E accumulated in the eye, and thus can be used as a first-in-class therapeutic agent capable of fundamentally treating ocular diseases such as dry macular degeneration, thereby completing the present invention.

[0025] The compounds of the present invention have more desirable properties as active ingredients in terms of physicochemical aspects such as solubility and melting point compared to compounds of similar structure having a benzene nucleus instead of pyridine in the pyridine structural position (3-phenylisoxazole derivatives), have excellent stability, have better properties as active ingredients in terms of pharmacokinetics (PK), have the advantage of being able to suppress hERG inactivation by having a lower clogP value, and can also be better in terms of cytotoxicity.

[0026] In addition, the present invention provides a pharmaceutical composition for preventing or treating eye diseases, particularly dry macular degeneration, containing a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0027] Furthermore, the present invention provides a health functional food composition for improving eye diseases, which contains a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0028] In addition, the present invention provides a method for preventing or treating an eye disease, particularly dry macular degeneration, comprising a step of administering a therapeutically effective amount of a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof to a subject in need of treatment.

[0029] Furthermore, the present invention provides the use of a compound represented by the chemical formula 1 or a pharmaceutically acceptable salt thereof in the manufacture of a drug for preventing or treating eye diseases.

[0030] In addition, the present invention provides a pharmaceutical or health functional food composition for protecting the retina from damage caused by blue light, containing a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0031] In addition, the present invention provides a method for improving or protecting retinal damage caused by blue light, comprising a step of administering a therapeutically effective amount of a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof to a subject in need of improvement or protection.

[0032] Furthermore, the present invention provides the use of a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof in the manufacture of a product for improving retinal damage caused by blue light.

[0033] The 3-pyridylisoxazole derivative, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof of the present invention increases autophagy activity, thereby promoting the removal of waste products such as metabolites such as A2E accumulated in the eye, and effectively suppresses damage or death of eye cells caused by A2E oxidized by blue light. Therefore, the compound of the present invention has a useful effect that can be provided as a new concept, first-in-class therapeutic agent for eye diseases such as dry macular degeneration, for which there is still no fundamental treatment.

[0034] Figure 1 is an experimental result showing changes in lysosome activity and A2E intensity (A2E removal effect) after treating human retinal pigment epithelial cells (ARPE-19) with the compound of the present invention.

[0035] Figures 2 and 3 show the results of an experiment measuring changes in LC3-II protein, an autophagy marker, after treating human retinal pigment epithelial cells (ARPE-19) with the compound of the present invention.

[0036] Hereinafter, the present invention will be described in detail.

[0037] The present invention provides a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0038] [Chemical Formula 1]

[0039]

[0040] In the above chemical formula 1,

[0041] X1 and X2 are independently N or CH, and at least one of X1 and X2 is N,

[0042] R1 is hydrogen, C 1-6 Alkyl, or C 3-6 Cycloalkyl, wherein optionally C 1-6 Alkyl or C 3-6 Cycloalkyl is a group in which one or more hydrogens are hydroxyl, C 1-3 substituted with one or more substituents independently selected from the group consisting of alkoxy and halogen (e.g., F),

[0043] R2 is hydrogen, -C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-6 Alkoxy, -C 1-3 Alkylene-ORa, -C 1-3 Alkylene-NRaRb, -C 1-3 Alkylene-heterocycloalkyl (preferably heterocycloalkyl is piperazine, piperidine, morpholine, pyrrolidine, 3,8-diazabicyclo[3.2.1]octane, or 2,5-diazabicyclo[2.2.2]octane), or -C 1-3 Alkylene-heteroaryl (preferably heteroaryl is 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine), where Ra and Rb are independently hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, allyl, benzyl, -C 1-3 Alkylene-NH-C 1-3 Alkyl, -C 1-3 Alkylene-OH, -C 1-3 Alkylene-COOH, -C 1-3 Alkylene-COO-C 1-3 Alkyl, pyrrolidine, -C 1-3Alkylene-pyrrolidine, aryl, or heteroaryl (e.g., quinazoline, pyridyl, etc.), wherein optionally the -C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-3 One or more hydrogens of alkylene or heterocycloalkyl are =O, -C 1-3 Alkyl, -OH, -COOH, -CO-C 1-3 Alkyl, -CONH2, -SO2-C 1-3 Alkyl, -NH2, -NHCH3, -N(CH3)2, -NHCOCH3, halogen, allyl, phenyl, benzyl, -C 1-3 Alkylene-OH, -C 1-3 Alkylene-COOH, -C 1-3 Alkylene-COOC 1-3 substituted with alkyl, methoxycarbonyl, ethoxycarbonyl, or tert-butoxycarbonyl,

[0044] R3 is hydrogen, halogen (preferably Br, F), C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, heterocycloalkyl (preferably morpholine), -CH2-CR4(=CR5R6), -CN, haloC 1-3 Alkyl, -C 1-3 Alkylene-OR4, -C(O)R4, -C 1-3 Alkylene-C(O)R4, -C 1-3 Alkylene-COOH, or -COOH, wherein R4, R5, and R6 are independently hydrogen, methyl, or -NH2.

[0045]

[0046] In a preferred embodiment of the present invention, the present invention comprises a compound represented by the above chemical formula 1.

[0047] One of X1 and X2 is N, and the other is CH,

[0048] R1 is hydrogen or C 1-6 Alkyl, and optionally C here 1-6Alkyl is a group in which one or more hydrogens are substituted with one or more substituents selected from halogen,

[0049] R2 is -C 1-6 Alkyl, -C 1-3 Alkylene-ORa, -C 1-3 Alkylene-NRaRb, -C 1-3 Alkylene-piperazine, -C 1-3 Alkylene-piperidine, -C 1-3 Alkylene-morpholine, -C 1-3 alkylene-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, -C 1-3 alkylene-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, -C 1-3 Alkylene-pyrrolidine, -C 1-3 Alkylene-3,8-diazabicyclo[3.2.1]octane, or -C 1-3 Alkylene-2,5-diazabicyclo[2.2.2]octane, where Ra and Rb are independently hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, allyl, benzyl, C 1-3 Alkylene-OH, -C 1-3 Alkylene-COOH, -C 1-3 Alkylene-COO-C 1-3 Alkyl, aryl, or heteroaryl, wherein optionally the above -C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-3 One or more hydrogens of alkylene or heterocycloalkyl are =O, -C 1-3 Alkyl, -OH, -COOH, -CO-C 1-3 Alkyl, -CONH2, -SO2-C 1-3 Alkyl, -NH2, -NHCH3, -N(CH3)2, -NHCOCH3, halogen, allyl, phenyl, benzyl, -C 1-3 Alkylene-OH, -C 1-3 Alkylene-COOH, -C 1-3 Alkylene-COOC 1-3substituted with alkyl, methoxycarbonyl, ethoxycarbonyl, or tert-butoxycarbonyl,

[0050] R3 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, heterocycloalkyl, -CH2-CR4(=CR5R6) (e.g., allyl), -CN, haloC 1-3 Alkyl, -C 1-3 Alkylene-OR4, -C(O)R4, -C 1-3 Alkylene-C(O)R4, -C 1-3 Alkylene-COOH, or -COOH, wherein R4, R5, and R6 are each independently hydrogen, methyl, or -NH2,

[0051] A compound or a pharmaceutically acceptable salt thereof is provided.

[0052]

[0053] In a more preferred embodiment of the present invention, the present invention comprises a compound represented by the above chemical formula 1.

[0054] One of X1 and X2 is N, and the other is CH,

[0055] R1 is hydrogen, methyl, or -CF3,

[0056] R2 is -C 1-6 Alkyl, -C 1-3 Alkylene-ORa, -C 1-3 Alkylene-piperazine, -C 1-3 Alkylene-piperidine, -C 1-3 Alkylene-morpholine, -C 1-3 Alkylene-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, or -C 1-3 Alkylene-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, where Ra and Rb are independently hydrogen, C 1-6 Alkyl, allyl, benzyl, -C 1-3 Alkylene-COO-C 1-3 Alkyl, phenyl, quinazoline, or pyridyl, wherein optionally the above -C 1-6 Alkyl, C1-3 One or more hydrogens of alkylene or heterocycloalkyl are =O, -C 1-3 Alkyl, -OH, -COOH, -CO-C 1-3 Alkyl, -CONH2, -SO2-C 1-3 Alkyl, halogen, allyl, phenyl, benzyl, -C 1-3 Alkylene-OH, -C 1-3 Alkylene-COOH, -C 1-3 Alkylene-COOC 1-3 substituted with alkyl, methoxycarbonyl, ethoxycarbonyl, or tert-butoxycarbonyl,

[0057] R3 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, heterocycloalkyl, -CH2-CR4(=CR5R6), -CN, -haloC 1-3 Alkyl, -C 1-3 Alkylene-OR4, -C(O)R4, -C 1-3 Alkylene-C(O)R4, -C 1-3 Alkylene-COOH, or -COOH, wherein R4, R5, and R6 are each independently hydrogen or methyl,

[0058] A compound or a pharmaceutically acceptable salt thereof is provided.

[0059]

[0060] In one specific embodiment of the present invention, a preferred example of the compound represented by the above chemical formula 1 is

[0061] (3-(5-allyl-2-methoxypyridin-3-yl)isoxazol-5-yl)methanol,

[0062] 3-(5-allyl-2-methoxypyridin-3-yl)-5-((allyloxy)methyl)isoxazole,

[0063] 3-(5-allyl-2-methoxypyridin-3-yl)-5-(piperazin-1-ylmethyl)isoxazole,

[0064] 3-(2-allyl-5-methoxypyridin-4-yl)-5-(piperazin-1-ylmethyl)isoxazole,

[0065] (3-(2-allyl-5-methoxypyridin-4-yl)isoxazol-5-yl)methanol,

[0066] 3-(2-allyl-5-methoxypyridin-4-yl)-5-((allyloxy)methyl)isoxazole,

[0067] 3-(2-allyl-5-(trifluoromethoxy)pyridin-4-yl)-5-(piperazin-1-ylmethyl)isoxazole,

[0068] (3-(2-allyl-5-(trifluoromethoxy)pyridin-4-yl)isoxazol-5-yl)methanol,

[0069] 3-(2-allyl-5-(trifluoromethoxy)pyridin-4-yl)-5-((allyloxy)methyl)isoxazole, or a pharmaceutically acceptable salt thereof.

[0070]

[0071] The compound represented by the above chemical formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and as a salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. The acid addition salt is obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc.; non-toxic organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates and alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids, etc.; organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. These pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, Includes phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, etc.The acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the derivative of chemical formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc., adding an organic acid or inorganic acid, filtering and drying the resulting precipitate, or by distilling the solvent and an excess acid under reduced pressure, drying, and crystallizing in the presence of an organic solvent.

[0072] In one aspect of the present invention, the pharmaceutically acceptable salt according to the present invention is a hydrochloride salt (e.g., dihydrochloride salt).

[0073] Additionally, pharmaceutically acceptable metal salts can be prepared using bases. Alkali metal or alkaline earth metal salts can be obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. Among the metal salts, sodium, potassium, or calcium salts are pharmaceutically suitable. Furthermore, the corresponding salts can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable anion salt (e.g., silver nitrate).

[0074] In this specification, the terms “substituent”, “radical”, “group”, “moiety”, and “fragment” are used interchangeably.

[0075] If a substituent is described as “optionally substituted” or “optionally substituted,” the substituent may be (1) unsubstituted or (2) substituted with one or more of the defined substituents. If a substitutable position is unsubstituted, the default substituent is hydrogen.

[0076] The term "alkyl" as used herein means a saturated straight-chain or branched non-cyclic hydrocarbon having 1 to 10 carbon atoms (where the number of carbon atoms is not specifically limited). "Lower alkyl" means a straight-chain or branched alkyl having 1 to 4 carbon atoms. Representative saturated straight-chain alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl and -n-decyl, while saturated branched alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, isopentyl, 2-methylhexyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimethylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-deethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and 3,3-diethylhexyl. In a preferred embodiment of the present invention, the alkyl is methyl, ethyl or isopropyl.

[0077] The term "alkoxy" as used herein means -O-(alkyl) including -OCH3, -OCH2CH3, -O(CH2)2CH3, -OC(CH3)2H, -OC(CH3)3, and the like, wherein alkyl is as defined above.

[0078] In this specification, “C 1-6”, “C1-6”, or “C1-C6”, this means that it has 1 to 6 carbon atoms. For example, C 1-6 Alkyl refers to alkyl having 1 to 6 carbon atoms.

[0079] As used herein, the terms "halogen" and "halo" mean fluorine, chlorine, bromine, or iodine. In a preferred embodiment of the present invention, the halogen is bromine or fluorine.

[0080] The terms "haloalkyl," "haloalkoxy," "haloalkenyl," or "haloalkynyl," as used herein, refer to an alkyl, alkoxy, alkenyl, or alkynyl group, respectively, in which one or more hydrogen atoms are replaced by a halogen atom. For example, haloalkyl includes -CF3, -CHF2, -CH2F, -CBr3, -CHBr2, -CH2Br, -CC13, -CHC12, -CH2CI, -CI3, -CHI2, -CH2I, -CH2-CF3, -CH2-CHF2, -CH2-CH2F, -CH2-CBr3, -CH2-CHBr2, -CH2-CH2Br, -CH2-CC13, -CH2-CHC12, -CH2-CH2CI, -CH2-CI3, -CH2-CHI2, -CH2-CH2I, and the like. In a preferred embodiment of the present invention, haloalkyl is CF3, wherein alkyl and halogen are as defined above.

[0081] The term "cycloalkyl" as used herein means a monocyclic or polycyclic saturated ring having carbon and hydrogen atoms and no carbon-carbon multiple bonds. Examples of monocyclic rings include, but are not limited to, (C3-C7)cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl). Examples of polycyclic rings include, but are not limited to, fused bicyclic rings such as octahydropentalene, decahydronaphthalene, etc.; spiro rings such as spiro[3.3]heptane, spiro[3.4]octane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[4.5]decane, spiro[5.5]undecane, etc.; and bridged bicyclic rings such as bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc. The cycloalkyl group may be optionally substituted. In one embodiment, the cycloalkyl group is a monocyclic ring.

[0082] As used herein, “heterocycle” or “heterocycloalkyl” means a saturated 4- to 7-membered monocyclic, or 7- to 12-membered bicyclic ring containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the nitrogen and sulfur heteroatoms can be optionally oxidized and the nitrogen heteroatom can be optionally quaternized. Representative heterocycles include oxiran, oxetan, tetrahydrofuran, tetrahydropyran, 1,4-dioxane, aziridine, azetidine, pyrrolidine, piperidine, piperazine, pyrrolidinone, hydantoine, valerolactam, thiirane, thietane, tetrahydrothiophene, tetrahydrothiopyra, morpholine, tetrahydropyridine, tetrahydropyrimidine, etc. Heterocycles include bicyclic rings in which some of the heterocycles are fused to a benzene or cyclopenta-1,3-diene ring. The heterocycles may be attached by heteroatoms or carbon atoms. Heterocycles also include fused bicyclic rings, spiro rings, and bridged bicyclic rings in which one or more carbon atoms of the aforementioned polycyclic rings are replaced by nitrogen, oxygen, or sulfur atoms.Examples of such include fused heterobicyclic rings such as octahydrocyclopenta[c]pyrrole, octahydropyrrolo[3,4-c]pyrrole, decahydroisoquinoline, decahydro-2,6-naphthyridine, etc., when the heteroatom is nitrogen; 2-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-azaspiro[3.4]octane, 2,6-diazaspiro[3.4]octane, 2-azaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, Spiro rings such as 2,7-diazaspiro[4.4]nonane, 8-azaspiro[4.5]decane, 2,8-diazaspiro[4.5]decane, 3-azaspiro[5.5]undecane, 3,9-diazaspiro[5.5]undecane, etc.; and bridged heterobicyclic rings such as 2-azabicyclo[2.1.1]hexane, 2-azabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, 2-azabicyclo[2.2.2]octane, 2,5-diazabicyclo[2.2.2]octane, 3,8-diazabicyclo[3.2.1]octane, etc., but are not limited thereto.

[0083] The term "aryl" as used herein refers to a carbon-cyclic aromatic group containing 5 to 10 ring atoms. Representative examples include, but are not limited to, phenyl (benzene), tolyl, xylyl, naphthyl, tetrahydronaphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like. The carbon-cyclic aromatic group may be optionally substituted.

[0084] As used herein, "heteroaryl" is a 5 to 10 membered aromatic heterocycle ring having at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, and containing at least one carbon atom, including mono- and bicyclic ring systems. Representative heteroaryls include furan, 4H-pyran, pyrrole, imidazole, pyrazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, thiophene, ozaxole, isoxazole, thiazole, isothiazole, oxadiazole, benzofuran, benzothiophene, quinoline, dihydroquinoline, These include isoquinoline, dihydroisoquinoline, indole, benzoxazole, benzimidazole, benzothiazole, cinnoline, phthalazine, quinazoline, 1H-azepine, thiadiazole, tetrahydroisoquinoline, and tetrahydropyrazolopyrazine. Unless otherwise specified in the above heteroaryl, dihydro and tetrahydro forms with hydrogen atoms added to the double bond, such as 2,3-dihydro-1H-benzo[d]imidazole, 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, and 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, are also included in the definition.

[0085]

[0086] As used herein, the term "compound of the present invention" is meant to include not only each compound of formula 1, but also clathrates, hydrates, solvates, or polymorphs thereof. In addition, the term "compound of the present invention" is meant to include pharmaceutically acceptable salts of the compounds of the present invention, unless a pharmaceutically acceptable salt thereof is mentioned. In one embodiment, the compounds of the present invention may exist as stereomerically pure compounds (e.g., substantially free of other stereoisomers (e.g., 85% ee or more, 90% ee or more, 95% ee or more, 97% ee or more, or 99% ee or more)). That is, when the compound of formula 1 according to the present invention or a salt thereof is a tautomeric isomer and / or a stereoisomer (e.g., a geometrical isomer and a conformational isomer), each of their separated isomers and mixtures are also included in the scope of the compound of the present invention. When the compound of the present invention or a salt thereof has an asymmetric carbon in its structure, their optically active compounds and racemic mixtures are also included in the scope of the compound of the present invention.

[0087] As used herein, the term "polymorph" means a solid crystalline form of a compound of the present invention or a complex thereof. Different polymorphs of the same compound exhibit different physical, chemical, and / or spectral properties. Differences in physical properties include, but are not limited to, stability (e.g., heat or light stability), compressibility and density (important for formulation and product manufacturing), and dissolution rate (which may affect bioavailability). Differences in stability may result from changes in chemical reactivity (e.g., differential oxidation, such as faster discoloration of one polymorph than of another), mechanical properties (e.g., tablet fragments stored as a kinetically favored polymorph transform to the thermodynamically more stable polymorph), or both (tablets of one polymorph are more susceptible to degradation at high humidity). Different physical properties of polymorphs may affect their processing. For example, one polymorph may be more likely to form solvates or more difficult to filter or wash than another polymorph, for example due to its shape or particle size distribution.

[0088] The term "solvent compound" as used herein refers to a compound of the present invention or a pharmaceutically acceptable salt thereof comprising a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic, and can be administered to humans in very small amounts.

[0089] The term "hydrate" as used herein means a compound of the present invention or a pharmaceutically acceptable salt thereof comprising a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0090] The term "clathrate" as used herein means a compound of the present invention or a salt thereof in the form of a crystal lattice that includes spaces (e.g., channels) that confine guest molecules (e.g., solvent or water).

[0091] The term "purified" as used herein means that when separated, the isolate is at least 90% pure, in one embodiment at least 95% pure, in another embodiment at least 99% pure, and in yet another embodiment at least 99.9% pure.

[0092] In addition, the present invention provides a pharmaceutical composition for preventing or treating eye diseases, particularly dry macular degeneration, containing a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0093] In one aspect of the present invention, the compound represented by chemical formula 1 according to the present invention increases autophagy activity and promotes autophagy flux, for example, increases the removal effect on unnecessary components accumulated in the eye, and thus the compound represented by chemical formula 1 of the present invention or a pharmaceutically acceptable salt thereof can be used for the prevention or treatment of eye diseases, for example, eye diseases caused by unnecessary components such as metabolites in cells of the eye, and can be particularly useful for the prevention or treatment of dry macular degeneration.

[0094] In the present invention, “treatment” means any act in which the symptoms of an eye disease are improved or beneficially changed by administering a composition according to the present invention.

[0095] In the present invention, “prevention” means any act of inhibiting or delaying the onset of an eye disease by administering a composition according to the present invention.

[0096] In the present invention, "eye disease" may include any disease caused by unnecessary components accumulating in the eye, and specifically may refer to a retinal disease caused by A2E and blue light. Specifically, the eye disease is dry macular degeneration. In addition, A2E and blue light may worsen glaucoma, retinitis pigmentosa, Stargardt disease, choroideremia, gyrate atrophy, dry eye syndrome, eye strain, etc., and the compound of the present invention or a pharmaceutically acceptable salt thereof may be useful for the treatment or prevention of these conditions.

[0097] The exact cause of age-related macular degeneration, especially dry macular degeneration, is known to be the accumulation of excessive pigment substances in retinal pigment epithelial cells due to aging, which appears in the early stages of macular degeneration. A2E, which is produced by the synthesis of all-trans-retinal and ethanolamine, is a substance that accumulates in retinal epithelial cells, and this can cause damage to retinal pigment epithelial cells when it produces singlet oxygen by blue light and oxidizes the double bond site between carbons.

[0098] Prevention or treatment of the above-mentioned ocular diseases, particularly dry macular degeneration, may be achieved by increasing autophagy activity and promoting autophagy flux in ocular cells. Furthermore, this may be achieved by inhibiting cell death induced by A2E and blue light.

[0099] In one aspect of the present invention, the prevention or treatment of the eye disease may be achieved by recovering the ONL (outer nuclear layer) and / or IS / OS (inner segments / outer segments layer) damaged by exposure to blue light of N-retinylidene-N-retinyl-ethanolamine (A2E) accumulated in the eye cells.

[0100] The compound represented by chemical formula 1 according to the present invention or a pharmaceutically acceptable salt thereof increases autophagy activity.

[0101] Autophagy is a natural destructive mechanism that breaks down unnecessary or non-functional cellular components. In various cells, unnecessary metabolites and other components are isolated from other components within the cell and surrounded by a double membrane, which is called the formation of autophagosomes. Autophagosomes then fuse with lysosomes and degrade their contents. For example, in the case of dry macular degeneration, metabolites such as A2E are the cause of the disease. A2E is a metabolite derived from retinol, and when trans-retinal meets phosphatidylethanolamine, A2E is created. When A2E is exposed to blue light, it forms an A2E-epoxide structure. In this process, reactive oxygen species are created, which causes irreversible damage or cell death of retinal cells. In young or healthy people, unnecessary metabolites such as A2E are removed from cells by autophagy activity. However, in people with reduced or impaired autophagy activity, such as the elderly, A2E is not removed smoothly from retinal cells, which ultimately causes retinal cell damage and death, leading to dry macular degeneration.

[0102] In one aspect of the present invention, it was surprisingly confirmed that the 3-pyridylisoxazole derivative represented by the chemical formula 1 according to the present invention increases autophagy activity, that is, promotes autophagy flux, thereby removing unnecessary metabolites, such as A2E, from retinal cells. Therefore, the compound represented by the chemical formula 1 of the present invention or a pharmaceutically acceptable salt thereof can be used for the prevention or treatment of eye diseases, for example, eye diseases caused by unnecessary components, such as metabolites, in ocular cells, and can be particularly useful for the prevention or treatment of dry macular degeneration. The compound of the present invention can be provided as a new concept of first-in-class therapeutic agent for dry macular degeneration, for which only indirect treatment methods existed in the past.

[0103] In one specific example of the present invention, when A2E was accumulated in retinal pigment epithelial cells and then treated with the compound of the present invention, the amount of accumulated A2E was confirmed to decrease in a concentration-dependent manner, confirming that the compound of the present invention directly removes A2E. In another specific example of the present invention, when retinal pigment epithelial cells were treated with the compound of the present invention, it was confirmed that LC3-II, an autophagy marker, was increased.

[0104] Therefore, the compound of the present invention, chemical formula 1, is useful for preventing or treating eye diseases, for example, eye diseases caused by unnecessary components accumulated in the eye, and is particularly useful for preventing or treating eye diseases caused by A2E and blue light.

[0105] The pharmaceutical composition of the present invention can be used as a single agent, or can be manufactured into a combination formulation by additionally including a pharmaceutical composition known to have an approved ocular disease prevention or treatment effect. The pharmaceutical composition can be formulated into a pharmaceutical unit dosage form by adding a pharmaceutically acceptable carrier, excipient, or diluent.

[0106] In the present invention, “pharmaceutically acceptable” means not significantly stimulating the organism and not inhibiting the biological activity and properties of the administered active substance.

[0107] In the present invention, the pharmaceutical composition comprising a pharmaceutically acceptable carrier may have any one dosage form selected from the group consisting of tablets, pills, powders, granules, capsules, suspensions, solutions, emulsions, syrups, sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories.

[0108] The above pharmaceutical composition may be administered orally or parenterally in various dosage forms. When formulated, it may be prepared using commonly used diluents or excipients, such as fillers, bulking agents, binders, wetting agents, disintegrants, and surfactants.

[0109] Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations can be prepared by mixing one or more compounds with at least one excipient, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc can also be used. Liquid preparations for oral administration include suspensions, oral solutions, emulsions, syrups, etc., and in addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives can be included.

[0110] Formulations for parenteral administration may include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases may include, but are not limited to, witepsol, macrogol, Tween 61, cacao butter, laurin butter, and glycerogelatin. Specifically, eye drops for intraocular administration, such as eye drops, may be included.

[0111] In the composition of the present invention, the compound of formula 1 may be included in a pharmaceutically effective amount. A "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment and not causing side effects. The effective dosage level may be determined based on factors including the patient's health condition, the type and severity of the disease, the activity and sensitivity of the drug, the method of administration, the time of administration, the route and excretion rate, the duration of treatment, drugs used in combination or simultaneously, and other factors well known in the medical field. The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or in multiple doses. It is important to administer an amount that can achieve the maximum effect with the minimum amount without side effects by taking all of the above factors into consideration, and this can be easily determined by those skilled in the art.

[0112] For example, the compounds of the present invention or pharmaceutically acceptable salts thereof may be administered by any suitable route in the form of a pharmaceutical composition suitable for such route, and in an effective dosage for the intended treatment. An effective dosage is generally from about 0.001 to about 100 mg / kg body weight / day, preferably from about 0.01 to about 50 mg / kg / day, in single or divided doses. Dosage levels below the lower end of this range may be appropriate depending on age, species, and the disease or condition being treated. In other cases, still higher dosages may be used without harmful side effects. A larger dosage may be divided into several smaller doses for administration throughout the day.

[0113] Furthermore, the present invention provides a health functional food composition for preventing or improving eye diseases, which contains a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0114] In the present invention, “improvement” means any action that reduces a parameter related to a condition being treated by ingestion of the composition, for example, the severity of a symptom.

[0115] The above health food refers to a food manufactured and processed into tablets, capsules, powders, granules, liquids, pills, etc. using raw materials or ingredients with functional properties useful to the human body. The health functional food of the present invention can be manufactured using methods commonly used in the art, and during the manufacturing process, raw materials and ingredients commonly added in the art can be added. In addition, the formulation of the health functional food can be manufactured without limitation as long as it is a formulation recognized as a health functional food.

[0116] In addition, the present invention provides a method for preventing or treating an eye disease, comprising a step of administering a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof to a subject in need of treatment.

[0117] In the present invention, the term "subject" includes all mammals and non-mammals that have developed or are likely to develop the above eye disease, and for example, all animals including monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits or guinea pigs, including humans, and is preferably humans.

[0118] In the present invention, "administration" means providing a predetermined substance to a patient by any appropriate method, and the route of administration of the composition of the present invention may be administered through any general route as long as it can reach the target tissue. Examples thereof include, but are not limited to, intravenous administration, oral administration, and topical administration.

[0119] In addition, the present invention provides a pharmaceutical or health functional food composition for protecting the retina from damage caused by blue light, containing a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0120] In addition, the present invention provides a method for improving or protecting retinal damage caused by blue light, comprising a step of administering a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof to a subject in need of improvement or protection.

[0121] Furthermore, the present invention provides the use of a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof in the manufacture of a product for improving retinal damage caused by blue light.

[0122]

[0123] Hereinafter, the present invention will be described in detail through examples and experimental examples.

[0124] However, the following examples and experimental examples are only illustrative of the present invention, and the content of the present invention is not limited to the following examples and experimental examples.

[0125]

[0126] <Example 1> Preparation of (3-(5-allyl-2-methoxypyridin-3-yl)isoxazol-5-yl)methanol

[0127] Step 1: Preparation of (E)-5-bromo-2-methoxynicotinaldehyde oxime

[0128] To a solution of 5-bromo-2-methoxy-nicotinaldehyde (0.50 g, 2.31 mmol) in 0.5 M NaOH H2O (18 mL) was added hydroxylamine hydrochloride (250 mg, 3.60 mmol). The mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with brine and water. The combined organic layers were dried over Na2SO4, concentrated under reduced pressure, and purified by flash column chromatography on silica gel (EtOAc / hexane = 1:9) to obtain the title compound (342 mg, 64%).

[0129] Step 2: Preparation of (Z)-5-bromo-N-hydroxy-2-methoxynicotinimidoyl chloride

[0130] To a solution of (E)-5-bromo-2-methoxynicotinaldehyde oxime (342 mg, 1.48 mmol) in DMF (1.5 mL) was added N-chlorosuccinimide (274 mg, 2.05 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate. The organic layer was then washed with brine and water. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure.

[0131] Step 3: Preparation of (3-(5-bromo-2-methoxypyridin-3yl)isoxazol-5-yl)methanol

[0132] Propargyl alcohol (0.10 mL, 1.71 mmol), CuSO were added to the mixture produced in step 2 above. 4·5H2O (11 mg, 0.04 mmol), sodium ascorbate (30 mg, 0.15 mmol), t-BuOH / H2O (1 / 1, 16 mL), and KHCO3 (440 mg, 4.39 mmol) were added. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with brine and water. The combined organic layers were dried over Na2SO4, concentrated under reduced pressure, and purified by flash column chromatography on silica gel (EtOAc / hexane = 1:3) to obtain the title compound (160 mg, 38%).

[0133] Step 4: Preparation of (3-(5-allyl-2-methoxypyridin-3-yl)isoxazol-5-yl)methanol

[0134] To a solution of (3-(5-bromo-2-methoxypyridin-3yl)isoxazol-5-yl)methanol (160 mg, 0.56 mmol) and Pd(PPh3)4 (65 mg, 0.06 mmol) in DMF (3 mL) was added allyltributyl tin(Sn) (0.21 mL, 0.67 mmol). Afterwards, nitrogen gas was bubbled through the solvent for 10 min to remove air. The mixture was heated to 90 °C and stirred for 4 h. The reaction mixture was quenched with NH4Cl solution, diluted with ethyl acetate, and the organic layer was washed with brine and water. The combined organic layers were dried over Na2SO4, concentrated under reduced pressure, and purified by flash column chromatography on silica gel (EtOAc / hexane = 1:3) to obtain the title compound (89 mg, 65%).

[0135]

[0136] <Example 2> Preparation of 3-(5-allyl-2-methoxypyridin-3-yl)-5-((allyloxy)methyl)isoxazole

[0137] Allyl bromide (0.03 mL, 0.36 mmol) was added to a DMF (2 mL) solution of the compound (58 mg, 0.24 mmol) prepared in Example 1. Then, NaH (12.70 mg, 0.53 mmol) was added at 0°C. The resulting mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched with NH4Cl solution and diluted with ethyl acetate. The combined organic layers were dried over Na2SO4, concentrated under reduced pressure, and purified by flash column chromatography on silica gel (EtOAc / hexane = 1:8) to obtain the target compound (46 mg, 68%).

[0138]

[0139] <Example 3> Preparation of 3-(5-allyl-2-methoxypyridin-3-yl)-5-(piperazin-1-ylmethyl)isoxazole

[0140] Synthesis was performed as in Example 1, except that tert-butyl 4-(prop-2-pin-1-yl)piperazine-1-carboxylate was used instead of propargyl alcohol in step 3. Thereafter, the Boc group was removed using a hydrochloric acid / dioxane solution to prepare the target compound.

[0141]

[0142] <Example 4> Preparation of 3-(2-allyl-5-methoxypyridin-4-yl)-5-(piperazin-1-ylmethyl)isoxazole

[0143] The target compound was prepared by synthesizing it as in Example 3 above, but using 2-bromo-5-methoxyisonicotinaldehyde as a starting material.

[0144]

[0145] <Example 5> Preparation of (3-(2-allyl-5-methoxypyridin-4-yl)isoxazol-5-yl)methanol

[0146] The target compound was prepared by synthesizing it as in Example 1, but using 2-bromo-5-methoxyisonicotinaldehyde as a starting material.

[0147]

[0148] <Example 6> Preparation of 3-(2-allyl-5-methoxypyridin-4-yl)-5-((allyloxy)methyl)isoxazole

[0149] The target compound was prepared by synthesizing it as in Example 2 above, but using 2-bromo-5-methoxyisonicotinaldehyde as a starting material.

[0150]

[0151] <Example 7> 3-(2-allyl-5-(trifluoromethoxy)pyridin-4-yl)-5-(piperazin-1-ylmethyl)isoxazole

[0152] The target compound was prepared by synthesizing it as in Example 3 above, but using 2-bromo-5-(trifluoromethoxy)isonicotinaldehyde as a starting material.

[0153]

[0154] <Example 8> Preparation of (3-(2-allyl-5-(trifluoromethoxy)pyridin-4-yl)isoxazol-5-yl)methanol

[0155] The target compound was prepared by synthesizing it as in Example 1, but using 2-bromo-5-(trifluoromethoxy)isonicotinaldehyde as a starting material.

[0156]

[0157] <Example 9> Preparation of 3-(2-allyl-5-(trifluoromethoxy)pyridin-4-yl)-5-((allyloxy)methyl)isoxazole

[0158] The target compound was prepared by synthesizing it as in Example 2 above, but using 2-bromo-5-(trifluoromethoxy)isonicotinaldehyde as a starting material.

[0159]

[0160] The NMR and mass measurement results of the compounds prepared in Example 1-9 are summarized and presented in the table below.

[0161]

[0162]

[0163] The chemical structures of the compounds prepared in the above examples 1-9 are summarized and shown in the table below.

[0164]

[0165]

[0166] <Experimental Example 1> Screening for compounds with A2E removal ability present in human retinal pigment epithelial cells.

[0167] The human retinal pigment epithelial cell line (ARPE-19) used in the experiment was obtained from the American Type Culture Collection (ATCC). The ARPE-19 cell line was cultured in DMEM / F-12 medium containing 10% FBS. After 10 4 Cells were dispensed into 96-well plates (Azenta life science) for confocal microscopy at a concentration of 10 cells / well and cultured for 24 hours. ARPE-19 cells were treated with A2E at a concentration of 40 μM for 2 hours to induce A2E accumulation in the ARPE-19 cell line. ARPE-19 cells in which A2E had accumulated, prepared by the above method, were treated with each test compound once at a concentration of 50 μM and then cultured for 48 hours. Each 96-well plate was treated with Hoecsht (for intracellular nuclear staining) and LysoTracker deep red (Thermo Fisher, for indirectly measuring lysosome activity through lysosome acidity). A2E removal ability and lysosomal activity were measured using a high-speed automated cell image analysis system (ImageXpress Confocal HT-ai, Molecular Devices) in the 96-well plate. The results are shown in Fig. 1.

[0168] As shown in Fig. 1, when ARPE-19 cells were treated with the compounds of the present invention after accumulating A2E in the cells, the A2E signal measured by fluorescence was confirmed to decrease. In addition, it was confirmed that the compound of Example 7 showed a significant increase in lysosomal activity. Therefore, it can be seen that the compounds of the present invention remove A2E by increasing lysosomal activity. In particular, the compounds of Examples 3, 7, and 8 showed high removal ability.

[0169]

[0170] The subsequent LC3-II generating ability of additional compounds was evaluated as follows: ARPE-19 was treated with 1Х10 5 The cells were dispensed into 6-well plates at a concentration of 1 cell / well and cultured for 24 hours. The cells were then treated with the compounds of the present invention at concentrations of 1, 5, 10, 25, and 50 μM for 24 hours. Afterwards, a cell lysis buffer containing a protease inhibitor was added to prepare a cell lysate. LC3-II levels were measured by Western immunoblotting using an anti-LC3-II antibody (Cell Signaling Technology, MA, USA). As an internal control, an antibody against β-actin (Cell Signaling Technology) was used, and the results were measured by Western immunoblotting in the same manner as above. The results are summarized in Figures 2 and 3.

[0171] As shown in Figures 2 and 3, treatment with the compounds of the present invention can be observed to increase the LC3-II protein, an autophagy marker. LC3-II is one of the major indicator proteins of autophagy activation. During autophagy, LC3 is converted from LC3-I to LC3-II in the autophagosome membrane. When autophagy is activated, LC3-II participates in autophagosome formation, forming puncta within the cytoplasm.

Claims

1. A compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof. [Chemical Formula 1] In the above chemical formula 1, X1 and X2 are independently N or CH, and at least one of X1 and X2 is N, R1 is hydrogen, C 1-6 Alkyl, or C 3-6 Cycloalkyl, wherein optionally C 1-6 Alkyl or C 3-6 Cycloalkyl is a group in which one or more hydrogens are hydroxyl, C 1-3 Substituted with one or more substituents independently selected from the group consisting of alkoxy and halogen, R2 is hydrogen, -C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-6 Alkoxy, -C 1-3 Alkylene-ORa, -C 1-3 Alkylene-NRaRb, -C 1-3 Alkylene-heterocycloalkyl, or -C 1-3 Alkylene-heteroaryl, where Ra and Rb are independently hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, allyl, benzyl, -C 1-3 Alkylene-NH-C 1-3 Alkyl, -C 1-3 Alkylene-OH, -C 1-3 Alkylene-COOH, -C 1-3 Alkylene-COO-C 1-3 Alkyl, pyrrolidine, -C 1-3 Alkylene-pyrrolidine, aryl, or heteroaryl, wherein optionally the above -C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-3 One or more hydrogens of alkylene or heterocycloalkyl are =O, -C 1-3 Alkyl, -OH, -COOH, -CO-C 1-3 Alkyl, -CONH2, -SO2-C 1-3 Alkyl, -NH2, -NHCH3, -N(CH3)2, -NHCOCH3, halogen, allyl, phenyl, benzyl, -C 1-3 Alkylene-OH, -C 1-3 Alkylene-COOH, -C 1-3 Alkylene-COOC 1-3 substituted with alkyl, methoxycarbonyl, ethoxycarbonyl, or tert-butoxycarbonyl, R3 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, heterocycloalkyl, -CH2-CR4(=CR5R6), -CN, haloC 1-3 Alkyl, -C 1-3 Alkylene-OR4, -C(O)R4, -C 1-3 Alkylene-C(O)R4, -C 1-3 Alkylene-COOH, or -COOH, wherein R4, R5, and R6 are each independently hydrogen, methyl, or -NH2, A compound or a pharmaceutically acceptable salt thereof.

2. In the first paragraph, in the chemical formula 1, One of X1 and X2 is N, and the other is CH, R1 is hydrogen or C 1-6 Alkyl, and optionally C here 1-6 Alkyl is a group in which one or more hydrogens are substituted with one or more substituents selected from halogen, R2 is -C 1-6 Alkyl, -C 1-3 Alkylene-ORa, -C 1-3 Alkylene-NRaRb, -C 1-3 Alkylene-piperazine, -C 1-3 Alkylene-piperidine, -C 1-3 Alkylene-morpholine, -C 1-3 alkylene-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, -C 1-3 alkylene-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, -C 1-3 Alkylene-pyrrolidine, -C 1-3 Alkylene-3,8-diazabicyclo[3.2.1]octane, or -C 1-3 Alkylene-2,5-diazabicyclo[2.2.2]octane, where Ra and Rb are independently hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, allyl, benzyl, C 1-3 Alkylene-OH, -C 1-3 Alkylene-COOH, -C 1-3 Alkylene-COO-C 1-3 Alkyl, aryl, or heteroaryl, wherein optionally the above -C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-3 One or more hydrogens of alkylene or heterocycloalkyl are =O, -C 1-3 Alkyl, -OH, -COOH, -CO-C 1-3 Alkyl, -CONH2, -SO2-C 1-3 Alkyl, -NH2, -NHCH3, -N(CH3)2, -NHCOCH3, halogen, allyl, phenyl, benzyl, -C 1-3 Alkylene-OH, -C 1-3 Alkylene-COOH, -C 1-3 Alkylene-COOC 1-3 substituted with alkyl, methoxycarbonyl, ethoxycarbonyl, or tert-butoxycarbonyl, R3 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, heterocycloalkyl, -CH2-CR4(=CR5R6) (e.g., allyl), -CN, haloC 1-3 Alkyl, -C 1-3 Alkylene-OR4, -C(O)R4, -C 1-3 Alkylene-C(O)R4, -C 1-3 Alkylene-COOH, or -COOH, wherein R4, R5, and R6 are each independently hydrogen, methyl, or -NH2, A compound or a pharmaceutically acceptable salt thereof.

3. In the second paragraph, in the chemical formula 1, One of X1 and X2 is N, and the other is CH, R1 is hydrogen, methyl, or -CF3, R2 is -C 1-6 Alkyl, -C 1-3 Alkylene-ORa, -C 1-3 Alkylene-piperazine, -C 1-3 Alkylene-piperidine, -C 1-3 Alkylene-morpholine, -C 1-3 Alkylene-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, or -C 1-3 Alkylene-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, where Ra and Rb are independently hydrogen, C 1-6 Alkyl, allyl, benzyl, -C 1-3 Alkylene-COO-C 1-3 Alkyl, phenyl, quinazoline, or pyridyl, wherein optionally the above -C 1-6 Alkyl, C 1-3 One or more hydrogens of alkylene or heterocycloalkyl are =O, -C 1-3 Alkyl, -OH, -COOH, -CO-C 1-3 Alkyl, -CONH2, -SO2-C 1-3 Alkyl, halogen, allyl, phenyl, benzyl, -C 1-3 Alkylene-OH, -C 1-3 Alkylene-COOH, -C 1-3 Alkylene-COOC 1-3 substituted with alkyl, methoxycarbonyl, ethoxycarbonyl, or tert-butoxycarbonyl, R3 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, heterocycloalkyl, -CH2-CR4(=CR5R6), -CN, -haloC 1-3 Alkyl, -C 1-3 Alkylene-OR4, -C(O)R4, -C 1-3 Alkylene-C(O)R4, -C 1-3 Alkylene-COOH, or -COOH, wherein R4, R5, and R6 are each independently hydrogen or methyl, A compound or a pharmaceutically acceptable salt thereof.

4. In the first paragraph, the compound (3-(5-allyl-2-methoxypyridin-3-yl)isoxazol-5-yl)methanol, 3-(5-allyl-2-methoxypyridin-3-yl)-5-((allyloxy)methyl)isoxazole, 3-(5-allyl-2-methoxypyridin-3-yl)-5-(piperazin-1-ylmethyl)isoxazole, 3-(2-allyl-5-methoxypyridin-4-yl)-5-(piperazin-1-ylmethyl)isoxazole, (3-(2-allyl-5-methoxypyridin-4-yl)isoxazol-5-yl)methanol, 3-(2-allyl-5-methoxypyridin-4-yl)-5-((allyloxy)methyl)isoxazole, 3-(2-allyl-5-(trifluoromethoxy)pyridin-4-yl)-5-(piperazin-1-ylmethyl)isoxazole, (3-(2-allyl-5-(trifluoromethoxy)pyridin-4-yl)isoxazol-5-yl)methanol, or 3-(2-allyl-5-(trifluoromethoxy)pyridin-4-yl)-5-((allyloxy)methyl)isoxazol A compound or a pharmaceutically acceptable salt thereof.

5. In the fourth paragraph, the compound 3-(5-allyl-2-methoxypyridin-3-yl)-5-(piperazin-1-ylmethyl)isoxazole, 3-(2-allyl-5-(trifluoromethoxy)pyridin-4-yl)-5-(piperazin-1-ylmethyl)isoxazole, or (3-(2-allyl-5-(trifluoromethoxy)pyridin-4-yl)isoxazol-5-yl)methanol A compound or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition for preventing or treating eye diseases, containing a compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient.

7. A pharmaceutical composition according to claim 6, characterized in that the eye disease is an eye disease in which N-retinylidene-N-retinyl-ethanolamine (A2E) accumulates in eye cells.

8. A pharmaceutical composition according to claim 6, wherein the eye disease is dry macular degeneration.

9. A composition for protecting the retina from damage caused by blue light, containing as an active ingredient a compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

10. A method for preventing or treating an eye disease, comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof to a subject in need of treatment for an eye disease.

11. A method according to claim 10, characterized in that the eye disease is an eye disease in which N-retinylidene-N-retinyl-ethanolamine (A2E) accumulates in eye cells.

12. A method according to claim 10, wherein the eye disease is dry macular degeneration.

13. A method for protecting the retina from damage caused by blue light, comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof to a subject in need of retinal protection.

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