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

Abstract

The present invention relates to a 3-phenyl iso # imgabs0 # azole derivative, a method for preparing the same, and a pharmaceutical composition for preventing or treating ocular diseases containing the same as an active ingredient. The 3-phenyl iso # imgabs 1 # azole derivative or the pharmaceutically acceptable salt thereof of the present invention increases autophagy activity, thereby promoting removal of metabolic residues such as A2E accumulated in eyeballs, and effectively inhibiting eye cell damage or death caused by oxidation of A2E by blue light. Therefore, a pioneering therapeutic agent serving as a new concept can be provided for eye diseases such as dry macular degeneration without a fundamental treatment method at present.

Description

Technical Field

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

[0002] The present invention relates to 3-phenylisothiazolinone Azole derivatives, preparation of 3-phenylisothiazolyl Methods of using oxazole derivatives and containing 3-phenylisothiazolyl The present invention relates to a pharmaceutical composition for preventing or treating eye diseases, wherein the azole derivative is used as an active agent. 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 Art

[0003] Modern people spend most of their time in front of various digital screens such as computers and smartphones. Affected by this environment, the rate of vision loss is accelerating. Since smart device screens use a large number of LEDs, blue light is damaging eye health. Blue light is blue light between 400nm and 500nm in visible light, which refers to the light emitted by digital devices or smartphones. The reason why digital devices appear blue when turned on at night 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 strong penetration, so if blue light enters the eye directly, it will focus on the retina, making it opaque and reducing clarity. If the eyes are exposed to blue light for a long time, it will cause retinal aging and degeneration. Known effects of blue light on the human body include dry eyes, eye fatigue, decreased vision, various eye diseases, accelerated retinal aging, macular degeneration, and insomnia caused by inhibiting the production of melatonin (Ganka Gakkai Zasshi. 2001 Oct; 105(10): 687-95; Archives of Ophthalmology 1992; 110: 99-104; Review of Ophthalmology Oct 15 2003; 10(10)).

[0005] Age-related macular degeneration is divided into two types: dry and wet. Dry macular degeneration accounts for 90% of patients with age-related macular degeneration and progresses through the accumulation of debris such as drusen on the retina, while wet macular degeneration accounts for about 10% of patients with age-related macular degeneration and progresses through angiogenesis within the macula, resulting in leakage of fluid components in the blood and the blood itself.

[0006] Retinal tissue, especially the retinal pigment epithelium, located below the central retina where rod photoreceptors are densely packed, is the most active site for the accumulation of metabolic waste. As humans reach a certain age threshold, the body's physiological ability to process these metabolic wastes within the retina decreases, resulting in the formation of drusen (yellow deposits in the retina) in the retinal pigment epithelium. These drusen are believed to cause age-related macular degeneration (AMD) by interfering with normal physiological / pathological activities that prevent adequate nutrients from reaching the photoreceptors and by inducing retinal pigment epithelial cell death.

[0007] These metabolic waste products are characterized by the presence of specific fluorophores. The most important of these is the lipofuscin component N-retinylidene-N-retinyl-ethanolamine (A2E). A2E is known to be the main cause of retinal diseases caused by phototoxicity, such as photooxidation when exposed to blue light, leading to the generation of reactive oxygen species.

[0008] Prevention and treatment methods differ depending on whether it is dry or wet macular degeneration. Prevention of wet macular degeneration is achieved by preventing the main factor, bleeding from abnormal blood vessels, and treatment methods mainly include injecting anti-angiogenic growth factors into the eye or administering photodynamic therapy (PDT) using a special laser. In addition, treatment of wet macular degeneration focuses on inhibiting or improving abnormal blood vessels.

[0009] On the other hand, there is currently no standard treatment for dry macular degeneration, and only hyperlipidemia drugs (statins) can be used to reduce the amount of lipids that serve as raw materials for waste products such as drusen, or to take powerful antioxidants in the flavonoid family such as lutein and zeaxanthin. However, these methods are all indirect treatments, and there is still no treatment method that directly removes the metabolites accumulated in retinal cells. Summary of the invention

[0010] Technical issues

[0011] The purpose of the present invention is to provide novel compounds for preventing or treating eye diseases, especially dry macular degeneration, for which there is currently no fundamental therapeutic drug. Specifically, the purpose of the present invention is to provide novel compounds that can prevent or treat eye diseases by removing accumulated A2E and directly inhibiting the damage or death of retinal cells caused by the oxidation of A2E by blue light.

[0012] Another object of the present invention is to provide a method for preparing the compound.

[0013] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating ocular diseases, especially dry macular degeneration, which comprises the compound as an active agent. That is, another object of the present invention is to provide a method for treating or preventing ocular diseases, especially dry macular degeneration, which comprises administering a compound according to the present invention to a subject in need of treating or preventing an ocular disease.

[0014] Another object of the present invention is to provide a nutritional composition that contributes to improving eye diseases, comprising the compound as an active agent.

[0015] Another object of the present invention is to provide a nutritional composition or a pharmaceutical composition for protecting the retina from damage caused by blue light. That is, another object of the present invention is to provide a method for protecting the retina from blue light damage, which comprises administering a compound according to the present invention to a subject in need of retinal protection.

[0016] Technical Solution

[0017] In order to achieve the above object, the present invention provides a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0018] [Chemical formula 1]

[0019]

[0020] In Chemical Formula 1,

[0021] R1 is hydrogen, C 1-6 Alkyl (preferably methyl) or C 3-6 Cycloalkyl, wherein C 1-6 Alkyl or C 3-6 At least one hydrogen of the cycloalkyl group is optionally substituted with at least one substituent independently selected from hydroxyl, C 1-3 Alkoxy and halogen (eg F),

[0022] 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 or 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine), wherein Ra and Rb are each independently hydrogen, C1-6 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 (eg quinazoline or pyridinyl), wherein -C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-3 At least one hydrogen of the alkylene or heterocycloalkyl group is optionally substituted with at least one substituent independently selected from the group consisting of: 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 alkyl, methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl,

[0023] 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, halogenated C 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, wherein R4, R5 and R6 are each independently hydrogen, methyl or -NH2.

[0024] In the above background, the inventors of the present invention are committed to developing new therapeutic agents for eye diseases, especially dry macular degeneration, for which there is no fundamental therapeutic drug at present. The azole derivative is excellent in all aspects of inhibiting retinal cell damage or death, and promotes the removal of waste products accumulated in the eye such as metabolites such as A2E by enhancing autophagic activity, so that it can be used as a first-of-its-kind therapeutic agent capable of fundamentally treating eye diseases such as dry macular degeneration, thereby completing the present invention.

[0025] In addition, the present invention provides a pharmaceutical composition for preventing or treating ocular diseases, particularly dry macular degeneration, comprising a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active agent.

[0026] In addition, the present invention provides a nutritional composition for improving eye diseases, which comprises the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active agent.

[0027] In addition, the present invention provides a method for preventing or treating ocular diseases, particularly dry macular degeneration, comprising administering a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof to a subject in need of treatment.

[0028] In addition, the present invention provides use of the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof in preparing a medicament for preventing or treating an eye disease.

[0029] In addition, the present invention provides a pharmaceutical composition or a nutritional composition for protecting the retina from blue light damage, comprising a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active agent.

[0030] In addition, the present invention provides a method for improving retinal damage caused by blue light or protecting the retina from blue light damage, which comprises administering the compound represented by the above Chemical Formula 1 or a pharmaceutically acceptable salt thereof to a subject in need of improvement or protection.

[0031] In addition, the present invention provides use of the compound represented by the above Chemical Formula 1 or a pharmaceutically acceptable salt thereof in the manufacture of a product for improving retinal damage caused by blue light.

[0032] Beneficial Effects

[0033] The 3-phenylisothiazolinone of the present invention The azole derivatives, their stereoisomers or pharmaceutically acceptable salts thereof increase autophagic activity, thereby promoting the removal of waste products accumulated in the eye, such as metabolites such as A2E, and effectively inhibiting the damage or death of eye cells caused by the oxidation of A2E by blue light, thereby being used as new-concept, first-in-class therapeutic agents to provide useful effects for eye diseases such as dry macular degeneration, for which there are currently no fundamental therapeutic drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1The photographs show changes in fluorescence intensity confirmed by concentration-dependent treatment with the compound 17 of the present invention after accumulation of fluorescently labeled A2E (A2E-BDP) in human retinal pigment epithelial cells (ARPE-19).

[0035] Figure 2 The results of measuring the amount of intracellular A2E by HPLC are shown to confirm the A2E removal effect confirmed by the concentration-dependent treatment of the compound 17 of the present invention after A2E accumulation in human retinal pigment epithelial cells (ARPE-19).

[0036] Figure 3 The photographs show the cell death inhibitory effect of the compound 17 of the present invention on blue light (BL) and A2E-induced death of human retinal pigment epithelial cells (ARPE-19) according to concentration-dependent treatment, and the results of evaluating cell activity.

[0037] Figure 4 The photographs show changes in cytoplasmic or nuclear proteins analyzed by Western immunoblotting to confirm the effects of treatment with different concentrations of the compound 17 of the present invention on NF-κB activation induced by blue light and A2E.

[0038] Figure 5 The graph shows the measurement of mRNA expression levels of inflammation-related genes to confirm the effects of different concentrations of compound 17 of the present invention on the inflammatory response of human retinal pigment epithelial cells (ARPE-19) induced by blue light and A2E.

[0039] Figure 6 The figure above is a graph measuring the changes in the autophagy marker LC3-II protein by western blotting to confirm the effect of different concentrations of compound 17 of the present invention on the changes in the autophagy activity of human retinal pigment epithelial cells (ARPE-19) induced by blue light and A2E. Figure 6 The lower figure is a photograph of GFP-LC3 puncta formation observed using a laser scanning confocal microscope (Nikon, Tokyo, Japan).

[0040] Figure 7 The present invention provides photographs of changes in the autophagy marker LC3-II protein analyzed by western blotting in the presence or absence of bafilomycin A1 to confirm the effect of increasing the autophagic flux of human retinal pigment epithelial cells (ARPE-19) by treatment with compound 17 of the present invention, and a quantitative graph of the autophagic flux is shown by calculating the difference in the amount of LC3-II protein caused by the presence or absence of bafilomycin A1.

[0041] Figure 8Western blot photographs and quantitative graphs showing the autophagy activation effect of compound 17 treatment according to the present invention on human retinal pigment epithelial cells (ARPE-19) in which A2E is accumulated.

[0042] Fig. 9 Western blot photographs and quantitative graphs showing the effect of treatment with compound 17 according to the present invention on increasing the autophagic flux of human retinal pigment epithelial cells (ARPE-19) in which A2E is accumulated.

[0043] Fig.10 Western blot photographs and quantitative graphs showing the effects of different concentrations of compound 17 of the present invention on the accumulation of p62 protein in cells caused by the inhibition of autophagy induced by blue light and A2E.

[0044] Fig.11 The photographs taken by a fundus camera show the retinal damage after the animals were irradiated with blue light and the improvement effect of the treatment with compound 17 of the present invention.

[0045] Fig.12 The results of evaluating the reduction and restoration of the outer nuclear layer (ONL) and inner segment / outer segment layer (IS / OS) thickness after treating animals exposed to blue light with compound 17 of the present invention are shown. The quantitative graph shows the average values ​​of ONL and IS / OS thickness measured by hematoxylin and eosin staining using the Axio VisionSE644 (ZEISS) program.

[0046] Fig.13 The results of the evaluation of A2E removal by the preferred example compounds of the present invention are shown after A2E-BDP accumulation in human retinal pigment epithelial cells (ARPE-19), confirmed by concentration-based treatment of the test compounds.

[0047] Fig.14 The results of evaluating the autophagy-activating effect of the preferred example compounds of the present invention using the concentration change of the p62 protein phosphorylated at the serine residue at position 349 (p-p62(S349)) are shown.

[0048] Fig.15 and Fig.16 The results of evaluating the autophagy activation of some example compounds according to the present invention using the change in the concentration of LC3-II protein are shown. DETAILED DESCRIPTION

[0049] Hereinafter, the present invention will be described in detail.

[0050] The present invention provides a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0051] [Chemical formula 1]

[0052]

[0053] In Chemical Formula 1,

[0054] R1 is hydrogen, C 1-6 Alkyl (preferably methyl) or C 3-6 Cycloalkyl, wherein C 1-6 Alkyl or C 3-6 At least one hydrogen of the cycloalkyl group is optionally substituted with at least one substituent independently selected from hydroxyl, C 1-3 Alkoxy and halogen (eg F),

[0055] 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 or 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine), wherein 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 (eg quinazoline or pyridinyl), wherein -C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-3 At least one hydrogen of the alkylene or heterocycloalkyl group is optionally substituted with at least one substituent independently selected from the group consisting of: 1-3 Alkyl, -OH, -COOH, -CO-C 1-3 Alkyl, -CONH2, -SO2-C 1-3Alkyl, -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 alkyl, methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl,

[0056] 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, halogenated C 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, wherein R4, R5 and R6 are each independently hydrogen, methyl or -NH2.

[0057] In one embodiment of the present invention, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound of Chemical Formula 1 has the structure of the following Chemical Formula 1a:

[0058] [Chemical formula 1a]

[0059]

[0060] In Chemical Formula 1a,

[0061] R1 is hydrogen, C 1-6 Alkyl (preferably methyl) or C 3-6 Cycloalkyl, wherein C 1-6 Alkyl or C 3-6 At least one hydrogen of the cycloalkyl group is optionally substituted with at least one substituent independently selected from hydroxyl, C 1-3 Alkoxy and halogen (eg F),

[0062] 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 1-3Alkylene-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 or 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine), wherein 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 (eg quinazoline or pyridinyl), wherein -C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-3 At least one hydrogen of the alkylene or heterocycloalkyl group is optionally substituted with at least one substituent independently selected from the group consisting of: 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 alkyl, methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl,

[0063] 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, halogenated C 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, wherein R4, R5 and R6 are each independently hydrogen, methyl or -NH2.

[0064] In a preferred embodiment of the present invention, the present invention provides a compound represented by Chemical Formula 1a or a pharmaceutically acceptable salt thereof, wherein

[0065] R1 is hydrogen or C 1-6 Alkyl (preferably methyl), wherein C 1-6 At least one hydrogen of the alkyl group is optionally substituted with at least one substituent independently selected from halogen (eg, F),

[0066] R2 is -C 1-6 Alkyl, -C 1-3 Alkylene -ORa, -C 1-3 Alkylene -NRaRb, -C 1-3 Alkylene-piperazine, -C 1-3 Alkylene-piperidine, -C 1-3 Alkylene-morpholine, -C 1-3 Alkylene-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, -C 1-3 Alkylene-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, -C 1-3 Alkylene-pyrrolidine, -C 1-3 Alkylene-3,8-diazabicyclo[3.2.1]octane or -C 1-3 Alkylene-2,5-diazabicyclo[2.2.2]octane, wherein 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 or pyridinyl), wherein -C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-3 At least one hydrogen of the alkylene or heterocycloalkyl group is optionally substituted with at least one substituent independently selected from the group consisting of: 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 1-3alkyl, methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl,

[0067] 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) (eg allyl), -CN, halogenated C 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, wherein R4, R5 and R6 are each independently hydrogen, methyl or -NH2.

[0068] In a more preferred embodiment of the present invention, the present invention provides a compound represented by Chemical Formula 1a or a pharmaceutically acceptable salt thereof, wherein

[0069] R1 is hydrogen, methyl or -CF3,

[0070] 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, -C 1-3 Alkylene-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, wherein Ra and Rb are each independently hydrogen, C 1-6 Alkyl, allyl, benzyl, -C 1-3 Alkylene-COO-C 1-3 Alkyl, phenyl, quinazoline or pyridinyl, where -C 1-6 Alkyl, C 1-3 At least one hydrogen of the alkylene or heterocycloalkyl group is optionally substituted with at least one substituent independently selected from the group consisting of: 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 alkyl, methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl,

[0071] R3 and R3' are each independently hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, heterocycloalkyl (preferably morpholine), -CH2-CR4 (=CR5R6) (eg allyl), -CN, halogenated C 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, wherein R4, R5 and R6 are each independently hydrogen or methyl.

[0072] In one embodiment of the present invention, a preferred example of the compound represented by Chemical Formula 1 is

[0073] (1) 3-(5-bromo-2-methoxyphenyl)-5-propyl isocyanate Azoles;

[0074] (2) 4-bromo-2-(5-propylisothiazolinone oxazol-3-yl)phenol;

[0075] (3) 3-(2-methoxy-5-propylphenyl)-5-propylisothiazolin Azoles;

[0076] (4) 3-(5-allyl-2-methoxyphenyl)-5-propylisothiazolin Azoles;

[0077] (5) 4-allyl-2-(5-propylisothiazolinyl) oxazol-3-yl)phenol;

[0078] (6) 4-propyl-2-(5-propylisothiazolinone oxazol-3-yl)phenol;

[0079] (7)(3-(5-bromo-2-methoxyphenyl)iso oxazol-5-yl)methanol;

[0080] (8) 4-bromo-2-(5-(hydroxymethyl)iso oxazol-3-yl)phenol;

[0081] (9) 5-((allyloxy)methyl)-3-(5-bromo-2-methoxyphenyl)iso Azoles;

[0082] (10)(3-(2-methoxy-5-propylphenyl)iso oxazol-5-yl)methanol;

[0083] (11) 5-((Benzyloxy)methyl)-3-(5-bromo-2-methoxyphenyl)iso Azoles;

[0084] (12) 2-((3-(5-bromo-2-methoxyphenyl)iso 4-(4-oxazol-5-yl)methoxy)ethyl acetate;

[0085] (13) 3-(5-bromo-2-methoxyphenyl)-5-(methoxymethyl)iso Azoles;

[0086] (14) 2-(5-(Hydroxymethyl)iso oxazol-3-yl)-4-propylphenol;

[0087] (15)(3-(5-allyl-2-methoxyphenyl)iso oxazol-5-yl)methanol;

[0088] (16) 4-allyl-2-(5-(hydroxymethyl)isopropyl oxazol-3-yl)phenol;

[0089] (17) 3-(5-allyl-2-methoxyphenyl)-5-((allyloxy)methyl)iso Azoles;

[0090] (18) 3-(5-allyl-2-methoxyphenyl)-5-((benzyloxy)methyl)iso Azoles;

[0091] (19) 2-((3-(5-allyl-2-methoxyphenyl)iso 4-(4-oxazol-5-yl)methoxy)ethyl acetate;

[0092] (20) 3-(2-methoxy-5-propylphenyl)-5-(methoxymethyl)iso Azoles;

[0093] (21) 4-((3-(5-bromo-2-methoxyphenyl)iso tert-butyl oxazol-5-yl)methyl)piperazine-1-carboxylate;

[0094] (22) 3-(5-allyl-2-methoxyphenyl)-5-((4-allylpiperazin-1-yl)methyl)iso Azoles;

[0095] (23) 3-(5-allyl-2-methoxyphenyl)-5-((4-benzylpiperazin-1-yl)methyl)iso Azoles;

[0096] (24) 2-(4-((3-(5-allyl-2-methoxyphenyl)iso oxazol-5-yl)methyl)piperazin-1-yl)ethyl acetate;

[0097] (25) 4-((3-(5-allyl-2-methoxyphenyl)iso tert-butyl oxazol-5-yl)methyl)piperazine-1-carboxylate;

[0098] (26) 4-((3-(2-methoxy-5-propylphenyl)iso tert-butyl oxazol-5-yl)methyl)piperazine-1-carboxylate;

[0099] (27) 4-allyl-2-(5-((allyloxy)methyl)iso oxazol-3-yl)phenol;

[0100] (28) 3-(5-bromo-2-methoxyphenyl)-5-(piperazin-1-ylmethyl)iso Azoles;

[0101] (29) 3-(5-allyl-methoxyphenyl)-5-(piperazin-1-ylmethyl)iso Azoles;

[0102] (30) 3-(2-methoxy-5-propylphenyl)-5-(piperazin-1-ylmethyl)iso Azoles;

[0103] (31)(3-(2-methoxy-5-(trifluoromethyl)phenyl)iso oxazol-5-yl)methanol;

[0104] (32) 2-(3-(2-methoxy-5-(trifluoromethyl)phenyl)iso oxazol-5-yl)propan-2-ol;

[0105] (33) 2-(3-(2-methoxy-5-(trifluoromethyl)phenyl)iso oxazol-5-yl)ethan-1-ol;

[0106] (34) 3-(2-methoxy-5-(trifluoromethyl)phenyl)-5-(piperazin-1-ylmethyl)iso Azoles;

[0107] (35) (3-(2-methoxy-4-(trifluoromethyl)phenyl)iso oxazol-5-yl)methanol;

[0108] (36) 2-((3-(2-methoxy-5-(trifluoromethyl)phenyl)iso oxazol-5-yl)methoxy)acetic acid;

[0109] (37) 4-((3-(2-methoxy-5-(trifluoromethyl)phenyl)iso oxazol-5-yl)methyl)-1-methylpiperazin-2-one;

[0110] (38) (3-(2-methoxy-5-morpholinophenyl)iso oxazol-5-yl)methanol;

[0111] (39) 2-(3-(5-allyl-2-methoxyphenyl)iso oxazol-5-yl)propan-2-ol;

[0112] (40) 2-(3-(2-methoxy-5-propylphenyl)iso oxazol-5-yl)propan-2-ol;

[0113] (41) 3-(5-allyl-2-methoxyphenyl)-5-((4-methylpiperazin-1-yl)methyl)iso Azoles;

[0114] (42) 3-(2-methoxy-5-propylphenyl)-5-((4-methylpiperazin-1-yl)methyl)iso Azoles;

[0115] (43) (3-(5-allyl-2-(trifluoromethoxy)phenyl)iso oxazol-5-yl)methanol;

[0116] (44)(3-(4-allyl-2-methoxyphenyl)iso oxazol-5-yl)methanol;

[0117] (45)(3-(5-isopropyl-2-methoxyphenyl)iso oxazol-5-yl)methanol;

[0118] (46) 4-((3-(5-isopropyl-2-methoxyphenyl)iso tert-butyl oxazol-5-yl)methyl)piperazine-1-carboxylate;

[0119] (47) 3-(5-isopropyl-2-methoxyphenyl)-5-(piperazin-1-ylmethyl)iso Azoles;

[0120] (48) 4-((3-(4-allyl-2-methoxyphenyl)iso tert-butyl oxazol-5-yl)methyl)piperazine-1-carboxylate;

[0121] (49) 3-(4-allyl-2-methoxyphenyl)-5-(piperazin-1-ylmethyl)iso Azoles;

[0122] (50) 4-((3-(5-allyl-2-(trifluoromethoxy)phenyl)iso tert-butyl oxazol-5-yl)methyl)piperazine-1-carboxylate;

[0123] (51) 3-(5-allyl-2-(trifluoromethoxy)phenyl)-5-(piperazin-1-ylmethyl)iso Azoles;

[0124] (52) 3-(5-allyl-2-(trifluoromethoxy)phenyl)-5-((4-methylpiperazin-1-yl)methyl)iso Azoles;

[0125] (53) (2S,6R)-4-((3-(2-methoxy-5-propylphenyl)iso oxazol-5-yl)methyl)-2,6-dimethylmorpholine;

[0126] (54) 3-(2-methoxy-5-propylphenyl)-5-((4-methoxypiperidin-1-yl)methyl)iso Azoles;

[0127] (55) 1-((3-(2-methoxy-5-propylphenyl)iso oxazol-5-yl)methyl)piperidine-4-carboxylic acid;

[0128] (56) 5-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)-3-(2-methoxy-5-propylphenyl)iso Azoles;

[0129] (57) 5-((5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)methyl)-3-(2-methoxy-5-propylphenyl)iso Azoles;

[0130] (58) 3-(4-fluoro-2-methoxy-5-propylphenyl)-5-(piperazin-1-ylmethyl)iso Azoles;

[0131] (59) 3-(4-fluoro-2-methoxy-5-propylphenyl)-5-((4-methylpiperazin-1-yl)methyl)iso Azoles;

[0132] (60) 5-((4-methylpiperazin-1-yl)methyl)-3-(5-propyl-2-(trifluoromethoxy)phenyl)iso Azoles;

[0133] (61) 2-(4-methoxy-3-(5-((4-methylpiperazin-1-yl)methyl)iso oxazol-3-yl)phenyl)ethan-1-ol;

[0134] (62) 3-(2-methoxy-5-(2-methoxyethyl)phenyl)-5-((4-methylpiperazin-1-yl)methyl)iso Azoles;

[0135] (63) 1-(4-((3-(5-isopropyl-2-methoxyphenyl)iso oxazol-5-yl)methyl)piperazin-1-yl)ethan-1-one;

[0136] (64) 3-(5-isopropyl-2-methoxyphenyl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)iso Azoles;

[0137] (65) 3-(5-allyl-2-methoxyphenyl)-5-((quinazolin-4-yloxy)methyl)iso Azoles;

[0138] (66) 4-((3-(2-methoxy-5-(2-methylallyl)phenyl)iso tert-butyl oxazol-5-yl)methyl)piperazine-1-carboxylate;

[0139] (67) 3-(2-methoxy-5-(2-methylallyl)phenyl)-5-(piperazin-1-ylmethyl)iso Azoles;

[0140] (68) (3-(2-methoxy-5-(2-methylallyl)phenyl)iso oxazol-5-yl)methanol;

[0141] (69) 3-(2-methoxy-5-(3-methylbut-2-en-1-yl)phenyl)-5-((4-methylpiperazin-1-yl)methyl)iso Azoles, or pharmaceutically acceptable salts thereof.

[0142] Among the above compounds (1) to (69), in particular, for various purposes of the present invention, more preferred are

[0143] (11) 5-((Benzyloxy)methyl)-3-(5-bromo-2-methoxyphenyl)iso Azoles;

[0144] (15)(3-(5-allyl-2-methoxyphenyl)iso oxazol-5-yl)methanol;

[0145] (17) 3-(5-allyl-2-methoxyphenyl)-5-((allyloxy)methyl)iso Azoles;

[0146] (18) 3-(5-allyl-2-methoxyphenyl)-5-((benzyloxy)methyl)iso Azoles;

[0147] (21) 4-((3-(5-bromo-2-methoxyphenyl)iso tert-butyl oxazol-5-yl)methyl)piperazine-1-carboxylate;

[0148] (25) 4-((3-(5-allyl-2-methoxyphenyl)iso tert-butyl oxazol-5-yl)methyl)piperazine-1-carboxylate;

[0149] (26) 4-((3-(2-methoxy-5-propylphenyl)iso tert-butyl oxazol-5-yl)methyl)piperazine-1-carboxylate;

[0150] (28) 3-(5-bromo-2-methoxyphenyl)-5-(piperazin-1-ylmethyl)iso Azoles;

[0151] (29) 3-(5-allyl-methoxyphenyl)-5-(piperazin-1-ylmethyl)iso Azoles;

[0152] (30) 3-(2-methoxy-5-propylphenyl)-5-(piperazin-1-ylmethyl)iso Azoles;

[0153] (34) 3-(2-methoxy-5-(trifluoromethyl)phenyl)-5-(piperazin-1-ylmethyl)iso Azoles;

[0154] (41) 3-(5-allyl-2-methoxyphenyl)-5-((4-methylpiperazin-1-yl)methyl)iso Azoles;

[0155] (42) 3-(2-methoxy-5-propylphenyl)-5-((4-methylpiperazin-1-yl)methyl)iso Azoles;

[0156] (43) (3-(5-allyl-2-(trifluoromethoxy)phenyl)iso oxazol-5-yl)methanol;

[0157] (44)(3-(4-allyl-2-methoxyphenyl)iso oxazol-5-yl)methanol;

[0158] (47) 3-(5-isopropyl-2-methoxyphenyl)-5-(piperazin-1-ylmethyl)iso Azoles;

[0159] (48) 4-((3-(4-allyl-2-methoxyphenyl)iso tert-butyl oxazol-5-yl)methyl)piperazine-1-carboxylate;

[0160] (50) 4-((3-(5-allyl-2-(trifluoromethoxy)phenyl)iso tert-butyl oxazol-5-yl)methyl)piperazine-1-carboxylate;

[0161] (51) 3-(5-allyl-2-(trifluoromethoxy)phenyl)-5-(piperazin-1-ylmethyl)iso Azoles;

[0162] (52) 3-(5-allyl-2-(trifluoromethoxy)phenyl)-5-((4-methylpiperazin-1-yl)methyl)iso Azoles;

[0163] (58) 3-(4-fluoro-2-methoxy-5-propylphenyl)-5-(piperazin-1-ylmethyl)iso Azoles;

[0164] (59) 3-(4-fluoro-2-methoxy-5-propylphenyl)-5-((4-methylpiperazin-1-yl)methyl)iso Azoles;

[0165] (60) 5-((4-methylpiperazin-1-yl)methyl)-3-(5-propyl-2-(trifluoromethoxy)phenyl)iso Azoles;

[0166] (66) 4-((3-(2-methoxy-5-(2-methylallyl)phenyl)iso tert-butyl 3-(2-methoxy-5-(2-methylallyl)phenyl)-5-(piperazin-1-ylmethyl)isothiazolyl ester; (67) tert-butyl 3-(2-methoxy-5-(2-methylallyl)phenyl)-5-(piperazin-1-ylmethyl)isothiazolyl ester Azoles;

[0167] (68) (3-(2-methoxy-5-(2-methylallyl)phenyl)iso oxazol-5-yl)methanol; or

[0168] or pharmaceutically acceptable salts thereof.

[0169] In particular, among the above compounds, (28) 3-(5-bromo-2-methoxyphenyl)-5-(piperazin-1-ylmethyl)isothiazolin-1-yl is more preferred for the various purposes of the present invention. Azoles;

[0170] (30) 3-(2-methoxy-5-propylphenyl)-5-(piperazin-1-ylmethyl)iso Azoles;

[0171] (34) 3-(2-methoxy-5-(trifluoromethyl)phenyl)-5-(piperazin-1-ylmethyl)iso Azoles;

[0172] (41) 3-(5-allyl-2-methoxyphenyl)-5-((4-methylpiperazin-1-yl)methyl)iso Azoles;

[0173] (42) 3-(2-methoxy-5-propylphenyl)-5-((4-methylpiperazin-1-yl)methyl)iso Azoles;

[0174] (47) 3-(5-isopropyl-2-methoxyphenyl)-5-(piperazin-1-ylmethyl)iso Azoles;

[0175] (58) 3-(4-fluoro-2-methoxy-5-propylphenyl)-5-(piperazin-1-ylmethyl)iso Azoles;

[0176] (59) 3-(4-fluoro-2-methoxy-5-propylphenyl)-5-((4-methylpiperazin-1-yl)methyl)iso Azoles;

[0177] (60) 5-((4-methylpiperazin-1-yl)methyl)-3-(5-propyl-2-(trifluoromethoxy)phenyl)iso Azoles; or

[0178] or pharmaceutically acceptable salts thereof.

[0179] The compound represented by the above chemical formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and for the salt, an acid addition salt formed from a pharmaceutically acceptable free acid is useful. Acid addition salts are 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 monocarboxylates and aliphatic dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates and alkandioates, aromatic acids, aliphatic sulfonic acids and aromatic sulfonic acids; and organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid and fumaric acid. Types of these pharmaceutically nontoxic salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, decanoates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioic acid Salt, hexane-1,6-dioic acid salt, 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, mandelate, etc. The acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the derivative of Chemical Formula 1 in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc., adding an organic acid or an inorganic acid, filtering and drying the resulting precipitate, or removing the solvent and excess acid by reduced pressure distillation, drying, and crystallizing the resulting product in an organic solvent.

[0180] In one embodiment of the present invention, the pharmaceutically acceptable salt according to the present invention is a hydrochloride salt (eg a dihydrochloride salt).

[0181] In addition, a base can also be used to prepare a pharmaceutically acceptable metal salt. For example, by dissolving the compound in an excess of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate to obtain an alkali metal salt or an alkaline earth metal salt. At this time, it is pharmaceutically suitable to prepare a sodium salt, a potassium salt or a calcium salt as a metal salt. In addition, the corresponding salt is obtained by reacting an alkali metal salt or an alkaline earth metal salt with a suitable anionic salt (e.g., silver nitrate).

[0182] As used herein, the terms "substituent," "radical," "group," "moiety," and "fragment" are used interchangeably.

[0183] If a substituent is described as "optionally substituted," the substituent may be (1) unsubstituted or (2) substituted with one or more than one of the substituents specified. If a substitutable position is unsubstituted, the default substituent is hydrogen.

[0184] As used herein, the term "alkyl" refers to a saturated straight-chain or branched acyclic hydrocarbon having from 1 to 10 carbon atoms, unless the context clearly dictates otherwise. "Lower alkyl" refers to an alkyl having from 1 to 4 carbon atoms. Representative saturated straight-chain alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl, and -n-decyl, while saturated branched alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl, etc. In a preferred embodiment of the present invention, the alkyl group is methyl, ethyl or isopropyl.

[0185] As used herein, the term "alkoxy" refers to -O-(alkyl), including -OCH3, -OCH2CH3, -O(CH2)2CH3, -OC(CH3)2H, -OC(CH3)3, and the like, wherein alkyl is as defined above.

[0186] As used herein, if the term "C 1-6 "," C1-6 "or "C1-C6 ", it means the number of carbon atoms is 1 to 6. For example, C 1-6 The alkyl group refers to an alkyl group having any integer of 1 to 6 carbon atoms.

[0187] As used herein, the terms "halogen" and "halo" refer to fluorine, chlorine, bromine or iodine. In a preferred embodiment of the present invention, halogen is bromine or fluorine.

[0188] As used herein, the term "haloalkyl", "haloalkoxy", "haloalkenyl" or "haloalkynyl" refers to an alkyl, alkoxy, alkenyl or alkynyl group in which one or more hydrogen atoms are replaced by a halogen atom. For example, haloalkyl includes -CF3, -CHF2, -CH2F, -CBr3, -CHBr2, -CH2Br, -CC13, -CHC12, -CH2CI, -CI3, -CHI2, -CH2I, -CH2-CF3, -CH2-CHF2, -CH2-CH2F, -CH2-CBr3, -CH2-CHBr2, -CH2-CH2Br, -CH2-CC13, -CH2-CHC12, -CH2-CH2CI, -CH2-CI3, -CH2-CHI2, -CH2-CH2I, etc., wherein alkyl, alkoxy and halogen are as described above. In a preferred embodiment of the present invention, haloalkyl is -CF3. wherein alkyl and halogen are as defined above.

[0189] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic ring having carbon atoms and hydrogen atoms and having no carbon-carbon multiple bonds. Examples of monocyclic rings include, but are not limited to, (C3-C7)cycloalkyl, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Examples of polycyclic rings include, but are not limited to, fused bicyclic rings such as octahydropentalene and decahydronaphthalene; spirocyclic rings such as spiro[3.3]heptane, spiro[3.4]octane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[4.5]decane, and spiro[5.5]undecane; and bridged bicyclic rings such as bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, and bicyclo[2.2.2]octane. Cycloalkyl can be unsubstituted or optionally substituted. In an embodiment of the present invention, the cycloalkyl is a monocyclic ring.

[0190] The term "heterocycle" or "heterocycloalkyl" refers to a 4- to 7-membered monocyclic or 7- to 12-membered bicyclic saturated heterocycle containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the nitrogen heteroatoms and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatoms may be optionally quaternized. Heterocycles include heteroaryls as defined above. Representative heterocycles include oxirane, oxetane, tetrahydrofuran, tetrahydropyran, 1,4-di ... The heterocyclic ring includes bicyclic rings, wherein a part of the heterocyclic ring is fused with a benzene ring or a cyclopenta-1,3-diene ring. The heterocyclic ring can be connected by any heteroatom or carbon atom. In addition, the heterocyclic ring includes fused bicyclic rings, spirocyclic rings and bridged bicyclic rings, wherein one or more carbon atoms in the above-mentioned polycyclic rings are replaced by nitrogen atoms, oxygen atoms or sulfur atoms. For example, when the heteroatom is nitrogen, these include, but are not limited to, fused heterobicyclic rings such as octahydrocyclopenta[c]pyrrole, octahydropyrrolo[3,4-c]pyrrole, decahydroisoquinoline, and decahydro-2,6-naphthyridine; spiro rings such as 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, 3-azaspiro[5.5]undecane and 3,9-diazaspiro[5.5]undecane; and bridged heterobicycles 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 and 3,8-diazabicyclo[3.2.1]octane.

[0191] As used herein, the term "aryl" refers to a carbocyclic aromatic group containing 5 to 10 atoms. Representative examples include, but are not limited to, phenyl (benzene), tolyl, xylyl, naphthyl, tetrahydronaphthyl, anthracenyl, fluorenyl, indenyl, and azulenyl. The carbocyclic aromatic group may be unsubstituted or optionally substituted.

[0192] As used herein, the term "heteroaryl" refers to an aromatic heterocyclic ring having 5 to 10 members, having at least one heteroatom selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both monocyclic and bicyclic ring systems. Representative heteroaryl groups are furan, 4H-pyran, pyrrole, imidazole, pyrazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, thiophene, Azoles, Isopropylamine Azoles, thiazoles, isothiazoles, oxadiazole, benzofuran, benzothiophene, quinoline, dihydroquinoline, isoquinoline, dihydroisoquinoline, indole, benzo Azoles, benzimidazoles, benzothiazoles, cinnolines, phthalazines, quinazolines, 1H-aza Thiadiazole, tetrahydroisoquinoline, tetrahydropyrazolopyrazine, etc. Unless otherwise specified, the above heteroaryl groups, in which the hydrogen atom is added to the double bond, such as dihydro-1H-benzo[d]imidazole, 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, are also included in the definition.

[0193] As used herein, the phrase "compounds of the present invention" includes any compound of Formula 1, as well as inclusion compounds, hydrates, solvates or polymorphs thereof. Moreover, even if the term "compound of the present invention" does not mention its pharmaceutically acceptable salt, the term also includes its salt. In one embodiment, the compounds of the present disclosure include stereochemically pure compounds, for example, compounds substantially free of (e.g., greater than 85% ee, greater than 90% ee, greater than 95% ee, greater than 97% ee or greater than 99% ee) other stereoisomers. That is, if the compound of Formula 1 of the present invention or its salt has tautomers and / or stereoisomers (e.g., geometric isomers and conformational isomers), these separated isomers and mixtures thereof are also included within the scope of the present invention. If there is an asymmetric carbon in the structure of the compound of the present invention or its salt, their active optical isomers and racemic mixtures thereof are also included within the scope of the present invention.

[0194] As used herein, the term "polymorph" refers to a solid crystalline form of a compound of the present disclosure or a complex thereof. Different polymorphs of the same compound may exhibit different physical, chemical and / or spectral properties. Different physical properties include, but are not limited to, stability (e.g., to heat or light), compressibility and density (important in formulation and product manufacturing), and dissolution rate (which may affect bioavailability). Differences in stability may be caused by changes in chemical reactivity (e.g., differential oxidation, causing the dosage form to change color faster when including one polymorph than when including another polymorph) or changes in mechanical properties (e.g., tablets break during storage due to the conversion of a kinetically favorable polymorph to a thermodynamically more stable polymorph) or both (e.g., tablets of one polymorph are more easily decomposed at high humidity). The different physical properties of polymorphs may affect their processing. For example, due to reasons such as the shape or size distribution of the particles, one polymorph may be more likely to form a solvate, or may be more difficult to filter or wash away impurities than another polymorph.

[0195] As used herein, the term "solvate" refers to a compound according to the present disclosure or a salt thereof, which further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic and can be administered to humans in trace amounts.

[0196] As used herein, the term "hydrate" refers to a compound according to the present disclosure or a salt thereof, which further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0197] As used herein, the term "clathrate" refers to a compound or a salt thereof in a crystalline lattice form, which contains spaces (eg, channels) in which guest molecules (eg, solvent or water) are trapped.

[0198] As used herein, the term "purified" means that when isolated, the isolate is greater than 90% pure, in one embodiment greater than 95% pure, in another embodiment greater than 99% pure, and in yet another embodiment greater than 99.9% pure.

[0199] In addition, the present invention provides a pharmaceutical composition for preventing or treating ocular diseases, particularly dry macular degeneration, comprising a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active agent.

[0200] In one embodiment of the present invention, the compound represented by Chemical Formula 1 according to the present invention can increase autophagic activity and promote autophagic flux, for example, increase the removal effect of unnecessary components accumulated in the eye, and thus the compound represented by Chemical Formula 1 of the present invention or a pharmaceutically acceptable salt thereof can be used to prevent or treat eye diseases, for example, eye diseases caused by unnecessary components such as metabolites in eye cells, and can be particularly used to prevent or treat dry macular degeneration.

[0201] In the present invention, "treatment" refers to all actions to improve or beneficially change the symptoms of eye diseases by administering the composition according to the present invention.

[0202] In the present invention, "prevention" refers to all actions to inhibit or delay the onset of an eye disease by administering the composition according to the present invention.

[0203] In the present invention, "eye disease" may include any disease caused by the accumulation of unnecessary components in the eye, for example, it may specifically refer to a retinal disease caused by A2E and blue light. Specifically, the eye disease is dry macular degeneration. In addition, A2E and blue light may aggravate glaucoma, retinitis pigmentosa, fundus yellow spot disease, choroidal coloboma, annular atrophy, dry eye, eye fatigue, etc. The compound of the present invention or a pharmaceutically acceptable salt thereof can be used to treat or prevent these diseases.

[0204] The exact cause of age-related macular degeneration, especially dry macular degeneration, is known to be excessive pigment substances accumulated in retinal pigment epithelial cells due to aging. These pigment substances appear in the early stages of macular degeneration, and A2E, which is synthesized from all-trans retinal and ethanolamine, is a substance typically accumulated in retinal epithelial cells. When it is irradiated with blue light, singlet oxygen is produced and the carbon-carbon double bond site is oxidized, which causes damage to the retinal pigment epithelial cells.

[0205] Prevention or treatment of the above-mentioned eye diseases, especially dry macular degeneration, can be achieved by increasing the autophagic activity of eye cells and promoting autophagic flux. It can also be achieved by inhibiting cell death caused by A2E and blue light.

[0206] In one embodiment of the present invention, prevention or treatment of eye diseases can be achieved by restoring ONL (outer nuclear layer) and / or IS / OS (inner segment / outer segment layer) damaged by exposure of N-retinylidene-N-retinyl-ethanolamine (A2E) accumulated in eye cells to blue light.

[0207] The compound represented by Chemical Formula 1 according to the present invention or a pharmaceutically acceptable salt thereof increases autophagic activity.

[0208] Autophagy is a destructive mechanism that naturally breaks down unnecessary or non-functional cellular components. Various cellular components such as unnecessary metabolites are separated from other components within the cell and surrounded by a double membrane, a phenomenon called autophagosome formation. The autophagosome then fuses with the lysosome and breaks down the contents. For example, dry macular degeneration is caused by metabolites such as A2E. A2E is a metabolite derived from retinol. When trans-retinol encounters phosphatidylethanolamine, A2E is generated. When A2E is exposed to blue light, it forms an A2E-epoxide structure and generates reactive oxygen species in the process, causing irreversible damage to retinal cells or cell death. In young or healthy people, unnecessary metabolites such as A2E are removed from cells through autophagic activity. However, in the elderly, due to reduced or impaired autophagic activity, A2E cannot be removed from retinal cells smoothly, which eventually leads to retinal cell damage and death and triggers dry macular degeneration.

[0209] In one embodiment of the present invention, it was unexpectedly confirmed that the 3-phenylisocyanate represented by Chemical Formula 1 of the present invention The azole derivative increases autophagic activity, i.e., promotes autophagic flux, thereby removing unnecessary metabolites such as A2E from retinal cells. Therefore, the compound represented by Chemical Formula 1 of the present invention or a pharmaceutically acceptable salt thereof can be used to prevent or treat ocular diseases, for example, ocular diseases caused by unnecessary components such as metabolites in ocular cells, and can be particularly used to prevent or treat dry macular degeneration. The compound of the present invention can be used as a first-in-class therapeutic agent for a new concept of treating dry macular degeneration, for which only indirect treatment existed in the past.

[0210] In a specific embodiment of the present invention, when A2E-fluorescent labeled substance (A2E-BDP) accumulated in retinal pigment epithelial cells and then treated with the compound of the present invention, it was confirmed that the A2E-BDP signal was significantly reduced, confirming that the compound of the present invention removed A2E-BDP (see Table 1 and Figure 1 ). In addition, when A2E was accumulated in retinal pigment epithelial cells and then treated with the compound of the present invention, it was confirmed that the amount of accumulated A2E decreased in a concentration-dependent manner, confirming that the compound of the present invention directly removed A2E (see Figure 2 ).

[0211] In another specific embodiment of the present invention, the death of retinal pigment epithelial cells was induced by A2E and blue light, and it was confirmed that when the compound of the present invention was treated, the cell death was inhibited in a concentration-dependent manner (see Figure 3 ).

[0212] In another specific embodiment of the present invention involving the activation of NF-κB, when retinal pigment epithelial cells induced by A2E and blue light were treated with the compound of the present invention, it was confirmed that the movement of p65 into the nucleus induced by A2E and blue light was inhibited, and the activation of NF-κB was inhibited (see Figure 4 ).

[0213] In another specific embodiment of the present invention, which relates to the increase in inflammatory gene expression induced by A2E and blue light in retinal pigment epithelial cells, when retinal pigment epithelial cells were treated with the compounds of the present invention, it was confirmed that the expression of inflammatory genes (IL-1β, IL-6 and CXCL8) was inhibited in a concentration-dependent manner (see Figure 5 ).

[0214] In another specific embodiment of the present invention, when retinal pigment epithelial cells were treated with the compounds of the present invention, it was confirmed that the autophagy marker LC3-II increased in a concentration-dependent manner (see Figure 6 ).

[0215] In another specific embodiment of the present invention, when retinal pigment epithelial cells were treated with the compounds of the present invention in the presence or absence of saturating concentrations of bafilomycin A1, it was confirmed that the autophagic flux was increased in a concentration-dependent manner (see Figure 7 ).

[0216] In another specific embodiment of the present invention, when retinal pigment epithelial cells in which A2E is accumulated are treated with the compound of the present invention, it is confirmed that the autophagy marker LC3-II increases in a concentration-dependent manner (see Figure 8 ).

[0217] In another specific embodiment of the present invention, when retinal pigment epithelial cells in which A2E has accumulated were treated with the compounds of the present invention in the presence or absence of saturating concentrations of bafilomycin A1, it was confirmed that the autophagic flux was increased in a concentration-dependent manner (see Fig. 9 ).

[0218] In another specific embodiment of the present invention, with respect to the autophagy of retinal pigment epithelial cells inhibited by A2E and blue light, when the retinal pigment epithelial cells were treated with the compound of the present invention, it was confirmed that the concentration of p62 protein decreased in a concentration-dependent manner, thereby restoring the autophagic activity of human retinal pigment epithelial cells decreased by A2E and blue light (see Fig.10 ).

[0219] In another specific embodiment of the present invention, when experimental animals were irradiated with blue light to damage retinal pigment epithelial cells and then treated with the compound of the present invention, it was confirmed that retinal damage was improved (see Fig.11 ), ONL and IS / OS thickness were also restored (see Fig.12 ).

[0220] Therefore, the compound of Chemical Formula 1 of the present invention can be used to prevent or treat eye diseases, such as eye diseases caused by unnecessary components accumulated in the eye, and particularly can be used to prevent or treat eye diseases caused by A2E and blue light.

[0221] The pharmaceutical composition of the present invention can be used as a single dose, or can be used as a combined preparation by adding a known pharmaceutical composition approved for the prevention or treatment of ophthalmic diseases, or can be formulated into a pharmaceutical unit dosage form by adding a pharmaceutically acceptable carrier, excipient or diluent.

[0222] In the present invention, "pharmaceutically acceptable" means having no significant irritation to organisms and not inhibiting the biological activities and properties of the administered active agent.

[0223] In the present invention, the pharmaceutical composition comprising a pharmaceutically acceptable carrier may have any dosage form selected from tablets, pills, powders, granules, capsules, suspensions, oral solutions, emulsions, syrups, sterile aqueous solutions, non-aqueous solvent preparations, suspensions, emulsions, lyophilized preparations and suppositories.

[0224] The pharmaceutical composition can be prepared into various oral dosage forms or parenteral dosage forms. When formulated, it can be prepared using commonly used diluents or excipients such as fillers, expanders, binders, wetting agents, disintegrants, and surfactants.

[0225] Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., which can be prepared by mixing one or more than one compound with at least one excipient such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc can also be used. Liquid preparations for oral administration include suspensions, oral solutions, emulsions, syrups, etc., which can contain various excipients such as wetting agents, sweeteners, flavoring agents and preservatives in addition to commonly used simple diluents such as water and liquid paraffin.

[0226] Preparations for parenteral administration may include sterile aqueous solutions, non-aqueous solvent preparations, suspensoids, emulsions, freeze-dried preparations and suppositories. Non-aqueous solvents and suspensoids 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, polyethylene glycol, Tween 61, cocoa butter, laurel oil and glycerin gelatin. Specifically, eye drops for intraocular administration may be included, such as aqueous eye preparations.

[0227] In the composition of the present invention, a pharmaceutically effective amount of a compound of formula 1 may be included. The term "pharmaceutically effective amount" refers to an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment and without causing side effects, and the effective dose level can be determined based on the patient's health, the type and severity of the disease, the activity of the drug, the sensitivity to the drug, the method of administration, the time of administration, the route of administration and the excretion rate, the treatment period, the combination of drugs or simultaneous use, and other factors known to the medical field. The composition of the present invention can be used as a single therapeutic agent or in combination with other therapeutic agents, can be used sequentially or simultaneously with conventional therapeutic agents, and can be administered in single doses or multiple doses. Taking all of the above factors into account, it is important to administer an amount that can obtain the maximum effect with a minimum amount and without side effects, which can be easily determined by those skilled in the art.

[0228] For example, the compound of the present invention or its pharmaceutically acceptable salt can be administered by any suitable route, in the form of a pharmaceutical composition suitable for such route, in a dosage effective for the intended treatment. The effective dose is generally about 0.001 mg per kg body weight per day to about 100 mg per kg body weight per day, preferably about 0.01 mg / kg / day to about 50 mg / kg / day, single dose or divided dose. Depending on age, species and the disease or condition treated, it may be suitable to be lower than the dosage level of this range lower limit. In other cases, a larger dosage can also be used without producing harmful side effects. A larger dosage can also be divided into several smaller dosages for full-day administration.

[0229] In addition, the present invention provides a nutritional composition for preventing or improving eye diseases, comprising the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active agent.

[0230] In the present invention, "improvement" refers to all actions that reduce the extent of parameters such as symptoms associated with the disorder treated by ingestion of the composition.

[0231] Health food refers to food produced and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc. using raw materials or ingredients that have beneficial functions to the human body. The nutritional composition of the present invention can be produced by a method commonly used in the art, or by adding raw materials and ingredients commonly added in the art during the manufacturing process. In addition, the dosage form of the nutritional composition can be produced without restriction as long as it is recognized as a dosage form of the nutritional composition.

[0232] In addition, the present invention provides a method for preventing or treating an eye disease, which comprises administering a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof to a subject in need of treatment.

[0233] In the present invention, the term "subject" includes mammals and non-mammals that have developed or may develop an eye disease, for example, all animals including monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits or guinea pigs, including humans and preferably humans.

[0234] In the present invention, the term "administer" refers to providing a predetermined substance to a patient by any appropriate method, and the administration route of the composition of the present invention can be any common route as long as it can reach the target tissue, including but not limited to intravenous administration, oral administration, topical administration, etc.

[0235] In addition, the present invention provides a pharmaceutical composition or a nutritional composition for protecting the retina from blue light damage, which comprises the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active agent.

[0236] In addition, the present invention provides a method for improving retinal damage caused by blue light or protecting the retina from blue light damage, which comprises administering the compound represented by the above Chemical Formula 1 or a pharmaceutically acceptable salt thereof to a subject in need of improvement or protection.

[0237] In addition, the present invention provides use of the compound represented by the above Chemical Formula 1 or a pharmaceutically acceptable salt thereof in the manufacture of a product for improving retinal damage caused by blue light.

[0238] Hereinafter, the present invention will be described in detail through Examples and Experimental Examples.

[0239] However, the following examples and experimental examples are only for illustrating the present invention, and the contents of the present invention are not limited to the following examples and experimental examples.

[0240] <Example 1> 3-(5-bromo-2-methoxyphenyl)-5-propyl isocyanate Preparation of azoles

[0241] The target compound was prepared by carrying out steps 1 and 2 of Example 17 described below and carrying out step 3 using pentyne instead of propargyl alcohol in step 3.

[0242] <Example 2> 4-bromo-2-(5-propylisothiazolinone Preparation of oxazol-3-yl)phenol

[0243] The target compound was prepared as in Example 1 above, except that 5-bromo-2-hydroxybenzaldehyde was used instead of 5-bromo-2-methoxybenzaldehyde as the starting material.

[0244] <Example 3> 3-(2-methoxy-5-propylphenyl)-5-propylisothiazolin Preparation of azoles

[0245] Steps 1 and 2 of Example 17 were performed, step 3 was performed using pentyne instead of propargyl alcohol in step 3, and step 4 was performed. The obtained compound was reacted with H2 and Pd / C in methanol, and the obtained product was purified to prepare the target compound.

[0246] <Example 4> 3-(5-allyl-2-methoxyphenyl)-5-propylisothiazolin Preparation of azoles

[0247] Steps 1 and 2 of Example 17 were carried out, and step 3 was carried out using pentene instead of propargyl alcohol in step 3. Then, step 4 was carried out to prepare the target compound.

[0248] <Example 5> 4-allyl-2-(5-propylisothiazolinyl) Preparation of oxazol-3-yl)phenol

[0249] The target compound was prepared as in Example 4 above, except that 5-bromo-2-hydroxybenzaldehyde was used instead of 5-bromo-2-methoxybenzaldehyde as the starting material.

[0250] <Example 6> 4-propyl-2-(5-propylisothiazolinyl) Preparation of oxazol-3-yl)phenol

[0251] The target compound was prepared as in Example 3 above, except that 5-bromo-2-hydroxybenzaldehyde was used instead of 5-bromo-2-methoxybenzaldehyde as the starting material.

[0252] <Example 7> (3-(5-bromo-2-methoxyphenyl) Preparation of oxazol-5-yl)methanol

[0253] The title compound was prepared by carrying out Step 3 of Example 17 described below.

[0254] <Example 8> 4-bromo-2-(5-hydroxymethyl)iso Preparation of oxazol-3-yl)phenol

[0255] The target compound was prepared as in Example 7 above, except that 5-bromo-2-hydroxybenzaldehyde was used as the starting material instead of 5-bromo-2-methoxybenzaldehyde.

[0256] <Example 9> 5-((allyloxy)methyl)-3-(5-bromo-2-methoxyphenyl)iso Preparation of azoles

[0257] The target compound was prepared by carrying out Steps 1, 2, 3 and 5 of Example 17 described below, except Step 4.

[0258] <Example 10> (3-(2-methoxy-5-propylphenyl)iso Preparation of oxazol-5-yl)methanol

[0259] After carrying out Step 4 of Example 17 described below, the resulting compound was reacted using H 2 and Pd / C in methanol, and the resulting product was purified to prepare the target compound.

[0260] <Example 11> 5-((Benzyloxy)methyl)-3-(5-bromo-2-methoxyphenyl)iso Preparation of azoles

[0261] After carrying out Step 3 of Example 17 described below, the obtained compound was reacted with NaH and benzyl bromide in DMF, and the obtained product was purified to prepare the target compound.

[0262] <Example 12> 2-((3-(5-bromo-2-methoxyphenyl)iso Preparation of ethyl 2-oxazol-5-yl)methoxy)acetate

[0263] The title compound was prepared as described in Example 11 above, except that ethyl 2-bromoacetate was used instead of benzyl bromide.

[0264] <Example 13> 3-(5-bromo-2-methoxyphenyl)-5-(methoxymethyl)iso Preparation of azoles

[0265] The title compound was prepared as described in Example 11 above, except that methyl bromide was used instead of benzyl bromide.

[0266] <Example 14> 2-(5-(Hydroxymethyl)iso Preparation of oxazolidin-3-yl)-4-propylphenol

[0267] The target compound was prepared as in Example 10 above, except that 5-bromo-2-hydroxybenzaldehyde was used as the starting material instead of 5-bromo-2-methoxybenzaldehyde.

[0268] <Example 15> (3-(5-allyl-2-methoxyphenyl)iso Preparation of oxazol-5-yl)methanol

[0269] The title compound was prepared by carrying out Step 4 of Example 17 described below.

[0270] <Example 16> 4-allyl-2-(5-hydroxymethyl)iso Preparation of oxazol-3-yl)phenol

[0271] The target compound was prepared as in Example 15 above, except that 5-bromo-2-hydroxybenzaldehyde was used as the starting material instead of 5-bromo-2-methoxybenzaldehyde.

[0272] <Example 17> 3-(5-allyl-2-methoxyphenyl)-5-((allyloxy)methyl)iso Preparation of azoles

[0273] Step 1: Preparation of (E)-5-bromo-2-methoxybenzaldehyde oxime

[0274] Hydroxylamine hydrochloride (320 mg, 4.60 mmol) was added to a 0.5 M NaOH H2O (23 mL) solution of 5-bromo-2-methoxybenzaldehyde (1 g, 4.65 mmol). The mixture was stirred at room temperature for 4 hours. 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 silica gel flash column chromatography (EtOAc / hexane=1:20) to obtain the target compound (960 mg, 90%).

[0275] 1H NMR (600MHz, CDCl3) δ8.39 (s, 1H), 7.78 (d, J = 2.5Hz, 1H), 7.43 (dd, J = 8.8, 2.5Hz, 1H), 3.84 (s, 3H). 13 C NMR (150MHz, CDCl3) δ156.7,145.7,133.8,129.8,122.6,113.3,113.0,56.0.

[0276] Step 2: Preparation of (Z)-5-bromo-N-hydroxy-2-methoxybenzyl chloride

[0277] N-Chlorosuccinimide (551 mg, 4.13 mmol) was added to a solution of (E)-5-bromo-2-methoxybenzaldehyde oxime (950 mg, 4.13 mmol) in DMF (4 mL). The mixture was stirred at room temperature for 1 hour. 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.

[0278] Step 3: (3-(5-bromo-2-methoxyphenyl)iso Preparation of oxazol-5-yl)methanol

[0279] To the mixture generated in step 2 above, propargyl alcohol (0.26 mL, 4.54 mmol), CuSO 4· 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 layer was dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel flash column chromatography (EtOAc / hexane=1:3) to give the target compound (630 mg, 54%).

[0280] 1 H NMR (600MHz, CDCl3) δ7.96 (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 (150MHz, CDCl3) δ171.1,159.1,156.4,133.9,132.0,119.7,113.3,113.3,103.5,56.6,56.0.

[0281] Step 4: (3-(5-allyl-2-methoxyphenyl)iso Preparation of oxazol-5-yl)methanol.

[0282] In a shielded tube, To a DMF (6 mL) solution of 1,4-dioxazol-5-yl)methanol (500 mg, 1.76 mmol) and Pd(PPh3)4 (203 mg, 0.176 mmol) was added allyltributyltin (Sn) (0.65 mL, 2.11 mmol). Afterwards, nitrogen was bubbled into the solvent for 10 minutes to remove air. The mixture was heated to 90 ° C and stirred for 2 hours. 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 layer was dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel flash column chromatography (EtOAc / hexane=1:4) to obtain the target compound (350 mg, 81%).

[0283] 1 H NMR (600MHz, CDCl3) δ7.70(d,J=2.3Hz,1H),7.23(dd,J=8.5,2.3Hz,1H),6.94(d,J=8.5Hz,1H),6.76(s,1H),5. 96(ddt,J=16.9,10.0,6.7Hz,1H),5.14-4.98(m,2H),4.82(d,J=4.8Hz,2H),3.88(s,3H),3.37(d,J=6.7Hz,2H). 13 C NMR (150MHz, CDCl3) δ170.4,160.3,155.8,137.5,132.7,131.4,129.7,117.8,116.1,111.7,103.7,56.8,55.8.

[0284] Step 5: 3-(5-allyl-2-methoxyphenyl)-5-((allyloxy)methyl)iso Preparation of azoles

[0285] To contain (3-(5-allyl-2-methoxyphenyl) To a solution of 1-oxazol-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 hours. The reaction mixture was quenched with NH4Cl solution and diluted with ethyl acetate. The combined organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel flash column chromatography (EtOAc / hexane=1:10) to obtain the target compound (370 mg, 93%).

[0286] <Example 18> 3-(5-allyl-2-methoxyphenyl)-5-((benzyloxy)methyl)iso Preparation of azoles

[0287] The title compound was prepared as described above in Example 17, except that benzyl bromide was used in place of allyl bromide in step 5.

[0288] <Example 19> 2-((3-(5-allyl-2-methoxyphenyl)iso Preparation of ethyl 2-oxazol-5-yl)methoxy)acetate

[0289] The title compound was prepared as described above in Example 17, except that ethyl 2-bromoacetate was used in place of allyl bromide in step 5.

[0290] <Example 20> 3-(2-methoxy-5-propylphenyl)-5-(methoxymethyl)iso Preparation of azoles

[0291] The procedure as in Example 17 above was carried out, except that methyl bromide was used in place of allyl bromide in step 5, the resulting compound was reacted using H 2 and Pd / C in methanol, and the resulting product was purified to obtain the target compound.

[0292] <Example 21> 4-((3-(5-bromo-2-methoxyphenyl)iso Preparation of tert-butyl (5-oxazol-5-yl)methyl)piperazine-1-carboxylate

[0293] The title compound was prepared as in step 3 of example 17 above, except that tert-butyl 4-(prop-2-yn-1-yl)piperazine-1-carboxylate was used in place of propargyl alcohol in step 3.

[0294] <Example 22> 3-(5-allyl-2-methoxyphenyl)-5-((4-allylpiperazin-1-yl)methyl)iso Preparation of azoles

[0295] 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.

[0296] <Example 23> 3-(5-allyl-2-methoxyphenyl)-5-((4-benzylpiperazin-1-yl)methyl)iso Preparation of azoles

[0297] The title compound was prepared as described above in Example 22, except benzyl bromide was used instead of allyl bromide.

[0298] <Example 24> 2-(4-((3-(5-allyl-2-methoxyphenyl)iso Preparation of ethyl 2-oxazol-5-yl)methyl)piperazin-1-yl)acetate

[0299] The title compound was prepared as described above in Example 22, except that ethyl bromoacetate was used instead of allyl bromide.

[0300] <Example 25> 4-((3-(5-allyl-2-methoxyphenyl)iso Preparation of tert-butyl (5-oxazol-5-yl)methyl)piperazine-1-carboxylate

[0301] The compound prepared in Example 21 above was reacted with Pd(PPh3)4 and allyltributyltin (Sn) in toluene to prepare the target compound.

[0302] <Example 26> 4-((3-(2-methoxy-5-propylphenyl)iso Preparation of tert-butyl (5-oxazol-5-yl)methyl)piperazine-1-carboxylate

[0303] The compound prepared in Example 25 was reacted by adding H2 and Pd / C to methanol, and the obtained product was purified to prepare the target compound.

[0304] <Example 27> 4-allyl-2-(5-((allyloxy)methyl)iso Preparation of oxazol-3-yl)phenol

[0305] The compound (15 mg) obtained in Example 17 was dissolved in 2 mL of dichloromethane. Boron tribromide (0.15 mL, 1 M dichloromethane solution) was then added at 0°C and stirred under a nitrogen atmosphere. After the reaction was completed, the mixture was diluted with dichloromethane and the organic layer was washed with brine and water. The combined organic layers were dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel flash column chromatography (EtOAc / hexane=1 / 3) to obtain the target compound (13 mg, 90%).

[0306] <Example 28> 3-(5-bromo-2-methoxyphenyl)-5-(piperazin-1-ylmethyl)iso Preparation of azole hydrochloride

[0307] The compound prepared in Example 21 (53 mg) was added to 1 mL of distilled water. The reaction mixture was concentrated under reduced pressure and the product was purified by silica gel flash column chromatography (dichloromethane / methanol=10 / 1) to obtain the target compound (30 mg, 66%).

[0308] <Example 29> 3-(5-allyl-methoxyphenyl)-5-(piperazin-1-ylmethyl)iso Preparation of azole hydrochloride

[0309] The compound prepared in Example 25 (25 mg) was added to 0.6 mL of distilled water. The reaction mixture was stirred for 4 hours in a solution of deionized water in oxane and the mixture was concentrated under reduced pressure, and the resultant was purified by silica gel flash column chromatography (dichloromethane / methanol=10 / 1) to obtain the target compound (14 mg, 77%).

[0310] <Example 30> 3-(2-methoxy-5-propylphenyl)-5-(piperazin-1-ylmethyl)iso Preparation of azole hydrochloride

[0311] The compound prepared in Example 26 (49 mg) was added to 1 mL of distilled water. The reaction mixture was stirred for 4 hours in a solution of deionized water in oxane and the mixture was concentrated under reduced pressure, and the resultant was purified by silica gel flash column chromatography (dichloromethane / methanol=10 / 1) to obtain the target compound (26 mg, 53%).

[0312] <Example 31> (3-(2-methoxy-5-(trifluoromethyl)phenyl)iso Preparation of oxazol-5-yl)methanol

[0313] The target compound was prepared by carrying out the procedures up to Step 3 in Example 17 above, except using 2-methoxy-5-trifluoromethylbenzaldehyde as a starting material.

[0314] <Example 32> 2-(3-(2-methoxy-5-(trifluoromethyl)phenyl)iso Preparation of oxazolidin-5-yl)propan-2-ol

[0315] The target compound was prepared in the same manner as in Example 31, except that 2,2-dimethylpropargyl alcohol was used in Step 3.

[0316] <Example 33> 2-(3-(2-methoxy-5-(trifluoromethyl)phenyl)iso Preparation of oxazol-5-yl)ethan-1-ol

[0317] The target compound was prepared in the same manner as in Example 31, except that but-3-yn-1-ol was used in Step 3.

[0318] <Example 34> 3-(2-methoxy-5-(trifluoromethyl)phenyl)-5-(piperazin-1-ylmethyl)iso Preparation of azoles

[0319] The intermediate was synthesized as described in Example 31 above, except that tert-butyl 4-(prop-2-yn-1-yl)piperazine-1-carboxylate was used instead of propargyl alcohol in step 3. The target compound was prepared by removing the Boc group with oxane solution.

[0320] <Example 35> (3-(2-methoxy-4-(trifluoromethyl)phenyl)iso Preparation of oxazol-5-yl)methanol

[0321] The target compound was synthesized according to the method of Example 31 above, except that 2-methoxy-4-trifluoromethylbenzaldehyde was used as the starting material.

[0322] <Example 36> 2-((3-(2-methoxy-5-(trifluoromethyl)phenyl)iso Preparation of oxazol-5-yl)methoxy)acetic acid

[0323] The compound prepared in Example 31 was reacted with tert-butyl bromoacetate / NaH in DMF, and then the tert-butyl group was removed with TFA (trifluoroacetic acid) in DCM to prepare the target compound.

[0324] <Example 37> 4-((3-(2-methoxy-5-(trifluoromethyl)phenyl)iso Preparation of oxazol-5-yl)methyl)-1-methylpiperazin-2-one

[0325] The target compound was synthesized by the method of Example 31 above, except that 1-methyl-4-(prop-2-yn-1-yl)piperazin-2-one was used instead of propargyl alcohol in Step 3.

[0326] <Example 38> (3-(2-methoxy-5-morpholinophenyl)iso Preparation of oxazol-5-yl)methanol

[0327] The target compound was prepared by carrying out step 4 of Example 17 using the compound prepared in the above Example 7, except that morpholine was reacted in the presence of RuPhos-Pd-G3 / cesium carbonate.

[0328] <Example 39> 2-(3-(5-allyl-2-methoxyphenyl)iso Preparation of oxazolidin-5-yl)propan-2-ol

[0329] Except for using 2-methylbut-3-yn-2-ol in Step 3, the steps up to Step 4 in the above-mentioned Example 17 were carried out to prepare the target compound.

[0330] <Example 40> 2-(3-(2-methoxy-5-propylphenyl)iso Preparation of oxazolidin-5-yl)propan-2-ol

[0331] The title compound was prepared by reducing the compound of Example 39 above using H2 and Pd / C in methanol.

[0332] <Example 41> 3-(5-allyl-2-methoxyphenyl)-5-((4-methylpiperazin-1-yl)methyl)iso Preparation of azoles

[0333] The target compound was prepared by carrying out the steps up to Step 4 in Example 17 above, except using 1-methyl-4-(prop-2-yn-1-yl)piperazine in Step 3.

[0334] <Example 42> 3-(2-methoxy-5-propylphenyl)-5-((4-methylpiperazin-1-yl)methyl)iso Preparation of azoles

[0335] The title compound was prepared by reducing the compound of Example 41 above using H2 and Pd / C in methanol.

[0336] <Example 43> (3-(5-allyl-2-(trifluoromethoxy)phenyl)iso Preparation of oxazol-5-yl)methanol

[0337] The target compound was prepared according to the method of Example 15 above, except that 5-bromo-2-(trifluoromethoxy)benzaldehyde was used as the starting material.

[0338] <Example 44> (3-(4-allyl-2-methoxyphenyl)iso Preparation of oxazol-5-yl)methanol

[0339] The target compound was prepared as in Example 15 above, except using 4-bromo-2-methoxybenzaldehyde as the starting material.

[0340] <Example 45> (3-(5-isopropyl-2-methoxyphenyl)iso Preparation of oxazol-5-yl)methanol

[0341] The target compound was prepared by carrying out the steps up to Step 3 in the above-mentioned Example 17, except using 5-isopropyl-2-methoxybenzaldehyde instead of 5-bromo-2-methoxybenzaldehyde as the starting material.

[0342] <Example 46> 4-((3-(5-isopropyl-2-methoxyphenyl)iso Preparation of tert-butyl (5-oxazol-5-yl)methyl)piperazine-1-carboxylate

[0343] The target compound was prepared by carrying out the procedures up to Step 3 in Example 17 above, except using 5-isopropyl-2-methoxybenzaldehyde as a starting material and using tert-butyl 4-(prop-2-yn-1-yl)piperazine-1-carboxylate instead of propargyl alcohol in Step 3.

[0344] <Example 47> 3-(5-isopropyl-2-methoxyphenyl)-5-(piperazin-1-ylmethyl)iso Preparation of azoles

[0345] After carrying out Example 46 above, using hydrochloric acid / dihydrochloric acid The target compound was prepared by removing the Boc group with oxane solution.

[0346] <Example 48> 4-((3-(4-allyl-2-methoxyphenyl)iso Preparation of tert-butyl (5-oxazol-5-yl)methyl)piperazine-1-carboxylate

[0347] The target compound was prepared by carrying out the steps up to Step 3 in Example 17 above, except using 4-bromo-2-methoxybenzaldehyde as a starting material and using tert-butyl 4-(prop-2-yn-1-yl)piperazine-1-carboxylate instead of propargyl alcohol in Step 3.

[0348] <Example 49> 3-(4-allyl-2-methoxyphenyl)-5-(piperazin-1-ylmethyl)iso Preparation of azoles

[0349] After carrying out Example 48 above, using hydrochloric acid / dihydrochloric acid The target compound was prepared by removing the Boc group with oxane solution.

[0350] <Example 50> 4-((3-(5-allyl-2-(trifluoromethoxy)phenyl)iso Preparation of tert-butyl (5-oxazol-5-yl)methyl)piperazine-1-carboxylate

[0351] The target compound was prepared by carrying out the steps up to Step 4 in Example 17 above, except using 5-bromo-2-(trifluoromethoxy)benzaldehyde as a starting material and using tert-butyl 4-(prop-2-yn-1-yl)piperazine-1-carboxylate instead of propargyl alcohol in Step 3.

[0352] <Example 51> 3-(5-allyl-2-(trifluoromethoxy)phenyl)-5-(piperazin-1-ylmethyl)iso Preparation of azoles

[0353] After carrying out the above Example 50, using hydrochloric acid / dihydrochloric acid The target compound was prepared by removing the Boc group with oxane solution.

[0354] <Example 52> 3-(5-allyl-2-(trifluoromethoxy)phenyl)-5-((4-methylpiperazin-1-yl)methyl)iso Preparation of oxazole: After carrying out the steps up to step 4 in Example 17 above, 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. The target compound was prepared as a salt from an oxane solution.

[0355] <Example 53> (2S, 6R)-4-((3-(2-methoxy-5-propylphenyl)iso Preparation of (5-oxazol-5-yl)methyl)-2,6-dimethylmorpholine

[0356] Step 1: (3-(2-methoxy-5-propylphenyl)iso oxazol-5-yl)methanol

[0357] The procedures up to Step 3 in Example 17 above were carried out except using 2-methoxy-5-propylbenzaldehyde as the starting material to give the target compound as a yellow solid.

[0358] LC-MS, m / z[M+1]=248.1

[0359] Step 2: 3-(2-methoxy-5-propylphenyl)iso Azole-5-carboxaldehyde

[0360] 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 and then filtered. The filter cake was washed with DCM (20 ml). The filtrate was concentrated to obtain the expected compound (1.7 g, 74% yield) as a yellow solid.

[0361] LC-MS, m / z[M+1]=246.1

[0362] Step 3: (2S,6R)-4-((3-(2-methoxy-5-propylphenyl)iso (2,6-dimethylmorpholine) (5-oxazol-5-yl)methyl)

[0363] The compound of step 2 (100mg, 0.41 mmol) is dissolved in DCM, and acetic acid (0.05mL) is added to a solution of (2S, 6R)-2,6-dimethylmorpholine (56mg, 0.49 mmol). The reactant is stirred at room temperature for 30 minutes, and NaBHAc3 (174mg, 0.82 mmol) is added to the reaction mixture. The reaction mixture is stirred at room temperature for 2 hours, quenched with water and the reaction mixture is extracted with ethyl acetate. The organic layer combined is washed with salt water, dried with Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by preparation HPLC to obtain the compound in the form of free alkali. It is treated with 2N HCl to obtain the title compound (94.8mg) in the form of HCl salt, which is a yellow solid.

[0364] <Example 54> 3-(2-methoxy-5-propylphenyl)-5-((4-methoxypiperidin-1-yl)methyl)iso Preparation of azoles

[0365] The target compound was prepared by the same procedure as in the above-mentioned Example 53, except that 4-methoxypiperidine was used instead of dimethylmorpholine in Step 3.

[0366] <Example 55> 1-((3-(2-methoxy-5-propylphenyl)iso Preparation of oxazol-5-yl)methyl)piperidine-4-carboxylic acid

[0367] The target compound was prepared by the same procedure as in the above-mentioned Example 53, except that piperidine-4-carboxylic acid was used instead of dimethylmorpholine in Step 3.

[0368] <Example 56> 5-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)-3-(2-methoxy-5-propylphenyl)iso Preparation of azoles

[0369] The target compound was prepared by the same method as Example 53, except using 4,5,6,7-tetrahydrothieno[3,2-c]pyridine instead of dimethylmorpholine in Step 3.

[0370] <Example 57> 5-((5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)methyl)-3-(2-methoxy-5-propylphenyl)iso Preparation of azoles

[0371] The target compound was prepared by the same procedure as Example 53, except using 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine instead of dimethylmorpholine in Step 3.

[0372] <Example 58> 3-(4-fluoro-2-methoxy-5-propylphenyl)-5-(piperazin-1-ylmethyl)iso Preparation of azoles

[0373] The procedure up to Step 3 in Example 17 above was carried out except that 2-methoxy-4-fluoro-5-propylbenzaldehyde was used as a starting material and tert-butyl 4-(prop-2-yn-1-yl)piperazine-1-carboxylate was used instead of propargyl alcohol in Step 3 to synthesize the intermediate, and then the reaction mixture was heated to 40 ℃ and then heated to 30 ℃ with hydrochloric acid / dihydrochloric acid. The target compound was prepared by removing the Boc group with oxane solution.

[0374] <Example 59> 3-(4-fluoro-2-methoxy-5-propylphenyl)-5-((4-methylpiperazin-1-yl)methyl)iso Preparation of azoles

[0375] The title compound was prepared similarly to Example 58 above, except that 4-methylpiperazine was used in step 3 instead of 4-(prop-2-yn-1-yl)-piperazine-1-carboxylic acid tert-butyl ester.

[0376] <Example 60> 5-((4-methylpiperazin-1-yl)methyl)-3-(5-propyl-2-(trifluoromethoxy)phenyl)iso Preparation of azoles

[0377] The target compound was prepared by carrying out the steps up to Step 3 in Example 17 above, except using 2-trifluoromethoxy-5-propylbenzaldehyde as a starting material and using 1-methyl-4-(prop-2-yn-1-yl)-piperazine in Step 3.

[0378] <Example 61> 2-(4-methoxy-3-(5-((4-methylpiperazin-1-yl)methyl)iso Preparation of oxazol-3-yl)phenyl)ethan-1-ol

[0379] The procedure up to Step 3 in Example 17 above was carried out except that 3-formyl-4-methoxyphenethyl acetate was used as a starting material and 1-methyl-4-(prop-2-yn-1-yl)piperazine was used in Step 3 to obtain the intermediate (4-methoxy-3-(5-((4-methylpiperazin-1-yl)methyl)isopropyl)piperazine wherein the hydroxyl group was protected by an acetyl group. The intermediate was hydrolyzed with lithium hydroxide solution to obtain the target compound.

[0380] <Example 62> 3-(2-methoxy-5-(2-methoxyethyl)phenyl)-5-((4-methylpiperazin-1-yl)methyl)iso Preparation of azoles

[0381] The target compound was obtained by carrying out the steps up to Step 3 in Example 17 above, except using 2-methoxy-5-(2-methoxyethyl)benzaldehyde as a starting material and using 1-methyl-4-(prop-2-yn-1-yl)-piperazine in Step 3.

[0382] <Example 63> 1-(4-((3-(5-isopropyl-2-methoxyphenyl)iso Preparation of oxazol-5-yl)methyl)piperazin-1-yl)ethan-1-one

[0383] The compound prepared in the above Example 29 was reacted with triethylamine and acetyl chloride in THF to prepare the target compound.

[0384] <Example 64> 3-(5-isopropyl-2-methoxyphenyl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)iso Preparation of azoles

[0385] The compound prepared in the above Example 29 was reacted with triethylamine and methanesulfonyl chloride in THF to prepare the target compound.

[0386] <Example 65> 3-(5-allyl-2-methoxyphenyl)-5-((quinazolin-4-yloxy)methyl)iso Preparation of azoles

[0387] The compound prepared in Example 15 above was added to 4-chloroquinazoline in DMF, and then NaH was added at 0°C, and reacted at room temperature to prepare the target compound.

[0388] <Example 66> 4-((3-(2-methoxy-5-(2-methylallyl)phenyl)iso Preparation of tert-butyl (5-oxazol-5-yl)methyl)piperazine-1-carboxylate

[0389] The target compound was prepared by carrying out the steps up to Step 4 in Example 17 above, except using 1-methyl-4-(prop-2-yn-1-yl)piperazine instead of propargyl alcohol in Step 3, and using tributyl(2-methylallyl)stannane instead of allyltributyltin(Sn) in Step 4.

[0390] <Example 67> 3-(2-methoxy-5-(2-methylallyl)phenyl)-5-(piperazin-1-ylmethyl)iso Preparation of azoles

[0391] After carrying out Example 66 above, using hydrochloric acid / dihydrochloric acid The target compound was prepared by removing the Boc group with oxane solution.

[0392] <Example 68> (3-(2-methoxy-5-(2-methylallyl)phenyl)iso Preparation of oxazol-5-yl)methanol

[0393] The title compound was prepared as described above in Example 15, except that tributyl(2-methylallyl)stannane was used in place of allyltributyltin(Sn) in step 4.

[0394] <Example 69> 3-(2-methoxy-5-(3-methylbut-2-en-1-yl)phenyl)-5-((4-methylpiperazin-1-yl)methyl)iso Preparation of azoles

[0395] After carrying out the steps up to step 4 in Example 17 above, a reaction mixture was prepared using hydrochloric acid / dichloromethane, except that 1-methyl-4-(prop-2-en-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 to prepare the target compound. The target compound was synthesized in the form of a salt from an oxane solution.

[0396] The results of NMR and mass spectrometry measurements of the compounds prepared in Examples 1 to 69 above are summarized and presented in the following table.

[0397] [Table 1]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403] The chemical structures of the compounds prepared in Examples 1 to 69 above are summarized in the following table.

[0404] [Table 2]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411] <Experimental Example 1> Screening for compounds capable of removing A2E fluorescent labeling substance (A2E-BDP) present in human retinal pigment epithelial cells

[0412] <1-1> Experimental methods

[0413] The human retinal pigment epithelial cell line (ARPE-19) used in the experiment was provided by ATCC (American Type Culture Collection). ARPE-19 cell line was cultured in DMEM medium containing 10% FBS. After culture, cells were plated at 4×10 3 The cells were dispensed into a 96-well plate at a concentration of 10 cells / well and cultured for 24 hours. ARPE-19 cells were treated with 10 μM A2E fluorescent labeling substance (A2E-BDP) for 24 hours to induce the accumulation of A2E-BDP in ARPE-19 cells.

[0414] In order 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. ARPE-19 cells prepared by the above method were treated once with each test compound at a concentration of 50 μM and then cultured for 24 hours. Cells were lysed 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 protease inhibitors to each 96-well plate. The prepared cell lysate was transferred to a white 96-well plate and analyzed using a fluorescent microplate reader (VICTOR TM X3, Perkin Elmer, USA) was used to measure the fluorescence intensity (excitation wavelength 485 nm, emission wavelength 535 nm). The results are shown in the following table.

[0415] <1-2> Experimental Results

[0416] [Table 3]

[0417] Example Ability to remove A2E-BDP at 50 μM (%) 1 20.8 2 28.2 3 0.6 4 24.7 5 26.9 6 24.0 7 16.6 8 -15.3 9 26.2 10 7.7 1 1 65.0 12 21.7 13 31.0 14 35.2 15 48.1 16 49.9 17 61.7 18 65.1 19 37.4 20 17.2 21 64.9 22 47.4 23 45.5 24 38.5 25 45.9 26 66.7

[0418] Referring to Table 3 above, it can be confirmed that when the cells were treated with the compounds of the examples of the present invention after the accumulation of the A2E fluorescent labeled substance (A2E-BDP) in ARPE-19 cells, the A2E-BDP signal measured by fluorescence was significantly reduced. Therefore, it can be seen that the compounds of the present invention removed A2E-BDP. In particular, the compounds of Examples 11, 17, 18, 21 and 26 showed a high removal ability of 60% or more.

[0419] The subsequent evaluation of LC3-II production capacity centered on other compounds was carried out as follows. ARPE-19 was added at 1×10 5 The concentration of each cell / well was distributed to 6-well plates and cultured for 24 hours. After that, cells were treated with the Example compounds according to the present invention listed in Table 4 below at a concentration of 1 μM, 5 μM, 10 μM, 25 μM and 50 μM for 12 hours. After that, a cell lysis buffer containing a protease inhibitor was added to prepare a cell lysate. LC3-II levels were measured by protein immunoblotting using anti-LC3-II antibodies (Cell Signaling Technology, MA, USA). As an internal control, levels were measured by protein immunoblotting using antibodies to beta-actin (Cell Signaling Technology) in the same manner as described above. The results are shown in Table 4.

[0420] [Table 4]

[0421]

[0422]

[0423] <Experimental Example 2> Effect of concentration on the removal of A2E fluorescent marker

[0424] <2-1> Experimental methods

[0425] ARPE-19 cells were cultured at 4 × 10 4 The concentration of 10 cells / well was distributed into a 24-well plate and cultured for 24 hours. To induce the accumulation of A2E-BDP in the ARPE-19 cell line, the cells were treated with A2E at a concentration of 10 μM for 24 hours. ARPE-19 cells containing A2E-BDP were treated with compound 17 (10 μM, 25 μM, 50 μM) for 24 hours. The level of A2E-BDP in each cell was measured based on fluorescence imaging at 510 nm using a Nikon Eclipse Ti-U fluorescence microscope (Tokyo, Japan). In addition, ordinary phase contrast microscopy was used to observe changes in the number of cells treated with the compounds, and the results are shown in Figure 2. Figure 1 At the same time, lutein was used as a control substance.

[0426] <2-2> Experimental Results

[0427] like Figure 1 As shown, after treatment with the compound of Example 17 of the present invention, the number of cells observed under a phase contrast microscope did not change significantly. Therefore, it was confirmed that the compound of Example 17 had no cytotoxicity to ARPE-19 cells at the concentration used in the experiment.

[0428] Meanwhile, when A2E and A2E-BDP accumulated in ARPE-19 cells and were observed under a fluorescence microscope (Nikon NIS-Elements, AR, Japan), A2E-BDP was easily identified, and in the experimental groups treated with the compound of Example 17 of the present invention at concentrations of 10 μM, 25 μM, and 50 μM together with A2E, a decrease in fluorescence intensity was observed in a concentration-dependent manner. This means that the amount of intracellular A2E-BDP was reduced as a result of the treatment with the compound of Example 17. In the case of the lutein-treated group used as a control group, a decrease in fluorescence intensity was observed, but it was confirmed that the compound of Example 17 of the present invention has a better ability to remove A2E-BDP than lutein.

[0429] <Experimental Example 3> Confirmation of the effect of removing A2E in human retinal pigment epithelial cells

[0430] In Table 1 and Figure 1 In order to measure the reduction of intracellular A2E by the compound, an A2E fluorescent substance (A2E-BDP) whose fluorescence is easily observed was used. In previous research reports, it was known that A2E-BDP has the same intracellular kinetics and characteristics as A2E, but since A2E is a substance that actually exists in living organisms, the quantitative changes of intracellular A2E were directly measured using the HPLC method as follows.

[0431] <3-1> Experimental methods

[0432] ARPE-19 cells were cultured at 4 × 10 3 The concentration of cells / well was distributed into a 6-well plate and cultured for 24 hours. The ARPE-19 cell line was treated with A2E at a concentration of 50 μM for 48 hours to accumulate A2E in the cells. ARPE-19 cells containing A2E were treated with compound 17 of the present invention (10 μM, 25 μM, 50 μM) for 24 hours to evaluate the ability to remove A2E. Thereafter, the ARPE-19 cells were washed with phosphate-buffered saline (PBS), and a cell lysis buffer containing a protease inhibitor was added to prepare a cell lysate. Chloroform and methanol (2:1, volume / volume) were added to the sample obtained above, shaken to extract A2E, and then centrifuged at 10000g for 10 minutes. The organic phase was dried under vacuum and redissolved in 100 mL of acetonitrile. LC-MS (Shimadzu LC-MS2010EV) analysis was performed using a C18 column (2'50 mm) with acetonitrile and 0.1% formic acid (gradient, 0% to 100%, 0 min to 10 min; flow rate 1.0 ml / min; monitoring at 503 nm). During the extraction of A2E present in the cytoplasm of ARPE-19 cells, all operations were performed under weak red light to prevent the destruction of A2E. The experimental results are shown in Figure 2 shown.

[0433] <3-2> Experimental Results

[0434] See also Figure 2 , it was confirmed that when ARPE-19 cells having accumulated A2E were treated with the compound of Example 17 of the present invention, the amount of accumulated A2E was significantly reduced in a concentration-dependent manner. Therefore, it can be seen that the compound of the present invention directly removes A2E.

[0435] <Experimental Example 4> Effect of inhibiting blue light-induced retinal pigment epithelial cell death

[0436] <4-1> Experimental methods

[0437] A2E accumulated in human retinal pigment epithelial cells is known to induce cytotoxicity by blue light irradiation. Using a human retinal pigment epithelial cell line, the effect of the compounds of the present invention on inhibiting cell death caused by blue light irradiation was measured.

[0438] ARPE-19 cells were cultured at 2×10 4 The cells were then distributed into 6-well plates at a concentration of 10 cells / well and cultured for 24 hours. In order to induce the accumulation of A2E in the ARPE-19 cell line, the cells were treated three times with A2E at a concentration of 25 μM at 48-hour intervals. 24 hours after the last A2E treatment, the cells were treated twice with the compound of Example 17 of the present invention at 24-hour intervals at concentrations of 10 μM, 25 μM and 50 μM, respectively. After another 24 hours of culture, blue light (BL, 430 nm, 7500 lux) was irradiated for 30 minutes and cultured for 24 hours. Cell death was observed under a microscope, and the number of viable cells was measured using Image J (National Institutes of Health, USA) to calculate quantitative cell activity. The results are shown in Table 3.

[0439] <4-2> Experimental Results

[0440] See also Figure 3 The results of the upper photographs confirmed that when A2E was accumulated alone (A2E group), no change in cell activity was observed, but when A2E and blue light irradiation were performed together (AB group), ARPE-19 cell death was induced. In the cell death model performed together with A2E and blue light irradiation, the experimental group treated with the compound of Example 17 of the present invention confirmed that cell death was significantly inhibited.

[0441] See also Figure 3 The experimental results in the lower part demonstrate that, in the cell viability quantified using Image J, treatment with the compound of Example 17 of the present invention statistically significantly inhibited cell death induced by A2E and blue light irradiation.

[0442] <Experimental Example 5> Inhibition of blue light-induced NF-κB activation in retinal pigment epithelial cells

[0443] <5-1> Experimental methods

[0444] When cells are stimulated by external pathogenic molecules (PAMPs), NF-κB dimers (p50-p65 dimers) are separated from IκB and activated. The separated NF-κB dimers pass through the nuclear membrane and enter the nucleus, where they bind to DNA and activate gene transcription, indicating the activation of NF-κB. Therefore, the inhibitory effect of the compounds of the present invention on NF-κB activation can be evaluated by measuring the changes in the cytoplasm or nuclear levels of p65. The experiment was performed as follows.

[0445] ARPE-19 cells were cultured at 2×10 4 The cells were seeded into 6-well plates at a concentration of 10 cells / well and cultured for 24 hours. To induce the accumulation of A2E in the ARPE-19 cell line, the cells were treated three times with A2E at a concentration of 25 μM at 48-hour intervals. 24 hours after the last A2E treatment, the cells were treated twice with compound 17 of the present invention at a concentration of 10 μM and 25 μM at 24-hour intervals. After another 24 hours of incubation, blue light (BL, 430 nm, 7500 lux) was irradiated for 30 minutes, and the cells were cultured for 24 hours. Cytoplasmic proteins were extracted using a cytoplasmic extraction buffer (10 mM HEPES, 60 mM KCl, 1 mM EDTA, 0.03%, 1 mM DTT, pH 7.6) containing protease inhibitors. After collecting the nuclei by centrifugation, nuclear proteins were extracted using Nuclear Extract 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. The level of p65 was measured by protein immunoblotting using anti-p65 antibody (Cell Signaling Technology, MA, USA). Antibodies against α-tubulin (Cell Signaling Technology) and histone H3 (Abcam, Cambridge, UK) were used as internal controls, respectively, and the cytoplasmic and nuclear fractions were measured by protein immunoblotting in the same manner as described above. The results are shown in Figure 2. Figure 4 shown.

[0446] <5-2> Experimental Results

[0447] like Figure 4As shown, when ARPE-19 cells were irradiated with A2E and blue light, p65 was observed to move into the nucleus, indicating the activation of NF-κB. At the same time, it can be seen that treatment with the compound of Example 17 of the present invention inhibited the movement of p65 into the nucleus, thereby inhibiting the activation of NF-κB.

[0448] <Experimental Example 6> Inhibition of blue light-induced inflammatory gene expression in retinal pigment epithelial cells

[0449] <6-1> Experimental methods

[0450] ARPE-19 cells were cultured at 2×10 4 The concentration of cells / well was seeded into a 6-well plate and cultured for 24 hours. The process of accumulating A2E in the ARPE-19 cell line, irradiating with blue light, and treating with the compound of Example 17 of the present invention was carried out in the same manner as in Experimental Example 5. After irradiating with blue light for 24 hours, total RNA was isolated from ARPE-19 cells using Trizol reagent (Invitrogen), and total RNA was quantified using Nanodrop (Nanodrop, Thermo Scientific). Thereafter, cDNA was synthesized using 0.5 μg of total RNA, and cDNA was amplified using the primers described in Table 5 below as templates and a real-time gene cycler LC480 (Roche) (PCR conditions: denaturation -95°C, 10 seconds; primer binding -60°C, 10 seconds; and extension -72°C, 10 seconds).

[0451] [Table 5]

[0452] #imgpt222#

[0453] At the same time, the PCR results of 18S were used as a control to correct the relative amount of genes measured in the ARPE-19 cell line. Figure 5 shown.

[0454] <6-2> Experimental Results

[0455] See also Figure 5 , it can be seen that the mRNA expression of inflammation-related genes (IL-1β, IL-6 and CXCL8) in the ARPE-19 cell line increased significantly due to A2E accumulation and blue light irradiation. However, treatment with the compound of Example 17 of the present invention resulted in a statistically significant decrease in the expression of these genes (P<0.05).

[0456] <Experimental Example 7> Effect of Activating Autophagy in Retinal Pigment Epithelial Cells

[0457] <7-1> Experimental methods

[0458] ARPE-19 was added at 1×105 The cells were then distributed into 6-well plates at a concentration of 10 cells / well and cultured for 24 hours. The cells were then treated with Example 17 of the present invention at concentrations of 10 μM, 25 μM, and 50 μM for 12 hours. Cell lysis buffer containing protease inhibitors was then added to prepare cell lysates. LC3-II levels were measured by protein immunoblotting using an anti-LC3-II antibody (Cell Signaling Technology, MA, USA). As an internal control, an anti-β-actin antibody (Cell Signaling Technology) was used and measured by protein immunoblotting in the same manner as described above, such as Figure 6 As shown (above).

[0459] At the same time, the formation of autophagosomes in cells was observed as follows. TM ARPE-19 cells were transfected with a plasmid expressing GFP-LC3 (Addgene Inc., MA, USA) using 2000 reagent (Invitrogen, Carlsbad, CA, USA). After 48 hours of culture, the cells were treated with the compound of Example 17 of the present invention at a concentration of 25 μM. After another 12 hours of culture, the cells were fixed with 4% paraformaldehyde for 10 minutes. The cells were then washed three times with PBS every 5 minutes. Finally, a confocal laser scanning microscope (Nikon, Tokyo, Japan) was used to observe the formation of GFP-LC3 spots. The cell nuclei were stained with 1 μg / mL Hoechst33342 (Thermo Scientific, Rockford, IL, USA), and the images observed were as follows. Figure 6 As shown (result in the photo below).

[0460] <7-2> Experimental Results

[0461] See also Figure 6 As a result, by treating the ARPE19 cell line with the compound of Example 17 of the present invention, an increase in the autophagy marker LC3-II was observed. LC3-II is one of the main indicator proteins for autophagy activation. When autophagy is activated, LC3-II participates in the formation of autophagosomes and forms spots in the cytoplasm.

[0462] observe Figure 6 According to the photographic results, intracellular LC3-II spots were observed after treatment with the compound of Example 17. Therefore, it was confirmed that the compound of the present invention activated the autophagy process.

[0463] <Experimental Example 8> Effect of improving autophagic flux of retinal pigment epithelial cells

[0464] <8-1> Experimental methods

[0465] Autophagic flux was measured by Western blotting by comparing the extent of changes in LC3-II protein formation when treated with Example 17 compound of the present invention in the presence and absence of bafilomycin A1 (Abcam, Cambridge, United Kingdom) (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).

[0466] The autophagic flux measurements in this experiment used saturating concentrations of bafilomycin A1, which is known to be an autophagy inhibitor. Bafilomycin A1 blocks autophagic flux by inhibiting lysosomal V-ATPase to prevent its acidification and by inhibiting the Ca2+ pump SERCA to prevent autophagosome-lysosome fusion. During autophagy, LC3 is converted from LC3-I to LC3-II in the autophagosome membrane, and LC3-II is subsequently degraded. Exposure to inhibitors such as bafilomycin A1 inhibits autophagosome-lysosome fusion, resulting in accumulation of LC3-II. Therefore, the effect of the embodiment compounds of the present invention on autophagic flux can be determined by detecting the level of LC3-II after treatment with the embodiment compounds of the present invention in the presence or absence of saturating concentrations of bafilomycin A1.

[0467] Specifically, in this experiment, ARPE-19 cells were cultured at 1×10 5 The concentration of cells / well was inoculated into a 6-well plate 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 10μM, 25μM and 50μM for 12 hours. A cell lysis buffer containing a protease inhibitor was added to prepare a cell lysate. The LC3-II level was measured by protein immunoblotting using a specific anti-LC3-II antibody (Cell Signaling Technology, MA, USA). At the same time, the amount of LC3-II was measured by protein immunoblotting after treatment with the compound of Example 17 in the same manner as above, under the condition of treatment with bafilomycin A1 at a concentration of 2nM for 4 hours. The amount of β-actin (CellSignaling Technology) was measured as an internal control. The band density obtained above was quantified using the Image J program, and the autophagic flux was measured by calculating the difference in the amount of LC3-II protein in the presence and absence of bafilomycin A1. The results are shown in Figure 2. Figure 7 shown.

[0468] <8-2> Experimental Results

[0469] like Figure 7 As shown, the Example 17 compound of the present invention showed a more significant increase in LC3-II in the presence of bafilomycin than in the absence of bafilomycin. This confirms that the Example 17 compound of the present invention is a compound that significantly increases the autophagic flux in the ARPE-19 cell line.

[0470] <Experimental Example 9> Effect of Activating Autophagy in Retinal Pigment Epithelial Cells Accumulating A2E

[0471] <9-1> Experimental methods

[0472] A2E is known to inhibit intracellular autophagy. Therefore, it was measured whether the Example 17 compound of the present invention also increases autophagy in the ARPE-19 cell line that accumulates A2E.

[0473] Specifically, ARPE-19 cells were cultured at 1×10 5 The cells were distributed into 6-well plates at a concentration of 10 cells / well and cultured for 24 hours. The cells were treated with A2E at a concentration of 25 μM for 24 hours. Thereafter, the cells were treated with Example 17 of the present invention at concentrations of 25 μM, 50 μM, and 100 μM for 12 hours. Thereafter, cell lysate preparation and LC3-II measurement by Western blotting were performed in the same manner as in Experimental Example 7, and the results are shown in FIG. Figure 8 shown.

[0474] <9-2> Experimental Results

[0475] like Figure 8 As shown, by treating the ARPE19 cell line in which A2E accumulates with the compound of Example 17 of the present invention, an increase in the autophagy marker LC3-II was observed. This confirms that the compound of the present invention can activate the autophagy process even in the ARPE-19 cell line in which A2E accumulates.

[0476] <Experimental Example 10> Effect of improving the autophagic flux of retinal pigment epithelial cells accumulating A2E

[0477] <10-1> Experimental methods

[0478] We measured whether the compound of Example 17 of the present invention increases the autophagic flux in the ARPE-19 cell line that accumulates A2E. That is, the ARPE-19 cell line was cultured at 1×10 5The concentration of cells / well was distributed into 6-well plates and cultured for 24 hours. The cells were treated with A2E at a concentration of 25 μM for 24 hours. The cells were treated with Example 17 compounds of the present invention at concentrations of 10 μM, 25 μM and 50 μM for 12 hours respectively. The method of treating with bafilomycin (2 nM, 4 hours), preparing cell lysates and measuring LC3-II by Western blotting was the same as in Experimental Example 8.

[0479] <10-2> Experimental Results

[0480] The experimental results are as follows Fig. 9 As shown. Fig. 9 As shown, in the presence of bafilomycin, the compound of Example 17 of the present invention showed a more significant increase in LC3-II in the ARPE-19 cell line that accumulated A2E. As a result, it was found that the compound of Example 17 significantly increased the autophagic flux in the ARPE-19 cell line that accumulated A2E, thereby finding that the compound of Example 17 increased the autophagic flux, thereby removing A2E accumulated in the cells.

[0481] <Experimental Example 11> Effect of Compounds on Improving Autophagy Inhibited by A2E and Blue Light

[0482] <11-1> Experimental methods

[0483] It is known that A2E can more significantly inhibit the autophagy process after being activated by blue light. Therefore, it was confirmed whether the compounds of the present invention can restore autophagy inhibited by A2E and blue light.

[0484] During the formation of autophagosomes, p62 specifically binds to the substance to be degraded and simultaneously binds to the 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 changes in intracellular p62 levels, the improvement effect of the compounds of the present invention on autophagy inhibited by A2E and blue light can be evaluated, and the experiment is performed as follows.

[0485] Specifically, ARPE-19 cells were cultured at 2×10 4The cells were seeded into 6-well plates at a concentration of 10 cells / well and cultured for 24 hours. In order to induce the accumulation of A2E in the ARPE-19 cell line, the cells were treated three times with A2E at a concentration of 25 μM at 48-hour intervals. 24 hours after the last A2E treatment, the cells were treated twice with the compound of Example 17 at 24-hour intervals. After another 24 hours of incubation, blue light (BL, 430 nm, 7500 lux) was irradiated for 30 minutes and the cells were cultured for 24 hours. Cell lysis buffer containing protease inhibitors was added to each cell to prepare cell lysate. The amount of intracellular p62 was measured by protein immunoblotting using an anti-p62 antibody (Santa Cruz, TX, USA). The amount of intracellular β-actin was measured in the same manner using an anti-β-actin antibody (Santa Cruz) and used as a control. The results are shown in FIG. Fig.10 shown.

[0486] <11-2> Experimental Results

[0487] The experimental results are as follows Fig.10 As shown. Fig.10 As shown in the figures, a significant increase in p62 protein was observed in the ARPE-19 cell line due to the accumulation of A2E and blue light irradiation. When the p62 protein increased due to the accumulation of A2E and blue light irradiation was treated with the compound of Example 17 of the present invention, it was confirmed that the p62 protein concentration decreased in a concentration-dependent manner. Therefore, it can be seen that the compound of the present invention has the effect of restoring the autophagic activity in human retinal pigment epithelial cells that is reduced by A2E and blue light, and promotes the removal of A2E accumulated in the cells by restoring the autophagic activity.

[0488] <Experimental Example 12> Improvement effect of the compound on the blue light-induced retinal damage animal model

[0489] The compounds of the present invention have been shown to improve blue light-induced retinal damage in experimental animals (Balb / c mice). The following experiments were performed by repeated oral administration of the example compounds for 4 weeks. All tests were performed at the non-clinical center of the Korea Construction and Living Environment Testing Institute (KCL) Biological Headquarters (Songdo, Incheon) and were performed after obtaining approval from the Animal Experiment Ethics Committee (approval number: IA20-04287).

[0490] <12-1> Experimental methods

[0491] Specific pathogen-free (SPF) male BALB / c mice (Orient Bio, Korea) were adapted for 1 week. Body weight was measured one day before administration and grouped by sorting the body weight using an excel program. Only animals within ±20% of the mean body weight were selected for the experiment. After grouping, dark room conditions were maintained for 24 hours and dark room conditions were maintained throughout the blue light exposure period.

[0492] After the experimental animals were anesthetized with isoflurane, they were irradiated with 10,000 lux of blue light using a blue light irradiation device, for a total of 14 times (1 hour / day) for 2 weeks. The compound of Example 17 of the present invention was dissolved in a 5% CMC Na solution of HP-β-cyclodextrin to prepare a test substance with a concentration of 10%. The dosage was 10 ml / kg / day, and 25 mg / kg / day was applied to each experimental animal. After grasping the skin on the back of the experimental animal and correcting it, the test substance was forcibly orally administered using an oral administration probe. The application time was the morning of the day of application, once a day, 7 days a week, for a total of 4 weeks. The first 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. On the day of application, the test substance was applied before blue light irradiation. All animals were examined in both eyes before the start of application and once a week. After the pupil was dilated by instilling a mydriatic, the fundus was observed with a fundus camera (Genesis-D, Kowa Co. Ltd., Japan), and each animal was photographed one week after the end of the test article administration.

[0493] After the experiment, all the animals' eyes were removed and fixed in Davidson's fixative. Hematoxylin and eosin (H&E) staining was performed, and the average thickness of ONL (outer nuclear layer) and IS / OS (inner segment / outer segment layer) was measured at 140 μm (left / right) from the retinal nerve center using the Axio Vision SE644 (ZEISS) program. The thickness of ONL and IS / OS in the contralateral eye was measured in a similar way, and the average of both eyes was used as the final thickness. One-way analysis of variance and t-test were used between the groups, and the results were considered statistically significant when p < 0.05 or less. Statistical analysis was performed using the commercially widely used SPSS12.0K program (SPSS, Chicago, IL, USA). Animals that did not form a test model were excluded from the statistics.

[0494] <12-2> Experimental Results

[0495] The experimental results are as follows Fig.11 and Fig.12As shown. The results of fundus camera observation showed that the retina of the blue light irradiation control group was damaged compared with the normal control group. The results of histomorphometric analysis of ocular tissue also confirmed that the ONL and IS / OS thickness of the blue light irradiation control group was reduced compared with the normal control group. On the other hand, in the group administered with the Example compound of the present invention at 25 mg / kg / day, fundus examination showed that retinal damage was improved ( Fig.11 In addition, the ONL and IS / OS thicknesses that were significantly reduced by blue light irradiation were statistically significantly (p<0.01) restored by the administration of the example compounds of the present invention ( Fig.12 ).

[0496] <Experimental Example 13> Evaluation of the A2E-BDP Removal Capacity by Concentration of Other Example Compounds

[0497] In the experimental results of Table 3 above, for the compounds of Examples 11, 17, 18, 21 and 26, the removal ability of A2E-BDP was re-evaluated by concentration, which showed a high removal ability of 60% or more. The removal ability of A2E-fluorescent labeled substance (A2E-BDP) was evaluated according to Experimental Example 1 (except that the test compound was treated at the indicated concentration). The results are as follows Fig.13 shown.

[0498] like Fig.13 As shown, it was confirmed that not only the compound of Example 17 according to the present invention, but also the compounds of Examples 11, 18, 21 and 26 showed a concentration-dependent decrease in the amount of A2E. Therefore, it can be seen that the compounds of the present invention directly remove A2E.

[0499] <Experimental Example 14> Evaluation of autophagy activation of other example compounds

[0500] The autophagy activation effect of the compounds of Examples 11, 17, 18, 21 and 26 in human retinal pigment epithelial cells was evaluated, and the high removal ability of 60% or higher was shown in the experimental results of Table 3 above. The cells were treated with the test compounds at the indicated concentrations, and the autophagy activation effect increased by p62 protein phosphorylated at serine residue 349 (p-p62 (S349)) was measured by Western immunoblotting using anti-p-p62 antibody. The results are shown in Table 3. Fig.14 As shown. The increase in intracellular P-p62 (S439) levels is one of the main indicators of autophagy activation.

[0501] like Fig.14 As shown, it was found that not only the compound of Example 17 according to the present invention but also the compounds of Examples 11, 18, 21 and 26 activated autophagy in a concentration-dependent manner.

[0502] <Experimental Example 15> Evaluation of autophagy activation of compounds of other examples

[0503] According to Experimental Example 7, the autophagy activation effect of the example compounds in Table 2 above that are expected to have autophagy activation ability and low cytotoxicity in human retinal pigment epithelial cells was evaluated. That is, by evaluating the autophagy activation effect of LC3-II increase in a concentration-dependent manner, the results are as follows: Fig.15 and Fig.16 shown.

[0504] like Fig.15 and Fig.16 As shown, the compounds of Examples 28, 30, 34, 41, 42, 47, 58, 59 and 60 according to the present invention showed excellent autophagy activation effects depending on the concentration of the compound.

Claims

1. A compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof, [Chemical formula 1] In Chemical Formula 1, R 1 For hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein C 1-6 Alkyl or C 3-6 At least one hydrogen of the cycloalkyl group is optionally substituted with at least one substituent independently selected from hydroxyl, C 1-3 Alkoxy and halogen, R 2 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, wherein 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 -C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-3 At least one hydrogen of the alkylene or heterocycloalkyl group is optionally substituted with at least one substituent independently selected from the group consisting of: 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 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, halogenated C 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 .

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of the following Chemical Formula 1a: [Chemical formula 1a] In Chemical Formula 1a, R 1 For hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein C 1-6 Alkyl or C 3-6 At least one hydrogen of the cycloalkyl group is optionally substituted with at least one substituent independently selected from hydroxyl, C 1-3 Alkoxy and halogen, R 2 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, wherein 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 -C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-3 At least one hydrogen of the alkylene or heterocycloalkyl group is optionally substituted with at least one substituent independently selected from the group consisting of: 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 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, halogenated C 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 .

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein in Chemical Formula 1a, R 1 is hydrogen or C 1-6 Alkyl, where C 1-6 At least one hydrogen of the alkyl group is optionally substituted with at least one substituent independently selected from halogen, R 2 For -C 1-6 Alkyl, -C 1-3 Alkylene -ORa, -C 1-3 Alkylene -NRaRb, -C 1-3 Alkylene-piperazine, -C 1-3 Alkylene-piperidine, -C 1-3 Alkylene-morpholine, -C 1-3 Alkylene-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, -C 1-3 Alkylene-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, -C 1-3 Alkylene-pyrrolidine, -C 1-3 Alkylene-3,8-diazabicyclo[3.2.1]octane or -C 1-3 Alkylene-2,5-diazabicyclo[2.2.2]octane, wherein 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 -C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-3 At least one hydrogen of the alkylene or heterocycloalkyl group is optionally substituted with at least one substituent independently selected from the group consisting of: 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 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, halogenated C 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 .

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein in Chemical Formula 1a, R 1 is hydrogen, methyl or -CF 3 , R 2 For -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 Ra and Rb are each independently hydrogen, C 1-6 Alkyl, allyl, benzyl, -C 1-3 Alkylene-COO-C 1-3 Alkyl, phenyl, quinazoline or pyridinyl, where -C 1-6 Alkyl, C 1-3 At least one hydrogen of the alkylene or heterocycloalkyl group is optionally substituted with at least one substituent independently selected from the group consisting of: 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 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, -halogenated C 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.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is (1) 3-(5-bromo-2-methoxyphenyl)-5-propyl isocyanate Azoles; (2) 4-bromo-2-(5-propylisothiazolinone oxazol-3-yl)phenol; (3) 3-(2-methoxy-5-propylphenyl)-5-propylisothiazolin Azoles; (4) 3-(5-allyl-2-methoxyphenyl)-5-propylisothiazolin Azoles; (5) 4-allyl-2-(5-propylisothiazolinyl) oxazol-3-yl)phenol; (6) 4-propyl-2-(5-propylisothiazolinone oxazol-3-yl)phenol; (7)(3-(5-bromo-2-methoxyphenyl)iso oxazol-5-yl)methanol; (8) 4-bromo-2-(5-(hydroxymethyl)iso oxazol-3-yl)phenol; (9) 5-((allyloxy)methyl)-3-(5-bromo-2-methoxyphenyl)iso Azoles; (10)(3-(2-methoxy-5-propylphenyl)iso oxazol-5-yl)methanol; (11) 5-((Benzyloxy)methyl)-3-(5-bromo-2-methoxyphenyl)iso Azoles; (12) 2-((3-(5-bromo-2-methoxyphenyl)iso 4-(4-oxazol-5-yl)methoxy)ethyl acetate; (13) 3-(5-bromo-2-methoxyphenyl)-5-(methoxymethyl)iso Azoles; (14) 2-(5-(Hydroxymethyl)iso oxazol-3-yl)-4-propylphenol; (15)(3-(5-allyl-2-methoxyphenyl)iso oxazol-5-yl)methanol; (16) 4-allyl-2-(5-(hydroxymethyl)isopropyl oxazol-3-yl)phenol; (17) 3-(5-allyl-2-methoxyphenyl)-5-((allyloxy)methyl)iso Azoles; (18) 3-(5-allyl-2-methoxyphenyl)-5-((benzyloxy)methyl)iso Azoles; (19) 2-((3-(5-allyl-2-methoxyphenyl)iso 4-(4-oxazol-5-yl)methoxy)ethyl acetate; (20) 3-(2-methoxy-5-propylphenyl)-5-(methoxymethyl)iso Azoles; (21) 4-((3-(5-bromo-2-methoxyphenyl)iso tert-butyl oxazol-5-yl)methyl)piperazine-1-carboxylate; (22) 3-(5-allyl-2-methoxyphenyl)-5-((4-allylpiperazin-1-yl)methyl)iso Azoles; (23) 3-(5-allyl-2-methoxyphenyl)-5-((4-benzylpiperazin-1-yl)methyl)iso Azoles; (24) 2-(4-((3-(5-allyl-2-methoxyphenyl)iso 4-((3-(5-allyl-2-methoxyphenyl)isothiazolyl)-1-yl)-4-((3-(5-allyl-2-methoxyphenyl ... tert-butyl oxazol-5-yl)methyl)piperazine-1-carboxylate; (26) 4-((3-(2-methoxy-5-propylphenyl)iso tert-butyl oxazol-5-yl)methyl)piperazine-1-carboxylate; (27) 4-allyl-2-(5-((allyloxy)methyl)iso oxazol-3-yl)phenol; (28) 3-(5-bromo-2-methoxyphenyl)-5-(piperazin-1-ylmethyl)iso Azoles; (29) 3-(5-allyl-methoxyphenyl)-5-(piperazin-1-ylmethyl)iso Azoles; (30) 3-(2-methoxy-5-propylphenyl)-5-(piperazin-1-ylmethyl)iso Azoles; (31)(3-(2-methoxy-5-(trifluoromethyl)phenyl)iso oxazol-5-yl)methanol; (32) 2-(3-(2-methoxy-5-(trifluoromethyl)phenyl)iso oxazol-5-yl)propan-2-ol; (33) 2-(3-(2-methoxy-5-(trifluoromethyl)phenyl)iso oxazol-5-yl)ethan-1-ol; (34) 3-(2-methoxy-5-(trifluoromethyl)phenyl)-5-(piperazin-1-ylmethyl)iso Azoles; (35) (3-(2-methoxy-4-(trifluoromethyl)phenyl)iso oxazol-5-yl)methanol; (36) 2-((3-(2-methoxy-5-(trifluoromethyl)phenyl)iso oxazol-5-yl)methoxy)acetic acid; (37) 4-((3-(2-methoxy-5-(trifluoromethyl)phenyl)iso oxazol-5-yl)methyl)-1-methylpiperazin-2-one; (38) (3-(2-methoxy-5-morpholinophenyl)iso oxazol-5-yl)methanol; (39) 2-(3-(5-allyl-2-methoxyphenyl)iso oxazol-5-yl)propan-2-ol; (40) 2-(3-(2-methoxy-5-propylphenyl)iso oxazol-5-yl)propan-2-ol; (41) 3-(5-allyl-2-methoxyphenyl)-5-((4-methylpiperazin-1-yl)methyl)iso Azoles; (42) 3-(2-methoxy-5-propylphenyl)-5-((4-methylpiperazin-1-yl)methyl)iso Azoles; (43) (3-(5-allyl-2-(trifluoromethoxy)phenyl)iso oxazol-5-yl)methanol; (44)(3-(4-allyl-2-methoxyphenyl)iso oxazol-5-yl)methanol; (45)(3-(5-isopropyl-2-methoxyphenyl)iso oxazol-5-yl)methanol; (46) 4-((3-(5-isopropyl-2-methoxyphenyl)iso tert-butyl oxazol-5-yl)methyl)piperazine-1-carboxylate; (47) 3-(5-isopropyl-2-methoxyphenyl)-5-(piperazin-1-ylmethyl)iso Azoles; (48) 4-((3-(4-allyl-2-methoxyphenyl)iso tert-butyl oxazol-5-yl)methyl)piperazine-1-carboxylate; (49) 3-(4-allyl-2-methoxyphenyl)-5-(piperazin-1-ylmethyl)iso Azoles; (50) 4-((3-(5-allyl-2-(trifluoromethoxy)phenyl)iso tert-butyl 3-(5-allyl-2-(trifluoromethoxy)phenyl)-5-(piperazin-1-ylmethyl)isothiazolyl-5-yl)methyl)piperazine-1-carboxylate; (51) 3-(5-allyl-2-(trifluoromethoxy)phenyl)-5-(piperazin-1-ylmethyl)isothiazolyl-5-yl)methyl)piperazine-1-carboxylate oxazole; (52) 3-(5-allyl-2-(trifluoromethoxy)phenyl)-5-((4-methylpiperazin-1-yl)methyl)iso Azoles; (53) (2S,6R)-4-((3-(2-methoxy-5-propylphenyl)iso oxazol-5-yl)methyl)-2,6-dimethylmorpholine; (54) 3-(2-methoxy-5-propylphenyl)-5-((4-methoxypiperidin-1-yl)methyl)iso Azoles; (55) 1-((3-(2-methoxy-5-propylphenyl)iso oxazol-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)iso oxadiazole; (57) 5-((5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)methyl)-3-(2-methoxy-5-propylphenyl)iso oxazole; (58) 3-(4-fluoro-2-methoxy-5-propylphenyl)-5-(piperazin-1-ylmethyl)iso Azoles; (59) 3-(4-fluoro-2-methoxy-5-propylphenyl)-5-((4-methylpiperazin-1-yl)methyl)iso Azoles; (60) 5-((4-methylpiperazin-1-yl)methyl)-3-(5-propyl-2-(trifluoromethoxy)phenyl)iso Azoles; (61) 2-(4-methoxy-3-(5-((4-methylpiperazin-1-yl)methyl)iso oxazol-3-yl)phenyl)ethan-1-ol; (62) 3-(2-methoxy-5-(2-methoxyethyl)phenyl)-5-((4-methylpiperazin-1-yl)methyl)iso Azoles; (63) 1-(4-((3-(5-isopropyl-2-methoxyphenyl)iso oxazol-5-yl)methyl)piperazin-1-yl)ethan-1-one; (64) 3-(5-isopropyl-2-methoxyphenyl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)iso Azoles; (65) 3-(5-allyl-2-methoxyphenyl)-5-((quinazolin-4-yloxy)methyl)iso Azoles; (66) 4-((3-(2-methoxy-5-(2-methylallyl)phenyl)iso tert-butyl 3-(2-methoxy-5-(2-methylallyl)phenyl)-5-(piperazin-1-ylmethyl)isothiazolyl ester; (67) tert-butyl 3-(2-methoxy-5-(2-methylallyl)phenyl)-5-(piperazin-1-ylmethyl)isothiazolyl ester Azoles; (68) (3-(2-methoxy-5-(2-methylallyl)phenyl)iso oxazol-5-yl)methanol; or (69) 3-(2-methoxy-5-(3-methylbut-2-en-1-yl)phenyl)-5-((4-methylpiperazin-1-yl)methyl)iso Azole.

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein the compound is (11) 5-((benzyloxy)methyl)-3-(5-bromo-2-methoxyphenyl)isothiazolidine Azoles; (15)(3-(5-allyl-2-methoxyphenyl)iso oxazol-5-yl)methanol; (17) 3-(5-allyl-2-methoxyphenyl)-5-((allyloxy)methyl)iso Azoles; (18) 3-(5-allyl-2-methoxyphenyl)-5-((benzyloxy)methyl)iso Azoles; (21) 4-((3-(5-bromo-2-methoxyphenyl)iso tert-butyl oxazol-5-yl)methyl)piperazine-1-carboxylate; (25) 4-((3-(5-allyl-2-methoxyphenyl)iso tert-butyl oxazol-5-yl)methyl)piperazine-1-carboxylate; (26) 4-((3-(2-methoxy-5-propylphenyl)iso tert-butyl oxazol-5-yl)methyl)piperazine-1-carboxylate; (28) 3-(5-bromo-2-methoxyphenyl)-5-(piperazin-1-ylmethyl)iso Azoles; (29) 3-(5-allyl-methoxyphenyl)-5-(piperazin-1-ylmethyl)iso Azoles; (30) 3-(2-methoxy-5-propylphenyl)-5-(piperazin-1-ylmethyl)iso Azoles; (34) 3-(2-methoxy-5-(trifluoromethyl)phenyl)-5-(piperazin-1-ylmethyl)iso Azoles; (41) 3-(5-allyl-2-methoxyphenyl)-5-((4-methylpiperazin-1-yl)methyl)iso Azoles; (42) 3-(2-methoxy-5-propylphenyl)-5-((4-methylpiperazin-1-yl)methyl)iso Azoles; (43) (3-(5-allyl-2-(trifluoromethoxy)phenyl)iso oxazol-5-yl)methanol; (44)(3-(4-allyl-2-methoxyphenyl)iso oxazol-5-yl)methanol; (47) 3-(5-isopropyl-2-methoxyphenyl)-5-(piperazin-1-ylmethyl)iso Azoles; (48) 4-((3-(4-allyl-2-methoxyphenyl)iso tert-butyl oxazol-5-yl)methyl)piperazine-1-carboxylate; (50) 4-((3-(5-allyl-2-(trifluoromethoxy)phenyl)iso tert-butyl oxazol-5-yl)methyl)piperazine-1-carboxylate; (51) 3-(5-allyl-2-(trifluoromethoxy)phenyl)-5-(piperazin-1-ylmethyl)iso Azoles; (52) 3-(5-allyl-2-(trifluoromethoxy)phenyl)-5-((4-methylpiperazin-1-yl)methyl)iso Azoles; (58) 3-(4-fluoro-2-methoxy-5-propylphenyl)-5-(piperazin-1-ylmethyl)iso Azoles; (59) 3-(4-fluoro-2-methoxy-5-propylphenyl)-5-((4-methylpiperazin-1-yl)methyl)iso Azoles; (60) 5-((4-methylpiperazin-1-yl)methyl)-3-(5-propyl-2-(trifluoromethoxy)phenyl)iso Azoles; (66) 4-((3-(2-methoxy-5-(2-methylallyl)phenyl)iso tert-butyl oxazol-5-yl)methyl)piperazine-1-carboxylate; (67) 3-(2-methoxy-5-(2-methylallyl)phenyl)-5-(piperazin-1-ylmethyl)iso Azoles; or (68) (3-(2-methoxy-5-(2-methylallyl)phenyl)iso oxazol-5-yl)methanol.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein the compound is (28) 3-(5-bromo-2-methoxyphenyl)-5-(piperazin-1-ylmethyl)isothiazol-1-yl Azoles; (30) 3-(2-methoxy-5-propylphenyl)-5-(piperazin-1-ylmethyl)iso Azoles; (34) 3-(2-methoxy-5-(trifluoromethyl)phenyl)-5-(piperazin-1-ylmethyl)iso Azoles; (41) 3-(5-allyl-2-methoxyphenyl)-5-((4-methylpiperazin-1-yl)methyl)iso Azoles; (42) 3-(2-methoxy-5-propylphenyl)-5-((4-methylpiperazin-1-yl)methyl)iso Azoles; (47) 3-(5-isopropyl-2-methoxyphenyl)-5-(piperazin-1-ylmethyl)iso Azoles; (58) 3-(4-fluoro-2-methoxy-5-propylphenyl)-5-(piperazin-1-ylmethyl)iso Azoles; (59) 3-(4-fluoro-2-methoxy-5-propylphenyl)-5-((4-methylpiperazin-1-yl)methyl)iso Azoles; or (60) 5-((4-methylpiperazin-1-yl)methyl)-3-(5-propyl-2-(trifluoromethoxy)phenyl)iso Azole.

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

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

10. The pharmaceutical composition according to claim 8, wherein the ocular disease is dry type macular degeneration.

11. A composition for protecting the retina from blue light damage, comprising as an active agent a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

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