Aminonaphthoquinone compounds for the treatment and / or prevention of optic neuropathy

Abstract

The present invention provides aminonaphthoquinone compounds for the treatment and / or prevention of optic neuropathy. [Solution] This disclosure provides methods and uses of aminonaphthaquinone compounds in the treatment and / or prevention of optic neuropathy. The present invention also provides a pharmaceutically acceptable composition for use in a method for preventing and / or treating optic neuropathy associated with apoptosis of RGCs, wherein the pharmaceutically acceptable composition comprises a compound of formula (I) described herein. The use of a pharmaceutically acceptable composition in the manufacture of a pharmaceutically acceptable composition for preventing and / or treating optic neuropathy associated with apoptosis of RGCs is also provided, wherein the pharmaceutically acceptable composition comprises a compound of formula (I) described herein.

Description

Technical Field

[0001] Detailed Description of the Invention Field of the Invention The present disclosure relates to the field of diseases. In particular, the present disclosure provides methods and uses of aminonaphthoquinone compounds in the treatment and / or prevention of optic neuropathy.

Background Art

[0002] Background of the Invention Retinal ganglion cells (RGCs) are essential components of the visual system that transmit visual information from the retina to the brain. Maintaining the health of RGCs and optimizing their physiological functions are important for normal vision. However, various eye diseases can cause RGC death, resulting in visual dysfunction or loss. Ischemic optic neuropathy is characterized by a reduction or obstruction in blood flow to the optic nerve, resulting in RGC apoptosis and pathological conditions of vision. The pathophysiological mechanisms contributing to RGC death are complex and associated with numerous interconnected pathways such as excitotoxicity, oxidative stress, and inflammatory responses. Understanding the complex mechanisms of RGC death in ischemic injury is essential for developing therapeutic strategies to maintain RGC function and improve visual recovery. Targeting these pathways may also prevent or attenuate RGC damage while minimizing the impact of ischemic injury on visual function.

Summary of the Invention

[0003] Summary of the Invention The present disclosure is based, at least in part, on the discovery of the use of aminonaphthoquinone compounds and their effective dosages in the prevention and / or treatment of optic neuropathy associated with apoptotic death of retinal ganglion cells (RGCs).

[0004] In one embodiment, the present disclosure is a method for preventing and / or treating optic neuropathy associated with apoptotic death of RGCs, comprising administering to a subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or isomer described herein as an active ingredient, [Chemical Formula] wherein, R1 is halogen; each R2 is H, C 1~10 alkyl, C 2~10 alkenyl, C 2~10 alkynyl, NH2, NO2, C 1~10 alkyloxy, C 1~10 alkylthio, C 1~10 alkylamino, C 1~10 alkyloxyC 1~10 alkyl, OH or CN, C 6~10 aryl or a C 5~7 heterocyclic ring having 1 to 3 heteroatoms selected from the group consisting of N, O and S, the same or different ones represented by; R3 is H, C 1~10 alkyl, C 2~10 alkenyl, C 2~10 alkynyl, NH2, NO2, OH or CN; R4 is H, C 1~10 alkyl, C 2~10 alkenyl, C 2~10 alkynyl, NH2, NO2, OH or CN; R5 is OH, C 3~8 cycloalkyl, phenyl, unsubstituted or phenyl substituted with 1 to 3 same or different substituents selected from OH, CN, halogen, NH2 or C 1~4 alkylpiperazinyl, C 1~6 alkylpiperazinyl, C 1~6 alkylpyridinyl, C 1~6Alkylpyrrolidinyl, pyridinyl, pyrimidinyl, pyrazinyl, piperazinyl, pyrrolidinyl, thiazolyl, benzimidazolyl, pyrazolyl, indazolyl, quinolinyl, indolyl, azaindolyl, azaindazolyl, deazaprinyl, indanyl, morpholinoyl or C 1~4 These are alkylmorpholinoyl compounds, each of which is either unsubstituted or contains OH, CN, halogen, NO2, C 1~4 Substituted with one, two, or three groups selected from alkyl or NH2; X is -C(O) Y is -N-; m is an integer between 0 and 3; and n is an integer between 1 and 7. Provide a method.

[0005] The present invention also provides a pharmaceutical composition for use in a method for preventing and / or treating optic neuropathy associated with apoptosis of RGCs, the pharmaceutical composition comprising a compound of formula (I) described herein. The use of a pharmaceutical composition in the manufacture of a pharmacopoeia for preventing and / or treating optic neuropathy associated with apoptosis of RGCs is also provided, the pharmaceutical composition comprising a compound of formula (I) described herein.

[0006] In some embodiments, m is 0; R1 is a halogen; n is any integer from 1 to 4; R3 is H; X is C(O); R4 is H; and R5 is OH, C 3~8 Cycloalkyl, phenyl, unsubstituted, or OH, CN, halogen, NH2 or C 1~4 Phenyl, C substituted with one to three identical or different substituents selected from alkylpiperazinyl 1~6 Alkylpiperazinyl, C 1~6 Alkylpyridinyl, C 1~6Alkylpyrrolidinyl, pyridinyl, pyrimidinyl, pyrazinyl, piperazinyl, pyrrolidinyl, thiazolyl, benzimidazolyl, pyrazolyl, indazolyl, quinolinyl, indolyl, azaindolyl, azaindazolyl, deazaprinyl, indanyl, morpholinoyl or C 1~4 These are alkylmorpholinoyl compounds, each of which is either unsubstituted or substituted with one, two, or three groups selected from OH, CN, halogens, or NH2.

[0007] In some embodiments, m is 0; R1 is a halogen; n is any integer between 1 and 2; R3 is H; X is C(O); R4 is H; and R5 is OH, C 3~8 Cycloalkyl, pyridinyl, phenyl, and containing NH2, halogen, OH, CN or C 1~4 Phenyl compounds substituted with 1-3 alkylpiperazinyl groups; unsubstituted or NO2, NH2, or C 1~4 Alkyl-substituted pyrimidinyl; unsubstituted or NO2, NH2 or C 1~4 Alkyl-substituted pyrazinyl; unsubstituted or NO2, NH2 or C 1~4 Alkyl-substituted thiazolyl; unsubstituted or NO2, NH2 or C 1~4 Alkyl-substituted benzimidazolyl; unsubstituted or NO2, NH2 or C 1~4 Alkyl-substituted pyrazolyl; unsubstituted or NO2, NH2 or C 1~4 Alkyl-substituted indazolyl; unsubstituted or NO2, NH2 or C 1~4 Alkyl-substituted quinolinyl; unsubstituted or NO2, NH2 or C 1~4 Alkyl-substituted indolyl; unsubstituted or NO2, NH2 or C 1~4 Alkyl-substituted azindazolyl; unsubstituted or NO2, NH2 or C 1~4 Alkyl-substituted deazaprinyl; unsubstituted or NO2, NH2 or C 1~4Alkyl-substituted indanyl; or unsubstituted or NO2, NH2 or C 1~4 It is an alkyl-substituted morpholinoyl.

[0008] In some embodiments, the compound of formula (I) is; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-hydroxybenzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(pyridine-2-yl)benzamide; N-(2-aminophenyl)-4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(pyridine-3-yl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(pyridine-4-yl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(3-fluorophenyl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(4-fluorophenyl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-phenylbenzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(2-fluorophenyl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(thiazole-2-yl)benzamide; N-(1H-benzo[d]imidazole-2-yl)-4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)amino)methyl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(4-hydroxyphenyl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(3-ethynylphenyl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(2-fluoro-4-iodophenyl)benzamide; N-(1H-benzo[d]imidazole-5-yl)-4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-cyclopropylbenzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-cyclopentylbenzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(1H-indazole-5-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(5-methylthiazole-2-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(5-methyl-3H-pyrazole-3-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(3-nitropyridine-4-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(quinoline-6-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(quinoline-8-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(quinoline-3-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(quinoline-5-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(2-methylquinoline-4-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(1H-indole-5-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(2-methyl-1H-indole-5-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(1H-indole-7-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(1H-indole-4-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(4-(4-ethylpiperazine-1-yl)phenyl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(1H-indazole-6-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(1H-pyrazolo[3,4-b]pyridine-5-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(7-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(2,3-dihydro-1H-inden-4-yl)benzamide; 4-(((3-bromo-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(pyridine-2-yl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(pyrimidine-4-yl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(pyrazine-2-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(pyridine-4-ylmethyl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(2-morpholinoethyl)benzamide; N-(2-(1H-indole-3-yl)ethyl)-4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(2-(dimethylamino)ethyl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(2-(pyrrolidine-1-yl)ethyl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(2-(diethylamino)ethyl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)amino)methyl)-N-(2-(piperidine-1-yl)ethyl)benzamide; and 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(2-(4-methylpiperazine-1-yl)ethyl)benzamide; Alternatively, it may be selected from a pharmaceutically acceptable salt, hydrate, or isomer thereof.

[0009] In further embodiments, the compounds disclosed herein are of the following formula: [ka] It is 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)amino)methyl)-N-(pyridine-4-yl)benzamide or a pharmaceutically acceptable salt, hydrate, or isomer thereof.

[0010] In some embodiments, treatment and / or prevention of optic neuropathy associated with apoptotic death of RGCs is mediated through the modulation of the Nrf2 and TXNIP / NLRP3 inflammasome pathways in the retina.

[0011] In some embodiments, the compounds disclosed herein enhance the expression of nuclear factor erythroid 2-related factor (Nrf2), downregulate thioredoxin-interacting protein (TXNIP) expression, inhibit NLR family pyrine domain-containing 3 (NLRP3) activation, and / or reduce the inflammatory factors interleukin (IL)-1P and IL-6 in the retina.

[0012] In some embodiments, optic neuropathy associated with apoptotic death of RGCs is a disease related to optic nerve ischemic injury.

[0013] In some embodiments, the optic nerve ischemic injury-related disease is anterior ischemic optic neuropathy (AION) or posterior ischemic optic neuropathy (PION). In further embodiments, the disease associated with optic nerve ischemic injury is AION.

[0014] In some further embodiments, AION is non-arteritic ischemic optic neuropathy (NAION) or arteritic anterior ischemic optic neuropathy (AAION). In some further embodiments, PION is non-arteritic posterior ischemic optic neuropathy (NPION) or arteritic posterior ischemic optic neuropathy (APION).

[0015] In one embodiment, the compounds described herein are administered subcutaneously. [Brief explanation of the drawing]

[0016] [Figure 1] Figures 1(A)-(C) show the effect of M01 treatment on promoting RGC survival in the AION model. RGCs were retrogradely labeled with Fluoro-gold, and their density in the central and midperiphery retina was quantified from retinal flat mounts in the sham, AION+PBS, AION+100 mg / Kg M01, and AION+200 mg / Kg groups (A). RGC survival rates were 45.73%, 77.20%, and 58.87% in the central retina (B), and 37.5%, 80.19%, and 63.82% in the midperiphery retina (C) in the AION+PBS, AION+100 mg / Kg M01, and AION+200 mg / Kg groups, respectively. n=6 in each group. *, p<0.05, **, p<0.01, ****, p<0.0001. Scale bar = 50|im.

[0017] [Figure 2]Figure 2 shows the effect of M01 treatment on maintaining visual function in the AION model. P1-N2 amplitudes in the sham and AION + 100 mg / kg M01 groups were significantly higher than those in the AION + PBS group, according to FVEP data. However, there was no statistically significant change in P1-N2 amplitude between AION and PBS. n=6 in each group. *, p<0.05, ***, p<0.001.

[0018] [Figure 3] Figures 3(A) and (B) show that M01 treatment mitigated ischemia-induced RGC apoptosis. RGC apoptosis was assessed by TUNEL (green), and the nuclei were labeled with DAPI (blue) (A). TUNEL-positive cells in the GCL layer of the retina were greatly enhanced by AION induction, while M01 therapy efficiently reduced TUNEL-positive cells in the GCL layer of the retina. n=6 in each group. **, p<0.01, ****, p<0.0001. Scale bar = 50|im(B).

[0019] [Figure 4] Figures 4(A) and (B) show that M01 treatment reduced ischemia-induced macrophage infiltration in ON. Anti-ED-1 (green) antibody was used to detect macrophage infiltration in ON, while DAPI (blue) was used to identify nuclei (A). The number of ED-1 positive cells in ON increased after ON infarction. However, M01 treatment reduced the amount of ED-1 positive cells in ON. *, p<0.05, ***, p<0.001. Scale bars = 100ym in the upper column and 50|im in the lower column (B).

[0020] [Figure 5]Figures 5(A)-(H) show that M01 reduced microglia infiltration in the retina and regulated microglia polarization in the AION model. (A), (C), (E) Immunofluorescence images and quantitative data of Iba1(B) and IL-6(D) expression in the retina, and Ym1(F) expression in ON. (G) Immunoblotting images and quantification of Arg1(H) protein expression levels and IL-ip(I) in the retina. M01 therapy significantly reduced ischemia-induced Iba1-positive cells and the pro-inflammatory cytokines IL1p and IL-6 in the retina, while significantly increasing the expression of M2 markers Ym1 and Arg1 after ischemic injury in ON. n=6 in each group. *, p<0.05, **, p<0.01, ***, p<0.001. Scale bar = 50|im in A and C. In E, the scale bars are 100ym in the upper column and 50ym in the lower column.

[0021] [Figure 6] Figures 6(A) and (B) show that M01 treatment reduced ischemic-induced ONH edema. Image-guided OCT was used to detect ONH edema in each group. OCT scans showed that ON infarction caused residual disc edema (A), and that M01 treatment significantly reduced disc edema 28 days after AION induction. n=6 in each group; p<0.05 (B).

[0022] [Figure 7] Figure 7 shows that M01 treatment attenuated ischemia-induced ON demyelination. Confocal images showed a significant reduction in CNPase levels in ON after ON infarction, while M01 treatment preserved myelin formation in ON. Longitudinal sections of ON were stained with antibody against CNPase (green), and the nuclei were stained with DAPI (blue). n=6 in each group. *, p<0.05, ****, p<0.0001. Scale bars = 100|im in the upper column; 50|im in the lower column.

[0023] [Figure 8]Figure 8 shows that M01 regulated the Nrf2 / TXNIP / NLRP3 axis after ON infarction. (A) Immunoblotting analysis showed Nrf2, NEDD4, TXNIP, and NLRP3 protein expression levels in the sham, AION+PBS, and AION+M01 groups. (B-D) Quantitative data from (A). GAPDH was used as an internal loading control. All data are shown as mean ± SD; n=6 in each group. [Modes for carrying out the invention]

[0024] Detailed description of the invention The present invention is at least in part based on the discovery of the use of aminonaphthoquinone compounds and their effective doses in the prevention and / or treatment of optic neuropathy associated with apoptosis death of retinal ganglion cells (RGCs).

[0025] When used herein, unless the context requires otherwise, the terms “comprise,” and variations such as “comprising,” “comprises,” and “comprised” are not intended to exclude other additives, components, integers, or steps.

[0026] When used herein, unless the context requires otherwise, the disclosed method steps are not intended to be restrictive, nor are they intended to indicate that each step is essential to the method or that each step must occur in the order disclosed.

[0027] As used herein, the use of “or” means “and / or” unless otherwise specified. In the context of multiple dependent claims, the use of “or” refers only selectively to one or more preceding independent or dependent claims.

[0028] When used herein, all numerical values ​​are approximations and may be modified to account for measurement errors and rounding of significant figures. The use of “approximately” before a particular measured quantity includes variations due to sample impurities, measurement errors, human error, and statistical variability, as well as rounding of significant figures.

[0029] As used herein, the term “pharmaceutically acceptable salt” refers to salts that are within the bounds of sound medical judgment, suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc., and that correspond to a reasonable benefit / risk ratio. Pharmacochemically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19. Pharmacochemically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or salts of amino groups formed with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or salts of amino groups formed by the use of other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, bicarbonate, boric acid, butyric acid, camphorate, camphosulfonate, citric acid, cyclopentanepropionic acid, digluconic acid, dodecyl sulfate, ethanesulfonic acid, formic acid, fumaric acid, glucoheptonic acid, glycerophosphate, gluconic acid, hemisulfate, heptanoic acid, hexanoic acid, hydroiodic acid, 2-H Examples include droxyethanesulfonic acid, lactobionic acid, lactic acid, lauric acid, lauryl sulfate, malic acid, maleic acid, malonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, pectinate, persulfate, 3-phenylpropionic acid, phosphoric acid, picric acid, pivalate, propionic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecanoic acid, and valerates. Examples of salts derived from appropriate bases include alkali metals, alkaline earth metals, and ammonium salts.Typical alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Furthermore, pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfons, and aryl sulfons.

[0030] The term "solvate" usually refers to a form of compound that has associated with a solvent through solvolysis. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, and diethyl ether.

[0031] As used herein, the terms “administer,” “administering,” or “administration” refer to the act of implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing the compounds or pharmaceutically active compositions of the present invention into or into a subject.

[0032] In this specification, the terms “condition,” “disease,” and “disorder” are to be used interchangeably.

[0033] In this specification, the “effective dose” of a compound refers to an amount sufficient to elicit the desired biological response, i.e., to treat a condition. As will be understood by those skilled in the art, the effective dose of a compound described herein may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the method of administration, and the age and health of the subject. The effective dose encompasses both therapeutic and prophylactic measures.

[0034] In this specification, the “therapeutic dose” of a compound is an amount sufficient to provide a therapeutic effect in the treatment of a condition, or to delay or minimize one or more symptoms associated with that condition. The therapeutic dose of a compound means the amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic effect in the treatment of that condition. The term “therapeutic dose” may include an amount that improves the overall therapy, reduces or avoids the symptoms or causes of the condition, and / or enhances the therapeutic efficacy of another therapeutic agent.

[0035] In this specification, the “preventive effective dose” of a compound is the amount sufficient to prevent a condition or one or more symptoms associated with that condition, or to prevent their recurrence. The preventive effective dose of a compound means the amount of therapeutic agent that, alone or in combination with other agents, provides a preventive effect in the prevention of that condition. The term “preventive effective dose” may include an amount that improves overall prevention or enhances the preventive efficiency of another preventive agent.

[0036] As used herein, the term “pharmaceutically acceptable carrier” refers to a conventional solid, semi-solid, or liquid filler, diluent, encapsulating material, formulation aid, or carrier in the art for use with a therapeutic agent for administration to a subject. A pharmaceutically acceptable carrier is non-toxic to the recipient at the dosage and concentration used, and is compatible with the other components of the formulation. A pharmaceutically acceptable carrier is determined in part by the particular composition to be administered, and similarly by the particular method used to administer the composition.

[0037] As used herein, the term “subject” is defined to include animals such as mammals, including but not limited to primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In certain embodiments, the subject is human. The terms “subject” and “patient” are used interchangeably herein to refer to mammalian subjects, such as humans.

[0038] As used herein, the terms “treat,” “treating,” and “treatment” refer to the eradication or remission of a disease or disorder, or one or more symptoms associated with a disease or disorder. In certain embodiments, the terms refer to minimizing the spread or exacerbation of a disease or disorder to a subject having such a disease or disorder, resulting from the administration of one or more prophylactic or therapeutic agents. In some embodiments, the terms refer to the administration of a compound or form of drug provided herein, with or without one or more additional active agents, after the diagnosis or onset of symptoms of a particular disease.

[0039] As used herein, the terms “prevent,” “preventing,” and “prevention” refer to the prevention of the onset, recurrence, or spread of a disease or disorder, or of one or more of its symptoms. In particular embodiments, the terms refer to treatment or administration of a compound, antibody, or drug form provided herein, with or without one or more other additional active agents, to a patient at risk of a disease or disorder provided herein, especially before the onset of symptoms. The terms encompass the inhibition or reduction of symptoms of a particular disease. In this regard, the term “prevention” may be used interchangeably with the term “preventive treatment.”

[0040] As used herein, the terms “co-administration” and “in combination” include, unless otherwise indicated, the administration of two or more therapeutic agents simultaneously, concurrently, separately, or consecutively, without specific time constraints. In one embodiment, the therapeutic agents are the same composition or in the form of a single dose. In other embodiments, the therapeutic agents are separate compositions or in the form of a single dose.

[0041] Apoptosis of retinal ganglion cells (RGCs) is a common pathological feature in different types of optic neuropathy, such as ischemic optic neuropathy and glaucoma, and leads to irreversible loss of visual function. Potent and effective protection against RGC death is a critical factor in the development of successful treatments for these optic neuropathy. This disclosure evaluates the neuroprotective effects of the compounds described herein, which are HECT domain-E3 ubiquitin ligase inhibitors, on retinal ganglion cells after ischemic injury. Administration of the compounds described herein significantly increased RGC survival after AION induction and maintained visual function. The number of TUNEL-positive and ED1-positive cells after ischemic infarction with compound treatment was significantly reduced, and optic disc edema was greatly alleviated. Furthermore, the compounds described herein effectively induced optic demyelination and enhanced M2 microglia polarization after AION induction. The compounds described herein enhance the expression of nuclear factor erythroid 2-related factor (Nrf2) in the retina after ischemic injury; downregulate thioredoxin-interacting protein (TXNIP) expression; inhibit NLR family pyrine domain-containing 3 (NLRP3) activation; and further reduce the inflammatory factors interleukin (IL)-1P and IL-6. These findings suggest that the compounds described herein have therapeutic potential in optic nerve ischemic injury-related disorders by modulating the Nrf2 and TXNIP / NLRP3 inflammasome pathways in the retina.

[0042] The compounds described herein may be prepared using methods known to those skilled in the art in view of this disclosure. The compounds described herein and methods for their preparation are disclosed in PCT / US2015 / 041767 and USSN62 / 199,207. For example, preferred compounds of the present invention may be prepared as shown in the following scheme. Scheme 1 [ka] Scheme 2 [ka]

[0043] In another embodiment, the compounds described herein are in the form of a pharmaceutical composition or combination comprising the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or isomer as an active ingredient. In one embodiment, the pharmaceutical composition or combination is in one or more unit dosage forms. Preferably, the dosage form is in one or more capsule or tablet forms. In one embodiment, the compound of formula (I) is 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)amino)methyl)-N-(pyridine-3-yl)benzamide.

[0044] In some embodiments, the pharmaceutical compositions of the present invention contain about 100 mg to about 300 mg, about 150 mg to about 300 mg, about 150 mg to about 250 mg, about 200 mg to about 250 mg, about 220 mg to about 280 mg, about 220 mg to about 250 mg, or about 200 mg to about 220 mg of the active ingredient in a single tablet; preferably, about 200 mg or 220 mg in a single tablet. In another further embodiment, the pharmaceutical composition of the present invention comprises about 100 mg to about 500 mg, about 150 mg to about 500 mg, about 180 mg to about 500 mg, about 200 mg to about 500 mg, about 150 mg to about 350 mg, about 150 mg to about 300 mg, about 200 mg to about 400 mg, about 200 mg to about 400 mg, about 350 mg, about 200 mg to about 300 mg, about 250 mg to about 500 mg, about 250 mg to about 400 mg, about 250 mg to about 350 mg, or about 250 mg to about 300 mg of the active ingredient in a single capsule; preferably, a single capsule contains about 250 mg of the active ingredient.

[0045] The compounds of the present invention may be administered as raw chemical substances, or they may be presented as pharmaceutical formulations. Accordingly, the present invention provides pharmaceutical formulations or compositions comprising a compound or a pharmaceutically acceptable salt, prodrug, or solvate thereof, together with one or more pharmaceutically acceptable carriers and, optionally, one or more other therapeutic components. The carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation and is not harmful to its recipient. The appropriate formulation depends on the chosen route of administration. The formulation may take the form of a tablet, pill, capsule, semi-solid, powder, sustained-release formulation, solution, suspension, elixir, aerosol, or any other suitable composition; comprising at least one compound of the present invention in combination with at least one pharmaceutically acceptable excipient. Suitable excipients are well known to those skilled in the art, and methods for formulating them and compositions can be found in standard references such as Remington's *The Science and Practice of Pharmacy*, A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, Pa. Suitable liquid carriers (especially for injectable solutions) include water, aqueous saline, aqueous dextrose solution, and glycol. The pharmaceutical compositions of the present invention can be produced by methods known in themselves, for example, by conventional mixing, dissolution, granulation, sugar-coated tablet preparation, powdering, emulsification, capsuleing, encapsulation, or compression processes.

[0046] The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intra-articular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal, and topical (including cutaneous, buccal, sublingual, and intraocular) administration, but the most suitable route may depend, for example, on the recipient's condition and impairment. Oral administration is the preferred route of administration. The formulations are conveniently presented in unit dosage forms and can be prepared by any method known in the field of pharmacy. All methods involve a step in which the compound of the present invention or a pharmaceutically acceptable salt, prodrug, or solvate ("active ingredient") undergoes association with a carrier constituting one or more auxiliary ingredients. Generally, formulations are prepared by homogeneous and close association of the active ingredient with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, by shaping the product into the desired formulation.

[0047] For oral administration, preferred pharmaceutical compositions of the present invention include powders, granules, pills, tablets, lozenges, chews, gels, and capsules, as well as liquids, syrups, suspensions, elixirs, and emulsions. These compositions may also contain antioxidants, flavorings, preservatives, suspending agents, thickeners or emulsifiers, colorants, flavorings, and other pharmaceutically acceptable additives. Formulations for oral administration may be formulated for immediate release or controlled release, where controlled release includes delayed, sustained, pulsed, controlled, targeted, and programmed release.

[0048] For parenteral administration, the compounds of the present invention are administered intravenously, intra-arterially, intraperitoneally, intramuscularly, subcutaneously, or via other injection or infusion to the bloodstream, muscle, or directly to the internal organs. Parenteral formulations may be prepared as aqueous injection solutions, which may contain, in addition to the compounds of the present invention, buffers, antioxidants, bacteriostatic agents, salts, carbohydrates, and other additives commonly used in such solutions. Parenteral administration may be immediate-release or controlled-release (e.g., injected or implanted depot formulations).

[0049] The compounds or compositions of the present invention may also be administered topically, intradermally, or transdermally to the skin or mucous membranes. Typical formulations include gels, hydrogels, lotions, solutions, creams, ointments, bandages, foams, skin patches, wafers, implants, and microemulsifications. The compounds or compositions of the present invention may also be administered by inhalation or intranasal administration as a dry powder, aerosol spray, or droplet. Additional routes of administration for the compounds of the present invention include vaginal and rectal administration (by means of suppositories, pessaries, or enemas), as well as to the eyes and ears.

[0050] The medication plan may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily, or the dose may be proportionally reduced as indicated by the urgency of the treatment situation.

[0051] For ease of administration and uniformity of dosage, it is particularly advantageous to formulate compounds in dosage units. As used herein, a dosage unit refers to a physical individual unit suitable as a unit dose for the target being treated; each contains a therapeutically effective amount of the compound and at least one pharmaceutical excipient. The drug product contains the dosage unit in a container labeled or accompanied by a label indicating the intended method of treatment.

[0052] It is understood that the examples described herein are merely illustrative of the present invention. Certain modifications to the articles and / or methods used may still achieve the objectives of the present invention. Such modifications are intended to remain within the scope of the claimed invention. [Examples]

[0053] material and method

[0054] animal

[0055] Uninbred adult male Wistar rats weighing 100-125 grams (4-6 weeks old) were procured from BioLASCO Co. in Taiwan and housed in filter-top cages at the Laboratory Animal Center of Tzu Chi University. The Institutional Animal Care and Use Committee (IACUC) of Tzu Chi University (No. 109069, April 15, 2021) approved the animal management and experimental protocols. For general anesthesia, a cocktail of ketamine (100 mg / kg) and xylazine (10 mg / kg) was delivered intramuscularly. In all trials, 0.5% alkaine (Alcon, Pools, Belgium) was used as a local anesthetic, and Mydrin-P (Santen Pharmaceutical Co., Ltd, Osaka, Japan) was used for pupillary dilation.

[0056] A rat model of ischemic optic neuropathy for experimental purposes (AION induction)

[0057] An experimental model of ischemic optic neuropathy was created using photodynamic thrombosis. 2.5 mM Rose Bengal (1 mL per kg of animal body weight) in pH 7.4 PBS was injected into the tail vein of rats. Immediately after injection (within 1 minute), the optic disc was subjected to an argon green laser (wavelength 514 nm, size 500 mm, and output 80 mW) for a total of 12 pulses (1 pulse per second).

[0058] Electroretinography (ERG) and flash visual evoked potentials (FVEP)

[0059] Full-field flash ERG and FVEP

[13] were performed 28 days after ischemic infarction using the CELERIS System (Diagnosys LLC, MA, USA). Primary visual cortical electrodes were considered active (positive) electrodes, frontal cortical electrodes were considered reference (negative) electrodes, and caudal electrodes were treated as ground electrodes. For FVEP, parameters were flash intensity of 0.5 cd.s / m2 without background illumination, flash frequency of 1.02 Hz, and light-adapted negative response (PhNR) intensity of 10 cd.s / m2. The mean of 100 sweeps was collected, and the P1-N2 amplitude of FVEP was recorded to assess the integrity of visual function. PhNR amplitude was measured from baseline after the b wave to the negative trough to assess RGC and endoretinal (amacrine and Müller-glial cell) function.

[0060] Image-guided OCT imaging

[0061] As previously described [8], image-guided OCT imaging was performed. Briefly, images of the minimum rim width at the Bruch membrane opening (expressed as optic nerve width (ONW)) were taken on days 1, 3, 7, 14, and 28 after AION. At least six clear captures were obtained for each eye. The mean ONW was calculated and analyzed using GraphPad Prism 7.0.

[0062] Retrograde labeling of RGCs and measurement of RGC density using fluorogold

[0063] RGCs were retrograde-labeled as previously described

[35] . Briefly, retrograde labeling was performed one week before euthanasia of the animals to avoid overcounting of macrophages or microglia cells. One week after labeling, the optic cups were removed and maintained in 10% formalin. Under a 100x fluorescence microscope, the retina was laid flat and 1 mm to 3 mm from the optic disc was examined, and central and peripheral RGC densities were calculated. The retina 1 mm to 3 mm from the center was examined, and central and peripheral RGC densities were calculated. At least 10 random locations were counted independently, and photographs were processed using ImageJ software.

[0064] Immunohistochemistry (IHC) in ON and retinal tissue

[0065] Using IHC, we identified a set of markers suggestive of the processes of neuroinflammation, autophagy, and microglial polarization, and evaluated the effects of an E3 ligase inhibitor (compound M01) on the structural and morphological aspects of the retina and optic nerve after ischemic injury. The detailed process has already been described [8]. Briefly, after blocking retinal or ON slices with blocking buffer, they were incubated overnight at 4°C with primary antibodies against ED1, Iba1, IL-6, Ym-1, and CNPase diluted in antibody dilution buffer (1% BSA, 0.1% coldfish skin gelatin, and 0.5% Triton® X-100; 1:200 in 1 PBS (pH 7.2)). Secondary antibodies were added to the tissue and incubated at room temperature for 1 hour. Photographs were taken using a Zeiss confocal laser scanning microscope (Carl Zeiss, Inc).

[0066] TUN EL assay

[0067] Apoptosis of retinal ganglion cells resulting from axonal degeneration is considered an early pathological change in ischemic optic neuropathy. Apoptotic cells in the ganglion cell layer (GCL) were visualized using the TUNEL assay (DeadEnd® Fluorometric TUNEL System; Promega Corporation, WI, USA) according to the manufacturer's instructions. Retinal sections were examined with a fluorescence microscope (Zeiss), and TUNEL+ cells in the GCL were counted using ImageJ software. Apoptotic cells were quantified by measuring TUNEL-positive cells from whole sections, and the average number of apoptotic cells per section was calculated from 6 sections from both eyes of 3 rats from each group.

[0068] Immunoblotting analysis

[0069] Immunoblotting was performed as previously described. Protein 50(ig) was isolated on a 10% SDS gel and transferred to a polyvinylidene difluoride (PVDF) membrane. The membrane was incubated with primary antibodies against Iba1, IL-6, IL-1B, NLRP3, TXNIP, NEDD4, Arg1, and GAPDH (1:2000; Sigma-Aldrich Co, MO). The membrane was further incubated with appropriate secondary antibodies. Images were captured and analyzed using the ChemiDoc MP System (Bio-Rad Laboratories, CA, USA).

[0070] statistical analysis

[0071] All data are given as mean ± SD. We performed statistical analysis using GraphPad Prism 7.0 (GraphPad Software, La Jolla, CA, USA). To compare more than two groups, we used the Kruskal-Wallis test after Dunn's multiple comparison test adjustment. P values ​​less than 0.05 were considered statistically significant, with * indicating p<0.05, ** indicating p<0.01, and *** indicating p<0.001.

[0072] Example 1: M01 promoted RGC survival after infarction.

[0073] RGCs were retrogradely labeled with Fluoro-gold, placed on the entire retina, and RGC survival after M01 treatment following AION induction was evaluated. M01 is 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(pyridine-4-yl)benzamide, which has the following formula: [ka]

[0074] RGCs in the central and mid-peripheral retina (Figure 1) were significantly more preserved in the 100 mg / Kg M01 treatment group 4 weeks after infarction compared to the PBS treatment group. 100 mg / Kg M01 treatment increased the RGC survival rate in the central retina to 31.47% (Sham: 2237 ± 257 cells / mm2, AION + PBS: 1023 ± 458 cells / mm2; AION + 100 mg / Kg M01: 1727 ± 485 cells / mm2). 2 ;AION+200mg / Kg M01:1317±846 cells / mm 2 ), and increased to 42.46% in the midperiphery retina (Sham: 1888±295 cells / mm2; AION+PBS: 708±322 cells / mm2). 2 ;AION+100mg / Kg M01:1514±391 cells / mm 2 ;AION+200mg / Kg M01:1205±662 cells / mm 2 ).

[0075] Example 2: M01 maintained visual function after infarction.

[0076] FVEP was recorded and visual function was monitored. P1-N2 amplitude was significantly reduced after AION induction compared to the Sham group (Figure 2), while 100 mg / Kg M01 treatment effectively maintained visual function at 28 days post-infarction (Sham: 24.29 ± 6.81 yV; AION + PBS: 12.34 ± 4.88 yV; AION + 100 mg / Kg M01: 20.10 ± 3.09 yV; AION + 200 mg / Kg M01: 19.57 ± 5.38 yV). 100 mg / Kg M01 therapy significantly increased RGC survival and visual function based on RGC density and FVEP measurement assessments. 100 mg / Kg M01 was selected for further treatment.

[0077] Example 3: M01 reduced RGC apoptosis after infarction.

[0078] Frozen retinal sections were prepared for the TUNEL experiment and examined by confocal microscopy to determine whether M01 reduces RGC apoptotic death after ischemic injury. Figure 3 shows that the mean number of TUNEL-positive cells in PBS-injected retina was significantly higher than in Sham retina (15.3±4.5 / HPF vs. 4.0±2.0 / HPF, n=6, p<0.001), while M01 treatment significantly reduced the mean number of TUNEL-positive cells in retina (7.1±3.9 / HPF vs. AION+PBS, n=6, p=0.0019). These findings suggest that M01 therapy effectively reduces the impact of photothrombosis on the optic nerve.

[0079] Example 4: M01 reduced microglial infiltration in ON and regulated microglial polarization after infarction.

[0080] In the pathogenesis of ischemic optic neuropathy, activated macrophages or microglia may induce apoptotic death of RGCs. We found ED1 (Figure 4) and Iba1-positive cells (Figures 5A and 5B) infiltrating the optic nerve and retina 28 days after ON infarction, demonstrating that microglial activation was more strongly controlled in the PBS-treated group compared to the sham group (ED-1:AION+PBS: 160.0±39.6 / HPF, sham: 17.5±11.3 / HPF, n=6, p<0.001). Compared to PBS treatment, M01 therapy reduced ED-positive and Iba1-positive cell infiltration in ON and the retina (ED-1:AION+M01: 36.9±17.6 / HPF vs. AION+PBS, n=6, p=0.0419). Furthermore, IHC and immunoblotting results showed that the PBS-treated group had significantly higher levels of M1 microglia markers, IL-6 (Figures 5C and 5D) and IL-13 (Figures 5G and 5I) than the sham group. In contrast, compared to the PBS-treated group, M2 microglia markers, Ym1 (Figures 5E and 5F) and Arg-1 (Figures 5G and 5H) were upregulated in the M01-treated group. These results suggest that M01 treatment minimized the inflammatory response by promoting M2 polarization and significantly reducing M1 microglia activation and pro-inflammatory cytokine secretion.

[0081] Example 5: Treatment with M01 reduced post-infarction ONH edema.

[0082] Optic disc swelling is one of the most common clinical features in ischemic optic neuropathy. Spectral domain OCT was performed to evaluate the effect of M01 treatment on the rAION model, and ONH width was monitored on days 1, 3, 7, 14, and 28 after AION (Figure 6). Four weeks after AION induction and M01 treatment, M01-treated AION eyes showed a significant reduction in ONH edema compared to PBS-treated AION eyes (AION+PBS: 321.26±18.60ym, n=6; AION+M01: 238.82±13.00ym, n=6, p<0.05).

[0083] Example 6: Treatment with M01 maintained myelin formation in ON after infarction.

[0084] Myelination is essential for protecting and supporting ON fibers and is responsible for the efficient transmission of visual signals along nerve fibers. Optic demyelination can develop derivatively in response to ischemic injury because obstruction or reduced blood flow can impair nutrient supply to myelin-producing cells, resulting in myelin destruction [36-38]. Therefore, after ischemic injury, we examined levels of 23-cyclic nucleotide 3'-phosphodiesterase (CNPase), a major myelin-related enzyme, in the CNS and optic nerve. CNPase levels were significantly lower in the PBS-treated group compared to the Sham group (Figure 7). M01 administration prevented a dramatic decrease in ON CNPase levels after AION induction. These findings suggest that M01 therapy maintained the integrity of ON myelination in ischemic injury.

[0085] Example 7: M01 induced Nrf2 signaling and suppressed TXNIP / NLRP3 activation after AION induction.

[0086] Nrf2 activation reduced oxidative damage to RGCs, controlled microglial polarization, attenuated ON and retinal inflammatory responses, and maintained visual function after ON ischemic injury. Furthermore, NEDD4 is an E3 ubiquitin ligase of Nrf2 and has been shown to facilitate Nrf2 ubiquitination. NEDD4 inhibition reduced oxidative stress by reducing Nrf2 degradation. To understand the further molecular mechanisms underlying the protective effect of M01 on RGCs, protein levels of Nrf2, NEDD4, TXNIP, and NLRP3 were assessed using immunoblotting. Immunoblotting data showed that TXNIP and NLRP3 expression levels were significantly higher in the AION+PBS group than in the Sham group. M01 therapy was able to increase Nrf2 expression while decreasing TXNIP and NLRP3 expression in the retina after AION induction (Figure 8). There were no significant differences in NEDD4 expression levels among the sham, AION+PBS, and AION+M01 groups. These findings suggest that M01 protected RGCs after ON ischemic injury by inhibiting TXNIP and NLRP3 activation via Nrf2 upregulation. Furthermore, M01 did not show any inhibitory effect on NEDD4 expression in the retina. The present invention provides, for example, the following items: (Item 1) A pharmaceutical composition for use in a method for preventing and / or treating optic neuropathy associated with apoptosis death of RGCs, wherein the pharmaceutical composition comprises an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or isomer, [ka] During the ceremony, R1 is a halogen; Each R2 is H, C 1~10 Alkyl, C 2~10 Alkenil, C 2~10 Alkinyl, NH2, NO2, C 1~10 Alkyloxy, C 1~10 Alkylthio, C 1~10 Alkylamino, C 1~10Alkyloxy C 1~10 Alkyl, OH, or CN, C 6~10 C having 1 to 3 heteroatoms selected from the group consisting of aryl or N, O, and S. 5~7 complex algebras, The same or different things represented by; R3 is H, C 1~10 Alkyl, C 2~10 Alkenil, C 2~10 Alkynyl, NH2, NO2, OH, or CN; R4 is H, C 1~10 Alkyl, C 2~10 Alkenil, C 2~10 Alkynyl, NH2, NO2, OH, or CN; R5 is OH, C 3~8 Cycloalkyl, phenyl, unsubstituted, or OH, CN, halogen, NH2 or C 1~4 Phenyl, C substituted with one to three identical or different substituents selected from alkylpiperazinyl 1~6 Alkylpiperazinyl, C 1~6 Alkylpyridinyl, C 1~6 Alkylpyrrolidinyl, pyridinyl, pyrimidinyl, pyrazinyl, piperazinyl, pyrrolidinyl, thiazolyl, benzimidazolyl, pyrazolyl, indazolyl, quinolinyl, indolyl, azaindolyl, azaindazolyl, deazaprinyl, indanyl, morpholinoyl or C 1~4 These are alkylmorpholinoyl compounds, each of which is either unsubstituted or contains OH, CN, halogen, NO2, C 1~4 Substituted with one, two, or three groups selected from alkyl or NH2; X is -C(O) Y is -N-; m is an integer between 0 and 3; and n is an integer between 1 and 7. Pharmaceutical composition. (Item 2) m is 0; R1 is a halogen; n is any integer from 1 to 4; R3 is H; X is C(O); R4 is H; and R5 is OH, C3~8 Cycloalkyl, phenyl, unsubstituted, or OH, CN, halogen, NH2 or C 1~4 Phenyl, C substituted with one to three identical or different substituents selected from alkylpiperazinyl 1~6 Alkylpiperazinyl, C 1~6 Alkylpyridinyl, C 1~6 Alkylpyrrolidinyl, pyridinyl, pyrimidinyl, pyrazinyl, piperazinyl, pyrrolidinyl, thiazolyl, benzimidazolyl, pyrazolyl, indazolyl, quinolinyl, indolyl, azaindolyl, azaindazolyl, deazaprinyl, indanyl, morpholinoyl or C 1~4 These are alkylmorpholinoyl compounds, each of which is either unsubstituted or substituted with one, two, or three groups selected from OH, CN, halogens, or NH2. A pharmaceutical composition for use as described in any one of the preceding items. (Item 3) m is 0; R1 is a halogen; n is any integer between 1 and 2; R3 is H; X is C(O); R4 is H; and R5 is OH, C 3~8 Cycloalkyl, pyridinyl, phenyl, and containing NH2, halogen, OH, CN or C 1~4 Phenyl compounds substituted with 1-3 alkylpiperazinyl groups; unsubstituted or NO2, NH2, or C 1~4 Alkyl-substituted pyrimidinyl; unsubstituted or NO2, NH2 or C 1~4 Alkyl-substituted pyrazinyl; unsubstituted or NO2, NH2 or C 1~4 Alkyl-substituted thiazolyl; unsubstituted or NO2, NH2 or C 1~4 Alkyl-substituted benzimidazolyl; unsubstituted or NO2, NH2 or C 1~4 Alkyl-substituted pyrazolyl; unsubstituted or NO2, NH2 or C 1~4 Alkyl-substituted indazolyl; unsubstituted or NO2, NH2 or C 1~4Quinolinyl substituted with alkyl; unsubstituted or NO2, NH2 or C 1~4 Indolyl substituted with alkyl; unsubstituted or NO2, NH2 or C 1~4 Azaindazolyl substituted with alkyl; unsubstituted or NO2, NH2 or C 1~4 Deazapurinyl substituted with alkyl; unsubstituted or NO2, NH2 or C 1~4 Indanyl substituted with alkyl; or unsubstituted or NO2, NH2 or C 1~4 A pharmaceutical composition for use according to any one of the preceding items, which is morpholinoyl substituted with alkyl. (Item 4) The compound of formula (I) is; 4 - ((((3 - chloro - 1,4 - dioxo - 1,4 - dihydronaphthalen - 2 - yl)amino)methyl)-N - hydroxybenzamide; 4 - ((((3 - chloro - 1,4 - dioxo - 1,4 - dihydronaphthalen - 2 - yl)amino)methyl)-N - (pyridin - 2 - yl)benzamide; N - (2 - aminophenyl)-4 - ((((3 - chloro - 1,4 - dioxo - 1,4 - dihydronaphthalen - 2 - yl)amino)methyl)benzamide; 4 - ((((3 - chloro - 1,4 - dioxo - 1,4 - dihydronaphthalen - 2 - yl)amino)methyl)-N - (pyridin - 3 - yl)benzamide; 4 - ((((3 - chloro - 1,4 - dioxo - 1,4 - dihydronaphthalen - 2 - yl)amino)methyl)-N - (pyridin - 4 - yl)benzamide; 4 - ((((3 - chloro - 1,4 - dioxo - 1,4 - dihydronaphthalen - 2 - yl)amino)methyl)-N - (3 - fluorophenyl)benzamide; 4 - ((((3 - chloro - 1,4 - dioxo - 1,4 - dihydronaphthalen - 2 - yl)amino)methyl)-N - (4 - fluorophenyl)benzamide; 4 - ((((3 - chloro - 1,4 - dioxo - 1,4 - dihydronaphthalen - 2 - yl)amino)methyl)-N - phenylbenzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(2-fluorophenyl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(thiazole-2-yl)benzamide; N-(1H-benzo[d]imidazole-2-yl)-4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)amino)methyl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(4-hydroxyphenyl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(3-ethynylphenyl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(2-fluoro-4-iodophenyl)benzamide; N-(1H-benzo[d]imidazole-5-yl)-4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-cyclopropylbenzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-cyclopentylbenzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(1H-indazole-5-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(5-methylthiazole-2-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(5-methyl-3H-pyrazole-3-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(3-nitropyridine-4-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(quinoline-6-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(quinoline-8-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(quinoline-3-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(quinoline-5-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(2-methylquinoline-4-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(1H-indole-5-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(2-methyl-1H-indole-5-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(1H-indole-7-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(1H-indole-4-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(4-(4-ethylpiperazine-1-yl)phenyl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(1H-indazole-6-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(1H-pyrazolo[3,4-b]pyridine-5-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(7-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(2,3-dihydro-1H-inden-4-yl)benzamide; 4-(((3-bromo-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(pyridine-2-yl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(pyrimidine-4-yl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(pyrazine-2-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(pyridine-4-ylmethyl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(2-morpholinoethyl)benzamide; N-(2-(1H-indole-3-yl)ethyl)-4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(2-(dimethylamino)ethyl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(2-(pyrrolidine-1-yl)ethyl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(2-(diethylamino)ethyl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)amino)methyl)-N-(2-(piperidine-1-yl)ethyl)benzamide; and 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(2-(4-methylpiperazine-1-yl)ethyl)benzamide; or selected from its pharmaceutically acceptable salts, hydrates, or isomers, A pharmaceutical composition for use as described in any one of the preceding items. (Item 5) The compound is given by the following formula: [ka] 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(pyridine-4-yl)benzamide or a pharmaceutically acceptable salt, hydrate or isomer thereof, A pharmaceutical composition for use as described in any one of the preceding items. (Item 6) A pharmaceutically acceptable composition for use according to any one of the preceding items, for the treatment and / or prevention of optic neuropathy associated with apoptosis death of RGCs, via the modulation of the Nrf2 and TXNIP / NLRP3 inflammasome pathways in the retina. (Item 7) The compound enhances the expression of nuclear factor erythroid 2-related factor (Nrf2), A pharmaceutical composition for use according to any one of the preceding items, which downregulates thioredoxin-interacting protein (TXNIP) expression, inhibits NLR family pyrine domain-containing 3 (NLRP3) activation, and / or reduces the inflammatory factors interleukin (IL)-1P and IL-6 in the retina. (Item 8) A pharmaceutical composition for use according to any one of the preceding items, wherein the optic neuropathy associated with apoptotic death of RGCs is an optic nerve ischemic injury-related disease. (Item 9) A pharmaceutical composition for use according to any one of the preceding items, wherein the optic nerve ischemic injury-related disease is anterior ischemic optic neuropathy (AION) or posterior ischemic optic neuropathy (PION). In a further embodiment, the disease associated with optic nerve ischemic injury is AION. (Item 10) A pharmaceutical composition for use according to any one of the preceding items, wherein AION is non-arteritic ischemic optic neuropathy (NAION) or arteritic anterior ischemic optic neuropathy (AAION). In some further embodiments, PION is non-arteritic posterior ischemic optic neuropathy (NPION) or arteritic posterior ischemic optic neuropathy (APION). (Item 11) A pharmaceutical composition for use according to any one of the preceding items, wherein the compound is administered subcutaneously.

Claims

1. A pharmaceutical composition for use in a method for preventing and / or treating optic neuropathy associated with apoptosis of RGC, wherein the pharmaceutical composition comprises an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or isomer, 【Transformation 8】 During the ceremony, R １ It is a halogen; Each R ２ is H, C １～１０ alkyl, C ２～１０ alkenyl, C ２～１０ alkynyl, NH ２ , NO ２ , C １～１０ alkyloxy, C １～１０ alkylthio, C １～１０ alkylamino, C １～１０ alkyloxyC １～１０ alkyl, OH or CN, C ６～１０ aryl or a C ５～７ heterocyclic ring having 1 to 3 heteroatoms selected from the group consisting of N, O and S The same or different things represented by; R ３ H, C １～１０ Alkyl, C ２～１０ Alkenil, C ２～１０ Alkinyl, NH ２ NO ２ , OH or CN; R ４ H, C １～１０ Alkyl, C ２～１０ Alkenil, C ２～１０ Alkinyl, NH ２ NO ２ , OH or CN; R ５ is OH, C ３～８ Cycloalkyl, phenyl, unsubstituted or OH, CN, halogen, NH ２ Or C １～４ Phenyl, C substituted with one to three identical or different substituents selected from alkylpiperazinyl １～６ Alkylpiperazinyl, C １～６ Alkylpyridinyl, C １～６ Alkylpyrrolidinyl, pyridinyl, pyrimidinyl, pyrazinyl, piperazinyl, pyrrolidinyl, thiazolyl, benzimidazolyl, pyrazolyl, indazolyl, quinolinyl, indolyl, azaindolyl, azaindazolyl, deazaprinyl, indanyl, morpholinoyl or C １～４ These are alkylmorpholinoyl compounds, each of which is either unsubstituted or contains OH, CN, halogen, NO. ２ , C １～４ Alkyl or NH ２ Substituted with one, two, or three groups selected from; X is -C(O) Y is -N-; m is an integer between 0 and 3; and n is an integer between 1 and 7. Pharmaceutical composition.

2. m is 0; R １ is a halogen; n is any integer from 1 to 4; R ３ is H; X is C(O); R ４ is H; and R ５ is OH, C ３～８ Cycloalkyl, phenyl, unsubstituted or OH, CN, halogen, NH ２ Or C １～４ Phenyl, C substituted with one to three identical or different substituents selected from alkylpiperazinyl １～６ Alkylpiperazinyl, C １～６ Alkylpyridinyl, C １～６ Alkylpyrrolidinyl, pyridinyl, pyrimidinyl, pyrazinyl, piperazinyl, pyrrolidinyl, thiazolyl, benzimidazolyl, pyrazolyl, indazolyl, quinolinyl, indolyl, azaindolyl, azaindazolyl, deazaprinyl, indanyl, morpholinoyl or C １～４ These are alkylmorpholinoyl compounds, each of which is either unsubstituted or contains OH, CN, halogen, or NH. ２ A pharmaceutical composition for use according to claim 1, which is substituted with one, two, or three groups selected from the above.

3. m is 0; R １ is a halogen; n is any integer between 1 and 2; R ３ is H; X is C(O); R ４ is H; and R ５ is OH, C ３～８ Cycloalkyl, pyridinyl, phenyl, and NH ２ , halogen, OH, CN or C １～４ Phenyl compounds substituted with one to three alkylpiperazinyl groups; unsubstituted or NO ２ NH ２ Or C １～４ Alkyl-substituted pyrimidinyl; unsubstituted or NO ２ NH ２ Or C １～４ Alkyl-substituted pyrazinyl; unsubstituted or NO ２ NH ２ Or C １～４ Alkyl-substituted thiazolyl; unsubstituted or NO ２ NH ２ Or C １～４ Alkyl-substituted benzimidazolyl; unsubstituted or NO ２ NH ２ Or C １～４ Alkyl-substituted pyrazolyl; unsubstituted or NO ２ NH ２ Or C １～４ Alkyl-substituted indazolyl; unsubstituted or NO ２ NH ２ Or C １～４ Alkyl-substituted quinolinyl; unsubstituted or NO ２ NH ２ Or C １～４ Alkyl-substituted indolyl; unsubstituted or NO ２ NH ２ Or C １～４ Alkyl-substituted azindazolyl; unsubstituted or NO ２ NH ２ Or C １～４ Deazapurine substituted with alkyl; unsubstituted or NO ２ , NH ２ or C １～４ Indanyl substituted with alkyl; or unsubstituted or NO ２ , NH ２ or C １～４ A pharmaceutical composition for use according to claim 1 or 2, which is morpholinoyl substituted with alkyl.

4. The compound of formula (I) is: 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-hydroxybenzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(pyridine-2-yl)benzamide; N-(2-aminophenyl)-4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(pyridine-3-yl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(pyridine-4-yl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(3-fluorophenyl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(4-fluorophenyl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-phenylbenzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(2-fluorophenyl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(thiazole-2-yl)benzamide; N-(1H-benzo[d]imidazole-2-yl)-4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(4-hydroxyphenyl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(3-ethynylphenyl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(2-fluoro-4-iodophenyl)benzamide; N-(1H-benzo[d]imidazole-5-yl)-4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-cyclopropylbenzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-cyclopentylbenzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(1H-indazole-5-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(5-methylthiazole-2-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(5-methyl-3H-pyrazole-3-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(3-nitropyridine-4-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(quinoline-6-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(quinoline-8-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(quinoline-3-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(quinoline-5-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(2-methylquinoline-4-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(1H-indole-5-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(2-methyl-1H-indole-5-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(1H-indole-7-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(1H-indole-4-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(4-(4-ethylpiperazine-1-yl)phenyl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(1H-indazole-6-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(1H-pyrrolo[2,3-b]pyridine-5-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(1H-pyrazolo[3,4-b]pyridine-5-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(7-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(2,3-dihydro-1H-inden-4-yl)benzamide; 4-(((3-bromo-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(pyridine-2-yl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(pyrimidine-4-yl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(pyrazine-2-yl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(pyridine-4-ylmethyl)benzamide; 4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)-N-(2-morpholinoethyl)benzamide; N-(2-(1H-indole-3-yl)ethyl)-4-((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-ylamino)methyl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(2-(dimethylamino)ethyl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(2-(pyrrolidine-1-yl)ethyl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(2-(diethylamino)ethyl)benzamide; 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(2-(piperidine-1-yl)ethyl)benzamide; and 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(2-(4-methylpiperazine-1-yl)ethyl)benzamide; A pharmaceutical composition for use according to any one of claims 1 to 3, selected from a pharmaceutically acceptable salt, hydrate, or isomer thereof.

5. The aforementioned compound is given by the following formula: 【Chemistry 9】 A pharmaceutical composition for use according to any one of claims 1 to 4, comprising 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalene-2-yl)aminomethyl)-N-(pyridine-4-yl)benzamide or a pharmaceutically acceptable salt, hydrate or isomer thereof.

6. A pharmaceutically acceptable composition for use according to any one of claims 1 to 5, wherein the treatment and / or prevention of the optic neuropathy associated with apoptotic death of RGCs is mediated by the regulation of the Nrf2 and TXNIP / NLRP3 inflammasome pathways in the retina.

7. A pharmaceutically acceptable composition for use according to any one of claims 1 to 6, wherein the compound enhances the expression of nuclear factor erythroid 2-related factor (Nrf2), downregulates the expression of thioredoxin-interacting protein (TXNIP), inhibits the activation of NLR family pyrine domain-containing 3 (NLRP3), and / or reduces the inflammatory factors interleukin (IL)-1P and IL-6 in the retina.

8. The pharmaceutical composition for use according to any one of claims 1 to 7, wherein the optic neuropathy associated with apoptotic death of RGC is an optic nerve ischemic injury-related disease.

9. The pharmaceutical composition for use according to claim 8, wherein the optic nerve ischemic injury-related disease is anterior ischemic optic neuropathy (AION) or posterior ischemic optic neuropathy (PION). In a further embodiment, the disease associated with optic nerve ischemic injury is AION.

10. The pharmaceutical composition for use according to claim 9, wherein AION is non-arteritic ischemic optic neuropathy (NAION) or arteritic anterior ischemic optic neuropathy (AAION). In some further embodiments, PION is non-arteritic posterior ischemic optic neuropathy (NPION) or arteritic posterior ischemic optic neuropathy (APION).

11. A pharmaceutical composition for use according to any one of claims 1 to 7, wherein the compound is administered subcutaneously.

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