Novel compound, and composition for preventing or treating eye diseases, comprising same

Abstract

The present invention relates to a novel compound, and a composition for preventing or treating eye diseases, comprising same, and, more specifically, to: a series of phenyl-triazole derivative compound or a pharmaceutically acceptable salt thereof; a pharmaceutical composition for preventing or treating eye disease, comprising the compound; a method for preventing or treating eye diseases, comprising administering the pharmaceutical composition; an autophagy activation composition comprising the compound or a pharmaceutically acceptable salt thereof; a food composition for preventing or alleviating eye diseases; and a feed composition.

Description

Novel compound and composition containing the same for preventing or treating eye diseases

[0001] The present invention relates to a novel compound and a composition for preventing or treating eye diseases comprising the same, and more particularly, to a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof; a pharmaceutical composition for preventing or treating eye diseases comprising the compound; a method for preventing or treating eye diseases comprising administering the pharmaceutical composition; an autophagy activating composition comprising the compound or a pharmaceutically acceptable salt thereof; a food composition for preventing or improving eye diseases; and a feed composition:

[0002] [Chemical Formula 1]

[0003]

[0004]

[0005] Light can be divided into ultraviolet rays, visible light, and infrared rays according to wavelength. Visible light is the light that can be commonly seen by the human eye, and its wavelength corresponds to the range of 380 to 780 nm. Among these, the blue series that exists between 380 and 500 nm can be classified as blue light, and this short-wavelength blue light has high energy and passes through the lens to affect retinal epithelial cells.

[0006] Humans are constantly exposed to blue light because they must adapt to constant changes in light, both indoors and outdoors. This leads to increased eye fatigue, which can trigger a vicious cycle of macular degeneration and vision loss. Furthermore, with the recent increase in electronic device use due to changes in our living environment, we are exposed to blue light not only from displays on smart devices like TVs, computers, and smartphones, but also from LED lighting devices. Research is being conducted on the potential harmful effects on the human body.

[0007] Moreover, the smartphone usage rate among adults in Korea was 97% as of 2022, the highest among the countries surveyed, and the age of smartphone use or usage is also decreasing every year.

[0008] The macula, the central nerve tissue of the retina, is located at the innermost part of the eye. It is home to the majority of photoreceptor cells and is where images are formed, making it crucial for vision. However, the macula can develop vision impairment due to various factors, including aging, genetics, toxicity, and inflammation. This condition, called macular degeneration, can lead to blindness in severe cases.

[0009] In addition, it is known that the accumulation of lipofuscin in the central part of the retina is greatest in the retinal pigment epithelial cells located beneath the central part of the retina. N-retinyl N-retinylidene ethanolamine (A2E) is the main chromophore of lipofuscin, and it causes the production of reactive oxygen species when exposed to blue light. In addition, visual impairment due to retinal cell dysfunction is closely related to the oxidation of A2E, and therefore can be a major cause of eye diseases including macular degeneration. Meanwhile, autophagy is a self-digestive system in which cellular components are broken down and recycled as a source of nutrients and energy. Aged or dysfunctional cellular organelles and damaged or improperly folded proteins are the targets of autophagy, and it regulates the protein degradation process essential for maintaining cellular homeostasis and genetic stability. It plays a central role in maintaining cellular homeostasis by regulating chemical metabolism, mitigating the production of reactive oxygen species (ROS) by regenerating damaged or long-lived mitochondria, and protecting cells from internal and external stimuli such as nutrient deficiency, oxygen depletion, invasion by pathogens including bacteria and viruses, and UV exposure. Consequently, if autophagy is not properly regulated, various diseases related to cellular homeostasis can develop.

[0010] As a prior study, Korean Patent Publication No. 10-2023-0140410 disclosed a 3-phenylisoxazole derivative and a pharmaceutical composition for preventing or treating eye diseases containing the same as an active ingredient.

[0011] Against this backdrop, the present invention was completed by researching compounds that are effective in treating diseases related to autophagy, particularly ophthalmic diseases such as dry macular degeneration, dry eye, eye fatigue, and decreased vision caused by aging and blue light, and confirming that a 4-phenyl-triazole derivative compound represented by chemical formula 1 inhibits death of human retinal pigment epithelial cells (ARPE-19) induced by A2E and blue light, removes A2E-fluorescent markers and A2E in ARPE-19, and activates autophagy.

[0012]

[0013] One object of the present invention is to provide a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof:

[0014] [Chemical Formula 1]

[0015] .

[0016] Another object of the present invention is to provide a method for preparing the compound or a pharmaceutically acceptable salt thereof.

[0017] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating ocular diseases, comprising the compound or a pharmaceutically acceptable salt thereof.

[0018] Another object of the present invention is to provide a method for preventing or treating an eye disease, comprising a step of administering the pharmaceutical composition.

[0019] Another object of the present invention is to provide an autophagy activating composition comprising the compound or a pharmaceutically acceptable salt thereof.

[0020] Another object of the present invention is to provide a food composition for preventing or improving eye diseases, comprising the compound or a pharmaceutically acceptable salt thereof.

[0021] Another object of the present invention is to provide a feed composition for preventing or treating eye diseases, comprising the compound or a pharmaceutically acceptable salt thereof.

[0022] Another object of the present invention is to provide a use of the compound or a pharmaceutically acceptable salt thereof for preventing, improving or treating ocular diseases.

[0023]

[0024] This is explained in detail as follows. Meanwhile, each description and embodiment disclosed in the present invention can also be applied to each other description and embodiment. In other words, all combinations of the various elements disclosed in the present invention fall within the scope of the present invention. Furthermore, the scope of the present invention should not be considered limited by the specific descriptions described below.

[0025]

[0026] One aspect of the present invention to achieve the above object provides a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof:

[0027] [Chemical Formula 1]

[0028]

[0029] In the above chemical formula 1,

[0030] R1 is hydrogen, C 1-4 Alkyl, carbamoyl-C 1-4 Alkyl, carboxy-C 1-4 Alkyl, C 1-4 Alkylcarbonyl, C 1-4 Alkoxycarbonyl-C 1-4 Alkyl, C 6-10 Arylcarbonyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 3 to 10 membered heterocyclyl-C 1-4 Alkyl, 3 to 10 membered heterocyclylcarbonyl, C 3-10 Cycloalkylcarbamoyl-C 1-4 Alkyl, or (C 1-4alkoxycarbonyl)(C 6-10 Aryl-C 1-4 Alkyl)carbamoyl-C 1-4 alkyl,

[0031] R2 is halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 6-10 Aryl, or 5-10 membered heteroaryl,

[0032] R3 is C 1-4 Alkyl, C 2-4 Alkenyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, or C 6-10 Aryl-C 1-4 alkyl,

[0033] C above 3-10 Cycloalkyl, C 6-10 Aryl, 3- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl are unsubstituted or substituted with hydroxy, halogen, C 1-4 Haloalkyl, C 1-4 Alkylsulfonyl, and C 1-4 It may be substituted with one or more selected from the group consisting of alkoxy.

[0034]

[0035] For example, in the above chemical formula 1, R1 may be, but is not limited to, hydrogen, methyl, carbamoylmethyl, carboxymethyl, methylcarbonyl, ethoxycarbonylmethyl, ethoxycarbonylisopropyl, tert-butoxycarbonyl-methyl, methylsulfonyl-substituted phenylcarbonylmethyl, pyridinylmethyl, piperidinylmethyl, isopropylsulfonyl-substituted piperidinylmethyl, tert-butoxycarbonyl-substituted piperidinylmethyl, morpholinylcarbonyl, cyclohexylcarbamoylmethyl, hydroxy-substituted cyclohexylcarbamoylmethyl or (methoxycarbonyl)(phenylethyl)carbamoylmethyl.

[0036]

[0037] For example, in the above chemical formula 1, R2 may be, but is not limited to, bromo, propyl, isobutyl, propenyl, cyclopentyl, cyclopentenyl, fluoro-substituted phenyl, pyridinyl or trifluoromethyl-substituted pyrazolyl.

[0038]

[0039] For example, in the above chemical formula 1, R3 may be, but is not limited to, propyl, propenyl, cyclobutylmethyl, or benzyl.

[0040]

[0041] Specifically, the compound is

[0042] 1-benzyl-4-(5-bromo-2-methoxyphenyl)-1H-1,2,3-triazole

[0043] 4-(5-allyl-2-methoxyphenyl)-1-benzyl-1H-1,2,3-triazole

[0044] 4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenol

[0045] Ethyl 2-(4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)acetate

[0046] 4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenyl acetate

[0047] (R)-methyl 2-(2-(4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)acetamido)-3-phenylpropanoate

[0048] (S)-methyl 2-(2-(4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)acetamido)-3-phenylpropanoate

[0049] tert-butyl 2-(4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)acetate

[0050] 2-(4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)-1-(4-(methylsulfonyl)phenyl)ethanone),

[0051] 2-((4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)methyl)pyridine

[0052] 3-((4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)methyl)pyridine

[0053] 4-((4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)methyl)pyridine),

[0054] 4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenyl morpholine-4-carboxylate

[0055] Ethyl 2-(4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)-2-methylpropanoate

[0056] 4-((4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)methyl)piperidine

[0057] 2-(4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)acetic acid

[0058] 4-((4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)methyl)-1-(isopropylsulfonyl)piperidine),

[0059] 2-(4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)acetamide,

[0060] 2-(4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)-N-cyclohexylacetamide),

[0061] 2-(4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)-N-(4-hydroxycyclohexyl)acetamide

[0062] tert-butyl 4-((4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)methyl)piperidine-1-carboxylate

[0063] 2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-bromophenol

[0064] ethyl 2-(2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-bromophenoxy)acetate

[0065] ethyl 2-(2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-isobutylphenoxy)acetate

[0066] Ethyl 2-(2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-cyclopentenylphenoxy)acetate

[0067] Ethyl 2-(3-(1-benzyl-1H-1,2,3-triazol-4-yl)-4'-fluorobiphenyl-4-yloxy)acetate

[0068] Ethyl 2-(2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-(1-(trifluoromethyl)-1H-pyrazol-4-yl)phenoxy)acetate

[0069] Ethyl 2-(2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-(pyridin-4-yl)phenoxy)acetate

[0070] Ethyl 2-(2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-cyclopentylphenoxy)acetate

[0071] 1-benzyl-4-(2-methoxy-5-propylphenyl)-1H-1,2,3-triazole,

[0072] 2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-propylphenol

[0073] 2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-propylphenyl acetate

[0074] ethyl 2-(2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-propylphenoxy)acetate

[0075] 4-allyl-2-(1-allyl-1H-1,2,3-triazol-4-yl)phenyl acetate

[0076] Ethyl 2-(4-allyl-2-(1-allyl-1H-1,2,3-triazol-4-yl)phenoxy)acetate

[0077] 4-(2-methoxy-5-propylphenyl)-1-propyl-1H-1,2,3-triazole

[0078] 4-propyl-2-(1-propyl-1H-1,2,3-triazol-4-yl)phenyl acetate

[0079] ethyl 2-(4-propyl-2-(1-propyl-1H-1,2,3-triazol-4-yl)phenoxy)acetate

[0080] 4-(5-bromo-2-methoxyphenyl)-1-(cyclobutylmethyl)-1H-1,2,3-triazole

[0081] 4-(5-allyl-2-methoxyphenyl)-1-(cyclobutylmethyl)-1H-1,2,3-triazole

[0082] 4-allyl-2-(1-(cyclobutylmethyl)-1H-1,2,3-triazol-4-yl)phenol

[0083] 4-allyl-2-(1-(cyclobutylmethyl)-1H-1,2,3-triazol-4-yl)phenyl acetate

[0084] Ethyl 2-(4-allyl-2-(1-(cyclobutylmethyl)-1H-1,2,3-triazol-4-yl)phenoxy)acetate

[0085] 1-(cyclobutylmethyl)-4-(2-methoxy-5-propylphenyl)-1H-1,2,3-triazole, or

[0086] Ethyl 2-(2-(1-(cyclobutylmethyl)-1H-1,2,3-triazol-4-yl)-4-propylphenoxy)acetate may be, but is not limited to.

[0087]

[0088] In the present invention, the term "alkyl" includes a straight-chain or branched-chain saturated hydrocarbon residue, unless otherwise specified. For example, "C1-6 alkyl" means an alkyl having a skeleton of 1 to 6 carbons. Specifically, C1-6 alkyl includes methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, sec-pentyl, neopentyl, hexyl, and the like.

[0089] “Alkoxy” refers to a radical in which alkyl is substituted through an oxygen atom. Here, alkyl refers to a saturated hydrocarbon, including both straight-chain and branched chains. For example, “C1-6 alkyl” refers to an alkyl having a skeleton of 1 to 6 carbons. Specifically, C1-6 alkyl includes methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, sec-pentyl, neopentyl, hexyl, etc., and C6 alkyl is a fully saturated hydrocarbon having 6 carbons, including all structural isomers that can be formed as a saturated hydrocarbon having 6 carbons. C1-10 alkoxy includes C1-6 alkoxy, C1-3 alkoxy, or methoxy.

[0090] The term “cycloalkyl”, unless otherwise specified, means a cyclic hydrocarbon residue which is a saturated hydrocarbon residue forming a ring, and “3-6 membered cycloalkyl” means a cyclic hydrocarbon residue containing 3 to 6 carbon atoms as ring atoms.

[0091] The term “heterocyclyl” means a monovalent saturated moiety consisting of 1 to 3 rings containing one or more (e.g., 1-5, 1-4, 1-3, 1-2, 1) heteroatoms selected from N, O or S, unless otherwise specified. It may be bicyclic or tricyclic containing 2 or 3 rings, wherein these 2 or 3 rings may be bridged, fused or spiro-shaped heterocycloalkyl. When composed of multiple rings, the heteroatoms may be present in all or only some of the rings.

[0092] The term “cycloalkenyl” means a monovalent monocyclic group having at least one unsaturated double bond within the ring and having no aromacy.

[0093] The term “aryl” refers to an aromatic radical having a single ring or two or three fused hydrocarbon aromatic rings, and C6-10 aryl refers to an aromatic ring compound containing 6 to 10 carbons, including phenyl or naphthyl.

[0094] The term “heteroaryl” means, unless otherwise specified, an aromatic radical having a single ring or two or three fused rings (the remaining ring atoms being C) containing one or more (e.g., 1-5, 1-4, 1-3, 1-2, 1) heteroatoms selected from N, O or S as ring atoms. When composed of multiple rings, the heteroatoms may be present in all or only some of the rings.

[0095] The term “halogen” refers to a halogen atom such as F, Cl, Br, or I, and when it is said to be substituted with “halogen,” it means that it is substituted with one or more halogen atoms. In this case, the halogen atoms to be substituted can be selected within the range of 1 to 5.

[0096]

[0097] The compound of the present invention may exist in the form of a pharmaceutically acceptable salt. Useful salts include acid salts formed with pharmaceutically acceptable free acids. The term "pharmaceutically acceptable salt" as used herein refers to a salt that is relatively nontoxic and harmless at a concentration that provides an effective effect on a patient, and any organic or inorganic addition salt of the compound represented by Chemical Formula 1, wherein the side effects caused by the salt do not diminish the beneficial effects of the compound.

[0098] Acid addition salts are prepared by conventional methods, for example, by dissolving the compound in an excess of an aqueous acid solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equimolar amounts of the compound and an acid or alcohol (e.g., glycol monomethyl ether) in water can be heated, and the mixture can then be evaporated to dryness, or the precipitated salt can be filtered off with suction.

[0099] At this time, organic acids and inorganic acids can be used as free acids, and inorganic acids such as hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, and tartaric acid can be used, and organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, and hydroiodic acid can be used, but are not limited thereto.

[0100] Additionally, pharmaceutically acceptable metal salts can be prepared using bases. Alkali metal salts or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering out the undissolved compound salt, and evaporating and drying the filtrate. In this case, sodium, potassium, or calcium salts are particularly suitable for pharmaceutical purposes, but are not limited thereto. Furthermore, the corresponding silver salt can be prepared by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

[0101] Pharmaceutically acceptable salts of the compounds of the present invention include salts of acidic or basic groups that may be present in the compounds of Formula 1, unless otherwise indicated. For example, pharmaceutically acceptable salts may include sodium, calcium, and potassium salts of hydroxyl groups, and other pharmaceutically acceptable salts of amino groups include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate), and p-toluenesulfonate (tosylate) salts, and may be prepared by methods known in the art for preparing salts.

[0102] As a salt of the compound represented by chemical formula 1 of the present invention, any salt that is pharmaceutically acceptable and exhibits pharmacological activity equivalent to that of the compound represented by chemical formula 1 may be used without limitation.

[0103]

[0104] In addition, the compound represented by the above chemical formula 1 according to the present invention includes, without limitation, not only its pharmaceutically acceptable salts but also solvates such as possible hydrates that can be prepared therefrom and all possible stereoisomers. The solvates and stereoisomers of the compound represented by the above chemical formula 1 can be prepared from the compound represented by the chemical formula 1 using methods known in the art.

[0105] Furthermore, the compound represented by the above chemical formula 1 according to the present invention can be prepared in a crystalline or amorphous form, and when prepared in a crystalline form, can be optionally hydrated or solvated. The present invention may include not only stoichiometric hydrates of the compound represented by the above chemical formula 1, but also compounds containing various amounts of water. The solvates of the compound represented by the above chemical formula 1 according to the present invention include both stoichiometric solvates and non-stoichiometric solvates.

[0106]

[0107] Another aspect of the present invention for achieving the above object provides a method for preparing a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof, comprising a first step of preparing a phenyl-triazole derivative having R3' substituted on a triazole ring by reacting 4-bromo-2-ethynyl-1-methoxybenzene with a mixture of R3'-X1 and NaN3 in the presence of CuBr and PMDETA (N,N,N',N",N"-pentamethyldiethylenetriamine).

[0108] At this time, the above R3' may be R3 or a precursor thereof, a halogen which is X1.

[0109]

[0110] For example, in the manufacturing method of the present invention, the first step may be performed by adding a reactant other than the above-mentioned temperature to a mixture of R3'-X1 and NaN3 mixed at room temperature and cooled to 0°C, reacting the mixture, and then heating the mixture to room temperature to further react the mixture, but is not limited thereto.

[0111]

[0112] For example, the manufacturing method of the present invention

[0113] Step a, in which Br on the phenyl ring of the product obtained from the previous step is replaced with R2';

[0114] Step b of replacing OMe on the phenyl ring of the product obtained from the previous step with OH; and

[0115] It may further include one or more steps selected from the group consisting of step c, which replaces OH on the phenyl ring of the product obtained from step b with R1',

[0116] The above R1' and R2' may be R1 or a precursor thereof, and R2 or a precursor thereof, respectively, but are not limited thereto.

[0117]

[0118] Specifically,

[0119] Step a is carried out by reacting i) R2'-SnBu3 or ii) R2'-boronic acid and Cs2CO3 in the presence of Pd(PPh3)4,

[0120] Step b is performed by reacting with B(X2)3 at -60°C to 0°C.

[0121] Step c is carried out i) in the presence of R1'-X3 and K2CO3, or ii) in the presence of acetic anhydride or R1'-X3 and Et3N (triethylamine) and optionally DMAP (4-dimethylaminopyridine),

[0122] The above step a may be performed after step 1 or after step c, but is not limited thereto.

[0123] At this time, X2 and X3 can each independently be halogen.

[0124]

[0125] For example, X1, X2, and X3 may each independently be bromo or chloro, but are not limited thereto.

[0126]

[0127] For example, the above step a may be performed by mixing the reactants, bubbling with nitrogen, and reacting at 80°C to 110°C under a nitrogen atmosphere, but is not limited thereto. At this time, microwaves may be used to achieve the above reaction temperature, but is not limited thereto.

[0128]

[0129] For example, in the above step b, B(X2)3 may be BCl3 or BBr3, and the reaction may be performed under a nitrogen atmosphere, but is not limited thereto.

[0130]

[0131] For example, the above step c can be performed at 50°C to 70°C in the case of i), at 0°C to 40°C in the case of ii), and i), ii) or both can be performed under a nitrogen atmosphere, but is not limited thereto.

[0132] In addition, the manufacturing method of the present invention may additionally include a step d of reducing R2', R3' or both to alkyl when R2', R3' or both contain alkenyl.

[0133] For example, the above step d can be performed in the presence of a Pd / C catalyst under an H2 atmosphere, but is not limited thereto.

[0134]

[0135] Furthermore, in the manufacturing method of the present invention, the precursors of R1, R2, and / or R3 may refer to functional groups that can be converted or substituted with R1, R2, and / or R3 through a known method. Therefore, the manufacturing method of the present invention may further include a step for additionally modifying one or more of R1, R2, R3, or their precursors. The additional step may be performed without limitation using a method known in the art.

[0136]

[0137] Meanwhile, each step of the manufacturing method of the present invention can be independently performed in an organic solvent. The organic solvent may be any solvent used in organic synthesis in the art without limitation. For example, the organic solvent may include DMF (dimethylformamide), toluene, dichloromethane, acetone, acetonitrile, THF (tetrahydrofuran), EtOAc (ethyl acetate), methanol, etc., which may be used alone or in a mixture of two or more thereof. Specifically, as the organic solvent, DMF may be used in step 1, DMF or toluene may be used in step a, dichloromethane may be used in step b, and EtOAc or methanol may be used in steps c and d, but is not limited thereto.

[0138]

[0139] Another aspect of the present invention for achieving the above purpose provides a pharmaceutical composition for preventing or treating an ocular disease, comprising the compound or a pharmaceutically acceptable salt thereof.

[0140]

[0141] The term "eye disease" in the present invention refers to eye-related diseases, also called ocular diseases, ophthalmic diseases, etc., and for the purposes of the present invention, may refer to eye diseases related to autophagy induced by A2E and blue light. Specifically, the eye disease may refer to, but is not limited to, dry macular degeneration, xerophthalmia, eye fatigue, or decreased vision.

[0142] The above term, "A2E (N-retinyl N-retinylidene ethanolamine)" is the main chromophore of lipofuscin in the central part of the retina, and is a substance that causes the production of reactive oxygen species when exposed to blue light. If A2E accumulates excessively within the cell, retinal pigment epithelial cells may die.

[0143] The term "blue light" refers to the blue light spectrum, which exists between 380 and 500 nm within the visible light spectrum. It is widely emitted from displays and LED lighting devices on smart devices such as TVs and computers. Short-wavelength blue light, known to have the highest energy among the types of light visible to the human eye, penetrates the lens and affects retinal epithelial cells.

[0144] The term "prevention" of the present invention means any act of inhibiting or delaying the worsening or progression of an eye disease by administering a pharmaceutical composition containing the compound as an active ingredient.

[0145] The term "treatment" of the present invention means any act in which symptoms of an eye disease are improved or beneficially changed by administering a pharmaceutical composition containing the compound as an active ingredient.

[0146] The term "pharmaceutical composition" of the present invention may further include a pharmaceutically acceptable carrier, excipient or diluent commonly used in its manufacture, and the carrier may include a non-naturally occurring carrier. Specific examples of the carrier, excipient and diluent include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil.

[0147] In addition, the pharmaceutical composition may have any one dosage form selected from the group consisting of tablets, pills, powders, granules, capsules, suspensions, oral solutions, emulsions, syrups, sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilizers, and suppositories, each according to a conventional method, and may be various oral or parenteral dosage forms. When formulated, it is prepared using diluents or excipients such as commonly used fillers, bulking agents, binders, wetting agents, disintegrants, and surfactants. Tablets, pills, powders, granules, capsules, etc. may be used as solid preparations for oral administration, and the solid preparations may use at least one or more excipients, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc may be used. Liquid preparations for oral administration include suspensions, solutions, emulsions, and syrups. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives can be used. Preparations for parenteral administration can include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, or suppositories. Non-aqueous solvents and suspensions can include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases include, but are not limited to, witepsol, macrogol, tween 61, cacao butter, laurin butter, and glycerogelatin.

[0148] The content of the compound in the pharmaceutical composition of the present invention can be appropriately adjusted depending on the symptoms and progression of the disease, the patient's condition, etc., and may be, for example, 0.0001 to 99.9 wt% or 0.001 to 50 wt% based on the total composition weight, but is not limited thereto.

[0149] In one embodiment of the present invention, in order to evaluate the autophagy activity by treatment with the compound represented by the above chemical formula 1 and its derivative compound (novel compound), human retinal pigment epithelial cells, ARPE-19, were used to confirm whether LC3-II, one of the major indicator proteins of autophagy activation, increased, and as a result, the autophagy activation effect by treatment with the novel compound was confirmed (Figs. 1a to 1b and Tables 2 to 3).

[0150] In addition, in one embodiment of the present invention, as a result of confirming the A2E-fluorescent labeling substance (A2E-BDP) and A2E removal ability by the novel compound treatment, it was confirmed that A2E-BDP and A2E accumulated in cells were removed by the compound treatment (Figs. 2a to 6c).

[0151] In addition, in one embodiment of the present invention, improvement in retinal damage and recovery of ocular tissue by treatment with the novel compound was confirmed using a blue light-induced retinal damage animal model (Figs. 7a to 7c).

[0152] These results suggest that the novel compound of the present invention can be useful for preventing or treating eye diseases.

[0153]

[0154] Another aspect of the present invention for achieving the above purpose provides a method for preventing or treating an eye disease comprising administering the pharmaceutical composition.

[0155] The pharmaceutical composition, ocular disease, prevention or treatment is as described above.

[0156] The term "subject" in the present invention refers to any animal, including humans, rats, livestock, etc., that has developed or may develop an eye disease. Specifically, it may refer to mammals such as cows, horses, sheep, pigs, goats, camels, antelopes, dogs, cats, etc., as well as humans, who require prevention or treatment of symptoms similar to the above-mentioned disease, but is not limited thereto.

[0157] The term "administration" of the present invention means introducing the composition of the present invention into a patient by any suitable method, and the route of administration of the composition may be through any common route as long as it can reach the target tissue.

[0158] The pharmaceutical composition of the present invention can be administered in a pharmaceutically effective amount.

[0159] The above term, "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dosage level can be determined according to factors including the type and severity of the individual, age, sex, activity of the drug, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field. For example, effective amounts of 0.001 mg / kg to 1000 mg / kg, 0.01 mg / kg to 100 mg / kg, or 0.1 to 20 mg / kg, or 0.1 to 500 mg / kg are included. The amount of the pharmaceutical composition of the present invention can be selected and implemented within an appropriate range by a person skilled in the art.

[0160] The above pharmaceutical composition can be administered as an individual treatment or in combination with other treatments, and can be administered sequentially or simultaneously with conventional treatments. Furthermore, it can be administered singly or in multiple doses. Considering all of the above factors, it is important to administer the amount that achieves maximum effect with the minimum amount possible without causing side effects. This can be readily determined by those skilled in the art.

[0161] In addition, the pharmaceutical composition may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically) depending on the intended method, and the dosage may vary depending on the patient's condition and weight, the severity of the disease, the drug form, the administration route, and the time, but may be appropriately selected by those skilled in the art. As a specific example, the dosage may generally be administered once or several times a day, but the preferred dosage may be appropriately selected by those skilled in the art depending on the patient's condition and weight, the severity of the disease, the drug form, the administration route, and the time.

[0162]

[0163] Another aspect of the present invention for achieving the above purpose provides a food composition for preventing or improving eye diseases, comprising the compound or a pharmaceutically acceptable salt thereof.

[0164] The above compounds, pharmaceutically acceptable salts, ophthalmic diseases and prevention thereof are as described above.

[0165] The term "improvement" of the present invention means any action that at least reduces a parameter associated with the condition being treated, for example, the severity of a symptom, by administration of a composition comprising the novel compound.

[0166] The term "food" of the present invention includes dairy products including meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, ice cream, various soups, beverages, tea, drinks, alcoholic beverages, vitamin complexes, health functional foods, and health foods, and includes all foods in the conventional sense.

[0167] The above health functional food is the same term as food for special health use (FoSHU), and refers to food with high medical and therapeutic effects that is processed to effectively exhibit bioregulatory functions in addition to providing nutrition.

[0168] Here, 'function (or function)' means to control nutrients for the structure and function of the human body or to obtain a useful effect for health purposes such as physiological functions. The health food mentioned above means a food that has a more active health maintenance or promotion effect than general food, and health supplement food means a food for the purpose of health supplementation. In some cases, the terms health functional food, health food, and health supplement food may be used interchangeably. Specifically, the health functional food mentioned above may mean a food that is prepared by adding the novel compound of the present invention to food materials such as beverages, teas, spices, gums, and confectionery, or by encapsulating, powdering, or making it into a suspension, and that when consumed, it may mean to bring about a specific health effect.

[0169] The food of the present invention can be manufactured by a method commonly used in the art, and can be manufactured by adding raw materials and ingredients commonly added in the art.

[0170] In addition, the food composition can be manufactured without limitation into various forms of formulations as long as it is a formulation recognized as a food.

[0171] In addition, the food composition may additionally include a food-related acceptable carrier, and the type of the carrier is not particularly limited, and any carrier commonly used in the relevant technical field may be used.

[0172] Additionally, the food composition may include additional ingredients commonly used in food compositions to improve odor, taste, and appearance. For example, the food composition may include vitamins A, C, D, E, B1, B2, B6, B12, niacin, biotin, folate, pantothenic acid, and the like. In addition, the food composition may include minerals such as zinc (Zn), iron (Fe), calcium (Ca), chromium (Cr), magnesium (Mg), manganese (Mn), copper (Cu), and chromium (Cr); and amino acids such as lysine, tryptophan, cysteine, and valine.

[0173] In addition, the food composition may include food additives such as preservatives (potassium sorbate, sodium benzoate, salicylic acid, sodium dehydroacetate, etc.), sterilizers (bleaching powder and high-purity bleaching powder, sodium hypochlorite, etc.), antioxidants (butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), etc.), colorants (tar colorants, etc.), color developers (sodium nitrite, sodium nitrite, etc.), bleaching agents (sodium sulfite), seasonings (MSG, monosodium glutamate, etc.), sweeteners (dulcin, cyclamate, saccharin, sodium, etc.), flavorings (vanillin, lactones, etc.), leavening agents (alum, D-potassium hydrogen tartrate, etc.), reinforcing agents, emulsifiers, thickeners (glucose fillers), film-forming agents, gum-forming agents, foam suppressants, solvents, and improvers. The above additives can be selected according to the type of food and used in an appropriate amount.

[0174]

[0175] Another aspect of the present invention for achieving the above purpose provides a feed composition for preventing or improving eye diseases, comprising the compound or a pharmaceutically acceptable salt thereof.

[0176] The above compounds, pharmaceutically acceptable salts, ophthalmic diseases, prevention and improvement are as described above.

[0177] The above term, "feed" means any natural or artificial diet, meal, etc. or ingredient of said meal, intended for or suitable for eating, ingesting and digesting by an animal.

[0178] The type of the above feed is not particularly limited, and feed commonly used in the relevant technical field can be used. Non-limiting examples of the above feed include plant-based feed such as grains, nuts, food processing by-products, algae, fiber, pharmaceutical by-products, oils, starches, meal, or grain by-products; and animal-based feed such as proteins, inorganic substances, oils, mineral substances, oils, single-cell proteins, zooplankton, or food. These may be used alone or in combination of two or more.

[0179]

[0180] Another aspect of the present invention for achieving the above object provides a use or purpose of the compound or a pharmaceutically acceptable salt thereof for preventing, improving or treating an ocular disease.

[0181] The above compounds, pharmaceutically acceptable salts, ophthalmic diseases, prevention, improvement and treatment are as described above.

[0182]

[0183] The novel compound and its derivative compound according to the present invention can be used to treat, prevent and improve autophagy-related diseases, particularly eye diseases, by inhibiting death of human retinal pigment epithelial cells (ARPE-19) induced by A2E and blue light, removing A2E-fluorescent markers and A2E in ARPE-19, and activating autophagy.

[0184]

[0185] Figures 1a and 1b illustrate the evaluation of autophagy activation by treatment with a compound represented by chemical formula 1.

[0186] Figures 2a to 2c show the ability to remove intracellular accumulated A2E-fluorescent labeling substance (A2E-BDP) by treatment with the compound represented by chemical formula 1 or the compound of Comparative Example 1.

[0187] Figure 3 shows the results of measuring the amount of A2E present in cells by treatment with a compound represented by Chemical Formula 1 or the compound of Comparative Example 1.

[0188] Figure 4 shows the ability to remove A2E-BDP accumulated in cells by treatment with various derivative compounds of the compound represented by chemical formula 1.

[0189] Figures 5a to 5b and 6a to 6c show the removal ability of A2E present in cells by treatment with the derivative compound.

[0190] Figures 7a to 7d show improvement in retinal damage and recovery of ocular tissue by treatment with the derivative compound or the compound of Comparative Example 1 using a blue light-induced retinal damage animal model.

[0191]

[0192] Hereinafter, the present invention will be described in more detail through examples. These examples are intended to explain the present invention more specifically, and the scope of the present invention is not limited by these examples.

[0193]

[0194] Comparative Example 1: Preparation of 3-(5-allyl-2-methoxyphenyl)-5-((allyloxy)methyl)isoxazole

[0195] The title compound was obtained in the same manner as in Korean Patent Publication No. 10-2023-0140410.

[0196]

[0197]

[0198]

[0199]

[0200] Manufacturing Example 1: Manufacturing of 4-bromo-2-ethynyl-1-methoxybenzene (b)

[0201] 5-Bromo-ortho-anisaldehyde (a, 2.0 g, 1 eq) and K2CO3 (1.67 g, 1.3 eq) were dissolved in methanol (40 mL). The mixture was cooled to 0°C, and Bestmann-Ohira reagent (0.1 M in MeOH, 1.3 eq) was slowly added at 0°C. The mixture was warmed to ambient temperature and stirred for 6 h. After the reaction was completed, the solution was quenched with water, and the solvent was removed in vacuo. The residue was diluted with EtOAc (100 mL), washed with water and brine, and the resulting organic layers were combined, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc / hexane = 1:20) to obtain the title compound (b, 1.8 g, 92%) as a white solid.

[0202]

[0203] Example 1: Preparation of 1-benzyl-4-(5-bromo-2-methoxyphenyl)-1H-1,2,3-triazole (GS27)

[0204] Benzyl bromide (0.26 mL, 1 eq) and NaN3 (142 mg, 1 eq) were dissolved in DMF (40 mL). The mixture was stirred at room temperature for 18 h. The mixture was cooled to 0 °C, and 4-bromo-2-ethynyl-1-methoxybenzene (b, 460 mg, 1 eq), Cu(I)Br (63 mg, 2 eq), and PMDETA (N,N,N',N",N"-pentamethyldiethylenetriamine, 0.89 mL, 2 eq) dissolved in DMF were added at 0 °C. After maintaining at the same temperature for 30 min, the mixture was warmed to room temperature and stirred for 3 h. After completion of the reaction, the mixture was diluted with EtOAc (100 mL), washed with water and brine. The obtained organic layers were combined, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc / hexane = 1:5) to obtain the title compound (GS27, 663 mg, 88%).

[0205] 1 H NMR (600 MHz, Chloroform-d) δ 8.49 (d,J= 2.6 Hz, 1H), 7.96 (s, 1H), 7.37 (m, 4H), 7.29 (ddt,J= 7.3, 1.5, 0.7 Hz, 2H), 6.81 (d,J= 8.8 Hz, 1H), 5.59 (s, 2H), 3.86 (s, 3H);

[0206] 13 C-NMR (150 MHz, Chloroform-d) δ 154.8, 142.5, 135.1, 131.5, 130.3, 129.2, 128.8, 127.9, 123.5, 121.4, 113.7, 112.6, 55.8, 54.2.

[0207]

[0208] Example 2: Preparation of 4-(5-allyl-2-methoxyphenyl)-1-benzyl-1H-1,2,3-triazole (GS28)

[0209] To a solution (0.8 M) of 1-benzyl-4-(5-bromo-2-methoxyphenyl)-1H-1,2,3-triazole (GS27, 660 mg, 1 eq) in DMF was added Pd(PPh3)4 (222 mg, 0.1 eq) and allyltributylstannane (0.89 mL, 1.5 eq). After bubbling with nitrogen, the mixture was stirred at 90°C for 5 h under a N2 atmosphere. The mixture was diluted with EtOAc and washed with water and brine. The obtained organic layers were combined, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc / hexane = 1:5) to obtain the title compound (GS28, 548 mg, 94%).

[0210] 1 H NMR (600 MHz, Chloroform-d) δ 8.19 (d,J= 2.3 Hz, 1H), 7.97 (s, 1H), 7.36 (m, 3H), 7.28 (m, 2H), 7.11 (dd,J= 8.4, 2.4 Hz, 1H), 6.88 (d,J= 8.4 Hz, 1H), 5.99 (ddt,J= 16.8, 10.0, 6.7 Hz, 1H), 5.59 (s, 2H), 5.07 (m, 2H), 3.86 (s, 3H), 3.41 (d,J= 6.7 Hz, 2H).

[0211]

[0212] Example 3: Preparation of 4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenol (GS30)

[0213] To a CH2Cl2 solution (6 mL) of 4-(5-allyl-2-methoxyphenyl)-1-benzyl-1H-1,2,3-triazole (GS28, 428 mg, 1 eq) was added boron tribromide (4.2 mL, 3 eq, 1.0 M solution in CH2Cl2) under N2 atmosphere at -20°C. After the reaction was completed, the solution was quenched with saturated NH4Cl. The reaction mixture was diluted with CH2Cl2, washed with water, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc / hexane = 1:4) to give the title compound (GS30, 370 mg, 90%) as a white solid.

[0214] 1 H NMR (600 MHz, Chloroform-d) δ 7.74 (s, 1H), 7.40 (m, 3H), 7.32 (m, 2H), 7.14 (m, 1H), 7.04 (dd,J= 8.4, 2.0 Hz, 1H), 6.98 (d,J= 8.4 Hz, 1H), 5.93 (ddt,J= 15.9, 10.8, 6.6 Hz, 1H), 5.60 (s, 2H), 5.05 (m, 1H), 5.03 (t,J= 1.5 Hz, 1H), 3.30 (d,J= 6.8 Hz, 1H);

[0215] 13 C NMR (150 MHz, CDCl3) δ 154.4, 148.4, 137.9, 134.3, 130.9, 130.3, 129.4, 129.2, 128.3, 125.8, 118.8, 117.8, 115.8, 113.7, 54.7, 39.4.

[0216]

[0217] Example 4: Preparation of ethyl 2-(4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)acetate (GS32)

[0218] To a solution of 4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenol (GS30, 400 mg, 1.0 eq) and K2CO3 (641 mg, 3 eq) in acetone was added ethyl 2-bromoacetate (0.26 mL, 1.5 eq). The mixture was stirred at 60°C for 3 h under N2 atmosphere. The reaction mixture was cooled to room temperature and then quenched with saturated NH4Cl. The mixture was diluted with EtOAc, washed with water, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc / hexane = 1:4) to give the title compound (GS32, 458 mg, 88%) as a white solid.

[0219] 1 H-NMR (400 MHz, Chloroform-d) δ 8.58 (d,J= 2.5 Hz, 1H), 8.26 (d,J= 2.2 Hz, 1H), 7.34 (d,J= 3.3 Hz, 5H), 7.09 (d,J= 8.4 Hz, 1H), 6.76 (d,J= 8.4 Hz, 1H), 5.98 (m, 1H), 5.61 (s, 2H), 5.08 (m, 2H), 4.64 (s, 2H), 4.26 (q,J= 7.3 Hz, 2H), 3.41 (d,J= 6.7 Hz, 2H), 1.29 (t,J= 7.2 Hz, 3H).

[0220]

[0221] Example 5: Preparation of 4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenyl acetate (GS33)

[0222] To a CH2Cl2 solution of GS30 (30 mg, 1.0 eq) and acetic anhydride (0.01 mL, 1 eq) were added DMAP (4-dimethylaminopyridine, 1.3 mg, 0.1 eq) and Et3N (triethylamine, 0.14 mL, 10 eq) under a N2 atmosphere at 0°C. The mixture was stirred at 0°C under a N2 atmosphere for 18 h. After the reaction was completed, the reaction mixture was quenched with water. The mixture was diluted with CH2Cl2, washed with water, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc / hexane = 1:4) to obtain the title compound (GS33, 26 mg, 73%) as a white solid.

[0223] 1 H-NMR (400 MHz, Chloroform-d) δ 7.42 (d, 1H), 7.40 (d, 1H), 7.38 (m, 3H), 7.31 (m, 2H), 7.17 (m, 1H), 7.06 (s, 1H), 5.97 (m, 1H), 5.58 (s, 2H), 5.10 (m, 2H), 3.42 (d, 2H), 2.12 (s, 3H);

[0224] 13 C-NMR (150 MHz, Chloroform-d) δ 169.0, 145.4, 143.5, 138.4, 136.9, 134.6, 129.2, 129.2, 128.9, 128.6, 128.2, 123.1, 122.9, 121.6, 116.3, 54.2, 39.6, 29.7, 21.1.

[0225]

[0226] Example 6: Preparation of (R)-methyl 2-(2-(4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)acetamido)-3-phenylpropanoate (GT01)

[0227] To a CH2Cl2 solution of 2-(4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)acetic acid (GT11, 30 mg, 1.0 eq) at 0°C were added methyl D-phenylalaninate (15.4 mg, 1.0 eq), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, 25 mg, 1.5 eq), 1-hydroxybenzotriazole (HOBt, 5.8 mg, 0.5 eq), and Et3N (36 μL, 3 eq). The mixture was stirred at room temperature for 4 h, and the reaction mixture was quenched with saturated NH4Cl. The mixture was diluted with CH2Cl2, washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc / hexane = 1:3) to obtain the title compound (GT01, 38 mg, 81%) as a white solid.

[0228] 1 H NMR (400 MHz, Chloroform-d) δ 7.90 (m, 2H), 7.73 (d,J= 8.5 Hz, 1H), 7.33 (m, 5H), 7.16 (m, 4H), 7.03 (dd,J= 7.0, 2.5 Hz, 2H), 6.83 (d,J= 8.3 Hz, 1H), 5.99 (ddt,J= 16.8, 9.8, 6.7 Hz, 1H), 5.53 (d,J= 14.9 Hz, 1H), 5.40 (d,J= 14.9 Hz, 1H), 5.11 (m, 2H), 5.01 (dt,J= 8.0, 6.0 Hz, 1H), 4.58 (d,J= 2.6 Hz, 2H), 3.77 (s, 3H), 3.41 (d,J= 6.7 Hz, 2H), 3.16 (m, 2H).

[0229]

[0230] Example 7: Preparation of (S)-methyl 2-(2-(4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)acetamido)-3-phenylpropanoate (GT02)

[0231] The reaction and purification were carried out in the same manner as in Example 6, except that methyl L-phenylalaninate (15.4 mg, 1.0 eq) was used instead of methyl D-phenylalaninate, to obtain the title compound (GT02, 35 mg, 79%) as a white solid.

[0232] 1 H NMR (400 MHz, Chloroform-d) δ 7.89 (m, 2H), 7.74 (d,J= 8.5 Hz, 1H), 7.33 (ddd,J= 19.8, 8.6, 5.1 Hz, 5H), 7.15 (m, 4H), 7.03 (dd,J= 6.9, 2.4 Hz, 2H), 6.83 (d,J= 8.4 Hz, 1H), 5.99 (ddt,J= 16.8, 9.8, 6.7 Hz, 1H), 5.53 (d,J= 14.8 Hz, 1H), 5.40 (d,J= 14.9 Hz, 1H), 5.11 (m, 2H), 5.01 (dt,J= 8.0, 6.0 Hz, 1H), 4.58 (d,J= 2.6 Hz, 2H), 3.77 (s, 2H), 3.41 (d,J= 6.7 Hz, 2H), 3.18 (m, 2H).

[0233]

[0234] Example 8: Preparation of tert-butyl 2-(4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)acetate (GT03)

[0235] The reaction and purification were performed in a similar manner as in Example 4, except that t-butyl-2-bromoacetate was used instead of ethyl 2-bromoacetate, to obtain the title compound (GT03, 170 mg, 72%) as a white solid.

[0236] 1 H NMR (400 MHz, Chloroform-d) δ 8.62 (s, 1H), 8.25 (s, 1H), 7.35 (d,J= 1.1 Hz, 2H), 7.07 (dd,J= 8.4, 2.2 Hz, 1H), 6.74 (d,J= 8.4 Hz, 1H), 5.98 (m, 1H), 5.60 (s, 2H), 5.08 (m, 2H), 4.52 (d,J= 1.2 Hz, 2H), 3.40 (d,J= 6.7 Hz, 2H), 1.49 (d,J= 1.2 Hz, 9H).

[0237]

[0238] Example 9: Preparation of 2-(4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)-1-(4-(methylsulfonyl)phenyl)ethanone (GT04)

[0239] The reaction and purification were performed in a similar manner as in Example 4, except that 2-bromo-1-(4-(methylsulfonyl)phenyl)ethanone was used instead of ethyl 2-bromoacetate, to obtain the title compound (GT04, 30 mg, 90%) as a white solid.

[0240] 1 H NMR (400 MHz, Chloroform-d) δ 8.63 (s, 1H), 8.23 ​​(s, 1H), 8.06 (m, 4H), 7.37 (m, 5H), 7.11 (d,J= 8.3 Hz, 1H), 6.86 (d,J= 8.3 Hz, 1H), 5.98 (ddt,J= 16.7, 9.4, 6.6 Hz, 1H), 5.60 (s, 1H), 5.32 (s, 2H), 5.09 (m, 2H), 3.41 (d,J= 6.7 Hz, 2H), 3.10 (s, 3H).

[0241]

[0242] Example 10: Preparation of 2-((4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)methyl)pyridine (GT05)

[0243] The reaction and purification were performed in a similar manner as in Example 4, except that 2-(bromomethyl)pyridine was used instead of ethyl 2-bromoacetate, to obtain the title compound (GT05, 19.6 mg, 75%) as a pale yellow solid.

[0244] 1 H NMR (400 MHz, Chloroform-d) δ 8.58 (d,J= 4.8 Hz, 1H), 8.22 (s, 1H), 8.13 (s, 1H), 7.58 (t,J= 7.7 Hz, 1H), 7.37 (m, 3H), 7.28 (m, 4H), 7.10 (d,J= 8.3 Hz, 1H), 6.93 (d,J= 8.3 Hz, 1H), 6.01 (ddt,J= 16.8, 9.4, 6.9 Hz, 1H), 5.58 (s, 2H), 5.27 (s, 2H), 5.10 (m, 2H), 3.43 (d,J= 6.7 Hz, 2H).

[0245]

[0246] Example 11: Preparation of 3-((4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)methyl)pyridine (GT06)

[0247] The reaction was carried out in a similar manner as in Example 4, except that 3-(bromomethyl)pyridine was used instead of ethyl 2-bromoacetate, and the resulting product was purified to obtain the title compound (GT06, 21 mg, 79%) as a white solid.

[0248] 1H NMR (400 MHz, Chloroform-d) δ 8.64 (s, 1H), 8.61 (d,J= 4.6 Hz, 1H), 8.20 (s, 1H), 7.74 (s, 1H), 7.61 (d,J= 7.8 Hz, 1H), 7.33 (m, 3H), 7.21 (m, 3H), 7.12 (d,J= 8.4 Hz, 1H), 6.94 (d,J= 8.3 Hz, 1H), 5.99 (ddt,J= 16.7, 9.7, 6.7 Hz, 1H), 5.49 (s, 2H), 5.09 (s, 2H), 5.08 (m, 2H), 3.41 (d,J= 6.7 Hz, 2H).

[0249]

[0250] Example 12: Preparation of 4-((4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)methyl)pyridine (GT07)

[0251] The reaction and purification were carried out in a similar manner as in Example 4, except that 4-(bromomethyl)pyridine was used instead of ethyl 2-bromoacetate, to obtain the title compound (GT07, 17 mg, 63%) as a white solid.

[0252] 1 H NMR (400 MHz, Chloroform-d) δ 8.53 (d,J= 5.1 Hz, 2H), 8.20 (s, 1H), 7.83 (s, 1H), 7.37 (m, 3H), 7.23 (m, 4H), 7.10 (d,J= 8.4 Hz, 1H), 6.87 (d,J= 8.4 Hz, 1H), 5.99 (ddt,J= 16.8, 9.6, 6.8 Hz, 1H), 5.53 (s, 2H), 5.09 (s, 2H), 5.08 (m, 2H), 3.41 (d,J= 6.7 Hz, 2H).

[0253]

[0254] Example 13: Preparation of 4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenyl morpholine-4-carboxylate (GT08)

[0255] To a CH2Cl2 solution of GS30 (20 mg, 1.0 eq) and DMAP (2 mg, 0.2 eq) were added morpholine-4-carbonyl chloride (0.12 mL, 1.5 eq) and Et3N (0.02 mL, 2 eq). The mixture was stirred at room temperature for 3 h under an N2 atmosphere, and the reaction mixture was quenched with saturated NH4Cl. The mixture was diluted with EtOAc, washed with water, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc / hexane = 1:3) to give the title compound (GT08, 20 mg, 72%) as a white solid.

[0256] 1 H NMR (600 MHz, Chloroform-d) δ 7.87 (d,J= 2.2 Hz, 1H), 7.50 (s, 1H), 7.40 (m, 3H), 7.30 (m, 2H), 7.16 (dd,J= 8.3, 2.2 Hz, 1H), 7.06 (d,J= 8.3 Hz, 1H), 5.97 (ddt,J= 16.8, 10.0, 6.7 Hz, 1H), 5.56 (s, 2H), 5.09 (m, 2H), 3.57 (d,J= 50.0 Hz, 4H), 3.42 (dd,J= 8.8, 3.9 Hz, 6H).

[0257]

[0258] Example 14: Preparation of ethyl 2-(4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)-2-methylpropanoate (GT09)

[0259] The reaction and purification were carried out in a similar manner to Example 4, except that ethyl 2-bromo-2-methylpropanoate was used instead of ethyl 2-bromoacetate and DMF was used as a solvent, to obtain the title compound (GT09, 18 mg, 64%) as a white solid.

[0260] 1 H NMR (400 MHz, Chloroform-d) δ 8.12 (s, 1H), 7.98 (s, 1H), 7.34 (m, 5H), 6.98 (m, 1H), 6.67 (d,J= 8.4 Hz, 1H), 5.97 (ddt,J= 16.8, 10.0, 6.8 Hz, 1H), 5.57 (s, 2H), 5.07 (m, 2H), 4.20 (q,J= 7.1 Hz, 2H), 3.38 (d,J= 6.7 Hz, 2H), 1.46 (s, 9H), 1.21 (t,J= 7.1 Hz, 5H).

[0261]

[0262] Example 15: Preparation of 4-((4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)methyl)piperidine (GT10)

[0263] To a CH2Cl2 solution of tert-butyl 4-((4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)methyl)piperidine-1-carboxylate (GT16, 30 mg) was added trifluoroacetic acid (1 mL) at 0°C under a N2 atmosphere. The mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (CH2Cl2 / MeOH = 15:1) to obtain the title compound (GT10-TFA salt, 29 mg, 97%) as a white solid TFA salt.

[0264] 1H NMR (400 MHz, Chloroform-d) δ 8.06 (s, 1H), 7.76 (s, 1H), 7.32 (m, 5H), 7.09 (d,J= 8.2 Hz, 1H), 6.80 (d,J= 8.5 Hz, 1H), 5.96 (ddt,J= 16.8, 9.8, 6.8 Hz, 2H), 5.57 (s, 3H), 5.06 (m, 3H), 4.80 (s, 8H), 3.84 (d,J= 6.3 Hz, 3H), 3.37 (d,J= 7.2 Hz, 6H), 2.72 (t,J= 12.7 Hz, 3H), 1.90 (s, 2H), 1.78 (d,J= 14.0 Hz, 3H), 1.54 (q,J= 11.3 Hz, 3H).

[0265]

[0266] Example 16: Preparation of 2-(4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)acetic acid (GT11)

[0267] The reaction and purification were carried out in a similar manner as in Example 15, except that tert-butyl 2-(4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)acetate (GT03) was used instead of tert-butyl 4-((4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)methyl)piperidine-1-carboxylate (GT16), to obtain the title compound (GT11-TFA salt, 130 mg, 99%) as a white solid TFA salt.

[0268] 1 H NMR (400 MHz, Methanol-d4) δ 8.76 (s, 1H), 7.98 (s, 1H), 7.35 (m, 5H), 7.11 (d,J= 8.4 Hz, 1H), 6.91 (d,J= 8.3 Hz, 1H), 5.97 (ddt,J= 16.8, 9.5, 6.7 Hz, 1H), 5.61 (s, 2H), 5.05 (m, 2H), 4.71 (s, 2H), 3.37 (d,J= 6.7 Hz, 2H).

[0269]

[0270] Example 17: Preparation of 4-((4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)methyl)-1-(isopropylsulfonyl)piperidine (GT12)

[0271] To an acetonitrile solution of 4-((4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)methyl)piperidine (GT10, 27 mg, 1.0 eq) and propane-2-sulfonyl chloride (propane-2-sulfonyl chloride, 0.01 mL, 1.2 eq) was added Et3N (0.03 mL, 3 eq). The mixture was stirred overnight at room temperature under N2 atmosphere, and the reaction mixture was quenched with saturated NH4Cl. The mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc / hexane / MeOH = 1:2:0.1) to obtain the title compound (GT12, 13 mg, 38%) as a white solid.

[0272] 1 H NMR (400 MHz, Chloroform-d) δ 8.15 (s, 1H), 7.87 (s, 1H), 7.35 (m, 5H), 7.08 (d,J= 8.4 Hz, 1H), 6.83 (d,J= 8.4 Hz, 1H), 5.98 (ddt,J= 16.8, 9.9, 6.7 Hz, 1H), 5.60 (s, 2H), 5.07 (m, 2H), 3.88 (d,J= 5.9 Hz, 2H), 3.80 (d,J= 13.1 Hz, 2H), 3.39 (d,J= 6.7 Hz, 2H), 3.18 (p,J=6.8 Hz, 1H), 2.79 (t,J= 12.1 Hz, 2H), 1.85 (m, 1H), 1.65 (m, 2H), 1.42 (m, 2H), 1.35 (d,J= 6.9 Hz, 6H).

[0273]

[0274] Example 18: Preparation of 2-(4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)acetamide (GT13)

[0275] A THF solution of 2-(4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)acetic acid (GT11, 26 mg, 1.0 eq) and CDI (carbonyldiimidazole, 24 mg, 2 eq) was stirred at room temperature for 4 h under a N2 atmosphere. Aqueous NH4OH solution (0.5 mL, excess) was added to the mixture and stirred for another 3 h at the same temperature. The reaction mixture was quenched with water. The mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc / hexane = 1:4) to give the title compound (GT13, 18 mg, 70%) as a white solid.

[0276] h1 H NMR (400 MHz, Chloroform-d) δ 7.79 (s, 1H), 7.59 (s, 1H), 7.35 (m, low 5H), 7.14 (d,J= 8.4 Hz, 1H), 6.86 (d,J= 8.5 Hz, 1H), 5.94 (ddt,J= 17.5, 8.5, 6.6 Hz, 1H), 5.57 (s, 2H), 5.07 (m, 2H), 4.57 (s, 2H), 3.36 (d,J= 6.6 Hz, 2H).

[0277]

[0278] Example 19: Preparation of 2-(4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)-N-cyclohexylacetamide (GT14)

[0279] A DMF solution of GT11 (31 mg, 1.0 eq), cyclohexylamine (13 mg, 1.5 eq), EDC (41 mg, 3 eq), HOBt (14 mg, 1 eq), DMAP (11 mg, 0.1 eq), and N,N-diisopropylethylamine (DIPEA, 0.15 mL, 10 eq) was stirred overnight at 60°C under a N2 atmosphere. The reaction mixture was cooled to room temperature and then quenched with water. The mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc / hexane = 1:2) to give the title compound (GT14, 23 mg, 60%) as a white solid.

[0280] 1 H NMR (400 MHz, Chloroform-d) δ 7.78 (s, 1H, -NH), 7.74 (d,J= 8.4 Hz, 1H), 7.59 (s, 1H), 7.35 (m, 5H), 7.12 (d,J= 8.3 Hz, 1H), 6.85 (d,J= 8.3 Hz, 1H), 5.94 (m, 1H), 5.60 (s, 2H), 5.06 (m, 2H), 4.56 (s, 2H), 3.84 (m, 1H), 3.36 (d,J= 6.6 Hz, 2H), 1.89 (m, 2H), 1.73 (m, 2H), 1.62 (m, 1H), 1.28 (m, 4H).

[0281]

[0282] Example 20: Preparation of 2-(4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)-N-(4-hydroxycyclohexyl)acetamide (GT15)

[0283] The reaction and purification were carried out in a similar manner as in Example 19, except that 4-aminocyclohexanol was used instead of cyclohexylamine, to obtain the title compound (GT15, 25 mg, 53%) as a white solid.

[0284] 1 H NMR (400 MHz, Chloroform-d) δ 8.29 (d,J= 8.2 Hz, 1H), 7.74 (s, 1H), 7.36 (m, 6H, including -NH), 7.12 (d,J= 8.4 Hz, 1H), 6.85 (d,J= 8.4 Hz, 1H), 5.92 (ddd,J= 16.4, 11.5, 6.8 Hz, 1H), 5.59 (s, 2H), 5.04 (m, 2H), 4.56 (s, 2H), 3.83 (m, 1H), 3.66 (m, 1H), 3.34 (d,J= 6.6 Hz, 2H), 1.99 (m, 4H), 1.78 (s, 1H, -OH), 1.41 (t,J= 9.5 Hz, 4H).

[0285]

[0286] Example 21: Preparation of tert-butyl 4-((4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)methyl)piperidine-1-carboxylate (GT16)

[0287] The reaction and purification were carried out in a similar manner as in Example 4, except that t-butyl 4-(bromomethyl)piperidine-1-carboxylate was used instead of ethyl 2-bromoacetate, to obtain the title compound (GT16, 43 mg, 51%) as a white solid.

[0288] 1H NMR (600 MHz, Chloroform-d) δ 8.16 (d,J= 2.3 Hz, 1H), 7.84 (s, 1H), 7.39 (m, 3H), 7.30 (m, 2H), 7.08 (dd,J= 8.4, 2.3 Hz, 1H), 6.83 (d,J= 8.4 Hz, 1H), 5.98 (ddt,J= 16.8, 10.0, 6.7 Hz, 1H), 5.57 (s, 2H), 5.06 (m, 2H), 4.07 (s, 2H), 3.83 (d,J= 6.5 Hz, 2H), 3.39 (d,J= 6.8 Hz, 2H), 2.62 (s, 2H), 1.85 (m, 1H), 1.61 (m, 2H), 1.48 (s, 9H), 1.15 (qd,J= 12.4, 4.4 Hz, 2H).

[0289]

[0290]

[0291]

[0292]

[0293] Example 22: Preparation of 2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-bromophenol (c)

[0294] To a CH2Cl2 solution (20 mL) of GS27 (857 mg, 1 eq) was added boron trichloride (7.47 mL, 3 eq, 1.0 M solution in CH2Cl2) under a N2 atmosphere at 0°C. After the reaction was completed, the solution was quenched with saturated NH4Cl. The reaction mixture was diluted with CH2Cl2, washed with water, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc / hexane = 1:4) to give the title compound (c, 821 mg, 100%) as a white solid.

[0295] 1H NMR (600 MHz, DMSO-d6) δ 10.52 (bs, 1H), 8.51 (s, 1H), 8.13 (d,J= 2.6 Hz, 1H), 7.36 (m, 5H), 7.31 (d,J= 2.6 Hz, 1H), 6.93 (d,J= 8.7 Hz, 1H), 5.68 (s, 2H).

[0296]

[0297] Example 23: Preparation of ethyl 2-(2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-bromophenoxy)acetate (d)

[0298] The reaction and purification were carried out in a similar manner as in Example 4, except that a DMF solution of 2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-bromophenol (c) was used instead of the acetone solution of GS30, to obtain the title compound (d, 753 mg, 71%) as a white solid.

[0299] 1 H NMR (600 MHz, Chloroform-d) δ 8.59 (s, 1H), 8.55 (d,J= 2.3 Hz, 1H), 7.35 (m, 6H), 6.68 (d,J= 8.6 Hz, 1H), 5.60 (s, 2H), 4.62 (s, 2H), 4.27 (q,J= 7.0 Hz, 2H), 1.30 (t,J= 7.1 Hz, 3H).

[0300]

[0301] Example 24: Preparation of ethyl 2-(2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-isobutylphenoxy)acetate (GT17)

[0302] To a solution of ethyl 2-(2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-bromophenoxy)acetate (d, 30 mg, 1 eq) in toluene (0.14 M) were added Pd(PPh3)4 (8.4 mg, 0.1 eq), isobutylboronic acid (14.7 mg, 2 eq), and Cs2CO3 (71 mg, 3 eq). After bubbling with nitrogen, the reaction was carried out using a microwave at 100 °C for 1.5 h. The reaction mixture was cooled to room temperature and quenched with saturated NH4Cl. The mixture was diluted with EtOAc and washed with water and brine. The obtained organic layers were combined, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc / hexane = 1:5) to obtain the title compound (GT17, 15.6 mg, 55%).

[0303] 1 H NMR (600 MHz, Chloroform-d) δ 8.58 (s, 1H), 8.22 (d,J= 2.3 Hz, 1H), 7.34 (m, 5H), 7.03 (dd,J= 8.3, 2.3 Hz, 1H), 6.73 (d,J= 8.4 Hz, 1H), 5.61 (s, 2H), 4.64 (s, 2H), 4.26 (q,J= 7.1 Hz, 2H), 2.49 (d,J= 7.2 Hz, 2H), 1.90 (m, 1H), 1.29 (t,J= 7.1 Hz, 3H), 0.90 (d,J= 6.6 Hz, 6H).

[0304]

[0305] Example 25: Preparation of ethyl 2-(2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-cyclopentenylphenoxy)acetate (GT18)

[0306] The title compound (GT18, 22.3 mg, 76%) was obtained by reaction and purification in a similar manner as Example 24, except that cyclopent-1-en-1-ylboronic acid was used instead of isobutylboronic acid.

[0307] 1 H NMR (600 MHz, Chloroform-d) δ 8.59 (s, 1H), 8.50 (d,J= 2.3 Hz, 1H), 7.35 (m, 6H), 6.77 (d,J= 8.5 Hz, 1H), 6.19 (m, 1H), 5.61 (s, 2H), 4.66 (s, 2H), 4.26 (q,J= 7.2 Hz, 2H), 2.75 (m, 2H), 2.53 (ddd,J= 10.2, 4.8, 2.4 Hz, 2H), 2.03 (m, 2H), 1.29 (t,J= 7.1 Hz, 3H).

[0308]

[0309] Example 26: Preparation of ethyl 2-(3-(1-benzyl-1H-1,2,3-triazol-4-yl)-4'-fluorobiphenyl-4-yloxy)acetate (GT19)

[0310] The title compound (GT19, 29.3 mg, 94%) was obtained by reaction and purification in a similar manner as Example 24, except that 4-fluorophenylboronic acid was used instead of isobutylboronic acid.

[0311] 1H NMR (600 MHz, Chloroform-d) δ 8.64 (d,J= 2.4 Hz, 1H), 8.62 (s, 1H), 7.61 (m, 2H), 7.45 (dd,J= 8.5, 2.4 Hz, 1H), 7.36 (m, 5H), 7.11 (t,J= 8.7 Hz, 2H), 6.88 (d,J= 8.5 Hz, 1H), 5.62 (s, 2H), 4.70 (s, 2H), 4.28 (q,J= 7.1 Hz, 2H), 1.31 (t,J= 7.2 Hz, 3H).

[0312]

[0313] Example 27: Preparation of ethyl 2-(2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-(1-(trifluoromethyl)-1H-pyrazol-4-yl)phenoxy)acetate (GT20)

[0314] The title compound (GT20, 31 mg, 91%) was obtained by reaction and purification in a similar manner as in Example 24, except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl)-1H-pyrazole was used instead of isobutylboronic acid.

[0315] 1 H NMR (600 MHz, Chloroform-d) δ 8.82 (d,J= 2.3 Hz, 1H), 8.65 (s, 1H), 7.91 (dd,J= 8.6, 2.3 Hz, 1H), 7.84 (d,J= 2.7 Hz, 1H), 7.36 (m, 5H), 6.89 (d,J= 8.6 Hz, 1H), 6.86 (d,J= 2.6 Hz, 1H), 5.63 (s, 2H), 4.71 (s, 2H), 4.28 (q,J= 7.1 Hz, 2H), 1.31 (t,J= 7.1 Hz, 3H).

[0316]

[0317] Example 28: Preparation of ethyl 2-(2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-(pyridin-4-yl)phenoxy)acetate (GT21)

[0318] To a solution (0.08 M) of d (60 mg, 1 eq) in DMF, Pd(PPh3)4 (16.7 mg, 0.1 eq) and 4-(tributylstannyl)pyridine (80 mg, 1.5 eq) were added. After bubbling with nitrogen, the reaction was carried out overnight at 90°C using a shielded tube. The reaction mixture was cooled to room temperature and quenched with saturated NH4Cl. The mixture was diluted with EtOAc and washed with water and brine. The resulting organic layers were combined, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc / hexane = 1:3) to give the title compound (GT21, 6.9 mg, 11.5%).

[0319] 1 H NMR (600 MHz, Chloroform-d) δ 8.98 (d,J= 2.3 Hz, 1H), 8.67 (ddd,J= 4.8, 1.8, 0.9 Hz, 1H), 8.64 (s, 1H), 8.09 (dd,J= 8.6, 2.4 Hz, 1H), 7.87 (dt,J= 8.0, 1.0 Hz, 1H), 7.75 (ddd,J= 8.0, 7.5, 1.8 Hz, 1H), 7.36 (m, 5H), 7.20 (ddd,J= 7.5, 4.8, 1.1 Hz, 1H), 6.94 (d,J= 8.6 Hz, 1H), 5.63 (s, 2H), 4.73 (s, 2H), 4.28 (q,J= 7.1 Hz, 2H), 1.31 (t,J= 7.1 Hz, 3H).

[0320]

[0321] Example 29: Preparation of ethyl 2-(2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-cyclopentylphenoxy)acetate (GT22)

[0322] An EtOAc solution of ethyl 2-(2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-cyclopentenylphenoxy)acetate (GT18, 10 mg, 1 eq) and Pd / C (5% wet, catalytic amounts) were stirred at room temperature under a H2 atmosphere. After the reaction was completed, the reaction mixture was filtered through a pad of Celite. The filtered solution was concentrated in vacuo, and the residue was purified by flash column chromatography (EtOAc / hexane = 1:5) to obtain the title compound (GT22, 6.3 mg, 63%).

[0323] 1 H NMR (600 MHz, Chloroform-d) δ 8.57 (s, 1H), 8.31 (d,J= 2.3 Hz, 1H), 7.34 (m, 5H), 7.13 (ddd,J= 8.4, 2.3, 0.6 Hz, 1H), 6.74 (d,J= 8.4 Hz, 1H), 5.60 (s, 2H), 4.63 (s, 2H), 4.26 (q,J= 7.1 Hz, 2H), 3.02 (m, 1H), 2.07 (m, 2H), 1.82 (m, 2H), 1.65 (m, 4H), 1.29 (t,J= 7.1 Hz, 3H).

[0324]

[0325]

[0326]

[0327] Example 30: Preparation of 1-benzyl-4-(2-methoxy-5-propylphenyl)-1H-1,2,3-triazole (GS29)

[0328] The title compound (GS29, 9 mg, 90%) was obtained by reaction and purification in a similar manner as Example 29, except that GS28 was used instead of GT18 and methanol was used as a solvent.

[0329] 1H-NMR (400 MHz, Chloroform-d) δ 8.18 (d, 1H), 7.97 (s, 1H), 7.36 (m, 3H), 7.30 (m, 2H), 7.10 (m, 1H), 6.87 (d, 1H), 5.60 (s, 2H), 3.86 (s, 3H), 2.60 (t, 2H), 1.66 (m, 2H), 0.94 (t, 3H);

[0330] 13 C-NMR (150 MHz, Chloroform-d) δ 153.8, 143.8, 135.2, 135.2, 129.0, 128.8, 128.5, 127.7, 127.6, 123.0, 118.9, 110.6, 55.4, 53.9, 37.2, 24.8, 13.8.

[0331]

[0332] Example 31: Preparation of 2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-propylphenol (GS31)

[0333] The title compound (GS31, 7.8 mg, 77%) was obtained by reaction and purification in a similar manner as Example 29, except that GS30 was used instead of GT18 and methanol was used as a solvent.

[0334] 1 H-NMR (400 MHz, Chloroform-d) δ 10.64 (s, 1H), 7.74 (s, 1H), 7.41 (m, 3H), 7.33 (m, 2H), 7.14 (d, 1H), 7.04 (m, 1H), 6.97 (m, 1H), 5.60 (s, 2H), 2.50 (t, 2H), 1.59 (m, 2H), 0.91 (t, 3H);

[0335] 13 C-NMR (150 MHz, Chloroform-d) δ 153.9, 148.3, 134.2, 133.5, 130.0, 129.3, 129.1, 128.1, 125.5, 118.7, 117.4, 113.4, 54.6, 37.2, 24.8, 13.8.

[0336]

[0337] Example 32: Preparation of 2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-propylphenyl acetate (GS34)

[0338] The title compound (GS34, 8.3 mg, 82%) was obtained by reaction and purification in a similar manner as in Example 29, except that 4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenyl acetate (GS33) was used instead of GT18 and EtOAc was used as a solvent.

[0339] 1 H-NMR (400 MHz, Chloroform-d) δ 7.89 (s, 1H), 7.59 (s, 1H), 7.39 (m, 3H), 7.31 (m, 2H), 7.15 (m, 1H), 7.03 (d, 1H), 5.58 (s, 2H), 2.62 (t, 2H), 2.12 (s, 3H), 1.66 (m, 2H), 0.95 (t, 3H);

[0340] 13 C-NMR (150 MHz, Chloroform-d) δ 169.1, 145.1, 143.6, 140.9, 134.6, 129.2, 129.1, 128.9, 128.4, 128.4, 128.2, 122.8, 122.7, 121.5, 54.2, 37.4, 24.5, 21.1, 13.8.

[0341]

[0342] Example 33: Preparation of ethyl 2-(2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-propylphenoxy)acetate (GS35)

[0343] The title compound (GS35, 8.3 mg, 82%) was obtained by reaction and purification in a similar manner as in Example 29, except that ethyl 2-(4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)acetate (GS32) was used instead of GT18 and EtOAc was used as a solvent.

[0344] 1 H-NMR (400 MHz, Chloroform-d) δ 8.58 (s, 1H), 8.25 (d, 1H), 7.34 (m, 5H), 7.07 (m, 1H), 6.74 (d, 1H), 5.61 (s, 2H), 4.64 (s, 2H), 4.26 (m, 2H), 2.61 (t, 2H), 1.66 (m, 2H), 1.28 (t, 3H), 0.92 (t, 3H);

[0345] 13 C-NMR (150 MHz, Chloroform-d) δ 168.6, 151.7, 143.3, 136.3, 135.3, 128.9, 128.6, 128.4, 127.9, 127.6, 124.1, 119.7, 111.3, 65.6, 61.4, 54.0, 37.2, 24.7, 14.2, 13.8.

[0346]

[0347]

[0348]

[0349] Example 34: Preparation of 4-allyl-2-(1-allyl-1H-1,2,3-triazol-4-yl)phenyl acetate (e)

[0350] To a CH2Cl2 solution of 4-allyl-2-(1-allyl-1H-1,2,3-triazol-4-yl)phenol (20 mg, 1.0 eq) and acetic anhydride (7 μL, 1.2 eq) was added Et3N (17 μL, 1.5 eq) at 0°C under N2 atmosphere. The mixture was stirred at room temperature under N2 atmosphere for 3 h. After the reaction was completed, the reaction mixture was quenched with water. The mixture was diluted with CH2Cl2, washed with water, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc / hexane = 1:4) to give the title compound (e, 20.5 mg, 87%).

[0351]

[0352] Example 35: Preparation of ethyl 2-(4-allyl-2-(1-allyl-1H-1,2,3-triazol-4-yl)phenoxy)acetate (GS50)

[0353] The reaction and purification were carried out in a similar manner as in Example 4, except that 4-allyl-2-(1-allyl-1H-1,2,3-triazol-4-yl)phenol was used instead of GS30, to obtain the title compound (GS50, 35 mg, 88%) as a white solid.

[0354] 1 H-NMR (400 MHz, Chloroform-d) δ 8.58 (s, 1H), 8.26 (d, 1H), 7.10 (m, 1H), 6.78 (d, 1H), 6.10 (m, 1H), 5.98 (m, 1H), 5.35 (m, 2H), 5.07 (m, 4H), 4.68 (s, 2H), 4.31 (q, 2H), 3.42 (d, 2H), 1.34 (t, 3H);

[0355] 13C-NMR (150 MHz, Chloroform-d) δ 168.6, 152.0, 143.0, 137.5, 133.7, 131.7, 128.6, 127.9, 124.0, 119.9, 119.6, 115.8, 111.5, 65.6, 61.4, 52.6, 39.5, 14.2.

[0356]

[0357]

[0358]

[0359] Example 36: Preparation of 4-(2-methoxy-5-propylphenyl)-1-propyl-1H-1,2,3-triazole (GS48)

[0360] The title compound (GS48, 13.2 mg, 87%) was obtained by reaction and purification in a similar manner as in Example 29, except that 1-allyl-4-(5-allyl-2-methoxyphenyl)-1H-1,2,3-triazole was used instead of GT18.

[0361] 1 H-NMR (400 MHz, Chloroform-d) δ 8.18 (d, 1H), 8.02 (s, 1H), 7.11 (m, 1H), 6.89 (d, 1H), 4.37 (t, 2H), 3.92 (s, 3H), 2.61 (t, 2H), 1.99 (m, 2H), 1.67 (m, 2H), 0.99 (t, 3H), 0.94 (t, 3H);

[0362] 13 C-NMR (150 MHz, Chloroform-d) δ 153.8, 143.2, 135.3, 128.6, 127.6, 122.9, 119.1, 110.7, 55.5, 51.8, 37.2, 24.8, 23.8, 13.8, 11.1.

[0363]

[0364] Example 37: Preparation of 4-propyl-2-(1-propyl-1H-1,2,3-triazol-4-yl)phenyl acetate (GS51)

[0365] The title compound (GS51, 13.7 mg, 90%) was obtained by reaction and purification in a similar manner as in Example 29, except that 4-allyl-2-(1-allyl-1H-1,2,3-triazol-4-yl)phenyl acetate (e) was used instead of GT18.

[0366] 1 H-NMR (400 MHz, Chloroform-d) δ 7.89 (d, 1H), 7.73 (s, 1H), 7.17 (m, 1H), 7.07 (d, 1H), 4.38 (t, 2H), 2.63 (t, 2H), 2.33 (s, 3H), 1.97 (m, 2H), 1.68 (m, 2H), 0.99 (t, 3H), 0.96 (t, 3H);

[0367] 13 C-NMR (150 MHz, DMSO) δ 169.4, 145.1, 143.3, 141.0, 129.1, 128.5, 122.9, 122.7, 121.5, 52.0, 37.5, 24.6, 23.9, 21.5, 13.9, 11.2.

[0368]

[0369] Example 38: Preparation of ethyl 2-(4-propyl-2-(1-propyl-1H-1,2,3-triazol-4-yl)phenoxy)acetate (GS52)

[0370] The title compound (GS52, 12.8 mg, 84%) was obtained by reaction and purification in a similar manner as in Example 29, except that ethyl 2-(4-allyl-2-(1-allyl-1H-1,2,3-triazol-4-yl)phenoxy)acetate (GS50) was used instead of GT18.

[0371] 1H-NMR (400 MHz, Chloroform-d) δ 8.63 (s, 1H), 8.25 (d, 1H), 7.09 (m, 1H), 6.77 (d, 1H), 4.69 (s, 2H), 4.40 (t, 2H), 4.33 (q, 2H), 2.61 (t, 2H), 2.02 (m, 2H), 1.67 (m, 2H), 1.35 (t, 3H), 0.99 (t, 3H), 0.93 (t, 3H);

[0372] 13 C-NMR (150 MHz, DMSO) δ 168.8, 151.6, 142.8, 136.3, 128.5, 127.5, 124.0, 119.7, 111.2, 65.5, 61.5, 51.9, 37.2, 24.8, 23.9, 14.3, 13.9, 11.2.

[0373]

[0374]

[0375]

[0376] Example 39: Preparation of 4-(5-bromo-2-methoxyphenyl)-1-(cyclobutylmethyl)-1H-1,2,3-triazole (GS36)

[0377] The title compound (GS36,407 mg, 89%) was obtained by reaction and purification in a similar manner as Example 1, except that (bromomethyl)cyclobutane was used instead of benzyl bromide.

[0378] 1 H-NMR (400 MHz, Chloroform-d) δ 8.48 (d, 1H), 7.97 (s, 1H), 7.38 (m, 1H), 6.84 (d, 1H), 4.41 (d, 2H), 3.93 (s, 3H), 2.89 (m, 1H), 2.12 (m, 2H), 1.90 (m, 4H);

[0379] 13C-NMR (150 MHz, Chloroform-d) δ 154.6, 141.8, 131.2, 130.2, 123.1, 121.5, 113.6, 112.5, 55.7, 55.2, 35.6, 25.8, 18.1.

[0380]

[0381] Example 40: Preparation of 4-(5-allyl-2-methoxyphenyl)-1-(cyclobutylmethyl)-1H-1,2,3-triazole (GS37)

[0382] The title compound (GS37, 302 mg, 86%) was obtained by reaction and purification in a similar manner as in Example 2, except that 4-(5-bromo-2-methoxyphenyl)-1-(cyclobutylmethyl)-1H-1,2,3-triazole (GS36) was used instead of GS27.

[0383] 1 H-NMR (400 MHz, Chloroform-d) δ 8.18 (d, 1H), 7.98 (s, 1H), 7.12 (m, 1H), 6.91 (d, 1H), 6.91 (m, 1H), 5.08 (m, 2H), 4.41 (d, 2H), 3.92 (s, 3H), 3.41 (d, 2H), 2.89 (m, 1H), 2.12 (m, 2H), 1.90 (m, 4H);

[0384] 13 C-NMR (150 MHz, Chloroform-d) δ 154.1, 143.0, 137.8, 132.7, 128.7, 127.8, 122.8, 119.4, 115.6, 110.9, 55.5, 55.1, 39.4, 35.6, 25.8, 18.1.

[0385]

[0386] Example 41: Preparation of 4-allyl-2-(1-(cyclobutylmethyl)-1H-1,2,3-triazol-4-yl)phenol (GS38)

[0387] The reaction was carried out in a similar manner to Example 3, except that 4-(5-allyl-2-methoxyphenyl)-1-(cyclobutylmethyl)-1H-1,2,3-triazole (GS37) was used instead of GS28 and the reaction was carried out at 0°C, to obtain the title compound (GS38, 257 mg, 90%) as a white solid.

[0388] 1 H-NMR (400 MHz, Chloroform-d) δ 10.76 (s, 1H), 7.80 (s, 1H), 7.221 (d, 1H), 7.05 (m, 1H), 6.99 (d, 1H), 5.97 (m, 1H), 5.06 (m, 2H), 4.45 (d, 2H), 3.34 (d, 1H), 2.91 (m, 1H), 2.15 (m, 2H), 1.91 (m, 4H) ;

[0389] 13 C-NMR (150 MHz, Chloroform-d) δ 154.3, 147.7, 137.8, 130.7, 130.0, 125.6, 118.5, 117.7, 115.6, 113.8, 55.6, 39.3, 35.5, 25.8, 18.1.

[0390]

[0391] Example 42: Preparation of 4-allyl-2-(1-(cyclobutylmethyl)-1H-1,2,3-triazol-4-yl)phenyl acetate (GS39)

[0392] The reaction and purification were carried out in a similar manner as in Example 34, except that 4-allyl-2-(1-allyl-1H-1,2,3-triazol-4-yl)phenol (GS38) was used instead of 4-allyl-2-(1-allyl-1H-1,2,3-triazol-4-yl)phenol, to obtain the title compound (GS39, 28 mg, 81%) as a white solid.

[0393] 1H-NMR (400 MHz, Chloroform-d) δ 7.90 (d, 1H), 7.67 (s, 1H), 7.19 (m, 1H), 7.09 (d, 1H), 6.00 (m, 1H), 5.11 (m, 2H), 4.42 (d, 2H), 3.44 (d, 2H), 2.87 (m, 1H), 2.33 (s, 3H), 2.14 (m, 2H), 1.93 (m, 4H);

[0394] 13 C-NMR (150 MHz, Chloroform-d) δ 169.1, 145.4, 143.1, 138.3, 136.9, 129.1, 128.7, 123.2, 122.9, 121.3, 116.3, 55.3, 39.6, 35.6, 25.9, 21.3, 18.1.

[0395]

[0396] Example 43: Preparation of ethyl 2-(4-allyl-2-(1-(cyclobutylmethyl)-1H-1,2,3-triazol-4-yl)phenoxy)acetate (GS40)

[0397] The reaction and purification were carried out in a similar manner as in Example 4, except that GS38 was used instead of GS30, to obtain the title compound (GS40, 36 mg, 90%) as a white solid.

[0398] 1 H-NMR (400 MHz, Chloroform-d) δ 8.58 (s, 1H), 8.26 (d, 1H), 7.09 (m, 1H), 6.78 (d, 1H), 5.98 (m, 1H), 5.07 (m, 2H), 4.68 (s, 2H), 4.43 (d, 2H), 4.33 (q, 2H), 3.41 (d, 2H), 2.91 (m, 1H), 2.12 (m, 2H), 1.90 (m, 4H), 1.35 (t, 3H);

[0399] 13C-NMR (150 MHz, Chloroform-d) δ 168.6, 151.9, 142.6, 137.6, 133.7, 128.5, 127.8, 123.9, 120.11, 115.7, 111.5, 65.5, 61.4, 55.2, 39.5, 35.6, 25.8, 18.1, 14.2.

[0400]

[0401]

[0402]

[0403] Example 44: Preparation of 1-(cyclobutylmethyl)-4-(2-methoxy-5-propylphenyl)-1H-1,2,3-triazole (GS41)

[0404] The title compound (GS41, 9 mg, 90%) was obtained by reaction and purification in a similar manner as in Example 29, except that GS37 was used instead of GT18.

[0405] 1 H-NMR (400 MHz, Chloroform-d) δ 8.17 (d, 1H), 7.97 (s, 1H), 7.10 (m, 1H), 6.89 (d, 1H), 4.41 (d, 2H), 3.91 (s, 3H), 2.90 (m, 1H), 2.60 (t, 1H), 2.11 (m, 2H), 1.91 (m, 4H), 1.66 (m, 2H), 0.94 (t, 1H);

[0406] 13 C-NMR (150 MHz, Chloroform-d) δ 153.8, 143.1, 135.3, 128.6, 127.6, 122.8, 119.1, 110.7, 55.5, 55.1, 37.2, 35.6, 25.8, 24.8, 18.1, 13.8.

[0407]

[0408] Example 45: Preparation of ethyl 2-(2-(1-(cyclobutylmethyl)-1H-1,2,3-triazol-4-yl)-4-propylphenoxy)acetate (GS44)

[0409] The title compound (GS44, 8.7 mg, 87%) was obtained by reaction and purification in a similar manner as in Example 29, except that ethyl 2-(4-allyl-2-(1-(cyclobutylmethyl)-1H-1,2,3-triazol-4-yl)phenoxy)acetate (GS40) was used instead of GT18.

[0410] 1 H-NMR (400 MHz, Chloroform-d) δ 8.58 (s, 1H), 8.24 (d, 1H), 7.08 (m, 1H), 6.76 (d, 1H), 4.68 (s, 2H), 4.44 (d, 2H), 4.33 (q, 2H), 2.91 (m, 1H), 2.60 (t, 2H), 2.12 (m, 2H), 1.91 (m, 4H), 1.67 (m, 2H), 1.35 (t, 3H), 0.94 (t, 3H);

[0411] 13 C-NMR (150 MHz, Chloroform-d) δ 168.7, 151.6, 142.7, 136.3, 128.4, 127.6, 123.9, 119.9, 111.3, 65.6, 61.4, 55.2, 37.2, 35.6, 25.8, 24.7, 18.1, 14.2, 13.8.

[0412]

[0413] The structural formulas of the compounds manufactured in Example 1-45 are summarized and shown in Table 1 below.

[0414]

[0415]

[0416]

[0417]

[0418] Experimental Example 1. Activation of autophagy by compound treatment in human retinal pigment epithelial cells.

[0419] To evaluate autophagy activity by treatment with the compound represented by the above chemical formula 1, Western immunoblotting was performed using human retinal pigment epithelial cells, ARPE-19, to confirm whether LC3-II, one of the major indicator proteins of autophagy activation, increased.

[0420] Specifically, the ARPE-19 cell line was cultured at 1×10 5 Cells were seeded into 6-well plates at a concentration of 10 cells / well and cultured for 24 h. The cells were then treated with the compound (GS-32) at concentrations of 25 and 50 μM for 6 h. Subsequently, a cell lysis buffer containing protease inhibitors (50 mM Tris-chloride, pH 8.0, 150 mM sodium chloride, 1% NP-40, 1% sodium deoxycholate, 1% sodium dodecyl sulfate, and 2 mM ethylenediamine tetraacetic acid) was added to prepare a cell lysate. LC3-II levels were measured using an anti-LC3-II antibody (Cell Signaling Technology, MA, USA), and an antibody against β-actin (Cell Signaling Technology) was used as an internal control.

[0421] As a result, as shown in Fig. 1a, it was confirmed that the level of LC3-II, an autophagy marker, increased in a concentration-dependent manner.

[0422]

[0423] In addition, when autophagy is activated, LC3-Ⅱ is involved in autophagosome formation, forming puncta in the cytoplasm, and thus intracellular autophagosome formation was observed.

[0424] Specifically, ARPE-19 cells were transfected with a plasmid expressing RFP-GFP-LC3 (Addgene Inc. MA, USA) using Lipofectamine™ 2000 reagent (Invitrogen, Carlsbad, CA, USA). After 48 h of incubation, the cells were treated with the compound (GS-32) at concentrations of 10, 25, and 50 μM. After an additional 12 h of incubation, the cells were fixed with 4% paraformaldehyde for 10 min and then washed three times with PBS every 5 min. Finally, the puncta formation of RFP-GFP-LC3 was observed using a confocal laser scanning microscope. The nuclei were stained with 1 μg / mL Hoechst 33342 (Thermo Scientific, Rockford, IL, USA).

[0425] As a result, as shown in Fig. 1b, treatment with the compound resulted in an increase in intracellular GFP-LC3-II puncta (GFP), but a more marked increase in RFP-LC3-II puncta was observed. When these two images were merged, RFP-LC3-II puncta were observed to be significantly more predominant.

[0426] The above results indicate that the compound of the present invention activates the autophagic flux.

[0427]

[0428] Experimental Example 2. Confirmation of removal of A2E-fluorescent labeling substance by compound

[0429]

[0430] Fluorescence spectrophotometry

[0431] In order to evaluate the intracellular A2E removal ability by treatment with the compound represented by the above chemical formula 1, an easily detectable A2E-fluorescent labeling substance (A2E-BDP) was used.

[0432] Specifically, the ARPE-19 cell line was cultured at 5×103 Cells / well were dispensed into 96-well plates and cultured for 24 hours. To induce A2E-BDP accumulation in ARPE-19 cells, A2E-BDP was treated at a concentration of 10 μM for 24 hours. The A2E-BDP-containing ARPE-19 cells were treated once with the compound (GS-32) or the compound of Comparative Example 1 (2, 10, 25 μM) and cultured for 24 hours. Cells were lysed by adding a cell lysis buffer containing a protease inhibitor to each 96-well, and the cell lysate was transferred to a white 96-well plate, and the fluorescence intensity was measured (excitation 485 nm, emission 535 nm) using a fluorescence microplate reader (VICTOR™ X3, PerkinElmer, USA).

[0433] As a result, as shown in Figures 2a and 2b, it was confirmed that the removal rate of A2E-fluorescent labeling substance (A2E-BDP) accumulated in ARPE-19 cells increased in a concentration-dependent manner by treatment with the compound. In addition, it was confirmed that it exhibited superior A2E removal ability than the compound of Comparative Example 1.

[0434]

[0435] Experimental Example 2-1. Confirmation of A2E removal by compound treatment

[0436]

[0437] HPLC method

[0438] A2E-BDP, confirmed in the above experimental example 2, is known to have the same intracellular dynamics and characteristics as A2E, but since the substance actually existing in the body is A2E, the quantitative change in intracellular A2E was directly measured using the HPLC method.

[0439] Specifically, the ARPE-19 cell line was cultured at 4×10 3Cells / well were dispensed into 6-well plates and cultured for 24 hours. After that, ARPE-19 cells were treated with A2E at a concentration of 50 μM for 48 hours to accumulate A2E within the cells. To evaluate the A2E removal ability, A2E-containing ARPE-19 cells were treated with the compound (GS-32) or the compound of Comparative Example 1 at 50 μM for 24 hours. After that, 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 homogenate. Chloroform and methanol (2:1, v / v) were added to the cell homogenate, shaken to extract A2E, and centrifuged at 10,000 g for 10 minutes. The organic phase was dried under vacuum and redissolved in 100 mL of acetonitrile. LC-MS (Shimadzu LC-MS 2010EV) analysis was performed using a C18 column (2'50 mm) with acetonitrile and 0.1% formic acid (gradient, 0-100%, 0-10 min; flow rate 1.0 ml / min; monitoring at 503 nm). All operations during the extraction of A2E present in the cytoplasm of ARPE-19 cells were performed under weak red light to prevent destruction of A2E.

[0440] As a result, as shown in Fig. 3, it was confirmed that the amount of A2E in ARPE-19 cells accumulated in A2E was significantly reduced by treatment with the compound of the present invention. In addition, it was confirmed that it exhibited superior A2E removal ability than the compound of Comparative Example 1.

[0441] The above results suggest that the compound represented by the above chemical formula 1 directly removes A2E present in ARPE-19 cells.

[0442]

[0443] Experimental Example 3. Autophagy-inducing activity of various derivative compounds

[0444]

[0445] The autophagy activation effect in human retinal pigment epithelial cells (ARPE-19) by various derivative compounds of the compound represented by the above chemical formula 1 was evaluated. The experimental method was the same as Experimental Example 1, and the autophagy activation effect through the increase in LC3-Ⅱ was evaluated and is shown in Tables 2 and 3 below. The results of the DMSO treatment group were used as a control.

[0446]

[0447] Derivative concentration (μM)LC3-Ⅱ±β-actinDMSO501.00GS-27251.32501.36GS-28252.79503.87GS-29251.11501.19GS-30251.56501.67GS-31 251.25501.58GS-32251.62502.47GS-33251.30501.47GS-35251.26501.56GS-37251.37501.49GS-38251.20501.09GS- 39250.88501.07GS-40251.40501.29GS-41251.14501.09GS-43251.20501.00GS-44251.37501.25GS-45251.08501.02G S-46250.81501.25GS-47251.16501.55GS-48251.90503.00GS-50251.48501.57GS-51250.97501.44GS-52251.07501.32

[0448] Derivative concentration (μM)LC3-Ⅱ±β-actinDMSO501.00GT-04251.35501.92GT-05253.64504.98GT-06252.71503.76GT-07 252.98503.42GT-09252.17502.52GT-102519.005017.32GT-11252.37503.38GT-12256.16505.89GT -13253.15503.43GT-14254.07503.49GT-15252.15502.87GT-16251.94501.57GT-17251.66501.81G T-18251.80502.09GT-19252.66502.54GT-20251.80502.81GT-21251.63503.80GT-22252.52502.10

[0449] As shown in Tables 2 and 3, the autophagy activation effect of derivative compounds of the compound represented by Chemical Formula 1 according to the present invention was confirmed.

[0450]

[0451] Experimental Example 4. Confirmation of removal of A2E-fluorescent labeling material by treatment with derivative compounds.

[0452]

[0453] Fluorescence spectrophotometry

[0454] The intracellular A2E removal ability by treatment with a compound represented by chemical formula 1 (GS-32 derivative compound) was evaluated using a fluorescence spectrophotometric method.

[0455] The experimental method was carried out in the same manner as Experimental Example 2, treating the compound at a concentration of 50 μM.

[0456] As a result, as shown in Fig. 4, it was confirmed that the level of A2E in ARPE-19 cells in which A2E-BDP was accumulated was significantly reduced by treatment with the compound.

[0457]

[0458] Experimental Example 5. Confirmation of A2E removal ability by treatment with derivative compounds.

[0459]

[0460] The intracellular A2E removal ability by treatment with a compound represented by chemical formula 1 (GS-32 derivative compound) was evaluated.

[0461] Specifically, ARPE-19 cell line was cultured at 2×10 4 After seeding in 6-well plates at a concentration of 10 cells / well and culturing for 24 h, the cells were treated with 5 μM A2E three times at 48-h intervals, and 24 h after the final A2E treatment, the cells were treated twice with 25 μM of each derivative at 24-h intervals. The cells treated with the derivatives were fixed with 4% paraformaldehyde for 10 min and then washed three times with PBS every 5 min. Finally, the intracellular accumulated A2E was observed using a confocal laser scanning microscope (Nikon, Minato, Tokyo, Japan). The nuclei were stained with 1 μg / mL Hoechst 33342 (Thermo Scientific, Rockford, IL, USA).

[0462] As a result, as shown in FIGS. 5a to 5d and 6a to 6c, the compounds of the present invention exhibited the effect of removing A2E accumulated in human retinal pigment epithelial cells (ARPE-19).

[0463]

[0464] Experimental Example 6. Inhibition of retinal damage in an animal model

[0465]

[0466] Exposure to blue light is a factor that increases oxidative stress in the retina, and the improving effects of the compound of the present invention were evaluated using a blue light-induced retinal damage animal model (Balb / c mice). All tests were conducted at the Non-Clinical Center of the Bio Headquarters (Songdo, Korea) of the Korea Conformity Laboratories (KCL) and were approved by the Animal Experiment Ethics Committee (Approval No.: IA20-04287).

[0467] Specifically, 80 specific pathogen-free (SPF) male BALB / c mice (Orient Bio, Korea) (5 weeks old) were acclimatized for 1 week. Body weight was measured the day before dosing, and only animals within ±20% of the mean body weight were used in the test. After group separation, the mice were kept in a dark room for 24 hours, and dark conditions were maintained throughout the blue light exposure period.

[0468] After anesthetizing the experimental animals with isoflurane, blue light of 10,000 lux was irradiated for a total of 14 times (1 hr / day) for 2 weeks using a blue light irradiation device. The test substance was prepared by dissolving HP-beta-cyclodextrin in a 5% CMC Na solution to make a 10% concentration, and the compound GS-32 of the present invention was dissolved in it. The dose was 25 mg / kg / day for each experimental animal, with 10 ml / kg / day as the administration amount. The test substance was administered orally by force using an oral administration sonde (feeding needle) after grasping and correcting the skin on the dorsum of the test animal, once / day, for 7 days / week, for 4 weeks, in the morning on the day of administration. The initial 2 weeks overlapped with the blue light irradiation period, and administration was performed for a total of 4 weeks, adding 2 weeks after the end of blue light irradiation. On the day of administration, the test substance was administered before blue light irradiation. Before the start of administration and once a week, mydriatic agents were instilled into both eyes of all animals to dilate the pupils. The fundus of the eyes was observed using a fundus camera (Genesis-D, Kowa Co. Ltd., Japan). Photographs were taken of each animal the week after the end of test substance administration.

[0469] After the experiment, both eyes of all animals were enucleated, fixed in Davidson's solution, and stained with H&E. The average thickness of the ONL (outer nuclear layer) and IS / OS (inner segments / outer segments layer) was measured at a location 140 μm (left / right) from the retinal nerve center using the Axio Vision SE644 (ZEISS) program. The ONL and IS / OS thickness of the contralateral eye were measured in a similar manner, and the average value of both eyes was used as the final thickness. One-way ANOVA test was used between each group, and statistical significance was determined when p<0.05 or less. The SPSS 12.0 K program (SPSS, Chicago, IL, USA), a widely used commercial statistical package, was used for statistical analysis.

[0470] As a result, as shown in Figures 7a to 7c, retinal damage was confirmed in the blue light irradiation control group compared to the normal control group, but it was confirmed that the retinal damage was improved in the group administered 25 mg / kg / day of the compound orally as determined by fundus examination (Figure 7a). In addition, the results of histomorphometric analysis of ocular tissues showed that the ONL and IS / OS thicknesses were reduced in the blue light irradiation control group compared to the normal control group, but it was confirmed that they were statistically significantly (p<0.01) recovered by compound administration (Figures 7b and 7c). In addition, it was confirmed that the compound of Comparative Example 1 had a superior effect on improving retinal damage and restoring ocular tissue.

[0471]

[0472] From the above description, those skilled in the art will understand that the present invention can be implemented in other specific forms without altering its technical spirit or essential characteristics. In this regard, it should be understood that the embodiments described above are illustrative in all respects and not restrictive. The scope of the present invention should be interpreted as encompassing all changes or modifications derived from the meaning and scope of the following claims and their equivalent concepts, rather than the detailed description above.

Claims

1. A compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above chemical formula 1, R 1 Silver hydrogen, C 1-4 Alkyl, carbamoyl-C 1-4 Alkyl, carboxy-C 1-4 Alkyl, C 1-4 Alkylcarbonyl, C 1-4 Alkoxycarbonyl-C 1-4 Alkyl, C 6-10 Arylcarbonyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 3 to 10 membered heterocyclyl-C 1-4 Alkyl, 3 to 10 membered heterocyclylcarbonyl, C 3-10 Cycloalkylcarbamoyl-C 1-4 Alkyl, or substituted C 6-10 Aryl-C 1-4 Alkyl-carbamoyl-C 1-4 Alkyl, where C is substituted 6-10 Aryl-C 1-4 Alkyl-carbamoyl-C 1-4 Alkyl is C 6-10 Aryl-C 1-4 C of alkyl 1-4 C in alkyl 1-4 Alkoxycarbonyl is substituted, R 2 is halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 6-10 Aryl, or 5-10 membered heteroaryl, R 3 Silver C 1-4 Alkyl, C 2-4 Alkenyl, C 3-10 Cycloalkyl-C 1-4 Alkyl, or C 6-10 Aryl-C 1-4 Alkyl, C above 3-10 Cycloalkyl, C 6-10 Aryl, 3- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl are unsubstituted or substituted with hydroxy, halogen, C 1-4 Haloalkyl, C 1-4 Alkylsulfonyl, and C 1-4 which may be substituted with one or more selected from the group consisting of alkoxycarbonyl.

2. In paragraph 1, R 1 A compound or a pharmaceutically acceptable salt thereof, wherein said compound is hydrogen, methyl, carbamoylmethyl, carboxymethyl, methylcarbonyl, ethoxycarbonylmethyl, ethoxycarbonylisopropyl, tert-butoxycarbonyl-methyl, methylsulfonyl-substituted phenylcarbonylmethyl, pyridinylmethyl, piperidinylmethyl, isopropylsulfonyl-substituted piperidinylmethyl, tert-butoxycarbonyl-substituted piperidinylmethyl, morpholinylcarbonyl, cyclohexylcarbamoylmethyl, hydroxy-substituted cyclohexylcarbamoylmethyl or N-(1-methoxycarbonyl-2-phenylethyl)carbamoylmethyl.

3. In paragraph 1, R 2 A compound or a pharmaceutically acceptable salt thereof, wherein the compound is bromo, propyl, isobutyl, propenyl, cyclopentyl, cyclopentenyl, fluoro-substituted phenyl, pyridinyl or trifluoromethyl substituted pyrazolyl.

4. In paragraph 1, R 3 A compound or a pharmaceutically acceptable salt thereof, wherein said compound is propyl, propenyl, cyclobutylmethyl, or benzyl.

5. In paragraph 1, 1-Benzyl-4-(5-bromo-2-methoxyphenyl)-1H-1,2,3-triazole 4-(5-allyl-2-methoxyphenyl)-1-benzyl-1H-1,2,3-triazole 4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenol Ethyl 2-(4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)acetate 4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenyl acetate (R)-methyl 2-(2-(4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)acetamido)-3-phenylpropanoate (S)-methyl 2-(2-(4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)acetamido)-3-phenylpropanoate tert-butyl 2-(4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)acetate 2-(4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)-1-(4-(methylsulfonyl)phenyl)ethanone), 2-((4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)methyl)pyridine), 3-((4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)methyl)pyridine), 4-((4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)methyl)pyridine), 4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenyl morpholine-4-carboxylate Ethyl 2-(4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)-2-methylpropanoate 4-((4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)methyl)piperidine), 2-(4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)acetic acid 4-((4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)methyl)-1-(isopropylsulfonyl)piperidine), 2-(4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)acetamide, 2-(4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)-N-cyclohexylacetamide), 2-(4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)-N-(4-hydroxycyclohexyl)acetamide tert-butyl 4-((4-allyl-2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenoxy)methyl)piperidine-1-carboxylate), 2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-bromophenol, Ethyl 2-(2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-bromophenoxy)acetate Ethyl 2-(2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-isobutylphenoxy)acetate Ethyl 2-(2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-cyclopentenylphenoxy)acetate Ethyl 2-(3-(1-benzyl-1H-1,2,3-triazol-4-yl)-4'-fluorobiphenyl-4-yloxy)acetate Ethyl 2-(2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-(1-(trifluoromethyl)-1H-pyrazol-4-yl)phenoxy)acetate Ethyl 2-(2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-(pyridin-4-yl)phenoxy)acetate Ethyl 2-(2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-cyclopentylphenoxy)acetate 1-benzyl-4-(2-methoxy-5-propylphenyl)-1H-1,2,3-triazole 2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-propylphenol, 2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-propylphenyl acetate Ethyl 2-(2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-propylphenoxy)acetate 4-allyl-2-(1-allyl-1H-1,2,3-triazol-4-yl)phenyl acetate Ethyl 2-(4-allyl-2-(1-allyl-1H-1,2,3-triazol-4-yl)phenoxy)acetate 4-(2-methoxy-5-propylphenyl)-1-propyl-1H-1,2,3-triazole 4-propyl-2-(1-propyl-1H-1,2,3-triazol-4-yl)phenyl acetate Ethyl 2-(4-propyl-2-(1-propyl-1H-1,2,3-triazol-4-yl)phenoxy)acetate 4-(5-bromo-2-methoxyphenyl)-1-(cyclobutylmethyl)-1H-1,2,3-triazole 4-(5-allyl-2-methoxyphenyl)-1-(cyclobutylmethyl)-1H-1,2,3-triazole 4-allyl-2-(1-(cyclobutylmethyl)-1H-1,2,3-triazol-4-yl)phenol 4-allyl-2-(1-(cyclobutylmethyl)-1H-1,2,3-triazol-4-yl)phenyl acetate Ethyl 2-(4-allyl-2-(1-(cyclobutylmethyl)-1H-1,2,3-triazol-4-yl)phenoxy)acetate 1-(cyclobutylmethyl)-4-(2-methoxy-5-propylphenyl)-1H-1,2,3-triazole, or A compound, which is ethyl 2-(2-(1-(cyclobutylmethyl)-1H-1,2,3-triazol-4-yl)-4-propylphenoxy)acetate, or a pharmaceutically acceptable salt thereof. 6.4-Bromo-2-ethynyl-1-methoxybenzene was prepared in the presence of CuBr and PMDETA (N,N,N',N",N"-pentamethyldiethylenetriamine) with R 3 '-X 1 and NaN 3 R on the triazole ring by reacting with a mixture 3 ' Comprising a first step of preparing a substituted phenyl-triazole derivative, A method for producing a compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, Above R 3 ' is R 3 or its precursor, X 1 A manufacturing method of a halogen-containing compound.

7. In paragraph 6, Br on the phenyl ring of the product obtained from the previous step is R 2 Step a, which replaces '; Step b of replacing OMe on the phenyl ring of the product obtained from the previous step with OH; and OH on the phenyl ring of the product obtained from step b is R 1 ', and further comprising at least one step selected from the group consisting of step c, Above R 1 ' and R 2 ' are each R 1 or a precursor thereof, and R 2 Or a method for manufacturing the same, which is a precursor thereof.

8. In paragraph 7, Step a is Pd(PPh 3 ) 4 i) R in existence 2 '-SnBu 3 or ii) R 2 '-Boronic acid and Cs 2 CO 3 and perform a reaction with Step b is B(X 2 ) 3 And the reaction is performed at -60℃ to 0℃. Step c is i) R 1 '-X 3 And K 2 CO 3 in the presence of, or ii) acetic anhydride or R 1 '-X 3 And Et 3 Carried out in the presence of N(triethylamine) and optionally DMAP(4-dimethylaminopyridine), The above step a is performed after step 1 or after step c. Above X 2 and X 3 A manufacturing method wherein each of them is independently a halogen.

9. In paragraph 6, R 2 ', R 3 ' or, if both contain alkenyl, a manufacturing method further comprising a step of reducing to alkyl.

10. In paragraph 9, The above step d is H 2 A manufacturing method, which is performed in the presence of a Pd / C catalyst under an atmosphere.

11. A pharmaceutical composition for preventing or treating an ocular disease, comprising a compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition according to claim 11, wherein the eye disease is at least one selected from the group consisting of dry macular degeneration, dry eye, eye fatigue, and decreased visual acuity.

13. In paragraph 11, The composition is a pharmaceutical composition that exhibits an effect of inhibiting or removing A2E (N-retinyl-N-retinylidene ethanolamine) accumulation in human retinal pigment epithelium cells (ARPE-19) and an effect of activating autophagy in human retinal pigment epithelium cells.

14. In paragraph 11, A pharmaceutical composition, wherein the composition additionally comprises a pharmaceutically acceptable carrier or excipient.

15. In paragraph 11, A pharmaceutical composition characterized in that the composition suppresses the worsening or progression of an eye disease.

16. A method for preventing or treating an eye disease, comprising administering the pharmaceutical composition of Article 11 to a subject other than a human.

17. An autophagy-activating composition comprising a compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

18. A food composition for preventing or improving eye disease, comprising a compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

19. A feed composition for preventing or improving eye disease, comprising a compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

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

21. Use of a compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing or treating eye diseases.

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