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

Abstract

The present invention relates to a 3-phenylisoxazole derivative, a method for producing the same, and a pharmaceutical composition for preventing or treating eye diseases, which contains the same as an active ingredient. The 3-phenylisoxazole derivative or a pharma- ceutical acceptable salt thereof according to the present invention increases autophagy activity, promotes the removal of waste products such as metabolites such as A2E accumulated in the eye, and effectively inhibits damage and death of eye cells caused by A2E oxidized by blue light, and can be provided as a first-in-class therapeutic agent with a new concept for eye diseases for which no fundamental therapeutic agent is available yet, such as dry macular degeneration.

Description

[Technical field]

[0001] This application claims priority to Korean Patent Application No. 10-2022-0037633, filed on March 25, 2022, the entire contents of which are incorporated herein by reference in their entirety in the specification and drawings.

[0002] The present invention relates to a 3-phenylisoxazole derivative, a method for producing the same, and a pharmaceutical composition for preventing or treating eye diseases containing the same as an active ingredient. That is, the present invention relates to a novel compound and its medical use. The present invention also relates to a method for preventing or treating eye diseases using the compound of the present invention. [Background technology]

[0003] Modern people spend most of their time in front of various digital screens such as computers and smartphones. Due to these environmental influences, the rate of vision loss is steadily increasing. As LEDs (Light Emitting Diodes) are widely used in smart device screens, blue light is deteriorating eye health. Blue light is light that is blue in the 400~500nm range of visible light and refers to light emitted from digital devices and smartphones. When using digital devices at night, the reason why the light seems bluish overall is due to blue light.

[0004] Long-term exposure to blue light stimulates the optic nerve of the eye, causing eye fatigue and various eye diseases. Blue light has high energy and high penetrating power, so if it enters the eye directly, it is focused opaquely on the retina, reducing clarity, and if it is exposed late, it can cause retinal aging and degeneration. The effects of blue light on the human body are known to include dry eye, 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] There are two types of age-related macular degeneration (AMD): dry and wet. Dry macular degeneration accounts for 90% of AMD patients and is caused by waste products such as drusen depositing on the retina, while wet macular degeneration accounts for about 10% of AMD patients and is caused by new blood vessels forming in the macula, causing leakage of fluid components in the blood and blood itself.

[0006] Retinal tissue, especially the RPE cells beneath the central retina where rod cell photoreceptors are densely packed, is the site of the most active accumulation of metabolic waste by-products. When humans reach a certain critical age, the physiological ability of the human body to process these metabolic waste by-products within the retina declines, leading to the formation of drusen (yellow deposits present in the retina) in the RPE layer. Drusen thus formed may contribute to age-related macular degeneration (AMD) by disrupting normal physiological / metabolic activity that allows adequate nutrients to reach the photoreceptors and inducing the death of RPE cells.

[0007] These metabolic waste by-products are characterized by specific fluorophores, the most important of which is the lipofuscin component N-retinylidene-N-retinyl-ethanolamine (A2E), which is known to be a major causative agent of phototoxic retinal diseases, including the generation of reactive oxygen species through photooxidation when exposed to blue light.

[0008] Due to the differences between dry macular degeneration and wet macular degeneration, the prevention and treatment methods are different. In the case of wet macular degeneration, prevention is carried out by preventing bleeding from abnormal blood vessels, which is the main cause, and treatment is mainly carried out by administering anti-angiogenic factor injections to the eye or photodynamic therapy (PDT) using a special laser. In addition, treatments for wet macular degeneration are mainly focused on suppressing or improving abnormal blood vessels.

[0009] Meanwhile, there is still no standardized treatment for dry macular degeneration, and the current situation is that hyperlipidemic drugs (statin drugs) are used to simply reduce the amount of lipids that are the source of waste products such as drusen, or powerful antioxidants such as flavonoids such as lutein and zeaxanthin are prescribed. However, these methods are all indirect treatments, and there is still no treatment that directly removes metabolic products accumulated in retinal cells. Summary of the Invention [Problem to be solved by the invention]

[0010] The object of the present invention is to provide a novel compound useful for preventing or treating eye diseases, particularly eye diseases for which no fundamental therapeutic drug is available, such as dry macular degeneration. In particular, the present invention aims to provide a novel compound capable of preventing or treating eye diseases by removing accumulated A2E and directly suppressing damage and death of retinal cells caused by A2E oxidized by blue light.

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

[0012] It is yet another object of the present invention to provide a pharmaceutical composition for preventing or treating an eye disease, particularly dry macular degeneration, comprising the compound as an active ingredient. That is, it is yet another object of the present invention to provide a method for treating or preventing an eye disease, particularly dry macular degeneration, which comprises administering the compound according to the present invention to an individual in need of treatment or prevention of an eye disease.

[0013] It is still another object of the present invention to provide a health functional food composition which contains the above compound as an active ingredient and is useful for improving eye diseases.

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

[0015] In order to achieve the above object, the present invention provides a compound represented by the following Chemical Formula 1 or a pharma- ceutically acceptable salt thereof:

[0016] [ka]

[0017] In Chemical Formula 1, R1 is hydrogen, C 1-6 Alkyl (preferably methyl), or C 3-6 cycloalkyl, where optionally C 1-6 Alkyl or C 3-6 Cycloalkyl is one where one or more hydrogen atoms are hydroxyl, C 1-3 substituted with one or more substituents independently selected from the group consisting of alkoxy and halogen (e.g., F); 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, the 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 each 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), where 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 may be ═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; R3 and R3' are each independently hydrogen, halogen (preferably Br, F), C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, heterocycloalkyl (preferably morpholine), -CH2-CR4(=CR5R6) (e.g., allyl), -CN, haloC 1-3 Alkyl (preferably CF3), -C 1-3 Alkylene-OR4, -C(O)R4, -C 1-3 Alkylene-C(O)R4, -C 1-3 alkylene -COOH, or -COOH, where R4, R5, and R6 are each independently hydrogen, methyl, or -NH2.

[0018] Under the above circumstances, the present inventors have been working to develop a novel therapeutic agent for eye diseases, particularly eye diseases such as dry macular degeneration, for which no fundamental therapeutic drug is available. As a result, the present inventors have confirmed that the 3-phenylisoxazole derivatives provided by the present invention are excellent in various aspects in suppressing damage and death of retinal cells, and can be used as a first-in-class therapeutic agent that can fundamentally treat eye diseases such as dry macular degeneration by increasing autophagy activity and promoting the removal of waste products such as metabolic products such as A2E accumulated in the eyeball, thereby completing the present invention.

[0019] The present invention also provides a pharmaceutical composition for preventing or treating eye diseases, particularly dry macular degeneration, comprising the compound represented by Chemical Formula 1 or a pharma- ceutical acceptable salt thereof as an active ingredient.

[0020] Furthermore, the present invention provides a health functional food composition for improving eye diseases, comprising the compound represented by Chemical Formula 1 or a pharma- ceutical acceptable salt thereof as an active ingredient.

[0021] The present invention also provides a method for preventing or treating an eye disease, particularly dry macular degeneration, comprising administering the compound represented by Formula 1 or a pharma- ceutically acceptable salt thereof to a subject in need of treatment.

[0022] The present invention further provides a use of the compound represented by Formula 1 or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the prophylaxis or treatment of an eye disease.

[0023] The present invention also provides a pharmaceutical or health functional food composition for protecting retina from blue light-induced damage, comprising the compound represented by Chemical Formula 1 or a pharma- ceutical acceptable salt thereof as an active ingredient.

[0024] The present invention also provides a method for improving or protecting against retinal damage caused by blue light, comprising administering the compound represented by Chemical Formula 1 or a pharma- ceutical acceptable salt thereof to a subject in need of such improvement or protection.

[0025] Furthermore, the present invention provides a use of the compound represented by Chemical Formula 1 or a pharma- ceutically acceptable salt thereof in the manufacture of a product for improving retinal damage caused by blue light. Effect of the Invention

[0026] The 3-phenylisoxazole derivative, its stereoisomer, or a pharma- ceutically acceptable salt thereof according to the present invention increases autophagy activity to promote the removal of waste products such as metabolic products such as A2E accumulated in the eye, and effectively inhibits damage and death of ocular cells caused by A2E oxidized by blue light, and can be provided as a first-in-class therapeutic agent with a new concept for eye diseases for which no fundamental therapeutic agent is currently available, such as dry macular degeneration. [Brief description of the drawings]

[0027] [Figure 1] 1 is a photograph showing the change in fluorescence intensity depending on the treatment concentration of the compound of Example 17 of the present invention after accumulation of fluorescently labeled A2E (A2E-BDP) in human retinal pigment epithelial cells (ARPE-19). [Diagram 2] This is a graph showing the results of measuring the amount of A2E in the cells using HPLC to confirm the A2E removal effect depending on the treatment concentration of the compound of Example 17 of the present invention after A2E accumulation in human retinal pigment epithelial cells (ARPE-19). [Diagram 3] 1 shows photographs illustrating the inhibitory effect of the compound of Example 17 of the present invention on the death of human retinal pigment epithelial cells (ARPE-19) caused by blue light (BL) and A2E, depending on the treatment concentration, and the results of evaluating cell viability. [Figure 4] This is a photograph showing the analysis of changes in proteins in the cytoplasm or nucleus confirmed by Western immunoblotting to confirm the effect of the compound of Example 17 of the present invention on the activation of NF-κB induced by blue light and A2E depending on the treatment concentration. [Diagram 5] This is a graph showing the mRNA expression levels of inflammation-related genes measured to confirm the effect of the compound of Example 17 of the present invention as a function of the treatment concentration on the inflammatory response in human retinal pigment epithelial cells (ARPE-19) induced by blue light and A2E. [Figure 6] The top graph shows the change in LC3-II protein, an autophagy marker, measured by Western immunoblotting to confirm the effect of the compound of Example 17 of the present invention depending on the treatment concentration on the change in autophagy activity in human retinal pigment epithelial cells (ARPE-19) induced by blue light and A2E. The bottom photographs show the formation of GFP-LC3 puncta observed using a confocal laser scanning microscope (Nikon Corporation, Tokyo, Japan). [Figure 7]FIG. 1 shows photographs in which changes in LC3-II protein, an autophagy marker, were analyzed in the presence or absence of bafilomycin A1 using Western immunoblotting to confirm the effect of improving autophagy flux in human retinal pigment epithelial cells (ARPE-19) by treating the compound of Example 17 of the present invention, and a graph quantitatively showing the autophagy flux by calculating the difference in the amount of LC3-II protein depending on the presence or absence of bafilomycin A1. [Figure 8] 1 shows Western immunoblotting photographs confirming the autophagy activation effect of treating human retinal pigment epithelial cells (ARPE-19) in which A2E has accumulated with the compound of Example 17 of the present invention, and a graph quantitatively showing the same. [Figure 9] 1 shows Western immunoblotting photographs confirming the effect of improving autophagic flux by treating human retinal pigment epithelial cells (ARPE-19) in which A2E has accumulated with the compound of Example 17 of the present invention, and a quantitative graph showing the same. [Figure 10] 1 shows Western immunoblotting photographs confirming the effect of the compound of Example 17 of the present invention depending on the treatment concentration on p62 protein accumulated in cells due to autophagy inhibition induced by blue light and A2E, and a quantitative graph showing the same. [Figure 11] 1 shows photographs of the fundus taken with a fundus camera, showing retinal damage and the improving effect of treating an animal with the compound of Example 17 of the present invention after irradiating it with blue light. [Figure 12] This is an evaluation result of the reduction and recovery of the thickness of the outer nuclear layer (ONL) and the inner segment (IS) / outer segment (OS) by treating animals irradiated with blue light with the compound of Example 17 of the present invention. This is a graph quantitatively showing the average thickness of the ONL and IS / OS measured by hematoxylin-eosin staining and Axio Vision SE644 (ZEISS) program. [Figure 13] 1 shows the results of A2E removal evaluation of the compounds of preferred examples of the present invention, confirmed according to the treatment concentration of the test compound after A2E-BDP was accumulated in human retinal pigment epithelial cells (ARPE-19). [Figure 14] FIG. 1 shows the results of evaluating the activation of autophagy by compounds according to preferred examples of the present invention, evaluated using changes in the concentration of p62 protein in which the 349th serine residue is phosphorylated (p-p62(S349)). [Figure 15] 1 shows the results of evaluating the autophagy activation of some examples of compounds according to the present invention, evaluated using changes in LC3-II protein concentration. [Figure 16] 1 shows the results of evaluating the autophagy activation of some examples of compounds according to the present invention, evaluated using changes in LC3-II protein concentration. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] The present invention will be described in detail below.

[0029] The present invention provides a compound represented by the following Chemical Formula 1 or a pharma- ceutically acceptable salt thereof:

[0030] [ka]

[0031] In Chemical Formula 1, R1 is hydrogen, C 1-6 Alkyl (preferably methyl), or C 3-6 cycloalkyl, where optionally C 1-6 Alkyl or C 3-6 Cycloalkyl is one where one or more hydrogen atoms are hydroxyl, C 1-3 substituted with one or more substituents independently selected from the group consisting of alkoxy and halogen (e.g., F); R2 is hydrogen, -C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-6 Alkoxy, -C1-3 Alkylene -ORa, -C 1-3 Alkylene-NRaRb, -C 1-3 alkylene-heterocycloalkyl (preferably, the 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 each 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), where 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 may be ═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 and R3' are each independently hydrogen, halogen (preferably Br, F), C 1-6Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, heterocycloalkyl (preferably morpholine), -CH2-CR4(=CR5R6) (e.g., allyl), -CN, haloC 1-3 Alkyl (preferably CF3), -C 1-3 Alkylene-OR4, -C(O)R4, -C 1-3 Alkylene-C(O)R4, -C 1-3 alkylene -COOH, or -COOH, where R4, R5, and R6 are each independently hydrogen, methyl, or -NH2.

[0032] In one embodiment of the present invention, the present invention relates to a compound having the structure of Formula 1a:

[0033] [ka]

[0034] In formula 1a, R1 is hydrogen, C 1-6 Alkyl (preferably methyl), or C 3-6 cycloalkyl, where optionally C 1-6 Alkyl or C 3-6 Cycloalkyl is one where one or more hydrogen atoms are hydroxyl, C 1-3 substituted with one or more substituents independently selected from the group consisting of alkoxy and halogen (e.g., F); 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, the heterocycloalkyl is piperazine, piperidine, morpholine, pyrrolidine, 3,8-diazabicyclo[3.2.1]octane, or 2,5-diazabicyclo[2.2.2]octane), or -C 1-3alkylene-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 each 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), where 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 may be ═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 and R3' are each independently hydrogen, halogen (preferably Br, F), C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, heterocycloalkyl (preferably morpholine), -CH2-CR4(=CR5R6) (e.g., allyl), -CN, haloC 1-3 Alkyl (preferably CF3), -C 1-3 Alkylene-OR4, -C(O)R4, -C 1-3Alkylene-C(O)R4, -C 1-3 The compound or a pharma- ceutically acceptable salt thereof is provided, wherein R4, R5, and R6 are each independently hydrogen, methyl, or -NH2.

[0035] In a preferred embodiment of the present invention, the present invention relates to a compound represented by formula 1a: R1 is hydrogen or C 1-6 alkyl (preferably methyl), where optionally C 1-6 The alkyl group has one or more hydrogens replaced with one or more substituents selected from halogen (e.g., F); R2 is -C 1-6 Alkyl, -C 1-3 Alkylene -ORa, -C 1-3 Alkylene-NRaRb, or -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 each 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 (e.g., quinazoline, pyridyl), where optionally said -C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-3One or more hydrogens of alkylene or heterocycloalkyl may be ═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 and R3' are each independently hydrogen, halogen (preferably Br, F), C 1-6 Alkyl, C 1-6 Alkoxy, heterocycloalkyl (preferably morpholine), -CH2-CR4(=CR5R6) (e.g., allyl), -CN, haloC 1-3 Alkyl (preferably CF3), -C 1-3 Alkylene-OR4, -C(O)R4, -C 1-3 Alkylene-C(O)R4, -C 1-3 The compound or a pharma- ceutically acceptable salt thereof is provided, wherein R4, R5, and R6 are each independently hydrogen, methyl, or -NH2.

[0036] In a further preferred embodiment of the present invention, the present invention relates to a compound represented by the formula 1a: 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 1-3alkylene-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, wherein Ra and Rb are each independently hydrogen, C 1-6 Alkyl, aryl, benzyl, -C 1-3 Alkylene-COO-C 1-3 alkyl, phenyl, quinazoline, or pyridyl, 1-6 Alkyl, C 1-3 One or more hydrogens of alkylene or heterocycloalkyl may be ═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 and R3' are each independently hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, heterocycloalkyl (preferably morpholine), -CH2-CR4(=CR5R6) (e.g., allyl), -CN, -haloC 1-3 Alkyl (preferably CF3), -C 1-3 Alkylene-OR4, -C(O)R4, -C 1-3 Alkylene-C(O)R4, -C 1-3 The compound or a pharma- ceutically acceptable salt thereof is provided, wherein R4, R5, and R6 are each independently hydrogen or methyl.

[0037] In a specific embodiment of the present invention, preferred examples of the compound represented by Chemical Formula 1 are (1) 3-(5-bromo-2-methoxyphenyl)-5-propylisoxazole; (2) 4-bromo-2-(5-propylisoxazol-3-yl)phenol; (3) 3-(2-methoxy-5-propylphenyl)-5-propylisoxazole; (4) 3-(5-allyl-2-methoxyphenyl)-5-propylisoxazole; (5) 4-allyl-2-(5-propylisoxazol-3-yl)phenol; (6) 4-propyl-2-(5-propylisoxazol-3-yl)phenol; (7) (3-(5-bromo-2-methoxyphenyl)isoxazol-5-yl)methanol; (8) 4-Bromo-2-(5-(hydroxymethyl)isoxazol-3-yl)phenol; (9) 5-((allyloxy)methyl)-3-(5-bromo-2-methoxyphenyl)isoxazole; (10) (3-(2-methoxy-5-propylphenyl)isoxazol-5-yl)methanol; (11) 5-((benzyloxy)methyl)-3-(5-bromo-2-methoxyphenyl)isoxazole; (12) Ethyl 2-((3-(5-bromo-2-methoxyphenyl)isoxazol-5-yl)methoxy)acetate; (13) 3-(5-bromo-2-methoxyphenyl)-5-(methoxymethyl)isoxazole; (14) 2-(5-(hydroxymethyl)isoxazol-3-yl)-4-propylphenol; (15) (3-(5-allyl-2-methoxyphenyl)isoxazol-5-yl)methanol; (16) 4-Allyl-2-(5-(hydroxymethyl)isoxazol-3-yl)phenol; (17) 3-(5-allyl-2-methoxyphenyl)-5-((allyloxy)methyl)isoxazole; (18) 3-(5-allyl-2-methoxyphenyl)-5-((benzyloxy)methyl)isoxazole; (19) Ethyl 2-((3-(5-allyl-2-methoxyphenyl)isoxazol-5-yl)methoxy)acetate; (20) 3-(2-methoxy-5-propylphenyl)-5-(methoxymethyl)isoxazole; (21) tert-Butyl 4-((3-(5-bromo-2-methoxyphenyl)isoxazol-5-yl)methyl)piperazine-1-carboxylate; (22) 3-(5-allyl-2-methoxyphenyl)-5-((4-allylpiperazin-1-yl)methyl)isoxazole; (23) 3-(5-allyl-2-methoxyphenyl)-5-((4-benzylpiperazin-1-yl)methyl)isoxazole; (24) Ethyl 2-(4-((3-(5-allyl-2-methoxyphenyl)isoxazol-5-yl)methyl)piperazin-1-yl)acetate; (25) tert-Butyl 4-((3-(5-allyl-2-methoxyphenyl)isoxazol-5-yl)methyl)piperazine-1-carboxylate; (26) tert-Butyl 4-((3-(2-methoxy-5-propylphenyl)isoxazol-5-yl)methyl)piperazine-1-carboxylate; (27) 4-Allyl-2-(5-((allyloxy)methyl)isoxazol-3-yl)phenol; (28) 3-(5-bromo-2-methoxyphenyl)-5-(piperazin-1-ylmethyl)isoxazole; (29) 3-(5-allyl-methoxyphenyl)-5-(piperazin-1-ylmethyl)isoxazole; (30) 3-(2-methoxy-5-propylphenyl)-5-(piperazin-1-ylmethyl)isoxazole; (31) (3-(2-methoxy-5-(trifluoromethyl)phenyl)isoxazol-5-yl)methanol; (32) 2-(3-(2-methoxy-5-(trifluoromethyl)phenyl)isoxazol-5-yl)propan-2-ol; (33) 2-(3-(2-methoxy-5-(trifluoromethyl)phenyl)isoxazol-5-yl)ethan-1-ol; (34) 3-(2-methoxy-5-(trifluoromethyl)phenyl)-5-(piperazin-1-ylmethyl)isoxazole; (35) (3-(2-methoxy-4-(trifluoromethyl)phenyl)isoxazol-5-yl)methanol; (36) 2-((3-(2-methoxy-5-(trifluoromethyl)phenyl)isoxazol-5-yl)methoxy)acetic acid; (37) 4-((3-(2-methoxy-5-(trifluoromethyl)phenyl)isoxazol-5-yl)methyl)-1-methylpiperazin-2-one; (38) (3-(2-methoxy-5-morpholinophenyl)isoxazol-5-yl)methanol; (39) 2-(3-(5-allyl-2-methoxyphenyl)isoxazol-5-yl)propan-2-ol; (40) 2-(3-(2-methoxy-5-propylphenyl)isoxazol-5-yl)propan-2-ol; (41) 3-(5-allyl-2-methoxyphenyl)-5-((4-methylpiperazin-1-yl)methyl)isoxazole; (42) 3-(2-methoxy-5-propylphenyl)-5-((4-methylpiperazin-1-yl)methyl)isoxazole; (43) (3-(5-allyl-2-(trifluoromethoxy)phenyl)isoxazol-5-yl)methanol; (44) (3-(4-allyl-2-methoxyphenyl)isoxazol-5-yl)methanol; (45) (3-(5-isopropyl-2-methoxyphenyl)isoxazol-5-yl)methanol; (46) tert-Butyl 4-((3-(5-isopropyl-2-methoxyphenyl)isoxazol-5-yl)methyl)piperazine-1-carboxylate; (47) 3-(5-isopropyl-2-methoxyphenyl)-5-(piperazin-1-ylmethyl)isoxazole; (48) tert-Butyl 4-((3-(4-allyl-2-methoxyphenyl)isoxazol-5-yl)methyl)piperazine-1-carboxylate; (49) 3-(4-allyl-2-methoxyphenyl)-5-(piperazin-1-ylmethyl)isoxazole; (50) tert-Butyl 4-((3-(5-allyl-2-(trifluoromethoxy)phenyl)isoxazol-5-yl)methyl)piperazine-1-carboxylate; (51) 3-(5-allyl-2-(trifluoromethoxy)phenyl)-5-(piperazin-1-ylmethyl)isoxazole; (52) 3-(5-allyl-2-(trifluoromethoxy)phenyl)-5-((4-methylpiperazin-1-yl)methyl)isoxazole; (53) (2S,6R)-4-((3-(2-methoxy-5-propylphenyl)isoxazol-5-yl)methyl)-2,6-dimethylmorpholine; (54) 3-(2-methoxy-5-propylphenyl)-5-((4-methoxypiperidin-1-yl)methyl)isoxazole; (55) 1-((3-(2-methoxy-5-propylphenyl)isoxazol-5-yl)methyl)piperidine-4-carboxylic acid; (56) 5-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)-3-(2-methoxy-5-propylphenyl)isoxazole; (57) 5-((5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)methyl)-3-(2-methoxy-5-propylphenyl)isoxazole; (58) 3-(4-fluoro-2-methoxy-5-propylphenyl)-5-(piperazin-1-ylmethyl)isoxazole; (59) 3-(4-fluoro-2-methoxy-5-propylphenyl)-5-((4-methylpiperazin-1-yl)methyl)isoxazole; (60) 5-((4-methylpiperazin-1-yl)methyl)-3-(5-propyl-2-(trifluoromethoxy)phenyl)isoxazole; (61) 2-(4-methoxy-3-(5-((4-methylpiperazin-1-yl)methyl)isoxazol-3-yl)phenyl)ethan-1-ol; (62) 3-(2-methoxy-5-(2-methoxyethyl)phenyl)-5-((4-methylpiperazin-1-yl)methyl)isoxazole; (63) 1-(4-((3-(5-isopropyl-2-methoxyphenyl)isoxazol-5-yl)methyl)piperazin-1-yl)ethan-1-one; (64) 3-(5-isopropyl-2-methoxyphenyl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)isoxazole; (65) 3-(5-allyl-2-methoxyphenyl)-5-((quinazolin-4-yloxy)methyl)isoxazole; (66) tert-Butyl 4-((3-(2-methoxy-5-(2-methylallyl)phenyl)isoxazol-5-yl)methyl)piperazine-1-carboxylate; (67) 3-(2-methoxy-5-(2-methylallyl)phenyl)-5-(piperazin-1-ylmethyl)isoxazole; (68) (3-(2-methoxy-5-(2-methylallyl)phenyl)isoxazol-5-yl)methanol; (69) 3-(2-Methoxy-5-(3-methylbut-2-en-1-yl)phenyl)-5-((4-methylpiperazin-1-yl)methyl)isoxazole, or a pharma- ceutically acceptable form thereof.

[0038] Among the compounds (1) to (69), in particular (11) 5-((benzyloxy)methyl)-3-(5-bromo-2-methoxyphenyl)isoxazole; (15) (3-(5-allyl-2-methoxyphenyl)isoxazol-5-yl)methanol; (17) 3-(5-allyl-2-methoxyphenyl)-5-((allyloxy)methyl)isoxazole; (18) 3-(5-allyl-2-methoxyphenyl)-5-((benzyloxy)methyl)isoxazole; (21) tert-Butyl 4-((3-(5-bromo-2-methoxyphenyl)isoxazol-5-yl)methyl)piperazine-1-carboxylate; (25) tert-Butyl 4-((3-(5-allyl-2-methoxyphenyl)isoxazol-5-yl)methyl)piperazine-1-carboxylate; (26) tert-Butyl 4-((3-(2-methoxy-5-propylphenyl)isoxazol-5-yl)methyl)piperazine-1-carboxylate; (28) 3-(5-bromo-2-methoxyphenyl)-5-(piperazin-1-ylmethyl)isoxazole; (29) 3-(5-allyl-methoxyphenyl)-5-(piperazin-1-ylmethyl)isoxazole; (30) 3-(2-methoxy-5-propylphenyl)-5-(piperazin-1-ylmethyl)isoxazole; (34) 3-(2-methoxy-5-(trifluoromethyl)phenyl)-5-(piperazin-1-ylmethyl)isoxazole; (41) 3-(5-allyl-2-methoxyphenyl)-5-((4-methylpiperazin-1-yl)methyl)isoxazole; (42) 3-(2-methoxy-5-propylphenyl)-5-((4-methylpiperazin-1-yl)methyl)isoxazole; (43) (3-(5-allyl-2-(trifluoromethoxy)phenyl)isoxazol-5-yl)methanol; (44) (3-(4-allyl-2-methoxyphenyl)isoxazol-5-yl)methanol; (47) 3-(5-isopropyl-2-methoxyphenyl)-5-(piperazin-1-ylmethyl)isoxazole; (48) tert-Butyl 4-((3-(4-allyl-2-methoxyphenyl)isoxazol-5-yl)methyl)piperazine-1-carboxylate; (50) tert-Butyl 4-((3-(5-allyl-2-(trifluoromethoxy)phenyl)isoxazol-5-yl)methyl)piperazine-1-carboxylate; (51) 3-(5-allyl-2-(trifluoromethoxy)phenyl)-5-(piperazin-1-ylmethyl)isoxazole; (52) 3-(5-allyl-2-(trifluoromethoxy)phenyl)-5-((4-methylpiperazin-1-yl)methyl)isoxazole; (58) 3-(4-fluoro-2-methoxy-5-propylphenyl)-5-(piperazin-1-ylmethyl)isoxazole; (59) 3-(4-fluoro-2-methoxy-5-propylphenyl)-5-((4-methylpiperazin-1-yl)methyl)isoxazole; (60) 5-((4-methylpiperazin-1-yl)methyl)-3-(5-propyl-2-(trifluoromethoxy)phenyl)isoxazole; (66) tert-Butyl 4-((3-(2-methoxy-5-(2-methylallyl)phenyl)isoxazol-5-yl)methyl)piperazine-1-carboxylate; (67) 3-(2-methoxy-5-(2-methylallyl)phenyl)-5-(piperazin-1-ylmethyl)isoxazole; (68) (3-(2-methoxy-5-(2-methylallyl)phenyl)isoxazol-5-yl)methanol; or a pharma- ceutically acceptable salt thereof, is preferred for various purposes of the present invention.

[0039] In particular, among the above compounds: (28) 3-(5-bromo-2-methoxyphenyl)-5-(piperazin-1-ylmethyl)isoxazole; (30) 3-(2-methoxy-5-propylphenyl)-5-(piperazin-1-ylmethyl)isoxazole; (34) 3-(2-methoxy-5-(trifluoromethyl)phenyl)-5-(piperazin-1-ylmethyl)isoxazole; (41) 3-(5-allyl-2-methoxyphenyl)-5-((4-methylpiperazin-1-yl)methyl)isoxazole; (42) 3-(2-methoxy-5-propylphenyl)-5-((4-methylpiperazin-1-yl)methyl)isoxazole; (47) 3-(5-isopropyl-2-methoxyphenyl)-5-(piperazin-1-ylmethyl)isoxazole; (58) 3-(4-fluoro-2-methoxy-5-propylphenyl)-5-(piperazin-1-ylmethyl)isoxazole; (59) 3-(4-fluoro-2-methoxy-5-propylphenyl)-5-((4-methylpiperazin-1-yl)methyl)isoxazole; (60) 5-((4-methylpiperazin-1-yl)methyl)-3-(5-propyl-2-(trifluoromethoxy)phenyl)isoxazole; or a pharma- ceutically acceptable salt thereof, is further preferred for various purposes of the present invention.

[0040] In the present invention, the compound represented by Chemical Formula 1 can be used in the form of a pharma- ceutically acceptable salt, and the salt can be an acid addition salt formed with a pharma- ceutically acceptable free acid. The acid addition salt can be 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., and 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. Such pharma- ceutically non-toxic salts include, but are not limited to, 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, hexaphosphate ... Examples of such benzoates include san-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate.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 an inorganic acid, filtering and drying the resulting precipitate, or by distilling the solvent and an excess amount of acid under reduced pressure, drying, and crystallizing in an organic solvent.

[0041] In one embodiment of the invention, a pharma- ceutically acceptable salt according to the invention is a hydrochloride salt (eg, a dihydrochloride salt).

[0042] Pharmaceutically acceptable metal salts can also be prepared using bases. Alkali metal or alkaline earth metal salts can be obtained, for example, by dissolving the compound in a solution of an excess of alkali metal hydroxide or alkaline earth metal hydroxide, filtering the undissolved compound salt, and evaporating and drying the filtrate. In this case, it is pharmacy-appropriate to prepare sodium, potassium, or calcium salts as metal salts. The corresponding salts can also be obtained by reacting alkali metal or alkaline earth metal salts with a suitable anion salt (e.g., silver nitrate).

[0043] As used herein, the terms "substituent," "radical," "group," "moiety," and "fragment" may be used interchangeably.

[0044] When a substituent is described as "optionally substituted" or "optionally substituted," the substituent can be (1) unsubstituted or (2) substituted with one or more of the defined substituents. When a substitutable position is unsubstituted, the default substituent is hydrogen.

[0045] As used herein, the term "alkyl" refers to a saturated, straight-chain or branched, non-cyclic hydrocarbon having 1 to 10 carbon atoms (unless the number of carbon atoms is specifically limited). A "lower alkyl" refers to 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, and 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-dimethyl In a preferred embodiment of the invention, the alkyl is methyl, ethyl or isopropyl.

[0046] The term "alkoxy" as used herein means -O-(alkyl), including -OCH, -OCHCH, -O(CH)CH, -OC(CH), and the like, where alkyl is as defined above. In this specification, "C 1-6When written as ", " ", "C1-6" or "C1-C6", this means that the number of carbon atoms is 1 to 6. For example, C 1-6 Alkyl means alkyl having 1 to 6 carbon atoms.

[0047] As used herein, the terms "halogen" and "halo" refer to fluorine, chlorine, bromine or iodine. In a preferred embodiment of the invention, the halogen is bromine or fluorine.

[0048] As used herein, the terms "haloalkyl", "haloalkoxy", "haloalkenyl" or "haloalkynyl" refer to an alkyl, alkoxy, alkenyl or alkynyl group in which one or more hydrogen atoms have been replaced with a halogen atom, respectively. 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 one embodiment of the present invention, haloalkyl is CF3, where alkyl and halogen are as defined above.

[0049] As used herein, the term "cycloalkyl" refers to a monocyclic or polycyclic saturated ring having 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, and the like; 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, and the like; and bridged bicyclic rings such as bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and the like. Cycloalkyl groups can be optionally substituted. In one embodiment, the cycloalkyl group is a monocyclic ring.

[0050] As used herein, "heterocycle" or "heterocycloalkyl" refers to a saturated 4-7 membered monocyclic or 7-12 membered bicyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where the nitrogen and sulfur heteroatoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. Representative heterocycles include oxirane, oxetane, tetrahydrofuran, tetrahydropyran, 1,4-dioxane, aziridine, azetidine, pyrrolidine, piperidine, piperazine, pyrrolidinone, hydantoin, valerolactam, thiirane, thietane, tetrahydrothiophene, tetrahydrothiopyran, morpholine, tetrahydropyridine, tetrahydropyrimidine, and the like. Heterocycles include bicyclic rings in which a portion of the heterocycle is fused to a benzene or cyclopenta-1,3-diene ring. Heterocycles can be attached through a heteroatom or a carbon atom and also include fused bicyclic, spiro, and bridged bicyclic rings in which one or more carbon atoms of the above mentioned polycyclic rings are replaced with a nitrogen, oxygen, or sulfur atom.Examples of such rings include, where the heteroatom is nitrogen, fused heterobicyclic rings such as octahydrocyclopenta[c]pyrrole, octahydropyrrolo[3,4-c]pyrrole, decahydroisoquinoline, decahydro-2,6-naphthyridine, and the like; 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, 2,7-diazaspiro[4.4]nonane, 8-azaspiro[4.5]decane, 2,8-diazaspiro[4.5]decane, 2,9-diazaspiro[4.5]diphenyldiazomethane, 2,10-diazaspiro[4.5]diphenyldiazomethane, 2,11-diazaspiro[4.5]diphenyldiazomethane, 2,12-diazaspiro[4.5]diphenyldiazomethane, 2,13-diazaspiro[4.5]diphenyldiazomethane, 2,14-diazaspiro[4.5]diphenyldiazomethane, 2,15-diazaspiro[4.5]diphenyldiazomethane, 2,16-diazaspiro[4.5]diphenyldiazomethane, 2,17-diazaspiro[4.5]diphenyldiazomethane, 2,18-diazaspiro[4.5]diphenyldiazomethane, 2,19-diazaspiro[4.5]diphenyldiazomethane, 2,20-diazaspiro[4.5]diphenyldiazomethane, 2 Spiro rings such as pyro[4.5]decane, 3-azaspiro[5.5]undecane, 3,9-diazaspiro[5.5]undecane, and the like; 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, and the like.

[0051] The term "aryl" as used herein means a carbocyclic 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. Carbocyclic aromatic groups may be optionally substituted.

[0052] As used herein, "heteroaryl" refers to a 5-10 membered aromatic heterocyclic ring containing at least one carbon atom, including monocyclic and bicyclic ring systems, and having at least one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur. Representative heteroaryls include furan, 4H-pyran, pyrrole, imidazole, pyrazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, thiophene, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, benzofuran, benzothiophene, quinoline, dihydroquinoline, isoquinoline, dihydroisoquinoline, indole, benzoxazole, benzimidazole, benzothiazole, cinnoline, phthalazine, quinazoline, 1H-azepine, thiadiazole, tetrahydroisoquinoline, tetrahydropyrazolopyrazine, and the like. Unless otherwise specified, the heteroaryl includes dihydro and tetrahydro forms in which a hydrogen atom is added to a 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.

[0053] The term "compound of the present invention" as used herein includes not only each compound of Chemical Formula 1, but also their clathrates, hydrates, solvates, or polymorphs. In addition, the term "compound of the present invention" includes pharma- ceutically acceptable salts of the compounds of the present invention, unless a pharma- ceutically acceptable salt is mentioned. In one embodiment, the compounds of the present invention may be present as stereoisomerically 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 Chemical Formula 1 or a salt thereof according to the present invention is a tautomeric isomer and / or a stereoisomer (e.g., a geometrical isomer and a conformational isomer), each of the separate isomers and mixtures thereof are also included in the scope of the compounds of the present invention. When the compound of the present invention or a salt thereof has an asymmetric carbon in the structure, the optically active compounds and racemic mixtures thereof are also included in the category of the compound of the present invention.

[0054] As used herein, the term "polymorph" refers to 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 terms of physical properties include, but are not limited to, stability (e.g., thermal or light stability), compressibility and density (important for formulation and manufacturing of products), and dissolution rate (which may affect bioavailability). Differences in stability may result in changes in chemical reactivity (e.g., differential oxidation resulting in faster discoloration when composed of one polymorph than when composed of another), or mechanical characteristics (e.g., purified fragments stored as a kinetically favored polymorph convert to a 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 morphology or particle size distribution.

[0055] The term "solvate" as used herein means a compound of the present invention or a pharma- ceutically acceptable salt thereof that contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents are volatile and non-toxic, and may be administered to humans in very small amounts.

[0056] As used herein, the term "hydrate" means a compound of the present invention or a pharma- ceutically acceptable salt thereof that contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0057] 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 contains spaces (e.g., channels) in which guest molecules (e.g., solvent or water) are trapped.

[0058] As used herein, the term "purified" means that upon isolation, 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.

[0059] The present invention also provides a pharmaceutical composition for preventing or treating eye diseases, particularly dry macular degeneration, comprising the compound represented by Chemical Formula 1 or a pharma- ceutical acceptable salt thereof as an active ingredient.

[0060] In one embodiment of the present invention, the compound represented by Chemical Formula 1 according to the present invention increases autophagy activity and promotes autophagy flux, thereby enhancing the removal effect of unnecessary components accumulated in, for example, the eyeball. Therefore, the compound represented by Chemical Formula 1 of the present invention or a pharma- ceutically acceptable salt thereof can be used to prevent or treat ocular diseases, for example, eye diseases caused by unnecessary components such as metabolic products in ocular cells, and can be particularly useful for preventing or treating dry macular degeneration.

[0061] In the present invention, "treatment" refers to any action in which the symptoms of an eye disease are improved or favorably altered by administration of a composition according to the present invention.

[0062] In the present invention, "prevention" refers to any action of suppressing or delaying the onset of an eye disease by administering the composition according to the present invention.

[0063] In the present invention, the term "ocular disease" includes, without limitation, any disease caused by unnecessary components accumulated in the eyeball, and specifically refers to a retinal disease caused by A2E and blue light. Specifically, the ocular disease is dry macular degeneration. In addition, A2E and blue light can aggravate glaucoma, retinitis pigmentosa, Stargardt disease, choroideremia, chorioretinal atrophy, dry eye syndrome, eye fatigue, etc., and the compound of the present invention or a pharma- ceutical acceptable salt thereof is effective for treating or preventing these conditions.

[0064] 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 is known to appear in the early stages of macular degeneration. A2E, which is generated by the synthesis of all-trans-retinal and ethanolamine, is a typical substance that accumulates in retinal epithelial cells, and it generates singlet oxygen when exposed to blue light, which oxidizes the carbon-carbon double bond site and may cause damage to retinal pigment epithelial cells.

[0065] The prevention or treatment of the eye disease, particularly dry macular degeneration, can be achieved by increasing autophagy activity and promoting autophagic flux in ocular cells, and by suppressing cell death caused by A2E and blue light.

[0066] In one embodiment of the present invention, the prevention or treatment of the eye disease may be achieved by restoring the ONL and / or IS / OS damaged by exposure of N-retinylidene-N-retinyl-ethanolamine (A2E) accumulated in ocular cells to blue light.

[0067] The compound represented by Chemical Formula 1 or a pharma- ceutically acceptable salt thereof according to the present invention increases autophagy activity.

[0068] Autophagy is a natural destruction mechanism that breaks down unnecessary or non-functional cellular components. Components such as metabolic products that are not needed by various cells are sequestered from other components in the cell and surrounded by a double membrane, which is called the formation of an autophagosome. The autophagosome then fuses with lysosomes to break down the contents. For example, in the case of dry macular degeneration, metabolic products such as A2E are responsible for the pathogenesis. A2E is a metabolic product derived from retinol, and A2E is generated when trans-retinal binds to phosphatidylethanolamine. When A2E is exposed to blue light, it forms an A2E-epoxide structure, which generates reactive oxygen species in the process, which causes irreversible damage or death of retinal cells. In young or healthy individuals, unnecessary metabolic products such as A2E are removed from cells through autophagy activity. However, in individuals with reduced or impaired autophagy activity, such as elderly people, A2E is not removed smoothly from retinal cells, resulting in damage and death of retinal cells, leading to dry macular degeneration.

[0069] In one embodiment of the present invention, it has been surprisingly confirmed that the 3-phenylisoxazole derivative represented by Chemical Formula 1 according to the present invention increases autophagy activity, i.e., promotes autophagy flux, and removes unnecessary metabolic products, such as A2E, from retinal cells. Therefore, the compound represented by Chemical Formula 1 of the present invention or a pharma- ceutically acceptable salt thereof can be used to prevent or treat ocular diseases, such as ocular diseases caused by unnecessary components, such as metabolic products, in ocular cells, and can be effectively used in the prevention or treatment of dry macular degeneration in particular. The compound of the present invention can be provided as a first-in-class therapeutic agent with a new concept in dry macular degeneration, which has only been an indirect treatment.

[0070] In one embodiment of the present invention, it was confirmed that when A2E-fluorescently labeled substance (A2E-BDP) was accumulated in retinal pigment epithelial cells and then treated with the compound of the present invention, the A2E-BDP signal was significantly reduced, and it was confirmed that the compound of the present invention removes A2E-BDP (see Table 1 and Figure 1). In addition, it was confirmed that 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 reduced in a concentration-dependent manner, and it was confirmed that the compound of the present invention directly removes A2E (see Figure 2).

[0071] In another specific example of the present invention, death of retinal pigment epithelial cells was induced by A2E and blue light, and it was confirmed that cell death was inhibited in a concentration-dependent manner when treated with the compound of the present invention (see Figure 3).

[0072] In yet another specific example of the present invention, it was confirmed that when the compound of the present invention was treated with respect to A2E and blue light-induced activation of NF-κB in retinal pigment epithelial cells, the translocation of p65 into the nucleus induced by A2E and blue light was suppressed, thereby inhibiting the activation of NF-κB (see Figure 4).

[0073] In yet another specific example of the present invention, it was confirmed that when the compound of the present invention was treated with retinal pigment epithelial cells in response to increased expression of inflammation-related genes induced by A2E and blue light, the expression of inflammatory genes (IL-1β, IL-6, and CXCL8) was suppressed in a concentration-dependent manner (see Figure 5).

[0074] In yet another specific example of the present invention, it was confirmed that when retinal pigment epithelial cells were treated with the compound of the present invention, the autophagy marker LC3-II was increased in a concentration-dependent manner (see FIG. 6).

[0075] In yet another specific example of the present invention, it was confirmed that when retinal pigment epithelial cells were treated with the compounds of the present invention with or without treatment with bafilomycin A1 at a saturating concentration, autophagic flux increased in a concentration-dependent manner (see Figure 7).

[0076] In yet another specific example of the present invention, it was confirmed that when retinal pigment epithelial cells in which A2E had accumulated were treated with a compound of the present invention, the autophagy marker LC3-II was increased in a concentration-dependent manner (see FIG. 8).

[0077] In yet another specific example of the present invention, it was confirmed that when retinal pigment epithelial cells in which A2E had accumulated were treated with the compounds of the present invention with or without treatment with bafilomycin A1 at a saturating concentration, autophagic flux increased in a concentration-dependent manner (see FIG. 9).

[0078] In yet another specific example of the present invention, when the autophagy of retinal pigment epithelial cells was inhibited by A2E and blue light, treatment with the compound of the present invention reduced the p62 protein concentration in a concentration-dependent manner, thereby confirming that the autophagy activity in human retinal pigment epithelial cells that had been reduced by A2E and blue light was restored (see FIG. 10 ).

[0079] In yet another specific example of the present invention, it was confirmed that when experimental animals were exposed to blue light to damage retinal pigment epithelial cells and then treated with a compound of the present invention, the retinal damage was improved (see Figure 11), and the thickness of the ONL and IS / OS was also restored (see Figure 12).

[0080] Therefore, the compound of the present invention represented by Chemical Formula 1 is useful for preventing or treating eye diseases, for example, eye diseases caused by unnecessary components accumulated in the eyeball, and is particularly useful for preventing or treating eye diseases induced by A2E and blue light.

[0081] The pharmaceutical composition of the present invention may be used as a single agent, or may be prepared as a combined preparation by further including an approved pharmaceutical composition known to have a preventive or therapeutic effect on eye diseases. It may be formulated into a pharmaceutical unit dose by adding a pharma- ceutical acceptable carrier, excipient, or diluent.

[0082] In the present invention, "pharmaceutical acceptable" means that it does not significantly irritate the organism and does not inhibit the biological activity and properties of the administered active substance.

[0083] In the present invention, the pharmaceutical composition containing a pharma- ceutically acceptable carrier may have any one dosage form selected from the group consisting of tablets, pills, powders, granules, capsules, suspensions, oral liquids, emulsions, syrups, sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories.

[0084] The pharmaceutical composition may be in various oral or parenteral dosage forms. When formulated, it may be prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, surfactants, etc.

[0085] Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such 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, talc, etc. can also be used. Liquid preparations for oral administration include suspensions, oral liquids, emulsions, syrups, etc., and can include various excipients such as wetting agents, sweeteners, flavorings, preservatives, etc. in addition to commonly used simple diluents such as water and liquid paraffin.

[0086] Preparations for parenteral administration may include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried 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 may be included.

[0087] In the composition of the present invention, the compound of formula 1 may be included in a pharma- tically effective amount. The term "pharma-tically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to any medical treatment and without causing side effects, and the effective dose level may be determined by factors including the patient's health condition, the type and severity of the disease, the activity of the drug, sensitivity to the drug, the method of administration, the administration time, the administration route and excretion rate, the duration of treatment, co-administered or co-used drugs, 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. Taking all of the above factors into consideration, it is important to administer an amount that provides maximum effect at a minimum amount without side effects, which may be easily determined by those skilled in the art.

[0088] For example, the compounds of the present invention or pharma- ceutically acceptable salts thereof may be administered via any suitable route, in the form of a pharmaceutical composition appropriate for such route, and in an effective dose for the intended treatment. Effective doses are generally about 0.001 to about 100 mg / kg body weight / day, preferably about 0.01 to about 50 mg / kg / day, in single or divided doses. Depending on the age, species, and disease or condition being treated, dosage levels below the lower limit of the above ranges may be appropriate. In other cases, larger doses may be used without adverse side effects. Larger doses may be administered divided into smaller doses over the course of a day.

[0089] Furthermore, the present invention provides a health functional food composition for preventing or improving eye diseases, comprising the compound represented by Chemical Formula 1 or a pharma- ceutical acceptable salt thereof as an active ingredient.

[0090] In the present invention, "amelioration" refers to any action that reduces a parameter associated with the condition that is treated by ingestion of the composition, such as the severity of the symptoms.

[0091] The health functional food refers to food produced and processed in the form of tablets, capsules, powders, granules, liquid phase, pills, etc., using raw materials or ingredients having useful functions for the human body. The health functional food of the present invention may be produced by a method commonly used in the art, and may be produced by adding raw materials and ingredients commonly added in the art during production. The dosage form of the health functional food may be produced without limitation as long as it is a dosage form recognized as a health functional food.

[0092] The present invention also provides a method for preventing or treating an eye disease, comprising administering the compound represented by Formula 1 or a pharma- ceutically acceptable salt thereof to a subject in need of treatment.

[0093] In the present invention, the term "subject" refers to all mammals and non-mammals that have or may develop the above-mentioned eye diseases, and means all animals including, for example, monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits, or guinea pigs, including humans, and preferably humans.

[0094] In the present invention, "administration" means providing a predetermined substance to a patient by any suitable method, and the administration route of the composition of the present invention may be any common route that can reach the target tissue, such as, but not limited to, intraocular administration, intravenous administration, oral administration, and topical administration.

[0095] The present invention also provides a pharmaceutical or health functional food composition for protecting retina from blue light-induced damage, comprising the compound represented by Chemical Formula 1 or a pharma- ceutical acceptable salt thereof as an active ingredient.

[0096] The present invention also provides a method for improving or protecting against retinal damage caused by blue light, comprising administering the compound represented by Chemical Formula 1 or a pharma- ceutically acceptable salt thereof to a subject in need of such improvement or protection.

[0097] Furthermore, the present invention provides a use of the compound represented by Chemical Formula 1 or a pharma- ceutically acceptable salt thereof in the manufacture of a product for improving retinal damage caused by blue light.

[0098] The present invention will be described in detail below with reference to examples and experimental examples.

[0099] However, the following examples and experimental examples are merely illustrative of the present invention, and the content of the present invention is not limited to the following examples and experimental examples.

[0100] Example 1: Preparation of 3-(5-bromo-2-methoxyphenyl)-5-propylisoxazole The target compound was prepared by carrying out steps 1 and 2 of Example 17 below, and then carrying out step 3 using pentyn instead of propargyl alcohol.

[0101] <Example 2> Preparation of 4-bromo-2-(5-propylisoxazol-3-yl)phenol The target compound was prepared in the same manner as in Example 1, except that 5-bromo-2-hydroxybenzaldehyde was used instead of 5-bromo-2-methoxybenzaldehyde as the starting material.

[0102] <Example 3> Preparation of 3-(2-methoxy-5-propylphenyl)-5-propylisoxazole Steps 1 and 2 of Example 17 below were carried out, and step 3 and step 4 were carried out using pentyne instead of propargyl alcohol in step 3. The resulting compound was reacted with H2 and Pd / C in methanol, and the resulting product was purified to produce the target compound.

[0103] <Example 4> Preparation of 3-(5-allyl-2-methoxyphenyl)-5-propylisoxazole Steps 1 and 2 of Example 17 below were carried out, and step 3 was carried out using pentane instead of propargyl alcohol, followed by step 4 to produce the target compound.

[0104] <Example 5> Preparation of 4-allyl-2-(5-propylisoxazol-3-yl)phenol The target compound was prepared in the same manner as in Example 4, except that 5-bromo-2-hydroxybenzaldehyde was used instead of 5-bromo-2-methoxybenzaldehyde as the starting material.

[0105] <Example 6> Preparation of 4-propyl-2-(5-propylisoxazol-3-yl)phenol The target compound was prepared in the same manner as in Example 3, except that 5-bromo-2-hydroxybenzaldehyde was used instead of 5-bromo-2-methoxybenzaldehyde as the starting material.

[0106] <Example 7> Preparation of (3-(5-bromo-2-methoxyphenyl)isoxazol-5-yl)methanol The target compound was prepared by following up to step 3 of Example 17 below.

[0107] <Example 8> Preparation of 4-bromo-2-(5-(hydroxymethyl)isoxazol-3-yl)phenol The target compound was prepared in the same manner as in Example 7, except that 5-bromo-2-hydroxybenzaldehyde was used instead of 5-bromo-2-methoxybenzaldehyde as the starting material.

[0108] <Example 9> Preparation of 5-((allyloxy)methyl)-3-(5-bromo-2-methoxyphenyl)isoxazole The target compound was prepared in the same manner as in Example 17 below, except that steps 1, 2, 3 and 5 were carried out, excluding step 4.

[0109] Example 10: Preparation of (3-(2-methoxy-5-propylphenyl)isoxazol-5-yl)methanol After carrying out the steps up to step 4 of Example 17 below, the obtained compound was reacted with H2 and Pd / C in methanol, and the obtained product was purified to produce the target compound.

[0110] <Example 11> Preparation of 5-((benzyloxy)methyl)-3-(5-bromo-2-methoxyphenyl)isoxazole After carrying out the procedure up to step 3 of Example 17 below, the obtained compound was reacted with NaH and benzyl bromide in DMF, and the obtained product was purified to prepare the target compound.

[0111] <Example 12> Preparation of ethyl 2-((3-(5-bromo-2-methoxyphenyl)isoxazol-5-yl)methoxy)acetate The target compound was prepared in the same manner as in Example 11, except that ethyl bromoacetate was used instead of benzyl bromide.

[0112] <Example 13> Preparation of 3-(5-bromo-2-methoxyphenyl)-5-(methoxymethyl)isoxazole The target compound was prepared in the same manner as in Example 11, except that bromomethane was used instead of benzyl bromide.

[0113] <Example 14> Preparation of 2-(5-(hydroxymethyl)isoxazol-3-yl)-4-propylphenol The target compound was prepared in the same manner as in Example 10, except that 5-bromo-2-hydroxybenzaldehyde was used instead of 5-bromo-2-methoxybenzaldehyde as the starting material.

[0114] <Example 15> Preparation of (3-(5-allyl-2-methoxyphenyl)isoxazol-5-yl)methanol The target compound was prepared by following up to step 4 of Example 17 below.

[0115] <Example 16> Preparation of 4-allyl-2-(5-(hydroxymethyl)isoxazol-3-yl)phenol The target compound was prepared in the same manner as in Example 15, except that 5-bromo-2-hydroxybenzaldehyde was used instead of 5-bromo-2-methoxybenzaldehyde as the starting material.

[0116] <Example 17> Preparation of 3-(5-allyl-2-methoxyphenyl)-5-((allyloxy)methyl)isoxazole Step 1: Preparation of (E)-5-bromo-2-methoxybenzaldehyde oxime To a solution of 5-bromo-2-methoxybenzaldehyde (1 g, 4.65 mmol) in 0.5 M NaOH HO (23 mL) was added hydroxylamine hydrochloride (320 mg, 4.60 mmol). The mixture was then stirred at room temperature for 4 h. The reaction mixture was diluted with dichloromethane. The organic layer was washed with brine and water. The combined organic layers were dried over NaSO, concentrated under reduced pressure, and purified by flash column chromatography on silica gel (EtOAc / Hexanes=1:20) to give the desired compound (960 mg, 90%).

[0117] 1 H NMR (600 MHz, CDCl3) δ 8.39 (s, 1H), 7.78 (d, J=2.5 Hz, 1H), 7.43 (dd, J=8.8, 2.5 Hz, 1H), 3.84 (s, 3H). 13 C NMR (150 MHz, CDCl3) δ 156.7, 145.7, 133.8, 129.8, 122.6, 113.3, 113.0, 56.0. Step 2: (Z)-5-Bromo-N-hydroxy-2-methoxybenzimidoyl chloride To a solution of (E)-5-bromo-2-methoxybenzaldehyde oxime (950 mg, 4.13 mmol) in DMF (4 mL) was added N-chlorosuccinimide (551 mg, 4.13 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with dichloromethane. The organic layer was then washed with brine and water. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure.

[0118] Step 3: Preparation of (3-(5-bromo-2-methoxyphenyl)isoxazol-5-yl)methanol To the mixture produced in step 2 was added propargyl alcohol (0.26 mL, 4.54 mmol), CuSO4·5H2O (31 mg, 0.12 mmol), sodium ascorbate (82 mg, 0.41 mmol), t-BuOH / H2O (1 / 1, 20 mL), and KHCO3 (1.24 g, 12.4 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane. 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 / hexanes=1:3) to give the desired compound (630 mg, 54%).

[0119] 1 H NMR (600 MHz, CDCl3) δ 7.96 (d, J=2.5 Hz, 1H), 7.47 (dd, J=8.8, 2.5 Hz, 1H), 6.85 (d, J=8.8 Hz, 1H), 6.72 (s, 1H), 4.80 (s, 2H), 3.85 (s, 3H), 2.61 (s, 2H). 13 C NMR (150 MHz, CDCl3) δ 171.1, 159.1, 156.4, 133.9, 132.0, 119.7, 113.3, 113.3, 103.5, 56.6, 56.0. Step 4: (3-(5-allyl-2-methoxyphenyl)isoxazol-5-yl)methanol To a solution of (3-(5-bromo-2-methoxyphenyl)isoxazol-5-yl)methanol (500 mg, 1.76 mmol) and Pd(PPh3)4 (203 mg, 0.176 mmol) in DMF (6 mL) was added allyltributyltin (Sn) (0.65 mL, 2.11 mmol) in a sealed tube. Nitrogen gas was then bubbled through the solvent for 10 min to remove air. The mixture was heated to 90 °C and stirred for 2 h. The reaction mixture was quenched with NH4Cl solution and 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 = 1:4) to give the target compound (350 mg, 81%).

[0120] 1 H NMR (600 MHz, CDCl3) δ 7.70 (d, J=2.3 Hz, 1H), 7.23 (dd, J=8.5, 2.3 Hz, 1H), 6.94 (d, J=8.5 Hz, 1H), 6.76 (s, 1H), 5.96 (ddt, J=16.9, 10.0, 6.7 Hz, 1H), 5.14-4.98 (m, 2H), 4.82 (d, J=4.8 Hz, 2H), 3.88 (s, 3H), 3.37 (d, J=6.7 Hz, 2H). 13 C NMR (150 MHz, CDCl3) δ 170.4, 160.3, 155.8, 137.5, 132.7, 131.4, 129.7, 117.8, 116.1, 111.7, 103.7, 56.8, 55.8. Step 5: Preparation of 3-(5-allyl-2-methoxyphenyl)-5-((allyloxy)methyl)isoxazole To a solution of (3-(5-allyl-2-methoxyphenyl)isoxazol-5-yl)methanol (340 mg, 1.39 mmol) in DMF (4 mL) was added allyl bromide (0.16 mL, 01.86 mmol). Then, NaH (57 mg, 1.43 mmol) was added at 0 °C. The resulting mixture was warmed to room temperature and stirred for 2 h. 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 / hexanes = 1:10) to give the target compound (370 mg, 93%).

[0121] <Example 18> Preparation of 3-(5-allyl-2-methoxyphenyl)-5-((benzyloxy)methyl)isoxazole The target compound was prepared in a similar manner to Example 17, except that benzyl bromide was used instead of allyl bromide in step 5.

[0122] <Example 19> Preparation of ethyl 2-((3-(5-allyl-2-methoxyphenyl)isoxazol-5-yl)methoxy)acetate The target compound was prepared in a similar manner to Example 17, except that ethyl bromoacetate was used instead of allyl bromide in step 5.

[0123] <Example 20> Preparation of 3-(2-methoxy-5-propylphenyl)-5-(methoxymethyl)isoxazole The same procedure as in Example 17 was carried out, except that bromomethane was used instead of allyl bromide in step 5, and the resulting compound was reacted with H2 and Pd / C in methanol, and the resulting product was purified to produce the target compound.

[0124] <Example 21> Preparation of tert-butyl 4-((3-(5-bromo-2-methoxyphenyl)isoxazol-5-yl)methyl)piperazine-1-carboxylate The target compound was prepared in a manner similar to that of Example 4, except that up to step 3 of Example 17 was carried out, but tert-butyl 4-(prop-2-pin-1-yl)piperazine-1-carboxylate was used instead of propargyl alcohol in step 3.

[0125] <Example 22> Preparation of 3-(5-allyl-2-methoxyphenyl)-5-((4-allylpiperazin-1-yl)methyl)isoxazole The compound prepared in Example 21 was reacted with Pd(PPh3)4 and allyltributyltin (Sn) in toluene. The obtained compound was reacted with CH2Cl2 in TFA to remove the Boc group, and then reacted with NaH and allyl bromide in THF to prepare the target compound.

[0126] <Example 23> Preparation of 3-(5-allyl-2-methoxyphenyl)-5-((4-benzylpiperazin-1-yl)methyl)isoxazole The target compound was prepared in the same manner as in Example 22, except that benzyl bromide was used instead of allyl bromide.

[0127] <Example 24> Preparation of ethyl 2-(4-((3-(5-allyl-2-methoxyphenyl)isoxazol-5-yl)methyl)piperazin-1-yl)acetate The target compound was prepared in the same manner as in Example 22, except that ethyl bromoacetate was used instead of allyl bromide.

[0128] <Example 25> Preparation of tert-butyl 4-((3-(5-allyl-2-methoxyphenyl)isoxazol-5-yl)methyl)piperazine-1-carboxylate The compound prepared in Example 21 was reacted with Pd(PPh3)4 and allyltributyltin (Sn) in toluene to prepare the target compound.

[0129] <Example 26> Preparation of tert-butyl 4-((3-(2-methoxy-5-propylphenyl)isoxazol-5-yl)methyl)piperazine-1-carboxylate The compound prepared in Example 25 was reacted in methanol with the addition of H2 and Pd / C, and the resulting product was purified to prepare the target compound.

[0130] <Example 27> Preparation of 4-allyl-2-(5-((allyloxy)methyl)isoxazol-3-yl)phenol The compound prepared in Example 17 (15 mg) was dissolved in 2 mL of dichloromethane. Then, boron tribromide (0.15 mL, 1 M dichloromethane solution) was added at 0° C. and stirred under nitrogen atmosphere. After the reaction was completed, it was diluted with dichloromethane and the organic layer was washed with brine and water. The combined organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified by flash column chromatography on silica gel (EtOAc / hexane=1 / 3) to obtain the target compound (13 mg, 90%).

[0131] <Example 28> Preparation of 3-(5-bromo-2-methoxyphenyl)-5-(piperazin-1-ylmethyl)isoxazole hydrochloride To the compound (53 mg) prepared in Example 21, 1 mL of hydrochloric acid dissolved in dioxane was added and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure and then purified by flash column chromatography on silica gel (dichloromethane / methanol=10 / 1) to obtain the target compound (30 mg, 66%).

[0132] <Example 29> Preparation of 3-(5-allyl-methoxyphenyl)-5-(piperazin-1-ylmethyl)isoxazole hydrochloride To the compound (25 mg) prepared in Example 25, 0.6 mL of hydrochloric acid dissolved in dioxane was added and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure and then purified by flash column chromatography on silica gel (dichloromethane / methanol=10 / 1) to obtain the target compound (14 mg, 77%).

[0133] <Example 30> Preparation of 3-(2-methoxy-5-propylphenyl)-5-(piperazin-1-ylmethyl)isoxazole hydrochloride To the compound prepared in Example 26 (49 mg), 1 mL of hydrochloric acid dissolved in dioxane was added and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure and then purified by flash column chromatography on silica gel (dichloromethane / methanol=10 / 1) to obtain the target compound (26 mg, 53%).

[0134] <Example 31> Preparation of (3-(2-methoxy-5-(trifluoromethyl)phenyl)isoxazol-5-yl)methanol The target compound was prepared by following step 3 of Example 17, except using 2-methoxy-5-trifluoromethylbenzaldehyde as the starting material.

[0135] <Example 32> Preparation of 2-(3-(2-methoxy-5-(trifluoromethyl)phenyl)isoxazol-5-yl)propan-2-ol The target compound was prepared in the same manner as in Example 4, except that the synthesis was performed in the same manner as in Example 31, except that 2,2-dimethylpropargyl alcohol was used in step 3.

[0136] <Example 33> Preparation of 2-(3-(2-methoxy-5-(trifluoromethyl)phenyl)isoxazol-5-yl)ethan-1-ol The target compound was prepared in the same manner as in Example 4, except that the synthesis was performed in the same manner as in Example 31, but but-3-yn-1-ol was used in step 3.

[0137] <Example 34> Preparation of 3-(2-methoxy-5-(trifluoromethyl)phenyl)-5-(piperazin-1-ylmethyl)isoxazole The synthesis was carried out in the same manner as in Example 31, but the intermediate was synthesized by using t-butyl-4-(prop-2-yn-1-yl)-piperazine-1-carboxylate instead of propargyl alcohol in step 3. The Boc group was then removed using a hydrochloric acid / dioxane solution to produce the target compound.

[0138] <Example 35> Preparation of (3-(2-methoxy-4-(trifluoromethyl)phenyl)isoxazol-5-yl)methanol The target compound was prepared in the same manner as in Example 4, except that the synthesis was carried out in a similar manner to that in Example 31, except that 2-methoxy-4-trifluoromethylbenzaldehyde was used as the starting material.

[0139] <Example 36> Preparation of 2-((3-(2-methoxy-5-(trifluoromethyl)phenyl)isoxazol-5-yl)methoxy)acetic acid The compound prepared in Example 31 was reacted with t-butyl bromoacetate / NaH in DMF, and then the t-butyl group was removed using TFA (trifluoroacetic acid) in DCM to prepare the target compound.

[0140] <Example 37> Preparation of 4-((3-(2-methoxy-5-(trifluoromethyl)phenyl)isoxazol-5-yl)methyl)-1-methylpiperazin-2-one The target compound was prepared in a similar manner to Example 4, except that the synthesis was performed in a similar manner to Example 31, except that 1-methyl-4-(prop-2-yn-1-yl)piperazin-2-one was used instead of propargyl alcohol in step 3.

[0141] <Example 38> Preparation of (3-(2-methoxy-5-morpholinophenyl)isoxazol-5-yl)methanol Step 4 of Example 17 was carried out using the compound prepared in Example 7, except that morpholine was reacted in the presence of RuPhos-Pd-G3 / cesium carbonate to prepare the target compound.

[0142] <Example 39> Preparation of 2-(3-(5-allyl-2-methoxyphenyl)isoxazol-5-yl)propan-2-ol The target compound was prepared in the same manner as in Example 4, except that up to step 4 of Example 17 was carried out, but 2-methylbut-3-yn-2-ol was used in step 3.

[0143] <Example 40> Preparation of 2-(3-(2-methoxy-5-propylphenyl)isoxazol-5-yl)propan-2-ol The compound prepared in Example 39 was reduced using H2 and Pd / C in methanol to prepare the target compound.

[0144] <Example 41> Preparation of 3-(5-allyl-2-methoxyphenyl)-5-((4-methylpiperazin-1-yl)methyl)isoxazole The target compound was prepared in a manner similar to that of Example 4, except that up to step 4 of Example 17 was carried out, but 1-methyl-4-(prop-2-yn-1-yl)piperazine was used in step 3.

[0145] <Example 42> Preparation of 3-(2-methoxy-5-propylphenyl)-5-((4-methylpiperazin-1-yl)methyl)isoxazole The compound prepared in Example 41 was reduced using H2 and Pd / C in methanol to prepare the target compound.

[0146] <Example 43> Preparation of (3-(5-allyl-2-(trifluoromethoxy)phenyl)isoxazol-5-yl)methanol The target compound was prepared in a similar manner to Example 4, except that the procedure of Example 15 was carried out in the same manner as Example 15, except that 5-bromo-2-(trifluoromethoxy)benzaldehyde was used as the starting material.

[0147] <Example 44> Preparation of (3-(4-allyl-2-methoxyphenyl)isoxazol-5-yl)methanol The target compound was prepared in a similar manner to Example 4, except that the procedure of Example 15 was repeated except that 4-bromo-2-methoxybenzaldehyde was used as the starting material.

[0148] <Example 45> Preparation of (3-(5-isopropyl-2-methoxyphenyl)isoxazol-5-yl)methanol The target compound was prepared in a manner similar to that of Example 4, except that up to Step 3 of Example 17, 5-isopropyl-2-methoxybenzaldehyde was used instead of 5-bromo-2-methoxybenzaldehyde as the starting material.

[0149] <Example 46> Preparation of tert-butyl 4-((3-(5-isopropyl-2-methoxyphenyl)isoxazol-5-yl)methyl)piperazine-1-carboxylate The target compound was prepared in a manner similar to that of Example 4, except that up to Step 3 of Example 17, 5-isopropyl-2-methoxybenzaldehyde was used as the starting material, and tert-butyl 4-(prop-2-yn-1-yl)piperazine-1-carboxylate was used instead of propargyl alcohol in Step 3.

[0150] <Example 47> Preparation of 3-(5-isopropyl-2-methoxyphenyl)-5-(piperazin-1-ylmethyl)isoxazole After carrying out the same procedure as in Example 46, the Boc group was removed using a hydrochloric acid / dioxane solution to produce the target compound.

[0151] <Example 48> Preparation of tert-butyl 4-((3-(4-allyl-2-methoxyphenyl)isoxazol-5-yl)methyl)piperazine-1-carboxylate The target compound was prepared in a manner similar to that of Example 4, except that up to Step 3 of Example 17, 4-bromo-2-methoxybenzaldehyde was used as the starting material, and tert-butyl 4-(prop-2-yn-1-yl)piperazine-1-carboxylate was used instead of propargyl alcohol in Step 3.

[0152] <Example 49> Preparation of 3-(4-allyl-2-methoxyphenyl)-5-(piperazin-1-ylmethyl)isoxazole After carrying out the same procedure as in Example 48, the Boc group was removed using a hydrochloric acid / dioxane solution to produce the target compound.

[0153] <Example 50> Preparation of tert-butyl 4-((3-(5-allyl-2-(trifluoromethoxy)phenyl)isoxazol-5-yl)methyl)piperazine-1-carboxylate The target compound was prepared in a manner similar to that of Example 4, except that up to Step 4 of Example 17, 5-bromo-2-(trifluoromethoxy)benzaldehyde was used as the starting material, and tert-butyl 4-(prop-2-yn-1-yl)piperazine-1-carboxylate was used instead of propargyl alcohol in Step 3.

[0154] <Example 51> Preparation of 3-(5-allyl-2-(trifluoromethoxy)phenyl)-5-(piperazin-1-ylmethyl)isoxazole After carrying out the same procedure as in Example 50, the Boc group was removed using a hydrochloric acid / dioxane solution to produce the target compound.

[0155] <Example 52> Preparation of 3-(5-allyl-2-(trifluoromethoxy)phenyl)-5-((4-methylpiperazin-1-yl)methyl)isoxazole The target compound was prepared in the same manner as in Example 4, except that after carrying out the steps up to step 4 of Example 17, the salt form was synthesized using hydrochloric acid / dioxane solution, but 5-bromo-2-(trifluoromethoxy)benzaldehyde was used as the starting material, and 1-methyl-4-(prop-2-yn-1-yl)piperazine was used instead of propargyl alcohol in step 3.

[0156] <Example 53> Preparation of (2S,6R)-4-((3-(2-methoxy-5-propylphenyl)isoxazol-5-yl)methyl)-2,6-dimethylmorpholine Step 1: (3-(2-methoxy-5-propylphenyl)isoxazol-5-yl)methanol Followed through step 3 of Example 17 but using 2-methoxy-5-propylbenzaldehyde as the starting material to give the desired compound as a yellow solid.

[0157] LC-MS, m / z[M+1]=248.1 Step 2: 3-(2-Methoxy-5-propylphenyl)isoxazole-5-carbaldehyde The compound of step 1 (2.3 g, 9.3 mmol) was dissolved in DCM (30 mL) and Dess-Martin periodinane (4.1 g, 8.1 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours, after which the reaction mixture was filtered. The filtered cake was washed with DCM (20 mL). The filtrate was concentrated to give the desired compound (1.7 g, 74% yield) in the form of a yellow solid.

[0158] LC-MS, m / z[M+1]=246.1 Step 3: (2S,6R)-4-((3-(2-methoxy-5-propylphenyl)isoxazol-5-yl)methyl)-2,6-dimethylmorpholine The compound from step 2 (100 mg, 0.41 mmol) was dissolved in DCM and acetic acid (0.05 mL) was added to a solution of (2S,6R)-2,6-dimethylmorpholine (56 mg, 0.49 mmol). The reaction was stirred at room temperature for 30 minutes, after which NaBHAc3 (174 mg, 0.82 mmol) was added to the reaction mixture. After stirring the reaction mixture at room temperature for 2 hours, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to obtain the free base form of the compound, which was treated with 2N HCl to obtain the HCl salt form of the desired compound (94.8 mg) as a yellow solid.

[0159] <Example 54> Preparation of 3-(2-methoxy-5-propylphenyl)-5-((4-methoxypiperidin-1-yl)methyl)isoxazole The target compound was prepared in a similar manner to Example 4, except that the synthesis was performed in a similar manner to Example 53, except that 4-methoxypiperidine was used instead of dimethylmorpholine in step 3.

[0160] <Example 55> Preparation of 1-((3-(2-methoxy-5-propylphenyl)isoxazol-5-yl)methyl)piperidine-4-carboxylic acid The target compound was prepared in a similar manner to Example 4, except that in step 3, piperidine-4-carboxylic acid was used instead of dimethylmorpholine, in a similar synthesis to that in Example 53.

[0161] <Example 56> Preparation of 5-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)-3-(2-methoxy-5-propylphenyl)isoxazole The target compound was prepared in a similar manner to Example 4, except that the synthesis was performed in a similar manner to Example 53, except that 4,5,6,7-tetrahydrothieno[3,2-c]pyridine was used instead of dimethylmorpholine in step 3.

[0162] <Example 57> Preparation of 5-((5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)methyl)-3-(2-methoxy-5-propylphenyl)isoxazole The target compound was prepared in a similar manner to Example 4, except that the synthesis was performed in a similar manner to Example 53, except that 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine was used instead of dimethylmorpholine in step 3.

[0163] <Example 58> Preparation of 3-(4-fluoro-2-methoxy-5-propylphenyl)-5-(piperazin-1-ylmethyl)isoxazole The procedure was repeated up to step 3 of Example 17, but 2-methoxy-4-fluoro-5-propylbenzaldehyde was used as the starting material, and t-butyl-4-(prop-2-yn-1-yl)-piperazine-1-carboxylate was used instead of propargyl alcohol in step 3 to synthesize an intermediate. The Boc group was then removed using a hydrochloric acid / dioxane solution to produce the target compound.

[0164] <Example 59> Preparation of 3-(4-fluoro-2-methoxy-5-propylphenyl)-5-((4-methylpiperazin-1-yl)methyl)isoxazole The procedure was carried out in a similar manner to Example 58, except that in step 3, 4-methylpiperazine was used instead of t-butyl-4-(prop-2-yn-1-yl)-piperazine-1-carboxylate, and the target compound was prepared in a similar manner to Example 4.

[0165] <Example 60> Preparation of 5-((4-methylpiperazin-1-yl)methyl)-3-(5-propyl-2-(trifluoromethoxy)phenyl)isoxazole The target compound was prepared in the same manner as in Example 4, except that up to step 3 of Example 17 was carried out, but 2-trifluoromethoxy-5-propylbenzaldehyde was used as the starting material, and 1-methyl-4-(prop-2-yn-1-yl)piperazine was used in step 3.

[0166] <Example 61> Preparation of 2-(4-methoxy-3-(5-((4-methylpiperazin-1-yl)methyl)isoxazol-3-yl)phenyl)ethan-1-ol The procedure was repeated up to step 3 of Example 17, but 3-formyl-4-methoxyphenethyl acetate was used as the starting material, and 1-methyl-4-(prop-2-yn-1-yl)piperazine was used in step 3 to obtain an intermediate (4-methoxy-3-(5-((4-methylpiperazin-1-yl)methyl)isoxazol-3-yl)phenethyl acetate) in which the hydroxy group was protected with an acetyl group. The intermediate was hydrolyzed with a lithium hydroxide solution to obtain the target compound.

[0167] <Example 62> Preparation of 3-(2-methoxy-5-(2-methoxyethyl)phenyl)-5-((4-methylpiperazin-1-yl)methyl)isoxazole The procedure was repeated up to step 3 of Example 17, except that 2-methoxy-5-(2-methoxyethyl)benzaldehyde was used as the starting material and 1-methyl-4-(prop-2-yn-1-yl)piperazine was used in step 3 to give the desired compound.

[0168] <Example 63> Preparation of 1-(4-((3-(5-isopropyl-2-methoxyphenyl)isoxazol-5-yl)methyl)piperazin-1-yl)ethan-1-one The compound prepared in Example 29 was reacted with triethylamine and acetyl chloride in THF to prepare the target compound.

[0169] <Example 64> Preparation of 3-(5-isopropyl-2-methoxyphenyl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)isoxazole The compound prepared in Example 29 was reacted with triethylamine and methanesulfonyl chloride in THF to prepare the target compound.

[0170] <Example 65> Preparation of 3-(5-allyl-2-methoxyphenyl)-5-((quinazolin-4-yloxy)methyl)isoxazole 4-Chloroquinazoline was added to the compound prepared in Example 15 in DMF, and then NaH was added at 0° C. and reacted at room temperature to prepare the target compound.

[0171] <Example 66> Preparation of tert-butyl 4-((3-(2-methoxy-5-(2-methylallyl)phenyl)isoxazol-5-yl)methyl)piperazine-1-carboxylate The target compound was prepared in the same manner as in Example 4, except that up to step 4 of Example 17 was carried out, but 1-methyl-4-(prop-2-yn-1-yl)piperazine was used instead of propargyl alcohol in step 3, and tributyl(2-methylallyl)stannane was used instead of allyltributyltin (Sn) in step 4.

[0172] <Example 67> Preparation of 3-(2-methoxy-5-(2-methylallyl)phenyl)-5-(piperazin-1-ylmethyl)isoxazole After carrying out the same procedure as in Example 66, the Boc group was removed using a hydrochloric acid / dioxane solution to produce the target compound.

[0173] <Example 68> Preparation of (3-(2-methoxy-5-(2-methylallyl)phenyl)isoxazol-5-yl)methanol The procedure was the same as in Example 15, except that in step 4, tributyl(2-methylallyl)stannane was used instead of allyltributyltin (Sn), to prepare the target compound in the same manner as in Example 4.

[0174] <Example 69> Preparation of 3-(2-methoxy-5-(3-methylbut-2-en-1-yl)phenyl)-5-((4-methylpiperazin-1-yl)methyl)isoxazole After carrying out the steps up to step 4 of Example 17, the target compound was synthesized in salt form using hydrochloric acid / dioxane solution, except that 1-methyl-4-(prop-2-yn-1-yl)piperazine was used instead of propargyl alcohol in step 3, and tributyl(3-methylbut-2-en-1-yl)stannane was used instead of allyltributyltin (Sn) in step 4. The target compound was prepared in the same manner as in Example 4.

[0175] The NMR and mass measurement results of the compounds prepared in the above Examples 1 to 69 are summarized in Table 1 below.

[0176] [Table 1]

[0177] [Table 2]

[0178] [Table 3]

[0179] [Table 4]

[0180] [Table 5]

[0181] The chemical structural formulae of the compounds prepared in the above Examples 1 to 69 are summarized in Table 2 below.

[0182] [Table 6]

[0183] [Table 7]

[0184] [Table 8]

[0185] [Table 9]

[0186] [Table 10]

[0187] [Table 11]

[0188] <Experimental Example 1> Screening of compounds capable of removing A2E-fluorescently labeled substances (A2E-BDP) present in human retinal pigment epithelial cells <1-1> Experimental method The human retinal pigment epithelial cell line (ARPE-19) used in the experiment was obtained from ATCC (American Type Culture Collection). The ARPE-19 cell line was cultured in DMEM medium containing 10% FBS. After culture, 4 × 10 3The cells were then plated at a concentration of 1000 cells / well into a 96-well plate and cultured for 24 hours. The ARPE-19 cells were treated with 10 μM A2E-fluorescently labeled substance (A2E-BDP) for 24 hours to induce accumulation of A2E-BDP in the ARPE-19 cells.

[0189] To evaluate the intracellular A2E removal ability of the compounds of the present invention, an easily detectable A2E-fluorescent labeling substance (A2E-BDP) was used. The ARPE-19 cells in which A2E-BDP had accumulated, prepared as described above, were treated once with each test compound at a concentration of 50 μM and then cultured for 24 hours. The cells were disrupted by adding a cell lysis buffer (50 mM Tris-chloride, pH 8.0, 150 mM sodium chloride, 1% NP-40, 1% sodium deoxycholate, 1% sodium dodecyl sulfate, and 2 mM ethylenediaminetetraacetic acid) containing a protease inhibitor to each 96-well. The cell lysate was transferred to a white 96-well plate, and the fluorescence intensity was measured using a fluorescence microplate reader (VICTOR® X3, Perkin Elmer, USA) (excitation 485 nm, emission 535 nm). The results are shown in Table 3 below.

[0190] <1-2> Experimental results

[0191] [Table 12]

[0192] From Table 3, it can be seen that when A2E-fluorescently labeled substance (A2E-BDP) was accumulated in ARPE-19 cells and then treated with the compounds of the examples of the present invention, the A2E-BDP signal measured by fluorescence measurement was significantly reduced. Therefore, it can be seen that the compounds of the present invention remove A2E-BDP. In particular, the compounds of Examples 11, 17, 18, 21 and 26 showed a high removal ability of 60% or more.

[0193] Additional compounds were assessed for their ability to generate subsequent LC3-II as follows: ARPE-19 at 1 × 105 The cells were then dispensed into a 6-well plate at a concentration of 1, 5, 10, 25, and 50 μM and cultured for 24 hours. The cells were then treated with the compounds of the examples of the present invention shown in Table 4 below at concentrations of 1, 5, 10, 25, and 50 μM for 12 hours. Then, a cell lysis buffer containing a protease inhibitor was added to prepare a cell lysate. The LC3-II level was 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 to measure the LC3-II level by Western immunoblotting in the same manner as above. The results are shown in Table 4.

[0194] [Table 13]

[0195] <Experimental Example 2> Removal effect of A2E-fluorescent labeled substances by concentration <2-1> Experimental method ARPE-19 cell line at 4 × 10 4 The cells were then dispensed into a 24-well plate at a concentration of 1000 cells / well and cultured for 24 hours. In order to induce accumulation of A2E-BDP in the ARPE-19 cell line, A2E was treated at a concentration of 10 μM for 24 hours. The A2E-BDP-containing ARPE-19 cells were treated with the compound of Example 17 (10, 25, 50 μM) for 24 hours. The amount of A2E-BDP in each cell was measured using a Nikon Eclipse Ti-U fluorescent microscope (Tokyo, Japan) at 510 nm to measure the fluorescence image. In addition, the change in cell number due to compound treatment was observed using a general phase contrast microscope, and the results are shown in Figure 1. Meanwhile, lutein was used as a control substance.

[0196] <2-2> Experimental results As shown in Figure 1, after treatment with the compound of Example 17 of the present invention, no significant change in cell number was observed under a phase contrast microscope. Therefore, it was confirmed that the compound of Example 17 has no cytotoxicity against ARPE-19 cells at the concentration used in the experiment.

[0197] Meanwhile, when A2E and A2E-BDP were accumulated in ARPE-19 cells and then observed under a fluorescence microscope (Nikon NIS-Elements, AR, Japan), A2E-BDP was easily confirmed, and a concentration-dependent decrease in fluorescence intensity was observed in the experimental groups treated with the compound of Example 17 of the present invention at concentrations of 10, 25, and 50 μM together with A2E. This means that the treatment with the compound of Example 17 caused a quantitative decrease in A2E-BDP in the cells. In the case of the lutein-treated group used as a control group, a decrease in fluorescence intensity was observed, and it was confirmed that the compound of Example 17 of the present invention has a better A2E-BDP removal ability than lutein.

[0198] <Experimental Example 3> Confirmation of A2E removal effect in human retinal pigment epithelial cells In Table 1 and Figure 1, an A2E-fluorescent substance (A2E-BDP), which is easy to observe fluorescently, was used to measure the decrease in A2E in cells by compounds. Previous research reports have shown that the intracellular dynamics and characteristics of A2E-BDP are identical to those of A2E, but since the substance actually present in the body is A2E, the quantitative change in A2E in cells was directly measured by the following experiment using HPLC.

[0199] <3-1> Experimental method ARPE-19 cell line at 4 × 10 3The cells were dispensed into a 6-well plate at a concentration of 10 ... LC-MS (Shimadzu LC-MS 2010EV) analysis was performed using a C18 column (2'50mm) with acetonitrile and 0.1% formic acid (concentration gradient, 0-100%, 0-10 min; flow rate 1.0 ml / min; monitoring at 503 nm). All operations in the extraction process of A2E present in the cytoplasm of ARPE-19 cells were performed under weak red light to prevent the destruction of A2E. The experimental results are shown in Figure 2.

[0200] <3-2> Experimental results 2, it can be seen that when ARPE-19 cells in which A2E has accumulated are treated with the compound of Example 17 of the present invention, the amount of accumulated A2E is significantly reduced in a concentration-dependent manner, indicating that the compound of the present invention directly removes A2E.

[0201] <Experimental Example 4> Inhibitory effect of blue light-induced retinal pigment epithelial cell death <4-1> Experimental method It is known that A2E accumulated in human retinal pigment epithelial cells induces cytotoxicity when irradiated with blue light. Using a human retinal pigment epithelial cell line, the effect of the compound of the present invention in suppressing cell death caused by irradiation with blue light was measured.

[0202] ARPE-19 cell line at 2 × 10 4The cells were dispensed into a 6-well plate at a concentration of 10 ...

[0203] <4-2> Experimental results The photographic results in the upper part of Figure 3 show that no change in cell viability was observed with A2E accumulation alone (A2E group), but that the combination of A2E and blue light irradiation (AB group) induced the death of ARPE-19 cells. It was confirmed that cell death was significantly suppressed in the experimental group treated with the compound of Example 17 of the present invention in the cell death model in which A2E and blue light irradiation were performed together.

[0204] As shown in the experimental results in the lower part of Figure 3, the cell viability quantified using Image J also confirmed that treatment with the compound of Example 17 of the present invention had a statistically significant effect of suppressing cell death caused by irradiation with A2E and blue light.

[0205] <Experimental Example 5> Inhibitory effect of blue light-induced NF-κB activation in retinal pigment epithelial cells <5-1> Experimental method When cells receive stimuli such as external pathogenic molecules (PAMP), NF-κB dimers (p50-p65 dimers) are separated from IκB and activated. The separated NF-κB dimers enter the nucleus through the nuclear membrane, bind to DNA, and activate gene transcription, which means activation of NF-κB. Therefore, the inhibitory effect of the compound of the present invention on NF-κB activation can be evaluated by measuring the change in the cytoplasmic or nuclear levels of p65. The experiment was carried out as follows.

[0206] ARPE-19 cell line at 2 × 10 4 The cells were dispensed into a 6-well plate at a concentration of 10 ... After collecting nuclei by centrifugation, nuclear proteins were extracted using nuclear extraction buffer (20 mM Tris.HCl, 420 mM NaCl, 1.5 mM MgCl2, 0.2 mM EDTA, and 25% glycerol, pH 8.0) containing protease inhibitors. p65 levels were measured by Western immunoblotting using anti-p65 antibodies (Cell Signaling Technology, MA, USA). As internal controls for the cytoplasmic and nuclear fractions, antibodies against α-tubulin (Cell Signaling Technology) and histone H3 (Abcam, Cambridge, UK) were used to measure p65 levels by Western immunoblotting as described above. The results are shown in Figure 4.

[0207] <5-2> Experimental results 4, when ARPE-19 cells were irradiated with A2E and blue light, the translocation of p65 into the nucleus was observed, which indicates the activation of NF-κB. On the other hand, it can be seen that the translocation of p65 into the nucleus was inhibited by treating the cells with the compound of Example 17 of the present invention, and the activation of NF-κB was inhibited.

[0208] <Experimental Example 6> Inhibitory effect of blue light-induced inflammatory gene expression in retinal pigment epithelial cells <6-1> Experimental method ARPE-19 cell line at 2 × 10 4 The cells were dispensed into a 6-well plate at a concentration of 10 ...

[0209] [Table 14]

[0210] At this time, the PCR results for 18S were used as a control to correct the relative amounts of genes measured in the ARPE-19 cell line, and the experimental results are shown in FIG. 5.

[0211] <6-2> Experimental results 5, it can be seen that the accumulation of A2E and the irradiation of blue light significantly increased the expression of mRNA of inflammation-related genes (IL-1β, IL-6, and CXCL8) in the ARPE-19 cell line. Meanwhile, it was confirmed that the expression of these genes was statistically significantly decreased by treating with the compound of Example 17 of the present invention (P<0.05).

[0212] <Experimental Example 7> Effect of autophagy activation in retinal pigment epithelial cells <7-1> Experimental method 1x10 ARPE-19 5 The cells were then dispensed into a 6-well plate at a concentration of 10, 25, and 50 μM and cultured for 24 hours. The compound of Example 17 of the present invention was then treated for 12 hours at concentrations of 10, 25, and 50 μM. A cell lysis buffer containing a protease inhibitor was then added to prepare a cell lysate. The LC3-II level was 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 to measure the LC3-II level by Western immunoblotting in the same manner as above, and the results are shown in Figure 6 (upper graph).

[0213] Meanwhile, the formation of autophagosomes in cells was observed as follows. Cells were transformed into ARPE-19 cell line with a plasmid expressing GFP-LC3 (Addgene Inc., MA, USA) using Lipofectamine® 2000 Reagent (Invitrogen, Carlsbad, CA, USA). After 48 hours of culture, the compound of Example 17 of the present invention was treated at a concentration of 25 μM. After an additional 12 hours of culture, the cells were fixed using 4% paraformaldehyde for 10 minutes. The cells were then washed three times with PBS every 5 minutes. Finally, the formation of puncta of GFP-LC3 was observed using a confocal laser scanning microscope (Nikon Corporation, Tokyo, Japan). Nuclei were stained with 1 μg / mL Hoechst 33342 (Thermo Scientific, Rockford, IL, USA), and the observed images are shown in FIG. 6 (lower photographic results).

[0214] <7-2> Experimental results As shown in the graph of Figure 6, an increase in LC3-II, an autophagy marker, was observed when the compound of Example 17 of the present invention was treated in the ARPE-19 cell line. LC3-II is one of the main indicator proteins of autophagy activation. When autophagy is activated, LC3-II is involved in autophagosome formation and forms puncta in the cytoplasm.

[0215] 6, intracellular LC3-II puncta was observed upon treatment with the compound of Example 17. This confirms that the compound of the present invention activates the autophagy process.

[0216] <Experimental Example 8> Improvement of autophagy flux in retinal pigment epithelial cells <8-1> Experimental method Autophagy flux was measured by comparing the degree of change in LC3-II protein formation by treatment with the compound of Example 17 of the present invention in the presence and absence of bafilomycin A1 (Abcam, Cambridge, UK) by Western blotting (Seranova E. et al. Autophagy: Methods and Protocols, Methods in Molecular Biology, vol. 1880, pp 389-428, 2019, https: / / doi.org / 10.1007 / 978-1-4939-8873-0_26).

[0217] In this experiment, the autophagy flux was measured using bafilomycin A1, a known autophagy inhibitor, at a saturating concentration. Bafilomycin A1 inhibits lysosomal V-ATPase to inhibit its acidification, and inhibits the Ca2+ pump SERCA to block autophagosome-lysosome fusion, thereby blocking autophagic flux. During autophagy, LC3 is converted from LC3-I to LC3-II in the autophagosomal membrane, and LC3-II is subsequently degraded, but exposure to an inhibitor such as bafilomycin A1 inhibits autophagosome-lysosome fusion, resulting in LC3-II accumulation. Therefore, the effect of the compound of the present invention on autophagic flux can be determined by observing the level of LC3-II by treating the compound of the present invention in the presence or absence of a saturating concentration of bafilomycin A1.

[0218] Specifically, this experiment involved the use of ARPE-19 cells at 1 × 10 5The cells were then dispensed into a 6-well plate at a concentration of 10, 25, and 50 μM and cultured for 24 hours. The ARPE-19 cell line was treated with the compound of Example 17 of the present invention at concentrations of 10, 25, and 50 μM for 12 hours. A cell lysis buffer containing a protease inhibitor was added thereto to prepare a cell lysate. The LC3-II level was measured by Western immunoblotting using a specific anti-LC3-II antibody (Cell Signaling Technology, MA, USA). Meanwhile, the compound of Example 17 was treated in the same manner as above under the condition of treatment with bafilomycin A1 at a concentration of 2 nM for 4 hours, and the amount of LC3-II was measured by Western immunoblotting. The amount of β-actin (Cell Signaling Technology) was measured as an internal control group. The density of the obtained band was quantified using the Image J program, and the difference in the amount of LC3-II protein in the presence and absence of bafilomycin A1 was calculated to measure the autophagy flux, and the results are shown in FIG. 7.

[0219] <8-2> Experimental results 7, the compound of Example 17 of the present invention showed a more significant increase in LC3-II in the presence of bafilomycin compared to the absence of bafilomycin. As a result, it was confirmed that the compound of Example 17 of the present invention is a compound that significantly increases autophagic flux in the ARPE-19 cell line.

[0220] <Experimental Example 9> Effect of autophagy activation in A2E-accumulated retinal pigment epithelial cells <9-1> Experimental method A2E is known to inhibit intracellular autophagy, so we examined whether the compound of Example 17 of the present invention also increases autophagy in the ARPE-19 cell line in which A2E accumulates.

[0221] Specifically, ARPE-19 cell line was cultured at 1 × 10 5The cells were dispensed into a 6-well plate at a concentration of 1000 cells / well and cultured for 24 hours. A2E was treated at a concentration of 25 μM for 24 hours. Then, the compound of Example 17 of the present invention was treated at concentrations of 25, 50, and 100 μM for 12 hours. Then, the preparation of the cell lysate and the measurement of LC3-II by Western immunoblotting were performed in the same manner as in Experimental Example 7, and the results are shown in FIG. 8.

[0222] <9-2> Experimental results As shown in Figure 8, an increase in LC3-II, an autophagy marker, was observed when the compound of Example 17 of the present invention was treated in the ARPE-19 cell line in which A2E was accumulated. This confirmed that the compound of the present invention activates the autophagy process even in the ARPE-19 cell line in which A2E is accumulated.

[0223] <Experimental Example 10> Improvement of autophagy flux in A2E-accumulated retinal pigment epithelial cells <10-1> Experimental method We determined whether the compound of Example 17 of the present invention also increases autophagic flux in the ARPE-19 cell line in which A2E has accumulated. 5 The cells were dispensed into a 6-well plate at a concentration of 1000 cells / well and cultured for 24 hours. A2E was treated at a concentration of 25 μM for 24 hours. The compound of Example 17 of the present invention was treated at concentrations of 10, 25, and 50 μM for 12 hours. Bafilomycin treatment (2 nM, 4-hour treatment), preparation of cell lysate, and measurement of LC3-II by the Western method were performed in the same manner as in Experimental Example 8.

[0224] <10-2> Experimental results The experimental results are shown in Figure 9. As shown in Figure 9, the compound of Example 17 of the present invention showed a more significant increase in LC3-II in the presence of bafilomycin even in the ARPE-19 cell line in which A2E was accumulated. As a result, it was found that the compound of Example 17 significantly increased autophagic flux in the ARPE-19 cell line in which A2E was accumulated, and that the compound of Example 17 improved autophagic flux, thereby removing A2E accumulated in the cells.

[0225] <Experimental Example 11> Improvement effect of compounds on autophagy inhibited by A2E and blue light <11-1> Experimental method It is known that A2E significantly inhibits the autophagy process after activation by blue light, so we examined whether the compounds of the present invention could restore autophagy inhibited by A2E and blue light.

[0226] During the process of autophagosome formation, p62 specifically binds to the substance to be degraded and simultaneously binds to LC3 protein to form autophagosomes. When autophagy is inhibited, aggregates composed of p62 and ubiquitinated proteins are formed, and p62 accumulates in cells. Therefore, by measuring the change in intracellular p62 level, the improving effect of the compound of the present invention on autophagy inhibited by A2E and blue light can be evaluated. The experiment was carried out as follows.

[0227] Specifically, ARPE-19 cell line was cultured at 2 × 10 4The cells were then dispensed into a 6-well plate at a concentration of 10 ...

[0228] <11-2> Experimental results The experimental results are shown in Figure 10. As shown in Figure 10, a significant increase in p62 protein due to A2E accumulation and blue light irradiation was observed in the ARPE-19 cell line. It was confirmed that the compound of Example 17 of the present invention was treated with the p62 protein increased by A2E accumulation and blue light irradiation, and the concentration of p62 protein was reduced in a concentration-dependent manner. Therefore, it can be seen that the compound of the present invention has the effect of restoring autophagy activity in human retinal pigment epithelial cells reduced by A2E and blue light, and promotes the removal of A2E accumulated in cells by restoring autophagy activity.

[0229] <Experimental Example 12> Improvement effect of the compound on blue light-induced retinal damage animal model The compound of the present invention was confirmed to have an improving effect on retinal damage induced by blue light in experimental animals (Balb / c mice). The compounds of the examples were orally administered repeatedly for 4 weeks and the following experiments were carried out. All tests were carried out at the non-clinical center of the Bio Headquarters (Songdo, Incheon) of Korea Conformity Laboratories (KCL) and were approved by the Animal Experiment Ethics Committee (approval number: IA20-04287).

[0230] <12-1> Experimental method Eighty specific pathogen-free (SPF) male BALB / c mice (Orient Bio, Korea) (5 weeks old) were acclimated for one week. Then, the body weight was measured the day before administration, and the mice were separated into groups based on the weight ranked using an Excel program. Only animals within ±20% of the average body weight were used for the test. After separation into groups, the mice were kept in the dark for 24 hours, and then the dark conditions were maintained for the blue light irradiation period.

[0231] After the experimental animals were anesthetized with isoflurane by inhalation, they were irradiated with 10,000 lux of blue light using a blue light irradiation device for 2 weeks, a total of 14 times (1 hour / day). The test substance was used by dissolving HP-β-cyclodextrin in a 5% CMC-Na solution to a concentration of 10%, and dissolving the compound of Example 17 of the present invention in the solution. The dose was 25 mg / kg / day per experimental animal, with the administration volume being 10 ml / kg / day. The test substance was administered by forcibly orally using an oral administration probe after grasping and correcting the skin on the back of the neck of the test animal. The substance was administered once a day, 7 days / week, for 4 weeks, in the morning on the day of administration. The initial 2 weeks overlapped with the blue light irradiation period, and 2 weeks were added after the end of the blue light irradiation, for a total of 4 weeks of administration. On the day of administration, the test substance was administered before the blue light irradiation. Both eyes of all animals were examined before the start of administration and once a week. After instilling a mydriatic to dilate the pupils, the fundus of the eye was observed using a fundus camera (Genesis-D, Kowa Co. Ltd., Japan), and photographs were taken for each animal the week after administration of the test substance was completed.

[0232] After the experiment, both eyes of all animals were enucleated and fixed in Davidson's solution. After hematoxylin and eosin staining (H&E), the mean thickness of the ONL (Outer Nuclear Layer) and IS (Inner Segment) / OS (Outer Segment) was measured at 140 μm (left / right) from the retinal nerve center using the Axio Vision SE644 (ZEISS) program. The thickness of the ONL and IS / OS of the contralateral eye was measured in a similar manner, and the mean value of both eyes was used as the final thickness. One-way ANOVA test and Student's t test were used between each group, and a p<0.05 or less was considered statistically significant. The statistical analysis program used was the SPSS 12.0K program (SPSS, Chicago, IL, USA), a widely used commercial statistical package. Animals that did not form the test model were excluded from the statistics.

[0233] <12-2> Experimental results The experimental results are shown in Figures 11 and 12. Observation using a fundus camera confirmed retinal damage in the blue light exposure control group compared to the normal control group. Histomorphological analysis of ocular tissue also confirmed a decrease in the thickness of the ONL and IS / OS in the blue light exposure control group compared to the normal control group. Meanwhile, in the group orally administered 25 mg / kg / day of the compound of the present invention, retinal damage was improved on fundus examination (Figure 11). Furthermore, the thickness of the ONL and IS / OS, which was significantly reduced by blue light exposure, was statistically significantly (p<0.01) restored by administration of the compound of the present invention (Figure 12).

[0234] <Experimental Example 13> Evaluation of A2E-BDP removal ability at each concentration of compounds of other examples The A2E-BDP removal ability at each concentration was further evaluated for the compounds of Examples 11, 17, 18, 21, and 26, which showed a high removal ability of 60% or more in the experimental results of Table 3. The A2E-fluorescent labeled substance (A2E-BDP) removal ability was evaluated according to Experimental Example 1 (except that the test compounds were treated at the indicated concentrations). The results are shown in Figure 13.

[0235] As shown in Figure 13, it was confirmed that the amount of A2E was reduced in a concentration-dependent manner not only by the compound of Example 17 according to the present invention, but also by the compounds of Examples 11, 18, 21 and 26. Therefore, it can be seen that the compounds of the present invention directly remove A2E.

[0236] <Experimental Example 14> Evaluation of autophagy activation by compounds of other examples The compounds of Examples 11, 17, 18, 21, and 26, which showed a high removal ability of 60% or more in the experimental results in Table 3, were evaluated for their effect of activating autophagy in human retinal pigment epithelial cells. The test compounds were treated at the concentrations shown, and the effect of activating autophagy through an increase in p62 protein (p-p62(S349)) in which the 349th serine residue was phosphorylated was measured by Western immunoblotting using an anti-p-p62 antibody, and the results are shown in Figure 14. An increase in the intracellular P-p62(S439) level is one of the main indicators of autophagy activation.

[0237] As shown in FIG. 14, it was found that not only the compound of Example 17 of the present invention, but also the compounds of Examples 11, 18, 21, and 26 activated autophagy in a concentration-dependent manner.

[0238] <Experimental Example 15> Evaluation of autophagy activation by compounds of other examples Among the compounds of the Examples in Table 2, the autophagy activating effect of the compounds of the Examples that are expected to have autophagy activating ability and low cytotoxicity in human retinal pigment epithelial cells was evaluated according to Experimental Example 7. That is, the autophagy activating effect through an increase in LC3-II was evaluated in a concentration-dependent manner, and the results are shown in FIG.

[0239] As shown in FIG. 15 and FIG. 16, the compounds of Examples 28, 30, 34, 41, 42, 47, 58, 59 and 60 according to the present invention exhibited excellent autophagy activating effects in a compound concentration-dependent manner.

Claims

1. A compound represented by the following chemical formula 1 or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 In Chemical Formula 1, R １ is hydrogen, C １－６ Alkyl, or C ３－６ cycloalkyl, where optionally C １－６ Alkyl or C ３－６ Cycloalkyl is one where one or more hydrogen atoms are hydroxyl, C １－３ substituted with one or more substituents independently selected from the group consisting of alkoxy and halogen; R ２ 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 each 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 said -C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Alkoxy, C １－３ One or more hydrogens of alkylene or heterocycloalkyl may be ═O, —C １－３ Alkyl, -OH, -COOH, -CO-C １－３ Alkyl, -CONH ２ , -SO ２ -C １－３ Alkyl, -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , -NHCOCH ３ , 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; R ３ and R ３ ' are each independently hydrogen, halogen, C １－６ Alkyl, C １－６ Alkoxy, C ３－６ Cycloalkyl, heterocycloalkyl, -CH ２ -CR ４ (=CR ５ R ６ ), -CN, HaloC １－３ Alkyl, -C １－３ Alkylene-OR ４ , -C(O)R ４ , -C １－３ Alkylene -C(O)R ４ , -C １－３ alkylene -COOH or -COOH, where R ４ , R ５ and R ６ are each independently hydrogen, methyl, or -NH ２ That is, A compound or a pharma- ceutically acceptable salt thereof.

2. The formula 1 has the structure of the following formula 1a: 【Chemistry 2】 In formula 1a, R １ is hydrogen, C １－６ Alkyl, or C ３－６ cycloalkyl, where optionally C １－６ Alkyl or C ３－６ Cycloalkyl is one where one or more hydrogen atoms are hydroxyl, C １－３ substituted with one or more substituents independently selected from the group consisting of alkoxy and halogen; R ２ 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 each 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 said -C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Alkoxy, C １－３ One or more hydrogens of alkylene or heterocycloalkyl may be ═O, —C １－３ Alkyl, -OH, -COOH, -CO-C １－３ Alkyl, -CONH ２ , -SO ２ -C １－３ Alkyl, -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , -NHCOCH ３ , 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; R ３ and R ３ ' are each independently hydrogen, halogen, C １－６ Alkyl, C １－６ Alkoxy, C ３－６ Cycloalkyl, heterocycloalkyl, -CH ２ -CR ４ (=CR ５ R ６ ), -CN, HaloC １－３ Alkyl, -C １－３ Alkylene-OR ４ , -C(O)R ４ , -C １－３ Alkylene -C(O)R ４ , -C １－３ alkylene -COOH or -COOH, where R ４ , R ５ and R ６ are each independently hydrogen, methyl, or -NH ２ That is, 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

3. In the above formula 1a, R １ is hydrogen or C １－６ alkyl, optionally C １－６ The alkyl group has one or more hydrogens replaced with one or more substituents selected from halogens; R ２ is -C １－６ Alkyl, -C １－３ Alkylene -ORa, -C １－３ Alkylene -NRaRb, or -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 each 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 said -C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Alkoxy, C １－３ One or more hydrogens of alkylene or heterocycloalkyl may be ═O, —C １－３ Alkyl, -OH, -COOH, -CO-C １－３ Alkyl, -CONH ２ , -SO ２ -C １－３ Alkyl, -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , -NHCOCH ３ , 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; R ３ and R ３ ' are each independently hydrogen, halogen, C １－６ Alkyl, C １－６ Alkoxy, heterocycloalkyl, -CH ２ -CR ４ (=CR ５ R ６ ), -CN, HaloC １－３ Alkyl, -C １－３ Alkylene-OR ４ , -C(O)R ４ , -C １－３ Alkylene -C(O)R ４ , -C １－３ alkylene -COOH or -COOH, where R ４ , R ５ and R ６ are each independently hydrogen, methyl, or -NH ２ That is, 3. The compound of claim 2 or a pharma- ceutically acceptable salt thereof.

4. In the above formula 1a, R １ is hydrogen, methyl, or -CF ３ and R ２ 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, wherein R and R are each independently hydrogen, C １－６ Alkyl, allyl, benzyl, -C １－３ Alkylene-COO-C １－３ alkyl, phenyl, quinazoline, or pyridyl, １－６ Alkyl, C １－３ One or more hydrogens of alkylene or heterocycloalkyl may be ═O, —C １－３ Alkyl, -OH, -COOH, -CO-C １－３ Alkyl, -CONH ２ , -SO ２ -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; R ３ and R ３ ' are each independently hydrogen, halogen, C １－６ Alkyl, C １－６ Alkoxy, heterocycloalkyl, -CH ２ -CR ４ (=CR ５ R ６ ), -CN, -HaloC １－３ Alkyl, -C １－３ Alkylene-OR ４ , -C(O)R ４ , -C １－３ Alkylene -C(O)R ４ , -C １－３ alkylene -COOH or -COOH, where R ４ , R ５ and R ６ are each independently hydrogen or methyl; 4. The compound of claim 3 or a pharma- ceutically acceptable salt thereof.

5. The compound is (1) 3-(5-bromo-2-methoxyphenyl)-5-propylisoxazole; (2) 4-bromo-2-(5-propylisoxazol-3-yl)phenol; (3) 3-(2-methoxy-5-propylphenyl)-5-propylisoxazole; (4) 3-(5-allyl-2-methoxyphenyl)-5-propylisoxazole; (5) 4-allyl-2-(5-propylisoxazol-3-yl)phenol; (6) 4-propyl-2-(5-propylisoxazol-3-yl)phenol; (7) (3-(5-bromo-2-methoxyphenyl)isoxazol-5-yl)methanol; (8) 4-bromo-2-(5-(hydroxymethyl)isoxazol-3-yl)phenol; (9) 5-((allyloxy)methyl)-3-(5-bromo-2-methoxyphenyl)isoxazole; (10) (3-(2-methoxy-5-propylphenyl)isoxazol-5-yl)methanol; (11) 5-((benzyloxy)methyl)-3-(5-bromo-2-methoxyphenyl)isoxazole; (12) Ethyl 2-((3-(5-bromo-2-methoxyphenyl)isoxazol-5-yl)methoxy)acetate; (13) 3-(5-bromo-2-methoxyphenyl)-5-(methoxymethyl)isoxazole; (14) 2-(5-(hydroxymethyl)isoxazol-3-yl)-4-propylphenol; (15) (3-(5-allyl-2-methoxyphenyl)isoxazol-5-yl)methanol; (16) 4-allyl-2-(5-(hydroxymethyl)isoxazol-3-yl)phenol; (17) 3-(5-allyl-2-methoxyphenyl)-5-((allyloxy)methyl)isoxazole; (18) 3-(5-allyl-2-methoxyphenyl)-5-((benzyloxy)methyl)isoxazole; (19) Ethyl 2-((3-(5-allyl-2-methoxyphenyl)isoxazol-5-yl)methoxy)acetate; (20) 3-(2-methoxy-5-propylphenyl)-5-(methoxymethyl)isoxazole; (21) tert-butyl 4-((3-(5-bromo-2-methoxyphenyl)isoxazol-5-yl)methyl)piperazine-1-carboxylate; (22) 3-(5-allyl-2-methoxyphenyl)-5-((4-allylpiperazin-1-yl)methyl)isoxazole; (23) 3-(5-allyl-2-methoxyphenyl)-5-((4-benzylpiperazin-1-yl)methyl)isoxazole; (24) Ethyl 2-(4-((3-(5-allyl-2-methoxyphenyl)isoxazol-5-yl)methyl)piperazin-1-yl)acetate; (25) tert-butyl 4-((3-(5-allyl-2-methoxyphenyl)isoxazol-5-yl)methyl)piperazine-1-carboxylate; (26) tert-butyl 4-((3-(2-methoxy-5-propylphenyl)isoxazol-5-yl)methyl)piperazine-1-carboxylate; (27) 4-allyl-2-(5-((allyloxy)methyl)isoxazol-3-yl)phenol; (28) 3-(5-bromo-2-methoxyphenyl)-5-(piperazin-1-ylmethyl)isoxazole; (29) 3-(5-allyl-methoxyphenyl)-5-(piperazin-1-ylmethyl)isoxazole; (30) 3-(2-methoxy-5-propylphenyl)-5-(piperazin-1-ylmethyl)isoxazole; (31) (3-(2-methoxy-5-(trifluoromethyl)phenyl)isoxazol-5-yl)methanol; (32) 2-(3-(2-methoxy-5-(trifluoromethyl)phenyl)isoxazol-5-yl)propan-2-ol; (33) 2-(3-(2-methoxy-5-(trifluoromethyl)phenyl)isoxazol-5-yl)ethan-1-ol; (34) 3-(2-methoxy-5-(trifluoromethyl)phenyl)-5-(piperazin-1-ylmethyl)isoxazole; (35) (3-(2-methoxy-4-(trifluoromethyl)phenyl)isoxazol-5-yl)methanol; (36) 2-((3-(2-methoxy-5-(trifluoromethyl)phenyl)isoxazol-5-yl)methoxy)acetic acid; (37) 4-((3-(2-methoxy-5-(trifluoromethyl)phenyl)isoxazol-5-yl)methyl)-1-methylpiperazin-2-one; (38) (3-(2-methoxy-5-morpholinophenyl)isoxazol-5-yl)methanol; (39) 2-(3-(5-allyl-2-methoxyphenyl)isoxazol-5-yl)propan-2-ol; (40) 2-(3-(2-methoxy-5-propylphenyl)isoxazol-5-yl)propan-2-ol; (41) 3-(5-allyl-2-methoxyphenyl)-5-((4-methylpiperazin-1-yl)methyl)isoxazole; (42) 3-(2-methoxy-5-propylphenyl)-5-((4-methylpiperazin-1-yl)methyl)isoxazole; (43) (3-(5-allyl-2-(trifluoromethoxy)phenyl)isoxazol-5-yl)methanol; (44) (3-(4-allyl-2-methoxyphenyl)isoxazol-5-yl)methanol; (45) (3-(5-isopropyl-2-methoxyphenyl)isoxazol-5-yl)methanol; (46) tert-butyl 4-((3-(5-isopropyl-2-methoxyphenyl)isoxazol-5-yl)methyl)piperazine-1-carboxylate; (47) 3-(5-isopropyl-2-methoxyphenyl)-5-(piperazin-1-ylmethyl)isoxazole; (48) tert-butyl 4-((3-(4-allyl-2-methoxyphenyl)isoxazol-5-yl)methyl)piperazine-1-carboxylate; (49) 3-(4-allyl-2-methoxyphenyl)-5-(piperazin-1-ylmethyl)isoxazole; (50) tert-butyl 4-((3-(5-allyl-2-(trifluoromethoxy)phenyl)isoxazol-5-yl)methyl)piperazine-1-carboxylate; (51) 3-(5-allyl-2-(trifluoromethoxy)phenyl)-5-(piperazin-1-ylmethyl)isoxazole; (52) 3-(5-allyl-2-(trifluoromethoxy)phenyl)-5-((4-methylpiperazin-1-yl)methyl)isoxazole; (53) (2S,6R)-4-((3-(2-methoxy-5-propylphenyl)isoxazol-5-yl)methyl)-2,6-dimethylmorpholine; (54) 3-(2-methoxy-5-propylphenyl)-5-((4-methoxypiperidin-1-yl)methyl)isoxazole; (55) 1-((3-(2-methoxy-5-propylphenyl)isoxazol-5-yl)methyl)piperidine-4-carboxylic acid; (56) 5-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)-3-(2-methoxy-5-propylphenyl)isoxazole; (57) 5-((5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)methyl)-3-(2-methoxy-5-propylphenyl)isoxazole; (58) 3-(4-fluoro-2-methoxy-5-propylphenyl)-5-(piperazin-1-ylmethyl)isoxazole; (59) 3-(4-fluoro-2-methoxy-5-propylphenyl)-5-((4-methylpiperazin-1-yl)methyl)isoxazole; (60) 5-((4-methylpiperazin-1-yl)methyl)-3-(5-propyl-2-(trifluoromethoxy)phenyl)isoxazole; (61) 2-(4-methoxy-3-(5-((4-methylpiperazin-1-yl)methyl)isoxazol-3-yl)phenyl)ethan-1-ol; (62) 3-(2-methoxy-5-(2-methoxyethyl)phenyl)-5-((4-methylpiperazin-1-yl)methyl)isoxazole; (63) 1-(4-((3-(5-isopropyl-2-methoxyphenyl)isoxazol-5-yl)methyl)piperazin-1-yl)ethan-1-one; (64) 3-(5-isopropyl-2-methoxyphenyl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)isoxazole; (65) 3-(5-allyl-2-methoxyphenyl)-5-((quinazolin-4-yloxy)methyl)isoxazole; (66) tert-butyl 4-((3-(2-methoxy-5-(2-methylallyl)phenyl)isoxazol-5-yl)methyl)piperazine-1-carboxylate; (67) 3-(2-methoxy-5-(2-methylallyl)phenyl)-5-(piperazin-1-ylmethyl)isoxazole; (68) (3-(2-methoxy-5-(2-methylallyl)phenyl)isoxazol-5-yl)methanol; or (69) 3-(2-methoxy-5-(3-methylbut-2-en-1-yl)phenyl)-5-((4-methylpiperazin-1-yl)methyl)isoxazole.

2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

6. The compound is (11) 5-((benzyloxy)methyl)-3-(5-bromo-2-methoxyphenyl)isoxazole; (15) (3-(5-allyl-2-methoxyphenyl)isoxazol-5-yl)methanol; (17) 3-(5-allyl-2-methoxyphenyl)-5-((allyloxy)methyl)isoxazole; (18) 3-(5-allyl-2-methoxyphenyl)-5-((benzyloxy)methyl)isoxazole; (21) tert-butyl 4-((3-(5-bromo-2-methoxyphenyl)isoxazol-5-yl)methyl)piperazine-1-carboxylate; (25) tert-butyl 4-((3-(5-allyl-2-methoxyphenyl)isoxazol-5-yl)methyl)piperazine-1-carboxylate; (26) tert-butyl 4-((3-(2-methoxy-5-propylphenyl)isoxazol-5-yl)methyl)piperazine-1-carboxylate; (28) 3-(5-bromo-2-methoxyphenyl)-5-(piperazin-1-ylmethyl)isoxazole; (29) 3-(5-allyl-methoxyphenyl)-5-(piperazin-1-ylmethyl)isoxazole; (30) 3-(2-methoxy-5-propylphenyl)-5-(piperazin-1-ylmethyl)isoxazole; (34) 3-(2-methoxy-5-(trifluoromethyl)phenyl)-5-(piperazin-1-ylmethyl)isoxazole; (41) 3-(5-allyl-2-methoxyphenyl)-5-((4-methylpiperazin-1-yl)methyl)isoxazole; (42) 3-(2-methoxy-5-propylphenyl)-5-((4-methylpiperazin-1-yl)methyl)isoxazole; (43) (3-(5-allyl-2-(trifluoromethoxy)phenyl)isoxazol-5-yl)methanol; (44) (3-(4-allyl-2-methoxyphenyl)isoxazol-5-yl)methanol; (47) 3-(5-isopropyl-2-methoxyphenyl)-5-(piperazin-1-ylmethyl)isoxazole; (48) tert-butyl 4-((3-(4-allyl-2-methoxyphenyl)isoxazol-5-yl)methyl)piperazine-1-carboxylate; (50) tert-butyl 4-((3-(5-allyl-2-(trifluoromethoxy)phenyl)isoxazol-5-yl)methyl)piperazine-1-carboxylate; (51) 3-(5-allyl-2-(trifluoromethoxy)phenyl)-5-(piperazin-1-ylmethyl)isoxazole; (52) 3-(5-allyl-2-(trifluoromethoxy)phenyl)-5-((4-methylpiperazin-1-yl)methyl)isoxazole; (58) 3-(4-fluoro-2-methoxy-5-propylphenyl)-5-(piperazin-1-ylmethyl)isoxazole; (59) 3-(4-fluoro-2-methoxy-5-propylphenyl)-5-((4-methylpiperazin-1-yl)methyl)isoxazole; (60) 5-((4-methylpiperazin-1-yl)methyl)-3-(5-propyl-2-(trifluoromethoxy)phenyl)isoxazole; (66) tert-butyl 4-((3-(2-methoxy-5-(2-methylallyl)phenyl)isoxazol-5-yl)methyl)piperazine-1-carboxylate; (67) 3-(2-methoxy-5-(2-methylallyl)phenyl)-5-(piperazin-1-ylmethyl)isoxazole; or (68) (3-(2-methoxy-5-(2-methylallyl)phenyl)isoxazol-5-yl)methanol.

6. The compound of claim 5 or a pharma- ceutically acceptable salt thereof.

7. The compound is (28) 3-(5-bromo-2-methoxyphenyl)-5-(piperazin-1-ylmethyl)isoxazole; (30) 3-(2-methoxy-5-propylphenyl)-5-(piperazin-1-ylmethyl)isoxazole; (34) 3-(2-methoxy-5-(trifluoromethyl)phenyl)-5-(piperazin-1-ylmethyl)isoxazole; (41) 3-(5-allyl-2-methoxyphenyl)-5-((4-methylpiperazin-1-yl)methyl)isoxazole; (42) 3-(2-methoxy-5-propylphenyl)-5-((4-methylpiperazin-1-yl)methyl)isoxazole; (47) 3-(5-isopropyl-2-methoxyphenyl)-5-(piperazin-1-ylmethyl)isoxazole; (58) 3-(4-fluoro-2-methoxy-5-propylphenyl)-5-(piperazin-1-ylmethyl)isoxazole; (59) 3-(4-fluoro-2-methoxy-5-propylphenyl)-5-((4-methylpiperazin-1-yl)methyl)isoxazole; or (60) 5-((4-methylpiperazin-1-yl)methyl)-3-(5-propyl-2-(trifluoromethoxy)phenyl)isoxazole.

7. The compound of claim 6 or a pharma- ceutically acceptable salt thereof.

8. A pharmaceutical composition for preventing or treating an eye disease, comprising the compound according to any one of claims 1 to 7 or a pharma- ceutically acceptable salt thereof as an active ingredient.

9. The pharmaceutical composition according to claim 8, wherein the eye disease is an eye disease in which N-retinylidene-N-retinyl-ethanolamine (A2E) accumulates in ocular cells.

10. The pharmaceutical composition of claim 8, wherein the eye disease is dry macular degeneration.

11. A composition for protecting retina from damage caused by blue light, comprising the compound according to any one of claims 1 to 7 or a pharma- ceutical acceptable salt thereof as an active ingredient.

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