Cyclic compounds for use in the treatment of retinal degeneration

Abstract

To provide a method for treating retinal degeneration in subjects requiring such treatment. [Solution] In some embodiments, the method comprises the step of administering to a subject a therapeutically effective amount of 3-(dibutylamino)-1-(1,3-dichloro-6-(trifluoromethyl)phenanthren-9-yl)propan-1-ol hydrochloride, or a compound selected from compounds having a structure according to formulas I, II, or III described herein, and / or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof. In some non-limiting examples, the subject has retinitis pigmentosa, LCA, Stargart macular dystrophy, cone-rod dystrophy, total choroidal atrophy, or age-related macular degeneration.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefit of the earliest priority date of U.S. Provisional Patent Application No. 63 / 047,858, filed on 2 July 2020, which is incorporated herein by reference in its entirety.

[0002] Gratitude for government support This invention was supported by the U.S. government under ZIAEY000474 and ZIAEY000546, awarded by the U.S. National Eye Institute. The U.S. government has certain rights in this invention.

[0003] field This disclosure relates to the field of retinal degenerative diseases, and more particularly to compounds used to treat retinal degeneration. [Background technology]

[0004] background The retina is a layer of specialized photosensitive nerve tissue located on the inner surface of the eye of vertebrates. Light that reaches the retina after passing through the cornea, lens, and vitreous humor is converted into chemical and electrical events that induce nerve impulses. The cells involved in transmission, the process of converting light into these biological processes, are specialized neurons called photoreceptor cells. Dysfunction and / or degeneration of photoreceptors, the photosensitive neurons of the retina, are a prominent feature of retinal diseases worldwide, significantly contributing to irreversible blindness.

[0005] Many eye diseases, such as (age-related) macular degeneration, macular dystrophy, such as Stargardt's disease and Stargardt-like diseases, Best disease (vitelliform macular dystrophy), adult vitelliform dystrophy, cone-rod dystrophy, Leber congenital amaurosis and retinitis pigmentosa, are associated with retinal dysfunction, degeneration or deterioration. In some animal models, photoreceptor rescue and preservation of visual function have been demonstrated to be achievable by subretinal transplantation of RPE cells or by gene therapy, but compounds are needed for use in the treatment of retinal degenerative diseases. SUMMARY OF THE INVENTION MEANS FOR SOLVING THE PROBLEM

[0006] Overview This specification discloses embodiments of a method for treating retinal degeneration in a subject. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of 3-(dibutylamino)-1-(1,3-dichloro-6-(trifluoromethyl)phenanthren-9-yl)propan-1-ol hydrochloride, or a compound having a structure according to a formula selected from Formula I, II or III [Chemical formula] thereby treating the retinal degeneration in the subject [wherein, Regarding Formula I, R 1 is heteroaliphatic, R 2 is OR 5 or NR 6 R 7 and each of R 5 , R 6 and R 7 is independently selected from hydrogen, aliphatic or aromatic, or an organic functional group, R 3 and each of R 4 is independently selected from aliphatic, aromatic, acyl, or sulfonyl, n can be an integer selected from 0 to 4, Regarding Equation II, R A These are selected from halogens, heteroaliphatic, haloaliphatic, or organic functional groups. R B It is an aromatic compound, R C and R D Each of these is independently selected from hydrogen, aliphatic, or heteroaliphatic. m is an integer selected from 0 to 4. Regarding Equation III, R' is selected from aliphatic, aromatic, halogen, heteroaliphatic, haloaliphatic, or organic functional groups. Each R'' is independently selected from halogen, heteroaliphatic, or amino. Each R''' is independently selected from halogen, heteroaliphatic, or amino. p is an integer selected from 0 to 4. q is an integer selected from 0 to 4. r is an integer selected from 0 or 1.

[0007] The aforementioned and other purposes and features of this disclosure will become more apparent from the following detailed description, which will proceed with reference to the attached figures. [Brief explanation of the drawing]

[0008] [Figure 1] Figures 1A and 1B are schematic diagrams illustrating typical autophagy pathways associated with retinal ciliary disease (Figure 1A) and 1B, respectively. Figure 1B is a proposed model of the mechanism of action of embodiments of the disclosed compound (Figure 1B). [Figure 2-1]Figures 2A-2G show the results obtained from the analysis of disease-related phenotypes in induced pluripotent stem cell-derived retinal organoids of CEP290-LCA subjects. Figure 2A shows immunostaining for RHO (rhodopsin, reddish-purple), OPN1SW (S opsin, red), and OPN1M / LW (L / M opsin, green), and Figure 2B shows immunostaining for RHO (rhodopsin, green) and ARL13B (ADP-ribosylation factor-like protein 13B, red), where the nuclei were stained with DAPI. The images are representative images of two cell lines for each subject, each of which underwent at least six experiments, and each experiment contained at least six retinal organoids. Figure 2C shows principal component analysis of gene profiles of iPSC-derived retinal organoids of controls and subjects at days D67, D90, D120, and D150. Figure 2D shows an overview of differentially expressed (DE) genes between control and target organoids over development. Figure 2E provides a Venn diagram showing DE genes in development- and age-matched pairwise comparisons of control and target samples. Figure 2F shows KEGG and Reactome pathway analysis of DE genes unique to the CEP290 mutation in the target sample. Figure 2G shows that the expression of phototransfer genes was largely downregulated in the target organoid. [Figure 2-2] Same as above. [Figure 2-3] Same as above. [Figure 2-4] Same as above. [Figure 2-5] Same as above. [Figure 3] Figure 3 shows a schematic diagram of the compound discovery pipeline, in which approximately 6,000 compounds at various concentrations were administered to dissociated cells containing photoreceptors from rd16 mouse (CEP290-LCA model) retinal organoids. The putative embodiments of the compounds were selected according to various criteria, and their hits were validated using mouse retinal organoids and then human retinal organoids (transcriptome analysis was performed to elucidate their mechanisms of action, and their effects were tested in vivo in degenerated mouse retinas). [Figure 4-1]Figures 4A–4D show embodiments of compounds that improved photoreceptor development in rd16 induced pluripotent stem cell (iPSC)-derived retinal organoids, along with associated results. Figure 4A shows a schematic diagram of small molecule treatment in rd16 retinal organoids. Figure 4B shows immunostaining for rhodopsin (green) and S-opsin (red), where the nuclei were stained with DAPI, and the images are representative from at least three experiments, each experiment containing at least three retinal organoids. Figures 4C and 4D show quantification of rhodopsin (Figure 4C) and S-opsin (Figure 4D) fluorescence intensity of untreated and treated rd16 retinal organoids from at least three experiments (each experiment containing at least three retinal organoids). [Figure 4-2] Same as above. [Figure 5-1] Figures 5A–5C show the results confirming the improvement of photoreceptor and ciliary biosynthesis by the compound embodiment in the target induced pluripotent stem cell (iPSC)-derived retinal organoids. Figure 5A shows a schematic diagram of the small molecule treatment in the target retinal organoids. Figure 5B shows immunostaining of rhodopsin (green), a rod cell marker, and ARL13B (red), a ciliary axoneme marker. Figure 5C shows that S cones and L / M cones were shown by immunostaining of OPN1L / MW (green) and OPN1SW (red), respectively, where the nuclei were stained with DAPI. The images are representative images from two cell lines per subject, each of which underwent at least three experiments, each containing at least three retinal organoids. [Figure 5-2] Same as above. [Figure 6]Figures 6A and 6B show results confirming that the injected compound embodiment (reserpine) maintained the outer granular layer in rd16 mice when administered in vivo. Figure 6A shows a schematic diagram of intravitreous injection in rd16 mice. Figure 6B shows immunostaining of rod cell markers rhodopsin (red-purple), PDEβ (red), and GFP (green), where GFP (green) indicates rod photoreceptors in the outer granular layer, and rhodopsin (red-purple) and PDEβ (red) are ciliated proteins located in the outer segment of the photoreceptor (nuclei are stained with DAPI, and the images are representative images of two of the three injected animals). [Figure 7-1] Figures 7A-7E show the results obtained from the evaluation of the drug effect on the target retinal organoids. Figure 7A shows the timeline of drug treatment for CEP290-LCA (IVS26+1655A>G p.C998X; c.5668G>T p.G1890X). Figure 7B shows the Western blot analysis of rhodopsin levels in the target organoids. Figure 7C shows a graph of the relative magnification change as a dose function, quantifying rhodopsin levels in the target organoids. Figures 7D and 7E show images obtained from immunostaining of rod (rhodopsin, green), S cone (S opsin, red), L / M cone (L / M-opsin, reddish-purple) photoreceptors (upper panel) and ciliary axonem (ARL13B, red) (lower panel) for subjects 1 and 2, respectively (nuclei were stained with DAPI, and the images are representative from at least three experiments, each experiment containing at least three retinal organoids. Arrowheads indicate relevant staining). [Figure 7-2] Same as above. [Figure 8-1]Figures 8A–8G show the results obtained from the analysis of autophagy misregulation in the target organoid. Figure 8A shows a simplified schematic diagram of autophagy. Figure 8B shows the timeline for the analysis. Figure 8C shows the Western blot analysis of certain autophagy components (p-ULK1 Ser757, ULK1, p62, and LC3-II) in the target organoid. Figures 8D–8G are bar graphs showing the relative amounts of proteins as a function of time, illustrating the quantification of these autophagy components in the target organoid. [Figure 8-2] Same as above. [Figure 9] Figures 9A and 9B show the results associated with the administration of autophagy inhibitors to the target organoids. Figure 9A shows a schematic diagram illustrating the effect of administering FDA-approved autophagy inhibitor drugs to the target organoids. Figure 9B shows the results obtained from immunostaining of rod (rhodopsin, green), S cone (S opsin, red), and L / M cone (L / M-opsin, reddish-purple) photoreceptors (nuclei were stained with DAPI, and the images are representative images from two experiments, each experiment containing at least six retinal organoids). [Figure 10-1]Figures 10A–10G show results obtained from an analysis of the ability of p62 to act as a mediator for the drug effect of reserpine. Figure 10A shows Western blot analysis of p62 and LC3-II. Figure 10B includes bar graphs showing the relative amounts of proteins as a function of treatment status, illustrating the quantification of p62 and LC3-II. Figure 10C shows the results of immunostaining of p62 and acetylated tubulin (DM1T) in organoids of treated subjects (nuclei were stained with DAPI, and the images are representative images from at least two experiments, each experiment containing at least three retinal organoids). Figure 10D shows Western blot analysis and quantification of other ciliary regulatory proteins in treated organoids, including HDAC6, the interaction partner of p62 / key driver of ciliary degradation, as well as IFT88 (intraflagellar transport), BBS6, and CEP164 (distal adnexal components for the initiation of ciliogenesis). Figure 10E includes a bar graph showing the relative amounts of these proteins as a function of treatment status, illustrating the quantification of these proteins. Figure 10F shows a TEM image of the organoid, which shows a reduction in defects in preciliary vesicle docking and ciliary membrane formation resulting from treatment with reserpine (upper panel), and longer ciliary axonee in the treated photoreceptor (lower panel). Figure 10G shows a TEM image of a well-organized, disk-like structure, rare in organoid cultures, demonstrating the favorable effect of reserpine on the development of the outer segment (primary cilia of the photoreceptor). [Figure 10-2] Same as above. [Figure 10-3] Same as above. [Figure 11]Figures 11A and 11B show results illustrating improved photoreceptor morphology after short-term treatment of induced pluripotent stem cell-derived retinal organoids targeting CEP290-LCA. Figure 11A is a schematic diagram illustrating the small molecule treatment paradigm for CEP290-LCA retinal organoids. Figure 11B shows immunostaining of rod cells (green), S cones (red), and L / M cones (purple) (nuclei were stained with DAPI, and the images are representative images from two experiments, each experiment containing at least three retinal organoids). [Modes for carrying out the invention]

[0009] Detailed explanation I. Explanation of Terms The following definitions of terms are provided to better describe this disclosure and to guide those skilled in the art to implement it. As used herein, “comprising” means “including,” and the singular “a,” “an,” or “the” includes multiple references unless otherwise indicated by context. The term “or” means a single element of the alternatives described, or a combination of two or more elements, unless otherwise indicated by context.

[0010] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this disclosure belongs. Similar or equivalent methods and materials may be used in the implementation or testing of the disclosure, but suitable methods and materials are listed below. Materials, methods, and examples are merely illustrative and not intended to be limiting unless otherwise indicated. Other features of this disclosure are evident from the following detailed description and claims.

[0011] Unless otherwise indicated, all numerical values ​​representing the amount, molecular weight, percentage, temperature, time, etc., of components should be understood to be modified by the term "approximately" when used herein or in the claims. Thus, unless otherwise indicated, implicitly or explicitly, the numerical parameters described are approximations that can vary depending on the desired properties and / or detection limits under standard test conditions / methods. Numerical values ​​in embodiments that directly and clearly distinguish embodiments from the prior art discussed herein are not approximations unless the term "approximately" is enumerated. Furthermore, not all substitutes enumerated herein are equivalents.

[0012] The embodiments of the compounds disclosed herein may contain one or more chiral elements, such as a chiral center, a chiral axis, or, for example, a chiral carbon atom, and therefore, chemical conjugates may exist in various stereoisomers. These embodiments of the compounds may be, for example, racemates or optically active forms. In addition, for embodiments of compounds having two or more chiral elements, these embodiments of the compounds may be mixtures of diastereomers. For embodiments of compounds having a chiral center, all optical isomers in their pure forms and mixtures thereof are encompassed by the corresponding general formula unless otherwise explicitly stated in the context or unless a clear statement excluding the isomers is provided. In such contexts, single enantiomers, i.e., optically active forms, can be obtained by methods known to those skilled in the art, e.g., asymmetric synthesis, synthesis from optically pure precursors, or by resolution of racemates. Resolution of racemates can also be achieved, for example, by conventional methods, e.g., crystallization in the presence of a resolving agent, or by chromatography using a chiral HPLC column. In this specification, all isomers are considered regardless of the method used to obtain them.

[0013] All forms of the activator (e.g., solvates, optical isomers, enantiomers, polymorphs, free compounds, and salts) may be used alone or in combination. The definitions and conventions of stereochemistry used herein generally follow those of SP. Parker, Ed., McGraw-Hill Dictionary. of Chemical Terms (1984) McGraw-Hill Book Company, New York, and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John According to Wiley & Sons, Inc., New York. Many organic compounds are optically active. It exists in a state that has the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes (+ / -)D and L or R and S are used to indicate the absolute configuration of the molecule around its chiral center. The prefixes d and l or (+) and (-) are used to specify the sign of rotation of plane-polarized light by the compound, and (-) or l means that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory.

[0014] To facilitate an overview of the various embodiments of this disclosure, a definition of specific terms is provided below. Certain terms relating to functional groups include the symbol "-", which is used to indicate how the defined functional group is bonded to or within the compound to which it is bonded.

[0015] Furthermore, in certain formulas described herein, the dashed bond (i.e., "---") indicates an "optional" bond with a substituent or atom other than hydrogen, meaning that the bond (and substituent in some embodiments) may or may not be present. In any formula containing a dashed bond, if the optional bond and / or any corresponding substituent is absent, the valence requirement of any atom bonded to it is satisfied by the bond with the hydrogen atom. As a mere example, in the following formula, the dashed bond between the carbon atom of the pyridine ring and the R' group may or may not be present, and instead a bond with a hydrogen atom is present. Also, the dashed bond in the fused ring of the formula may or may not be a double bond; if absent, a single bond is present, indicating that the corresponding carbon atom is bonded to a hydrogen atom in addition to any other substituent already bonded to it. Furthermore, with respect to this particular formula, if r is 0 (as provided herein), the valence of each carbon atom of pyridine is instead satisfied by the bond with hydrogen, contrary to the fused ring. [ka]

[0016] symbol" [ka] The symbol '' is used to indicate a break in bonding in the simplified structures / formulas provided herein. Those skilled in the art will recognize that the definitions provided below and the compounds and formulas included herein are not intended to include unacceptable substitution patterns (e.g., a methyl group substituted with five different groups). Such unacceptable substitution patterns are readily recognizable to those skilled in the art. In the formulas and compounds disclosed herein, hydrogen atoms are present and satisfy any formal valence requirements (but may not necessarily be shown) even if functional groups or other atoms are not shown anywhere. For example, [ka] The phenyl rings shown as include hydrogen atoms bonded to each carbon atom of the phenyl ring other than the carbon of "a," even if hydrogen atoms are not shown. Any functional groups disclosed herein and / or defined herein may be substituted or unsubstituted unless otherwise indicated herein. Any embodiments of any compound described herein may be deuterated or undeuterated unless otherwise indicated herein. Suitable positions in which a compound can be deuterated will be readily apparent to those skilled in the art.

[0017] Those skilled in the art will recognize that compounds may exhibit phenomena such as tautomerism, conformational isomerism, geometric isomerism, and / or optical isomerism. For example, a particular compound disclosed may contain one or more chiral centers and / or double bonds, and as a result may exist as stereoisomers, e.g., double bond isomers (i.e., geometric isomers), enantiomers, diastereomers, and mixtures thereof, e.g., racemic mixtures. As another example, a particular compound disclosed may exist in several tautomers, including enol forms, keto forms, and mixtures thereof. Since the names, formulas, and diagrams of various compounds in this specification and the claims may represent only one of the possible tautomers, conformational isomers, optical isomers, or geometric isomers, those skilled in the art will recognize that the disclosed compounds encompass any tautomers, conformational isomers, optical isomers, and / or geometric isomers of the compounds described herein, as well as mixtures of these various different isomers. Mixtures of different isomers, including mixtures of enantiomers and / or stereoisomers, can be separated using techniques known to those skilled in the art, particularly those who benefit from the present invention, to provide distinct enantiomers and / or stereoisomers. Atropisomers are also possible, for example, around an amide bond or between two directly bonded rings such as a pyridinyl ring or a biphenyl group, when rotation is controlled, and are also particularly included in the compounds disclosed herein.

[0018] In any embodiment, any hydrogen present in the compound, or in any particular group or part of the compound, may be replaced by deuterium or tritium. Therefore, the list of alkyls includes deuterated alkyls, in which case one to the maximum number of hydrogens present may be replaced by deuterium. For example, methyl may be CH3, or CD x H 3-x This refers to both CH3 groups in which 1 to 3 hydrogen atoms are replaced by deuterium.

[0019] As used herein, the term “substituted” refers to all modifying phrases that follow a given term, for example, in the term “substituted aliphatic-aromatic,” the substitution may occur on the “aliphatic” moiety, the “aromatic” moiety, or both the aliphatic-aromatic group.

[0020] "Substitutable" means that, when used to modify a particular group or moiety, at least one, possibly two or more, hydrogen atoms of a particular group or moiety are independently replaced by the same or different substituents. In certain embodiments, a group, moiety, or substituent may be substituted or unsubstituted unless explicitly defined as either "unsubstituted" or "substituted." Thus, none of the functional groups specified herein may be substituted or unsubstituted unless otherwise specified in the context or unless a particular structural formula excludes substitution. In certain embodiments, substituents may or may not be explicitly defined as substituted, but are still considered substituted as necessary. For example, an "aliphatic" or "cyclic" moiety may be substituted or unsubstituted, while an "unsubstituted aliphatic" or "unsubstituted cyclic" is unsubstituted. In one embodiment, a substituted group has at least one substituent, up to the maximum number possible for a particular moiety, e.g., one substituent, two substituents, three substituents, or four substituents.

[0021] Any group or part defined herein may be bonded to any other part of the disclosed structure, e.g., the parent or core structure, in a manner that can be understood by those skilled in the art, for example, by considering the rules of valence, comparing with exemplary species, and / or considering the functionality, unless the bond between the group or part and other parts of the structure is not explicitly described or implied by the context.

[0022] Ashiru:-C(O)R a (R a (Selected from aliphatic, heteroaliphatic, haloaliphatic, haloheteroaromatic, aromatic, or organic functional groups).

[0023] Acyl halide: -C(O)X (where X is a halogen, e.g., Br, F, I, or Cl).

[0024] Age-related macular degeneration (AMD): A leading cause of blindness in the United States and other developed industrial nations. (Evans J, Wormald R., British Journal Ophthalmology 80:9-14, 1996; Klein R, Klein BEK, Linton KLP, Ophthalmology 99:933-943, 1992; Vingerling JR, Ophthalmology 102:205-210, 1995). Early AMD is clinically characterized by drusen, which are extracellular deposits of proteins, lipids, and cellular debris located directly beneath the retinal pigment epithelium (RPE) (Hageman GS, Mullins RF, Mol Vis 5:28, 1999). The RPE provides nutritional, metabolic, and phagocytic functions for the photoreceptors covering it. Significant vision loss arises from the dysfunction or death of photoreceptors in the macula (geographic atrophy of retinal pigment epithelial cells and subretinal neovascularization), which is associated with the later stages of AMD.

[0025] Aldehyde: -C(O)H.

[0026] Aliphatic: At least 1 carbon atom to 50 carbon atoms (C) 1~50 ), for example, 1 to 25 carbon atoms (C 1~25 ), or 1 to 10 carbon atoms (C 1~10 A hydrocarbon group having ), including alkanes (or alkyls), alkenes (or alkenyls), and alkynes (or alkynyls) (including their cyclic groups, as well as linear and branched configurations, and all stereoisomers and positional isomers).

[0027] Alkenyl: at least 2 carbon atoms to 50 carbon atoms (C) 2~50 ), for example, 2 to 25 carbon atoms (C 2~25 ), or 2 to 10 carbon atoms (C 2~10 ), and a monovalent unsaturated hydrocarbon having at least one carbon-carbon double bond (a monovalent unsaturated hydrocarbon can be derived by removing one hydrogen atom from one carbon atom of the parent alkene). The alkenyl group may be branched, linear, cyclic (e.g., cycloalkenyl), cis, or trans (e.g., E or Z).

[0028] Alkoxy: -O-aliphatic, e.g., -O-alkyl, -O-alkenyl, -O-alkynyl. Exemplary embodiments include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy (any of the aliphatic components of such groups may or may not contain double or triple bonds, or may contain one or more double and / or triple bonds).

[0029] Alkyl: at least 1 carbon atom to 50 carbon atoms (C 1~50 ), for example, 1 to 25 carbon atoms (C 1~25 ), or 1 to 10 carbon atoms (C 1~10A monovalent saturated hydrocarbon having (a monovalent saturated hydrocarbon can be derived by removing one hydrogen atom from one carbon atom of the parent compound (e.g., an alkane)). The alkyl group may be branched, linear, or cyclic (e.g., cycloalkyl).

[0030] Alkynyl: at least 2 carbon atoms to 50 carbon atoms (C) 2~50 ), for example, 2 to 25 carbon atoms (C 2~25 ), or 2 to 10 carbon atoms (C 2~10 ), and a monovalent unsaturated hydrocarbon having at least one carbon-carbon triple bond (a monovalent unsaturated hydrocarbon can be derived by removing one hydrogen atom from one carbon atom of the parent alkyne). The alkynyl group may be branched, linear, or cyclic (e.g., cycloalkynyl).

[0031] Amide:-C(O)NR a R b or -NR a C(O)R b (R a and R b Each of these is independently selected from hydrogen, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaromatic, aromatic, or organic functional groups.

[0032] Amino:-NR a R b (R a and R b Each of these is independently selected from hydrogen, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaromatic, aromatic, or organic functional groups.

[0033] Aromatic: Unless otherwise specified, a conjugated cyclic group or cyclic moiety of 5 to 15 ring atoms having a single ring (e.g., phenyl) or multiple fused rings (of which at least one ring is aromatic (e.g., naphthyl, indolyl, or pyrazolopyridinyl), i.e., at least one ring, and optionally multiple fused rings, have a continuous delocalized π-electron system). Typically, the number of out-of-plane π-electrons corresponds to Hückel's rule (4n+2). Bonding to the parent structure is typically via the aromatic moiety of the fused ring system. For example, [ka] However, in certain cases, the context or clear disclosure may indicate that the bonding site is via a non-aromatic moiety of a fused ring system. For example, [ka] The aromatic group or aromatic moiety may contain only carbon atoms in the ring, such as in an aryl group or aryl moiety, or it may contain one or more ring carbon atoms and one or more ring heteroatoms (e.g., S, O, N, P, or Si) containing lone pairs of electrons, such as in a heteroaryl group or heteroaryl moiety. The aromatic group may be substituted with one or more groups other than hydrogen, such as an aliphatic, heteroaliphatic, haloaliphatic, haloheteroaromatic, aromatic, or organic functional group.

[0034] Aryl: at least 5 carbon atoms to 15 carbon atoms (C5~C) 15 ), for example, 5 to 10 carbon atoms (C5 to C 10 An aromatic carbocyclic group comprising ) having a single ring or multiple fused rings (the fused rings may be aromatic or not aromatic, provided that the bonding points to the rest of the compound disclosed herein are via atoms of the aromatic carbocyclic group). The aryl group may be substituted with one or more groups other than hydrogen, such as aliphatic, heteroaliphatic, haloaliphatic, haloheteroaromatic, aromatic, or organic functional groups.

[0035] Aroxy: -O-aromatic.

[0036] Azo: -N=NR a (R a (These are hydrogen, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaromatic, aromatic, or organic functional groups.)

[0037] Carbamate: -OC(O)NR a R b (R a and R b Each of these is independently selected from hydrogen, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaromatic, aromatic, or organic functional groups.

[0038] Carboxyl: -C(O)OH.

[0039] Carboxylate: -C(O)O - or its salt (the negative charge of the carboxylate group is the counterion M + And it can be in equilibrium, M + This is an alkaline ion, for example, K + kaNa + Li + ammonium ions, for example + N(R b )4(R b (H is aliphatic, heteroaliphatic, haloaliphatic, haloheteroaromatic, or aromatic), or alkaline earth ions, such as [Ca 2+ ] 0.5 [Mg 2+ ] 0.5 Or this Ba 2+ ] 0.5 (This is acceptable.)

[0040] Carrier: An excipient that acts as an ingredient capable of delivering the compounds described herein. In some embodiments, the carrier may be a suspension aid, a solubilizer, or an aerosolizing aid. Generally, the properties of the carrier depend on the specific method of administration used. For example, parenteral formulations typically contain an injectable fluid, such as a pharmaceutically and physiologically acceptable fluid as a vehicle, e.g., water, saline, equilibrium salt solution, glucose aqueous solution, glycerol, etc. In some examples, the pharmaceutically acceptable carrier may be sterilized to be suitable for administration to a subject (e.g., by parenteral, intramuscular, or subcutaneous injection). The pharmaceutical formulation to be administered may contain, in addition to the biologically neutral carrier, small amounts of non-toxic adjuvants, such as humectants or emulsifiers, preservatives, and pH buffers, e.g., sodium acetate or sorbitan monolaurate.

[0041] Choroidal atrophy (Chorioderemia): An X-linked recessive hereditary retinal degeneration affecting males. Morphology. This disease causes progressive blindness, beginning with night blindness in childhood, followed by loss of peripheral vision, and progressing to loss of central vision in later years. Total choroidal atrophy is caused by loss-of-function mutations in the CHM gene, which encodes Rab escort protein 1 (REP1), a protein involved in the lipid modification of Rab proteins. The initial symptom for many individuals with a precursor to total choroidal atrophy is a significant loss of night vision. Loss of peripheral vision occurs gradually, beginning as part of vision loss, and progressing to "tunnel vision" in adulthood. Individuals with total choroidal atrophy tend to maintain good vision until their 40s, but ultimately lose all vision by the time they reach 50-70 years of age.

[0042] Cone-rod dystrophy: The initial signs and symptoms of cone-rod dystrophy, which often occur in childhood, are usually decreased visual acuity and increased sensitivity to light (photophobia). Typically, these features are followed by color blindness, a blind spot in the center of the visual field, and partial peripheral vision loss. Affected individuals may develop night blindness and worsening of their peripheral vision over time, which can limit their ability to move independently. Cone dystrophy is characterized by progressive dysfunction of the light-adaptation system, with preservation of dark-adaptation function. Abnormal rod function may be part of the initial symptoms, but rod involvement may be less severe or occur later than cone dysfunction. There are more than 30 types of cone-rod dystrophy, which are distinguished by their genetic causes and their inheritance patterns: autosomal recessive, autosomal dominant, and X-linked. It is known that mutations in more than 30 genes cause rod-pyramidal dystrophy. Approximately 20 of these genes are associated with autosomal recessive patterns of inherited rod-pyramidal dystrophy. Mutations in the GUCY2D and CRX genes account for about half of the autosomal dominant forms of this disease.

[0043] Cyano:-CN.

[0044] Disulfide:-SSR a (R a (Selected from hydrogen, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaromatic, aromatic, or organic functional groups).

[0045] Dithiocarboxylic acid:-C(S)SR a (R a (Selected from hydrogen, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaromatic, aromatic, or organic functional groups).

[0046] Effective dose: The amount of a particular drug or therapeutic agent sufficient to achieve the desired effect in the subject or cells being treated with the drug. The effective dose of a drug, such as a nucleic acid molecule, depends on several factors, including the subject or cells being treated and the method of administration of the therapeutic composition, but is not limited to the following. The effective dose may be sufficient to treat a subject with retinopathy.

[0047] Ester:-C(O)OR a or -OC(O)R a (R a (Selected from aliphatic, heteroaliphatic, haloaliphatic, haloheteroaromatic, aromatic, or organic functional groups).

[0048] Ether: -Aliphatic-O-Aliphatic, -Aliphatic-O-Aromatic, -Aromatic-O-Aliphatic, or -Aromatic-O-Aromatic.

[0049] Halo (or halide or halogen): fluoro, chloro, bromo, or iodine.

[0050] Haloaliphatic: An aliphatic group in which one or more hydrogen atoms, for example 1 to 10 hydrogen atoms, are independently replaced by halogen atoms, such as fluoro, bromo, chloro, or iodine.

[0051] Haloalkyl: An alkyl group in which one or more hydrogen atoms, for example 1 to 10 hydrogen atoms, are independently replaced by halogen atoms, for example fluoro, bromo, chloro, or iodine. In an independent embodiment, the haloalkyl group may be CX3 (each X can be independently selected from fluoro, bromo, chloro, or iodine).

[0052] Heteroaliphatic: an aliphatic group comprising at least one heteroatom to 20 heteroatoms, e.g., 1 to 15 heteroatoms, or 1 to 5 heteroatoms, which can be selected from oxygen, nitrogen, sulfur, silicon, boron, selenium, phosphorous acid, and their oxidized forms, but is not limited to the following. Alkoxy, ether, amino, disulfide, peroxy, and thioether groups are exemplary (but not limited) examples of heteroaliphatic groups. In some embodiments, for example, if the heteroaliphatic group is a heterocyclic group, a fluorophore may also be referred to as a heteroaliphatic group herein.

[0053] Heteroaryl: An aryl group containing at least one heteroatom to six heteroatoms, e.g., one to four heteroatoms, which can be selected from oxygen, nitrogen, sulfur, silicon, boron, selenium, phosphorous acid, and their oxidized forms in the ring, but is not limited to the following. Such a heteroaryl group may have a single ring or multiple fused rings (the fused rings may be aromatic or non-aromatic and / or contain heteroatoms, provided that the bonding site is through an atom of the aromatic heteroaryl group). The heteroaryl group may be substituted with one or more groups other than hydrogen, e.g., aliphatic, heteroaliphatic, haloaliphatic, haloheteroaromatic, aromatic, or organic functional groups. In some embodiments, fluorophores may also be referred to as heteroaryl groups herein.

[0054] Heteroatoms: Atoms other than carbon or hydrogen, such as (but not limited to) oxygen, nitrogen, sulfur, silicon, boron, selenium, or phosphorous acid. In particularly disclosed embodiments, heteroatoms do not include halogen atoms, for example, if not permitted by valence constraints.

[0055] Inhibition: For example, inhibiting the complete onset of a disease or condition in a person at risk of disease such as retinopathy, LCA, or AMD, but not limited to the following.

[0056] Intraocular administration: Direct administration of a drug to the eye, for example, by delivery to the vitreous humor or anterior chamber, or subretinally. Indirect intraocular delivery (e.g., by diffusion across the cornea) is not considered direct administration to the eye.

[0057] Intravitreal administration: The administration of a drug into the vitreous cavity. The vitreous cavity is the space that occupies most of the volume of the eye's core, with the lens and its suspension system (zonules of Zinn) at its anterior border and the retina and its covering membrane at its periphery. Intravitreal administration can be achieved by injection, pump infusion, or implantation.

[0058] Leber congenital amaurosis (LCA) is a rare, hereditary eye disorder that appears at birth or in early life (infancy or early childhood) and primarily affects the retina. Its symptoms can vary as it is associated with multiple genes. However, it is characterized by nystagmus, photophobia, drowsiness or lack of pupillary response, and severe vision loss or blindness. The common modes of inheritance are autosomal recessive and autosomal dominant.

[0059] Normally, the pupil expands and contracts in response to the amount of light entering the eye, but in this condition, the pupil does not respond normally to light. Instead, the pupil expands and contracts more slowly than normal, or does not respond to light at all. In addition, the transparent covering at the front of the eye (cornea) may become cone-shaped and abnormally thin, a condition known as keratoconus.

[0060] A specific behavior called Franceschetti's oculo-digital sign is characteristic of Leber congenital amaurosis. This sign consists of poking, pressing, and rubbing the eye with the knuckles or fingers.

[0061] Opsins are a group of proteins made photosensitive by retinal chromophores (or variants) found in retinal photoreceptor cells. Opsins are lighttransmitters. Mammalian opsins are seven-transmembrane proteins belonging to the G protein receptor superfamily. Ciliary (c) opsins, found in vertebrates and cnidarians, bind to ciliary structures such as rods and cones. Rod-type opsins bind to light-harvesting organelles called rodids. Ciliary opsins (or c opsins) are expressed in ciliary photoreceptor cells, including vertebrate visual opsins and brain opsins. These opsins convert light signals into nerve impulses via cyclic nucleotide-dependent ion channels that act by increasing the charge difference across the cell membrane (hyperpolarization). Vertebrates typically possess four pyramidal opsins (long-wave sensitive (LWS), short-wave sensitive (SWS)1, SWS2, and rhodopsin-like (Rh)2) inherited from the first vertebrates (and therefore existing before the first vertebrates), as well as the rod opsin, rhodopsin (Rh1). In humans, RHO is an opsin expressed in rod cells. Human pyramidal cells express the following: a) Long-wave sensitive (OPN1LW) opsin: λmax at 560 nm in the yellow-green region of the electromagnetic spectrum, also known as "red opsin," "red cone pigment (erythrolabe)," or "L-opsin." It is also called "LWS opsin". b) Medium-wave sensitive (OPN1MW) opsins: λmax at 530 nm in the green region of the electromagnetic spectrum, also known as "green opsins," "green cone pigment (chlorolabe)," "M opsins," or "MWS opsins." c) Shortwave-sensitive (OPN1SW) opsin: λmax at 430 nm in the blue region of the electromagnetic spectrum, also known as "blue opsin," "cyanolabe," "S opsin," "opsin-S," or "SWS opsin."

[0062] Organic functional groups: Can be provided by any combination of aliphatic, heteroaliphatic, aromatic, haloaliphatic, and / or haloheteroaromatic groups, or can be selected from, but are not limited to, aldehydes, alloxys, acyl halides, nitros, cyanos, azides, carboxyls (or carboxylates), amides, acyls, carbonates, imines, azos, carbamates, hydroxyls, thiols, sulfonyls (or sulfonates), oximes, esters, thiocyanates, thioacyls, thiocarboxylic acids, thioesters, dithiocarboxylic acids or dithiocarboxylic acid esters, phosphonates, phosphates, silyl ethers, sulfinyls, thials, or combinations thereof.

[0063] Oxime:-CR a =NOH(R a (These are hydrogen, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaromatic, aromatic, or organic functional groups.)

[0064] Peroxy:-O-OR a (R a (These are hydrogen, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaromatic, aromatic, or organic functional groups.)

[0065] pharmaceutically acceptable excipients: substances other than the compound that are included in the formulation of a compound. As used herein, excipients may be incorporated into the particles of the pharmaceutical composition or physically mixed with the particles of the pharmaceutical composition. Excipients may also be in the form of solutions, suspensions, emulsions, etc. Excipients can be used, for example, to dilute activators and / or to modify the properties of the pharmaceutical composition. Excipients may include, but are not limited to, anti-adhesives, binders, coatings, enteric coatings, disintegrants, flavoring agents, sweeteners, colorants, lubricants, flow enhancers, adsorbents, preservatives, adjuvants, carriers or vehicles. Excipients may be starches and modified starches, cellulose and cellulose derivatives, sugars and their derivatives, e.g., disaccharides, polysaccharides and sugar alcohols, proteins, synthetic polymers, crosslinked polymers, antioxidants, amino acids or preservatives. Exemplary excipients include, but are not limited to, magnesium stearate, stearic acid, vegetable stearic acid, sucrose, lactose, starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, xylitol, sorbitol, maltitol, gelatin, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), tocopheryl polyethylene glycol 1000 succinate (also known as vitamin E TPGS, or TPGS), carboxymethylcellulose, dipalmitoylphosphatidylcholine (DPPC), vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium citrate, methylparaben, propylparaben, sugar, silica, talc, magnesium carbonate, sodium starch glycolate, tartrazine, aspartame, benzalkonium chloride, sesame oil, propyl gallate, sodium metabisulfite, or lanolin. In independent embodiments, water is not intended as a pharmaceutically acceptable excipient.

[0066] pharmaceutically acceptable salts: As is well known to those skilled in the art, pharmaceutically acceptable salts of the compounds described herein are derived from a variety of organic and inorganic counterions, and include, to the best of our knowledge, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and, if the molecule contains a basic functional group, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc. "pharmaceutically acceptable acid addition salts" are a subset of "pharmaceutically acceptable salts" that are formed by an acid partner while simultaneously retaining the biological effects of a free base. In particular, embodiments of the disclosed compounds form salts with a variety of pharmaceutically acceptable acids, including, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, as well as organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, benzenesulfonic acid, isethionic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. "Pharmacologically acceptable base addition salts" are subsets of "pharmaceutically acceptable salts" derived from inorganic bases, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Exemplary salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydravamin, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, and salts of polyamine resins.Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. (See, for example, S.M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66:1-19, which is incorporated herein by reference).

[0067] Phosphate: -O-P(O)(OR a )2 (each R a is independently hydrogen, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaromatic, aromatic or an organic functional group, or one or more R a groups are absent, and thus the phosphate group has at least one negative charge that can be balanced by counterion M + , each M + is independently an alkali ion such as K + , Na + , Li + , an ammonium ion such as + N(R b )4 (R b is H, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaromatic or aromatic), or an alkaline earth ion such as [Ca 2+ 0.5 , [Mg 2+ 0.5 or [Ba 2+ 0.5 ).

[0068] Phosphonate: -P(O)(OR a )2 (each R a is independently hydrogen, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaromatic, aromatic or an organic functional group, or one or more R a groups are absent, and thus the phosphate group has at least one negative charge that can be balanced by counterion M + , each M + is independently an alkali ion such as K + , Na​​​+ Li + ammonium ions, for example + N(R b )4(R b (H is aliphatic, heteroaliphatic, haloaliphatic, haloheteroaromatic, or aromatic), or alkaline earth ions, such as [Ca 2+ ] 0.5 [Mg 2+ ] 0.5 Or this Ba 2+ ] 0.5 (This is acceptable.)

[0069] Photoretinopathy: Damage to the retina, such as the macula, due to prolonged exposure to solar radiation or other bright light, such as lasers or arc welding machines. This term includes retinopathy caused by sunlight, lasers, and welding machines. In some embodiments, photoretinopathy is caused by intense artificial light or sunlight. The light may be ultraviolet (UV-B, 295–320 nm; UV-A, 320–400 nm) or visible light (400–700 nm). Phototoxic damage may occur in the retinal pigment epithelial cells, choroid, and rod outer segments. Photoretinopathy results in prolonged vision loss and central or paracentral scotoma. Fundus changes are usually (but not always) bilateral.

[0070] Prodrug: Most typically, an embodiment of a compound disclosed herein that is converted in vivo, for example, by enteric hydrolysis or enzymatic transformation, to yield a biologically active compound, particularly the parent compound. Common examples of prodrug moieties include, but are not limited to, pharmaceutically acceptable ester and amide forms of compounds having an active form supporting a carboxylic acid moiety. Examples of pharmaceutically acceptable esters of embodiments of the compounds disclosed herein include esters of phosphate groups and carboxylic acids, such as aliphatic esters, particularly alkyl esters (e.g., C11). 1~6 Examples of prodrug moieties include alkyl esters, but are not limited to them. Other prodrug moieties include phosphate esters, for example, -CH2-OP(O)(OR a )2 or its salt (R a is hydrogen or aliphatic (e.g., C1~6 This includes alkyl esters. Acceptable esters include, but are not limited to, cycloalkyl esters and arylalkyl esters, such as benzyl. Examples of pharmaceutically acceptable amides of embodiments of the compounds of this disclosure include, but are not limited to, primary amides, as well as secondary and tertiary alkylamides (e.g., having between 1 and 6 carbon atoms). The amides and esters of the embodiments of the compounds of this disclosure, and the exemplary embodiments disclosed, can be prepared according to conventional methods. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol 14 of the ACS Symposium Series, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

[0071] The retina is the part of the eye that is sensitive to light (photons) and contains photoreceptors (cones and rods) for light. The layers of the retina include a) the internal limiting membrane, b) the optic nerve fiber layer, c) the ganglion cell layer, d) the internal plexiform layer, e) the internal granular layer, f) the external plexiform layer, g) the external granular layer, h) the external limiting (limtans) membrane, i) the rod-cone layer (internal and external segments of photoreceptors), and j) the retinal pigment epithelium. In wild-type (non-disease) adult humans, the entire retina is approximately 72% of a sphere with a diameter of about 22 mm. The entire retina contains about 7 million cones and 75 to 150 million rods. Rods and cones perceive light through the use of photosensitive pigments, which are lighttransmitters that initiate the visual cycle, and therefore, rods and cones are photoreceptors that form vision. Photosensitive pigments include proteins called opsins and chromophores called retinal, which are variants of vitamin A. Rods contain rhodopsin, while cones contain cone opsins, such as S opsin, M opsin, and L opsin. Rods and cones transmit signals via continuous neurons that induce nerve discharges in the output cells and ganglion cells of the retina. Visual signals are transmitted by the optic nerve to the lateral geniculate nucleus, from where they are transmitted to the visual cortex (occipital lobe) and registered as visual stimuli. Rod cells, or rods, are photoreceptor cells in the retina of the eye, but can function in less intense light than cone cells, the other type of visual photoreceptor. Rods are concentrated at the outer edge of the retina and are used in the peripheral vision. Rods are slightly longer and thinner than cones but share the same structural basis. Opsins or pigments are located lateral to the retinal pigment epithelium and complete the cell's homeostasis. The ends of this epithelium contain many stacked discs. Rods have a large area for photoreceptor pigments and therefore possess substantial light absorption efficiency. Like cones, rod cells have synaptic terminals, an internal segment, and an external segment. The synaptic terminals form synapses with other neurons, such as bipolar cells. The internal and external segments are connected by connecting cilia arranged in a row at the terminal segment. The internal segment contains organelles and the cell nucleus, while the external segment of the rod, which extends towards the back of the eye, contains light-absorbing material.Light-induced activation of photosensitive pigments signals rod cells by hyperpolarizing them, preventing them from releasing their neurotransmitters, which then connect to bipolar cells, which release the neurotransmitters at bipolar ganglion synapses, exciting the synapses. Cone cells, or cones, are photoreceptors involved in color vision and function best in relatively bright light. Cone cells are densely packed in the fovea, a 0.3 mm diameter region that does not contain rods and has very fine, densely packed cones (their number rapidly decreasing towards the periphery of the retina). There are approximately 6 to 7 million cones in the human eye, most concentrated towards the macula. Cones are less sensitive to light than the rod cells in the retina (which support vision at low light levels), but they enable the perception of color. Cones also have a faster response time to stimuli than rods, allowing them to perceive finer details and more rapid changes in images. In humans, cones are typically one of three types, each possessing a different pigment: S-cones, M-cones, and L-cones. Therefore, each cone is sensitive to visible wavelengths corresponding to short, medium, and long wavelength light. Depending on the individual, the three types have peak wavelengths close to 420-440 nm, 534-545 nm, and 564-580 nm, respectively.

[0072] Retinal pigment epithelium: In mammals, this is a layer of hexagonal cells located just outside the sensory nerve retina, connected to the underlying choroid, that exists in vivo. These cells are densely packed with pigment granules and protect the retina from incident light. The retinal pigment epithelium also acts as a transport limiting factor, maintaining the retinal environment by supplying small molecules such as amino acids, ascorbic acid, and D-glucose, while remaining a robust barrier to blood-mediated substances in the choroid.

[0073] Retinitis pigmentosa (RP) is a hereditary degenerative eye disorder that causes severe visual impairment due to progressive degeneration of rod photoreceptor cells in the retina. This form of retinal dystrophy presents with early symptoms independent of age. Early retinal degeneration symptoms of retinitis pigmentosa are characterized by decreased night vision (nyctalopia) and loss of central and peripheral vision. Rod photoreceptor cells, which are involved in low-light vision and are oriented towards the periphery of the retina, are the first retinal processes affected during the non-symptomatic form of the disease. Visual impairment progresses relatively rapidly in the far peripheral vision and eventually extends to the central vision as tunneling vision increases. Visual acuity and color vision may be impaired due to accompanying abnormalities in cone photoreceptor cells involved in color vision, visual acuity, and visual field in the central vision. The progression of disease symptoms is symmetrical, with both the left and right eyes experiencing symptoms at a similar rate. There are several genes that, when mutated, can cause the phenotype of retinitis pigmentosa. The inheritance patterns of RP have been identified as autosomal dominant, autosomal recessive, X-linked, and acquired from the mother (through mitochondria), and depend on specific RP gene mutations present in the parental generation.

[0074] Rhodopsin: A photosensitive G protein-coupled receptor protein involved in visual light transmission. Rhodopsin consists of two components: a protein molecule also called rod visual opsin and a cofactor called retinal, which is covalently bound to it. Rod visual opsin is a photosensitive G protein-coupled receptor opsin embedded in the lipid bilayer of the cell membrane using the protein's seven transmembrane domain. These domains form a pocket in which the photoreactive chromophore retinal is aligned horizontally with the cell membrane and linked to the lysine residue of the protein's seven transmembrane domain. Thousands of rhodopsin molecules are found in each outer segment disk of host rod cells. Retinal is produced in the retina from dietary beta-carotene-derived vitamin A. Photocatalytic isomerization from 11-cis-retinal to all-trans-retinal initiates a series of conformational changes ("bleaching") in the opsin, ultimately transforming it into a form called metalrhodopsin II (meta-II), which activates the associated G protein transducin, inducing a second messenger cascade of cyclic guanosine monophosphate (cGMP). An exemplary human rhodopsin protein sequence is disclosed in GENBANK® accession number NP_000530, available June 1, 2020, incorporated herein by reference, and an exemplary mRNA encoding human rhodopsin is disclosed in GENBANK® accession number NM_000539, available June 1, 2020, incorporated herein by reference.

[0075] Rod-cyclic GMP phosphodiesterase 6β (PDE6β): The beta subunit of the protein complex PDE6, encoded by the PDE6B gene. PDE6 is critically important in the transmission and amplification of visual signals, and mutations in this subunit cause retinal degermation, such as in retinitis pigmentosa or statutory night blindness. Exemplary human orthologues are disclosed, for example, in GENBANK® accession numbers NM_000283 (mRNA) and NP_000274 (protein), which became available on June 1, 2020, and are incorporated herein by reference.

[0076] Cyril Ether:-OSiR a R b (R a and R b Each of these is independently selected from hydrogen, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaromatic, aromatic, or organic functional groups.

[0077] Stargardt disease: Also known as juvenile macular degeneration, it is the most common single-gene hereditary retinal disorder. Stargardt disease is usually autosomal recessive, caused by a mutation in the ABCA4 gene. Rarely, Stargardt disease is autosomal dominant, caused by a defect in the ELOVL4 or PROM1 gene. Stargardt disease is characterized by macular degeneration, which begins in childhood, adolescence, or adulthood and leads to progressive blindness.

[0078] Symptoms typically appear in childhood or adolescence, but there is no upper age limit for symptom onset. The main symptom is uncorrectable vision loss. The vision loss usually manifests as a loss of the ability to see fine details when reading or looking at distant objects. Symptoms typically begin before the age of 20 (median age of onset: approximately 17 years), and include wavy vision, blind spots, blurred vision, loss of depth perception, sensitivity to glare, color vision impairment, and impaired adaptation to dim light (delayed dark adaptation). Peripheral vision is usually less affected than the fine central (foveal) vision.

[0079] Target: Mammals and other animals, such as humans, pets (e.g., dogs, cats, rabbits, etc.), working animals, and domesticated animals. Therefore, the disclosed methods can be applied to both human therapeutic and veterinary applications.

[0080] Sulfinyl:-S(O)R a (R a (Selected from hydrogen, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaromatic, aromatic, or organic functional groups).

[0081] Sulfonyl:-SO2R a (R a (Selected from hydrogen, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaromatic, aromatic, or organic functional groups).

[0082] Sulfonamide:-SO2NR a R b or -N(R a )SO2R b (R a and R b Each of these is independently selected from hydrogen, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaromatic, aromatic, or organic functional groups.

[0083] Sulfonate: -SO3 - (The negative charge of the sulfonate group is the counterion M + And it can be in equilibrium, M + This is an alkaline ion, for example, K + kaNa + Li + ammonium ions, for example + N(R b )4(R b (H is aliphatic, heteroaliphatic, haloaliphatic, haloheteroaromatic, or aromatic), or alkaline earth ions, such as [Ca 2+ ] 0.5 [Mg 2+ ] 0.5 Or this Ba 2+ ] 0.5 (This is acceptable.)

[0084] Therapeutic dose: The amount of a compound sufficient to treat a specific disorder or disease, or to alleviate or eliminate one or more symptoms of a disease or disorder, such as retinal degeneration, and / or prevent their onset. The amount of compound constituting the "therapeutic dose" varies depending on the compound, the condition and its severity, the age of the person being treated, etc. The therapeutic dose can be determined by a person skilled in the art.

[0085] Chiar:-C(S)H.

[0086] Thioacyl:-C(S)R a (R a (Selected from hydrogen, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaromatic, aromatic, or organic functional groups).

[0087] Thiocarboxylic acid: -C(O)SH or -C(S)OH.

[0088] Thiocyanates: -S-CN or -N=C=S.

[0089] Thioester:-C(O)SR a or -C(S)OR a (R a (Selected from hydrogen, aliphatic, heteroaliphatic, haloaliphatic, haloheteroaromatic, aromatic, or organic functional groups).

[0090] Thioethers: -S-aliphatic or -S-aromatic, e.g., -S-alkyl, -S-alkenyl, -S-alkynyl, -S-aryl or -S-heteroaryl, or -aliphatic-S-aliphatic, -aliphatic-S-aromatic, -aromatic-S-aliphatic or -aromatic-S-aromatic.

[0091] Treatment, intervention, and therapy: any success or sign of success in reducing or mitigating an injury, pathology, or condition, including any objective or subjective parameters, such as recovery, remission, reduction of symptoms or making the condition more tolerable for the subject, slowing the rate of degeneration or decline, reducing the debilitation at the end of the degeneration, improving the physical or mental well-being of the subject, or improving vision. Treatment may be assessed by objective or subjective parameters, including the results of a physical examination, neurological examination, or psychiatric evaluation. The term “mitigation,” referring to a disease or pathological condition, refers to any observable beneficial effect of treatment. Beneficial effects may be demonstrated, for example, by delaying the onset of clinical symptoms of the disease in a susceptible subject, reducing the severity of some or all clinical symptoms of the disease, slower disease progression, improvement of the subject's overall health or well-being, or other parameters well known in the art and specific to a particular disease, such as improvement of vision. “Prophylactic” treatment is treatment administered to a subject who is not showing signs of the disease or is showing very early signs, with the aim of reducing the risk of developing the pathology.

[0092] As used herein, the terms “disease” and “condition” may be interchangeable, or they may differ in that a particular illness or condition does not appear to have a known causative agent (and therefore its etiology has not yet been determined), and therefore is not yet recognized as a disease, but is recognized merely as an undesirable condition or syndrome (to varying degrees, a specific set of symptoms has been identified by a clinician).

[0093] II. Introduction This specification discloses compounds for treating and / or preventing retinal degeneration of a given condition. In some embodiments, the compounds can maintain photoreceptor survival. For example, in some embodiments, the compounds improve rhodopsin expression and polarity and / or increase S-opsin expression and polarization in cone photoreceptors. In further embodiments, the compounds can increase ciliary proteins in photoreceptors. In some embodiments, the compounds are autophagy inhibitors that can reduce the autophagy pathway, and therefore improve ciliary biosynthesis and maintain photoreceptor survival in retinal degenerative diseases. In retinal ciliary-related diseases, the autophagy pathway is activated by stress resulting from ciliary defects (e.g., mislocalization of outer segment proteins in inner segment). Subsequently, p62 levels decrease due to accelerated proteolysis, leading to an increase in its interaction partners at the photoreceptor HDAC6, which is a driver of ciliary degradation (Figure 1A). Embodiments of the compounds of this disclosure inhibit autophagosome fusion with lysosomes, thereby increasing p62 and repairing HDAC6 degradation (Figure 1B). Embodiments of the compound can maintain photoreceptor survival in retinal degenerative diseases, such as LCA or retinitis pigmentosa (not limited to the following), by reducing the autophagy pathway and improving subsequent ciliary biosynthesis.

[0094] Embodiments of methods for treating retinal degeneration in subjects requiring such treatment are also disclosed. In some embodiments, the method comprises the step of administering to a subject a therapeutically effective amount of 3-(dibutylamino)-1-(1,3-dichloro-6-(trifluoromethyl)phenanthren-9-yl)propan-1-ol hydrochloride, or a compound having a structure according to a formula selected from formulas I, II, or III, as provided herein. In some non-limiting examples, the subject has retinitis pigmentosa, LCA, Stargardt macular dystrophy, cone-rodyl dystrophy, total choroidal atrophy, or age-related macular degeneration. Further embodiments of compounds, including pharmaceutically acceptable salts, prodrugs, solvates, hydrates, and / or tautomers thereof, are described herein along with embodiments of compositions containing such compounds.

[0095] III. Embodiments of Compounds Embodiments of the compounds of this disclosure, including pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or tautomers thereof, may have structures conforming to any one of the following formulas I to III. [ka] [ka]

[0096] With respect to Equation I, the following enumeration of variables can be applied: R 1 If present (for example, if n is a non-zero integer), it may be a heteroaliphatic element. R 2 is OR 5 or NR 6 R 7 You can choose from R 5 , R 6 , and R 7 Each of these is independently selected from hydrogen, aliphatic or aromatic, or organic functional groups. R 3 and R 4Each of these can be independently selected from aliphatic, aromatic, acyl, or sulfonyl. n can be an integer selected from 0 to 4.

[0097] In the embodiment of formula I, if n is 0, a person skilled in the art will know otherwise any R 1 It will be recognized that hydrogen atoms exist in order to satisfy the valence of one of the carbon atoms that should be bonded to the base.

[0098] With respect to Equation II, the following enumeration of variables can be applied: R A If present (for example, if m is a non-zero integer), it can be selected from halogens, heteroaliphatic, haloaliphatic, or organic functional groups. R B It may be an aromatic compound. R C and R D Each of these can be independently selected from hydrogen, aliphatic, or heteroaliphatic, or R C and R D These can, together with the nitrogen atoms to which they are bonded, form a heterocyclic ring system. m can be an integer selected from 0 to 4.

[0099] In the embodiment of formula II, if m is 0, a person skilled in the art will know otherwise any R A It will be recognized that hydrogen atoms exist in order to satisfy the valence of one of the carbon atoms that should be bonded to the base.

[0100] With respect to Equation III, the following enumeration of variables can be applied: If R' is present (for example, if there is a bond as needed represented by a dashed line), it can be selected from aliphatic, aromatic, halogen, heteroaliphatic, haloaliphatic, or organic functional groups. Each R'', if present (for example, if p is a non-zero integer), can be independently selected from halogen, heteroaliphatic, or amino. Each R''' can be independently selected from halogen, heteroaliphatic, or amino if present (for example, if q is a non-zero integer and r is 1). p is an integer selected from 0 to 4. q is an integer selected from 0 to 4. r is an integer selected from 0 or 1.

[0101] In embodiments of formula III, if p and / or q are 0, a person skilled in the art will recognize that a hydrogen atom is present to satisfy the valence of any carbon atom that would otherwise be bonded to any R' or R'' group. A person skilled in the art will also recognize that if r is 0, the valence of each carbon atom that the fused ring would otherwise be bonded to is satisfied by a hydrogen atom. Furthermore, a person skilled in the art will recognize that if none of the required bonds represented by the dashed lines in formula III are present, the valence of the corresponding carbon atom in the formula is satisfied by bonding with a hydrogen atom.

[0102] In certain embodiments of formula I (and any of the following formulas IA to IE), the following enumeration of variables may be applied: R 1 These are alkoxys, such as -OMe, -OEt, -OPr, -OiPr, -OnBu, -O t Bu or similar names are also acceptable. R 2 is -OR 5 or -NR 6 R 7 It may be R 5 , R 6 , and R 7 Each of them independently consists of hydrogen and alkyl (e.g., C 1~6 Alkyl or C 3~ C6 cycloalkyl), heteroaryl (e.g., C 3~6 Heteroaryl), or aryl (e.g., C6~10 You can choose from (Aryl). R 3 and R 4 Each of them independently has an alkyl group (e.g., C 1~6 Alkyl or C 3~6 Cycloalkyl); heteroaryl (e.g., C 3~10 Heteroaryl); aryl (for example, C 6~10 The organic functional group can be selected from aryl, sulfonyl, or acyl groups. In some embodiments, the sulfonyl group is of the formula -SO2R 9 It can have R 9 The acyl group can be selected from aliphatic, amine, or aromatic groups. In some embodiments, the acyl group is of the formula -C(O)R 8 It can have R 8 is alkyl (for example, C 1~10 Alkyl, C 1~10 Cycloalkyl, C 1~10 Alkenyl, or C 1~10 Cycloalkenyl; heteroaryl (e.g., C 4~10 Heteroaryl; halogen, -CF3, -CN, -OH, C 1~6 Alkyl, C 1~6 Alkoxy, sulfonyl, sulfonamide (e.g., C 1~6 Alkyl sulfonyl amino acids, e.g., -SO2NHC 1~6 Alkyl), amide (for example, C 1~6 Alkylaminocarbonyl, e.g., -C(O)NHC 1~6 Heteroaryl (e.g., C) containing one or more substituents selected from alkyl 4~10 Heteroaryl); aryl (for example, C 6~10 Aryl; halogen, -CF3, -CN, -OH, C 1~6 Alkyl, C 1~6 Alkoxy, sulfonyl, sulfonamide (e.g., C 1~6 Alkyl sulfonyl amino acids, e.g., -SO2NHC 1~6 Alkyl), amide (for example, C 1~6 Alkylaminocarbonyl, e.g., -C(O)NHC 1~6aryl (e.g., C) containing one or more substituents selected from (alkyl) 6~10 can be selected from aryl), n is 0, 1, 2, 3, or 4.

[0103] In some embodiments of Formula I, the compound can have the stereochemistry shown in the following Formula IA, including its pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or tautomers.

Chemical formula

[0104] In some embodiments, embodiments of the compounds of Formula I and / or IA can further have a structure according to the following Formula IB, IC, ID, or IE, including their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or tautomers.

Chemical formula

[0105] In a further embodiment of Formula I or any of IA - IE, R 4 can be selected from any of the following groups.

Chemical formula

Chemical formula

[0106] In a representative embodiment, R 1 and R 2 are both -OMe, R 3 is methyl, and R 4 is selected from any of the groups shown above. In certain embodiments, the compound of Formula I is selected from any of the following, including any pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or tautomers thereof.

Chemical formula

[0107] In some embodiments, the compound may be selected from any of the following, including its pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or tautomers: Methyl(1S,2R,3R,4aS,13bR,14aS)-2,11-dimethoxy-3-((3,4,5-trimethoxybenzoyl)oxy)-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydroindo[2',3':3,4]pyrido[1,2-b]isoquinoline-1-carboxylate (also known herein as "reserpine" or "NCGC0091250"); Methyl(1S,2R,3R,4aS,13bR,14aS)-2-methoxy-3-((3,4,5-trimethoxybenzoyl)oxy)-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydroindo[2',3':3,4]pyrido[1,2-b]isoquinoline-1-carboxylate; Methyl(1S,2R,3R,4aS,13bR,14aS)-3-(((E)-3-(4-hydroxy-3-methoxyphenyl)acryloyl)oxy)-2,11-dimethoxy-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydroindo[2',3':3,4]pyrido[1,2-b]isoquinoline-1-carboxylate (also known herein as "Resimetol" or "NCGC00253604"); Methyl(1S,2R,3R,4aS,13bR,14aS)-2,11-dimethoxy-3-(2-(4-methoxyphenoxy)acetoxy)-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydroindo[2',3':3,4]pyrido[1,2-b]isoquinoline-1-carboxylate; Methyl(1S,2R,3R,4aS,13bR,14aS)-2,11-dimethoxy-3-(((E)-3-(3,4,5-trimethoxyphenyl)acryloyl)oxy)-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydroindo[2',3':3,4]pyrido[1,2-b]isoquinoline-1-carboxylate; Methyl(1S,2R,3R,4aS,13bR,14aS)-3-((4-((ethoxycarbonyl)oxy)-3,5-dimethoxybenzoyl)oxy)-2,11-dimethoxy-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydroindo[2',3':3,4]pyrido[1,2-b]isoquinoline-1-carboxylate; Methyl(1S,2R,3R,4aS,13bR,14aS)-3-hydroxy-2,11-dimethoxy-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydroindo[2',3':3,4]pyrido[1,2-b]isoquinoline-1-carboxylate; (1S,2R,3R,4aS,13bR,14aS)-3-hydroxy-2,11-dimethoxy-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydroindro[2',3':3,4]pyrido[1,2-b]isoquinoline-1-carboxylic acid; Methyl 2,11-dimethoxy-3-((3,4,5-trimethoxybenzoyl)oxy)-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydroindo[2',3':3,4]pyrido[1,2-b]isoquinoline-1-carboxylate; Methyl 2-methoxy-3-((3,4,5-trimethoxybenzoyl)oxy)-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydroindo[2',3':3,4]pyrido[1,2-b]isoquinoline-1-carboxylate; Methyl(E)-3-((3-(4-hydroxy-3-methoxyphenyl)acryloyl)oxy)-2,11-dimethoxy-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydroindo[2',3':3,4]pyrido[1,2-b]isoquinoline-1-carboxylate; Methyl 2,11-dimethoxy-3-(2-(4-methoxyphenoxy)acetoxy)-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydroindo[2',3':3,4]pyrido[1,2-b]isoquinoline-1-carboxylate; Methyl(E)-2,11-dimethoxy-3-((3-(3,4,5-trimethoxyphenyl)acryloyl)oxy)-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydroindo[2',3':3,4]pyrido[1,2-b]isoquinoline-1-carboxylate; Methyl 3-((4-((ethoxycarbonyl)oxy)-3,5-dimethoxybenzoyl)oxy)-2,11-dimethoxy-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydroindo[2',3':3,4]pyrido[1,2-b]isoquinoline-1-carboxylate; Methyl 3-hydroxy-2,11-dimethoxy-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydroindo[2',3':3,4]pyrido[1,2-b]isoquinoline-1-carboxylate; or 3-Hydroxy-2,11-dimethoxy-1,2,3,4,4a,5,7,8,13,13b,14,14a-Dodecahydroindo[2',3':3,4]pyrido[1,2-b]isoquinoline-1-carboxylic acid.

[0108] In certain embodiments of Equation II (or Equation IIA below), the following enumeration of variables may be applied: Each R A These can be independently selected from halogens (e.g., Cl, F, Br, or I), -OMe, -CN, or -CF3. R B is an aryl (for example, C6~10 Aryl; halogen, -CF3, -CN, -OH, alkyl (e.g., C 1~6 Alkyl), alkoxy (e.g., C 1~6 aryl (e.g., C) containing one or more substituents selected from alkoxy) 6~10 aryl); heteroaryl (for example, C 4~10 Heteroaryl; halogen, -CF3, -CN, -OH, alkyl (e.g., C 1~6 Alkyl), alkoxy (e.g., C 1~6 Heteroaryl (e.g., C) containing one or more substituents selected from alkoxy 4~10 You can choose from heteroaryls. R C and R D Each of them independently consists of hydrogen and alkyl (e.g., C 1~12 Alkyl or C 3~8 Cycloalkyl), amino (for example, C 1~12 Alkylaminoalkyl, for example, N,N-diethylaminobutanyl, or C 3~8 You can choose from cycloalkylaminoalkyl or R C and R D Together, they can form 4-membered, 5-membered, 6-membered, or 7-membered heterocyclic ring systems, including aromatic and non-aromatic ring systems, along with the nitrogen atoms to which they are bonded. m is 0, 1, 2, 3, or 4.

[0109] In some embodiments, embodiments of the compound of formula II may further have a structure according to formula IIA, including pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or tautomers thereof. [ka]

[0110] In some further embodiments of formula II or IIA, R B The following can be selected from the following bases. [ka] [Chemistry]

[0111] In a representative embodiment, m is 2 and each R A is, independently, halogen (e.g., Cl), R B is absent or is a bithiophene group, R C and R D one of which is hydrogen and the other is N,N - diethylaminobutanil. In certain embodiments, the compound is [Chemistry] N1-(3-( [2,2’-bithiophene]-5-yl)-6,7 - dichloroquinoxalin - 2 - yl)-N4,N4 - diethylbutane - 1,4 - diamine (also referred to herein as "NCGC00263128") or any pharmaceutically acceptable salt, prodrug, solvate, hydrate or tautomer thereof.

[0112] In certain embodiments of formula III (or any one of formulas IIIA - IIID), the following enumeration of variables can be applied: R', when present, is halo, -CN, -CF3, -OCF3, alkyl (e.g., C 1~12 alkyl), heteroalkyl (e.g., containing one or more nitrogen atoms, one or more oxygen atoms, one or more sulfur atoms, or combinations thereof, including its cyclic and acyclic heteroalkyl, C 1~12 heteroalkyl), aminoaryl (e.g., -NR a’ -aryl, or -NR a’ -aryl containing one or more substituents selected from halogen, -CN, -CF3, -OCF3, amino, heteroalkyl, amide or sulfonamide), and can be selected from R'', when present, is halogen, alkoxy, or -NR a’ Rb’ You can choose from R a’ and R b’ Each of them independently has an alkyl group (e.g., C 1~12 Alkyl), heteroalkyl (for example, C 1~12 Heteroalkyls), benzyls (e.g., -CH2 aromatics, or -CH2 aromatics containing one or more substituents selected from alkoxy, halogen, or amide), acyls (e.g., -C(O) alkyl, -C(O) alkenyl, -C(O) heteroalkyl, -C(O) aromatics; -C(O) aromatics containing one or more substituents selected from alkyl, halogen, -CF3, -OCF3, or -CN), sulfonyls (e.g., -SO2R a Here, R a (Selected from hydrogen, alkyl, aromatic; aromatics containing one or more substituents selected from alkyl, amide, or alkoxy) R''', if present, is a halogen, alkoxy, or -NR a’ R b’ You can choose from R a’ and R b’ Each of them independently has an alkyl group (e.g., C 1~12 Alkyl), heteroalkyl (for example, C 1~12 Heteroalkyls), benzyls (e.g., -CH2 aromatics, or -CH2 aromatics containing one or more substituents selected from alkoxy, halogen, or amide), acyls (e.g., -C(O) alkyl, -C(O) alkenyl, -C(O) heteroalkyl, -C(O) aromatics; -C(O) aromatics containing one or more substituents selected from alkyl, halogen, -CF3, -OCF3, or -CN), sulfonyls (e.g., -SO2R a Here, R a (Selected from hydrogen, alkyl, aromatic; aromatics containing one or more substituents selected from alkyl, amide, or alkoxy) Each of p and q is an integer independently selected from 0, 1, 2, 3, or 4. r is either 0 or 1.

[0113] In some further embodiments, R' exists, R'' exists, R''' does not exist, and r is 0. In other embodiments, R', R'', and R''' each exist, and R'' and R''' are the same. In yet another set of embodiments, R'' and R''' each exist, and R' does not exist. In yet another set of embodiments, R' exists, and neither R'' nor R''' exists, and in such embodiments, r may also be 1, and the resulting ring may be saturated. In certain embodiments, R'' and R''' each may be the same or different. Exemplary formulas representing at least some of these options are shown below. [ka]

[0114] In some further embodiments of formulas IIIA to IIID, R ’ The following can be selected from the following bases. [ka] [ka]

[0115] R'' and / or R''' are -NR a’ R b’ In this embodiment, R a’ and / or R b’ Each of these can be selected from one of the following groups and hydrogen. [ka] [ka]

[0116] In typical embodiments, R' is a heteroalkyl, and R'' and R''' are present, being Cl and OMe, respectively. In specific embodiments, the compound of formula III is selected from the following, including any pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof. [ka] [ka]

[0117] In some embodiments, the compound can be selected from the following: N4-(6-chloro-2-methoxyacrycridin-9-yl)-N1,N1-diethylpentan-1,4-diamine; N,N'-(piperazine-1,4-diylbis(propane-3,1-diyl))bis(6-chloro-2-methoxyacrylidine-9-amine); N4-(6-chloro-2-methoxyacridin-9-yl)-N1,N1-diethylpentan-1,4-diamine dihydrochloride dihydrate (also referred to herein as "quinacrine dihydrochloride dihydrate" or "NCGC0015874"); N,N'-(piperazine-1,4-diylbis(propane-3,1-diyl))bis(6-chloro-2-methoxyacrylidine-9-amine); N1,N7-Bis(1,2,3,4-tetrahydroacridine-9-yl)heptan-1,7-diamine; N4-(7-chloroquinoline-4-yl)-N1,N1-diethylpentan-1,4-diamine (also referred to herein as "chloroquine"); 2-((4-((7-chloroquinoline-4-yl)amino)pentyl)(ethyl)amino)ethane-1-ol (also known herein as "hydroxychloroquine"); 1-((2-((2-((7-chloroquinoline-4-yl)amino)ethyl)(methyl)amino)ethyl)amino)-4-methyl-9H-thioxanthene-9-one (also known herein as "ROC-325"); Acridine-3,6-diamine; Acridine-3,6-diaminehemisulfate (also referred to herein as "proflavinhemisulfate"); 6-Chloro-2-methoxy-9-(2-methoxyethoxy)acridine; N1-(7-chloroquinoline-4-yl)-N2-(2-((7-chloroquinoline-4-yl)amino)ethyl)ethane-1,2-diamine (also known herein as "Lys05"); or 6-Chloro-2-methoxy-9-(piperidine-4-yloxy)acridine.

[0118] In independent embodiments, the compound may be 3-(dibutylamino)-1-(1,3-dichloro-6-(trifluoromethyl)phenanthren-9-yl)propan-1-ol hydrochloride (or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof), and structure [ka] It has.

[0119] In another independent embodiment, the compound may be N-[3-[[5-cyclopropyl-2-[(2-methyl-3,4-dihydro-1H-isoquinoline-6-yl)amino]pyrimidine-4-yl]amino]propyl]cyclobutanecarboxamide (or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or tautomer thereof), and structure [ka] It has.

[0120] IV. Method for preparing embodiments of the compound Embodiments of methods for preparing embodiments of the compounds of this disclosure are also described. Exemplary embodiments of the methods are described in the examples of this disclosure.

[0121] In some embodiments, a method for producing a compound according to formula I can be described below.

[0122] In some embodiments for preparing the compound of formula I, methyl(1S,2R,3R,4aS,13bR,14aS)-3-hydroxy-2,11-dimethoxy-1,2,3,4,4a,5,7,8,13,13b,14,14a-dodecahydroindo[2',3':3,4]pyrido[1,2-b]isoquinoline-1-carboxylate can be used as a starting material (compound 100 in scheme 1 below). In certain embodiments, R 4 The group can be incorporated into this starting compound using any of the embodiments of the following methods. Any such method further involves R as described above for any of formulas I and IA-IE. 3 It can be used to provide a base.

[0123] In some embodiments, a certain R 4 The group can be incorporated under basic conditions shown in Scheme 1 using Williamson ether synthesis by reaction of alkyl halides with 100, thereby providing product 102. Further embodiments are provided below, and typical methods are described in the Examples section. [ka]

[0124] In other embodiments, a certain R 4 The group can be incorporated by a reaction with the corresponding acyl or carboxylic acid, as shown in schemes 1A and 1B, respectively, thereby providing product 104. [ka]

[0125] In further embodiments, a certain R 4 The group can be incorporated by a reaction of 100 with the corresponding sulfonyl chloride, as shown in scheme 1C, thereby providing product 106. [ka]

[0126] In some embodiments, different R 2 The above-mentioned compound of formula I, which contains a group (different from the methyl ester group shown in schemes 1 and 1A-1C), can be prepared according to the following embodiment of the method shown in scheme 1D, which provides product 110 or 112. [ka]

[0127] Furthermore, embodiments of a method for producing the compound represented by formula II (and / or formula IIA) are disclosed. In such embodiments, the method uses the starting material 200 shown in Scheme 2 below, which is coupled with the corresponding palladium coupling reagent 202, thereby R B The process may include a step of providing a group. Scheme 2 shows a palladium-based coupling reaction using a boronic acid coupling partner (202), but a Still-based coupling (e.g., R) may also be used. B Sn(Bu)4(R B This is R as described in the definition section. B (can be selected from the base) or Negishi-based coupling (for example, R B ZnX'(R B This is R as described in the definition section. BOther coupling partners can also be used, including those suitable for the group X' (which may be a halogen, triflate, ester, etc.). Further embodiments are provided below, and representative methods are described in the Examples section. [ka]

[0128] In some embodiments, the method may include steps such as those outlined in Scheme 2A, where X'' may be CH or N (or an oxidized form thereof), and Y may be selected from aromatic (e.g., aryl or heteroaryl); aromatic (e.g., aryl or heteroaryl) containing one or more substituents selected from halogens, -CN, alkoxy, and -OCF3; or aliphatic (e.g., cyclic aliphatic). [ka]

[0129] Furthermore, embodiments of methods for producing compounds represented by formula III (and / or formulas IIIA-IIID) are disclosed. In such embodiments, the method may include the step of reacting a precursor compound 300 (where Z is a halogen, e.g., chloro) with a suitable coupling component under suitable coupling conditions to provide product 302, or reacting a precursor compound 304 (where Z' and Z'' may each be independently an amine group or a hydroxyl group) with a suitable coupling component under suitable coupling conditions to provide product 306. Further embodiments are provided below, and representative methods are described in the Examples section. [ka]

[0130] In some embodiments, the method may include steps such as those outlined in Scheme 3A, where the R group of the RONa reagent may be alkyl or heteroalkyl, each Y' may be selected from amino, heteroaliphatic, amide, or sulfonamide, and m' is an integer selected from 0 to 5. [ka]

[0131] In some embodiments, the method may include steps such as those outlined in Scheme 3B, which uses starting material 314 (the starting material is any R a’ or R b’ The process involves using a starting material that includes, in addition to the group, at least one hydrogen atom bonded to each of the indicated amine groups, and two of the same or different acyl and / or sulfonyl groups can be coupled to the starting material using the corresponding acyl or sulfonyl coupling reagent (e.g., acyl and / or sulfonyl halides). Referring to Scheme 3B, the R bonded to each amine in product 316 a’ or R b’ At least one of the groups is an acyl group or a sulfonyl group. a’ R b’ Symmetric products of product 316 with the same group can be prepared, or each NR a’ R b’ Asymmetric products of product 316 with different groups can be prepared. [ka]

[0132] In some additional embodiments, the method may include steps such as those outlined in Scheme 3C, where the starting material 314 is converted to product 316 using a series of protection, addition, and deprotection steps. Such embodiments can be used in certain examples to provide compounds in which the amine nitrogen is bonded to at least one aliphatic, heteroaliphatic, haloaliphatic, or aromatic group. [ka]

[0133] V. How to use This specification discloses embodiments of methods for treating and / or preventing retinal degeneration in subjects. Embodiments of methods may include the step of selecting subjects having retinal degeneration or subjects at risk of retinal degeneration. Generally, a therapeutically effective amount of the compound disclosed herein is administered. In some embodiments, the compound may be 3-(dibutylamino)-1-(1,3-dichloro-6-(trifluoromethyl)phenanthren-9-yl)propan-1-ol hydrochloride, or another pharmaceutically acceptable salt, prodrug, solvate, hydrate, and / or tautomer of 3-(dibutylamino)-1-(1,3-dichloro-6-(trifluoromethyl)phenanthren-9-yl)propan-1-ol. In further embodiments, the compound may have a structure according to any of the compounds disclosed herein, including one of formulas I, II, or III, or any pharmaceutically acceptable salt thereof, prodrug, solvate, hydrate, or tautomer. This administration is sufficient to treat, inhibit, and / or prevent retinal degeneration. In some embodiments, the subject has ongoing photoreceptor degeneration. In further embodiments, the method treats the retinal degeneration of the subject.

[0134] By using embodiments of the compounds disclosed herein, various conditions of the eye can be treated or prevented. These conditions include retinal dysfunction or deterioration, retinal injury, and / or retinal diseases or disorders generally associated with loss of retinal pigment epithelium. The disclosed methods are used to treat retinal degenerative diseases, retinal (or retinal pigment) epithelial dysfunction, retinal deterioration, and retinal (or retinal pigment) epithelial injury. The disclosed methods are also used to treat loss of retinal pigment epithelium. The methods include the step of administering an embodiment of the compound (or a composition thereof) to the eye of interest, for example, by topical administration.

[0135] In some embodiments, retinal degenerative diseases include Stargardt macular dystrophy, retinitis pigmentosa, age-related macular degeneration, diabetic retinopathy, Leber congenital amaurosis (LCA), late-onset retinal degeneration, hereditary or acquired retinal degeneration, total choroidal atrophy, Best's disease, Sausby's retinal degeneration, gynostosis, total choroidal atrophy, pattern dystrophy, or cone-rod dystrophy. In non-limiting specific cases, subjects have retinitis pigmentosa, LCA, Stargardt macular dystrophy, cone-rod dystrophy, total choroidal atrophy, or age-related macular degeneration.

[0136] In some embodiments, the method may include a step of selecting a subject for treatment. In some embodiments, the method may include a step of selecting a subject having Stallgart macular dystrophy, retinitis pigmentosa, age-related macular degeneration, diabetic retinopathy, Leber congenital amaurosis, late-onset retinal degeneration, hereditary or acquired retinal degeneration, total choroidal atrophy, Best's disease, Sausby's retinal degeneration, gynostosis, total choroidal atrophy, pattern dystrophy, or cone-rod dystrophy. In certain non-limiting examples, the subject may have retinitis pigmentosa, LCA, Stallgart macular dystrophy, cone-rod dystrophy, total choroidal atrophy, or age-related macular degeneration. Thus, the method may include a step of selecting a subject having retinal degeneration, for example, a subject having retinitis pigmentosa, LCA, Stallgart macular dystrophy, cone-rod dystrophy, total choroidal atrophy, or age-related macular degeneration, but is not limited to the following. In further embodiments, the subject may have diabetic retinopathy. The method may include the step of selecting subjects having diabetic retinopathy or subjects at risk of diabetic retinopathy, for example, subjects with diabetes. After selection, subjects are administered an effective amount of one or more compounds, including any pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or tautomers thereof, of the embodiments disclosed herein.

[0137] In certain embodiments, embodiments of the methods of the present disclosure can be used to treat any type of retinitis pigmentosa. In some embodiments, retinitis pigmentosa is caused by mutations in the rhodopsin gene, the peripherin gene, and / or other genes expressed in the rods. Retinitis pigmentosa may result from a genetic condition inherited in an autosomal dominant, autosomal recessive, or X-linked manner. X-linked retinitis pigmentosa may be recessive, affecting males, or dominant, and therefore affect both males and females. Retinitis pigmentosa may be associated with rod-cone retinal degeneration present with central macular pigment changes (target maculopathy). Retinitis pigmentosa may also be total choroidal atrophy, which is an X-linked recessive retinal degenerative disease. Generally, retinitis pigmentosa (RP) is characterized by progressive photoreceptor cell loss.

[0138] In further embodiments, the methods of the present disclosure can be used to prevent or treat age-related macular degeneration (AMD). In some embodiments, the subject has atrophic AMD (also known as “dry” AMD), and the subject has central vision loss due to retinal atrophy. In other embodiments, the subject has exudative AMD.

[0139] In further embodiments, the disclosed method is used to treat subjects having LCA. In further embodiments, the disclosed method is used to treat LCA which may have defects in the CEP290 protein and therefore defects in ciliary protein transport.

[0140] In further embodiments, the subject has Stargard macular dystrophy. In even further embodiments, the subject has cone-rod dystrophy. In even further embodiments, the subject has total choroidal atrophy.

[0141] Diagnosis can utilize tests that examine the fundus and / or evaluate the visual field. These include electroretinography, fluorangiography, and visual examination. Fundus examination aims to assess the condition of the retina and evaluate the presence of characteristic pigment spots on the retinal surface. Visual field testing makes it possible to assess the sensitivity of different parts of the retina to light stimuli. Electroretinography (ERG) can be used to record the electrical activity of the retina in response to specific light stimuli and to separately evaluate the functionality of two different types of photoreceptors (e.g., cone cells and rod cells).

[0142] Combinations of compounds, including those that act synergistically, can be used. Therefore, in any of the disclosed methods, two, three, four or more types of compounds can be administered.

[0143] In some embodiments, the compound is administered for 10, 15, 20, 25, or 30 days. In further embodiments, the compound is administered for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months. In further embodiments, the compound may be administered for up to 6 months, or up to 1 year, up to 2 years, up to 3 years, or longer. In some examples, the compound may be administered once daily, every other day, every three days, or once weekly for a specified period. Sustained-release formulations, such as drug depots or sustained-release implants or devices that release the compound, may also be used. In some examples, the compound is administered once daily.

[0144] Systemic administration methods include oral and parenteral routes. Parenteral routes include, for example, intravenous, intra-arterial, intramuscular, intradermal, subcutaneous, intranasal, and intraperitoneal routes. Compounds administered systemically may be modified or formulated to target the component to the eye, such as intravitreous administration, but are not limited to the following. In other embodiments, the compound is administered orally.

[0145] Suitable oral formulations of the compound include, for example, tablets or capsules containing about 10 mg / kg, about 20 mg / kg, about 30 mg / kg, or about 40 mg / kg of the compound, preferably tablets. In some embodiments, the compound may be administered as a single dose or in divided doses in a dose range of about 20 mg / kg to about 160 mg / kg per day, for example, about 20 mg / kg to about 80 mg / kg, or for example, about 20 mg / kg to about 40 mg / kg. In non-limiting specific examples, this dose is administered once daily.

[0146] In other embodiments, the compound is administered orally in doses of approximately 10 mg / kg to approximately 80 mg / kg. In other embodiments, the compound is administered orally in doses of approximately 40 mg / kg to approximately 80 mg / kg. In some examples, the compound is administered orally in doses of approximately 40 mg / kg, approximately 45 mg / kg, approximately 50 mg / kg, approximately 55 mg / kg, approximately 60 mg / kg, approximately 65 mg / kg, approximately 70 mg / kg, approximately 75 mg / kg, or approximately 80 mg / kg. In certain non-limiting examples, this dose is administered once daily.

[0147] In further embodiments concerning humans, the compound is administered orally once daily at a dose of approximately 0.8 mg / kg to approximately 6.5 mg / kg (approximately 10 mg / kg / day, roughly equivalent to a dose of 0.81 mg / kg / day in adult humans). In some non-limiting examples, the compound is administered orally once daily at a dose of approximately 3.2 mg / kg to approximately 6.5 mg per kg. Appropriate doses include approximately 0.8 mg / kg, 0.9 mg / kg, 1 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg, 2 mg / kg, 2.1 mg / kg, 2.2 mg / kg, 2.3 mg / kg, 2.4 mg / kg, 2.5 mg / kg, 2.6 mg / kg, 2.7 mg / kg, 2.8 mg / kg, 2.9 mg / kg, 3 mg / kg, 3.1 mg / kg, 3.2 mg / kg, 3.3 mg / kg, 3.4 mg / kg, 3.5 mg / kg, 3.6 mg / kg, and 3.7 mg / kg. g includes, but is not limited to, approximately 3.8 mg / kg, 3.9 mg / kg, 4.0 mg / kg, 4.1 mg / kg, 4.2 mg / kg, 4.3 mg / kg, 4.4 mg / kg, 4.5 mg / kg, 4.6 mg / kg, 4.7 mg / kg, 4.8 mg / kg, 4.9 mg / kg, 5.0 mg / kg, 5.1 mg / kg, 5.2 mg / kg, 5.3 mg / kg, 5.4 mg / kg, 5.5 mg / kg, 5.6 mg / kg, 5.7 mg / kg, 5.8 mg / kg, 4.9 mg / kg, 6.0 mg / kg, 6.1 mg / kg, 6.2 mg / kg, 6.3 mg / kg, 6.4 mg / kg, and 6.5 mg / kg. The compound can be formulated for administration in any oral formulation, including solid or liquid forms. The compound can be administered once daily.

[0148] In a non-limiting example, the compound is administered orally once daily at a dose of approximately 40 mg / kg to approximately 80 mg / kg for a minimum of 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months. In another non-limiting example, the compound is administered orally once daily at a dose of approximately 0.8 mg / kg to approximately 6.5 mg / kg for a minimum of 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months. In a further embodiment, the compound can be administered orally once daily at a dose of approximately 0.8 mg / kg to approximately 6.5 mg / kg for up to 6 months, or up to 1 year, up to 2 years, up to 3 years, or longer. In some cases, the compound may be administered orally once daily, every other day, every three days, or once weekly for a specified period. In some cases, the compound is administered orally once daily. In some non-limiting cases, the compound is administered orally once daily at a dose of approximately 40 mg / kg to approximately 80 mg / kg for at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months. In even more non-limiting cases, the compound is administered orally once daily at a dose of approximately 0.8 mg / kg to approximately 6.5 mg / kg for at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months.

[0149] The compound can be administered topically to the eye. Topical administration methods include, for example, intraocular, intraorbital, subconjunctival, subtenon's capsule, subretinal, or transscleral routes. In one embodiment, when administered topically (e.g., intravitreal), an effect can be exerted with a significantly smaller amount of the component compared to systemic administration (e.g., intravenous). In one embodiment, the compound is delivered subretinally, for example, by subretinal injection. Subretinal injection can be performed directly on the macula, for example, by submacular injection. Exemplary methods include intraocular injection (e.g., retroocular, subretinal, submacular, intravitreal, and intrachoridal), iontophoresis, This includes eye drops and intraocular injections (e.g., intravitreal, sub-Tenon's capsule, and subconjunctival).

[0150] In one embodiment, the system disclosed herein is delivered by intravitreal injection. Intravitreal injection carries a relatively low risk of retinal detachment. Methods for administering drugs to the eye are known in the medical field and can be used to administer the components described herein.

[0151] Administration may be provided as a single dose, a periodic bolus, or a continuous infusion. In some embodiments, administration is performed from an internal reservoir (e.g., from an implant positioned in an intraocular or extraocular location, see, for example, U.S. Patents 5,443,505 and 5,766,242, the relevant parts of which are incorporated herein by reference) or from an external reservoir (e.g., from an infusion bag). The component may be administered by continuous release over a specific period of time from a sustained-release drug delivery device fixed to the inner wall of the eye, or by targeted transscleral controlled release into the choroid (see, for example, PCT / US00 / 00207, PCT / US02 / 14279, Ambati, the relevant parts of which are incorporated herein by reference). et al., Invest. Opthalmol. Vis. Sci. 41:1181-1185, 2000 and Ambati et al. See, al., Invest. Opthalmol. Vis. Sci. 41:1186-1191, 2000. Various devices suitable for topical administration of components into the inner eye are known in the art and can be selected for use in this disclosure. See, for example, U.S. Patents 6,251,090, 6,299,895, 6,416,777, 6,413,540, and PCT application PCT / US00 / 28187, the relevant parts of which are incorporated herein by reference.

[0152] The drug administration procedure may be a single-dose or multi-dose schedule to ultimately deliver a previously determined amount. Dosage may be intermittent. Furthermore, the subject may be administered the required number of doses. In some embodiments, the subject is administered the compound before the onset of the condition.

[0153] Individual doses are typically the amount required to produce at least a measurable effect on the subject and can be determined based on the pharmacokinetic and pharmacological effects of the composition of the subject or its by-products, on the absorption, distribution, metabolism, and elimination ("ADME"), and therefore on the properties of the composition in the subject. This includes consideration of the route of administration and dosage, which can be adjusted for topical and systemic (e.g., oral) application. Effective dosages and / or dosing regimens can be readily determined empirically from preclinical assays, safety and escalation and dose-range studies, individual clinician-patient relationships, and in vitro and in vivo assays. Generally, these assays assess retinal degeneration or the expression of biological components (cytokines, specific inflammatory cells, microglia, etc.) that affect retinal degeneration. In some embodiments, the dose may be (i) an intermittent high dose of 20 μM or 30 μM in vitro, or (ii) an in vivo dose corresponding to a sustained low dose of 10 μM in vitro when administered in an in vitro assay of CEP290-LCA used to determine the efficacy of the compound in rhodopsin staining and / or improvement of ciliary axoneme development.

[0154] In some embodiments, the method of the subject provides therapeutic benefits, such as preventing the onset of retinal degeneration, halting the progression of retinal degeneration, and / or reversing the progression of retinal degeneration. The subject may have any form of retinal degeneration as previously disclosed.

[0155] In some embodiments, the method includes a step of detecting that a therapeutic benefit has been achieved. Measures of therapeutic effectiveness can be applied to specific diseases being modified, and a person of the art, at least one with ordinary skills in the art, who would benefit from this disclosure, would recognize a detection method suitable for use in measuring therapeutic effectiveness. In further embodiments, embodiments of the compounds disclosed herein (including any pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or tautomers thereof) can increase the number of photoreceptors in the retina compared to a control. In yet another embodiment, treatment using embodiments of the compounds disclosed herein (including any pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or tautomers thereof) can maintain the thickness of the granular layer of photoreceptors in the retina over time. In further embodiments, embodiments of the compounds disclosed herein (including any pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or tautomers thereof) can increase the expression of phototransmission proteins, such as opsins, rhodopsins, and / or rod-cyclic GMP phosphodiesterase 6β (PDE6β), compared to a control. In some embodiments, embodiments of the compounds disclosed herein (including any pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or tautomers thereof) can increase the expression of rhodopsin and / or S-opsin compared to a control. In further embodiments, embodiments of the compounds disclosed herein (including any pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or tautomers thereof) can increase the expression of phototransmission proteins, such as photoreceptors (but not limited to them), compared to a control. In further embodiments, embodiments of the compounds disclosed herein (including any pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or tautomers thereof) can improve (e.g., increase) ciliary axoneme generation and / or elongation, ciliary biosynthesis (e.g., ciliary pocket formation), and / or p62 expression.In further embodiments, embodiments of the compounds disclosed herein (including any pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or tautomers thereof) can inhibit autophagosome fusion with lysosomes, thereby increasing p62 expression and repairing HDAC6 degradation. Appropriate controls include standard values, mean values ​​of subjects not treated with the compound, or values ​​of subjects before treatment. Appropriate exemplary tests are disclosed in the Examples.

[0156] In some embodiments, therapeutic efficacy can be observed by fundus photography or evaluation of ERG response. The method may include a step of comparing the test results after administration of the subject composition with the test results before administration of the subject composition.

[0157] As another example, therapeutic efficacy in the treatment of progressive cone dysfunction may be observed as a reduction in the rate of progression of cone dysfunction, as a cessation of the progression of cone dysfunction, or as an improvement in cone function, and the effect may be observed, for example, by electroretinography (ERG) and / or cERG, color vision tests, functional adaptive optics, and / or visual acuity tests, for example, by comparing the test results after administration of the composition of the subject with the test results before administration of the composition of the subject to detect changes in cone survival and / or function. In some embodiments, embodiments of the compounds disclosed herein (including any pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or tautomers thereof) delay photoreceptor loss, reduce photoreceptor dysfunction, and / or reduce loss of visual function.

[0158] In another example, therapeutic effectiveness in treating visual impairment may be demonstrated as changes in an individual's vision, such as their perception of red, green, and / or blue wavelengths. Such effects can be observed by using cERG and color vision tests, for example, by comparing test results obtained after administration of the compound of the Disclosure to a subject with test results obtained before administration of the compound of the Disclosure, and by detecting changes in cone and rod viability and / or function. In some embodiments, the method includes evaluation of morphological and structural retention, as well as / or ERG.

[0159] VI. Overview of Some Embodiments This specification provides embodiments of a method for treating retinal degeneration of a subject, comprising the step of administering a therapeutically effective amount of a compound to the subject, thereby treating the retinal degeneration of the subject, wherein the compound has a structure according to a formula selected from formulas I, II, or III. [ka] Embodiments of the method are disclosed, which may involve a pharmaceutically acceptable salt thereof, a prodrug, a solvate, a hydrate or tautomer, 3-(dibutylamino)-1-(1,3-dichloro-6-(trifluoromethyl)phenanthren-9-yl)propan-1-ol hydrochloride, or another pharmaceutically acceptable salt thereof, or a method selected from the prodrug, solvate, hydrate or tautomer. [In the formula, (i) Regarding equation I, R 1 It is heterolipid, R 2 is OR 5 or NR 6 R 7 And R 5 , R 6 , and R 7 Each of these is independently selected from aliphatic, hydrogen, aromatic, or organic functional groups. R 3 These are selected from aliphatic, aromatic, acyl, or sulfonyl compounds. R 4These are selected from acyl, aliphatic, aromatic, or sulfonyl compounds. n is an integer selected from 0 to 4. (ii) Regarding equation II, R A These are selected from halogens, heteroaliphatic, haloaliphatic, or organic functional groups. R B It is an aromatic compound, R C and R D Each of these is independently selected from hydrogen, aliphatic, or heteroaliphatic. m is an integer selected from 0 to 4. (iii) Regarding equation III, R' is selected from aliphatic, aromatic, halogen, heteroaliphatic, haloaliphatic, or organic functional groups. Each R'' is independently selected from halogen, heteroaliphatic, or amino. Each R''' is independently selected from halogen, heteroaliphatic, or amino. p is an integer selected from 0 to 4. q is an integer selected from 0 to 4. r is an integer selected from 0 or 1.

[0160] In some embodiments, the subject has retinitis pigmentosa, LCA, Stargard macular dystrophy, cone-rod dystrophy, total choroidal atrophy, or age-related macular degeneration.

[0161] In any or all of the embodiments described above, the compound is administered orally.

[0162] In any or all of the embodiments described above, the compound is administered topically to the eye of the subject.

[0163] In any or all of the embodiments described above, the compound is administered intravitreously.

[0164] In any or all of the embodiments described above, the subject is a human being.

[0165] In any or all of the embodiments described above, the compound maintains the thickness of the granular layer of photoreceptors in the retina of the eye in question.

[0166] In any or all of the embodiments described above, the compound increases the expression of photoreceptor ciliary opsins and / or phototransduction proteins in the eye in question.

[0167] In any or all of the embodiments described above, the photoreceptor ciliary opsin is rhodopsin or S-opsin, or rod-cyclic GMP phosphodiesterase 6β (PDE6β).

[0168] In any or all of the embodiments described above, the compound increases the number of target photoreceptor cells.

[0169] In any or all of the embodiments described above, the method further includes the step of evaluating the vision of the subject.

[0170] In any or all of the embodiments described above, the method includes the step of performing an electroretinography on the subject.

[0171] In any or all of the embodiments described above, the compound has a structure according to one of formulas IA, IC, or IE, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof. [ka]

[0172] In any or all of the embodiments described above, the compound is R 1 However, it is an alkoxy, R 2 However, -OR 5 or -NR 6 R 7 And R 5 , R 6 , and R 7Each of these is independently selected from hydrogen, alkyl, heteroaryl, or aryl. R 3 However, selected from alkyl, heteroaryl, aryl, sulfonyl, or acyl, R 4 However, selected from acyl, alkyl, heteroaryl, aryl, or sulfonyl, n is 0, 1, 2, 3, or 4. It has a structure according to formula I, IA, IC, or IE, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof.

[0173] In any or all of the embodiments described above, the compound is R 4 but, [ka] [ka] Selected from, It has a structure according to formula I, IA, IC, or IE, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof.

[0174] In any or all of the embodiments described above, the compound is [ka] [ka] Alternatively, a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof may be selected.

[0175] In any or all of the embodiments described above, the compound has a structure according to formula IIA, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof. [ka]

[0176] In any or all of the embodiments described above, the compound is Each R A However, they can be independently selected from halogen, -OMe, -CN, or -CF3. R B However, selected from aryl; aryl containing one or more substituents selected from halogen, -CF3, -CN, -OH, alkyl, or alkoxy; heteroaryl; heteroaryl containing one or more substituents selected from halogen, -CF3, -CN, -OH, alkyl, or alkoxy, R C and R D Each of these is independently selected from hydrogen, alkyl, or amino. m is 0, 1, 2, 3, or 4. It has a structure according to formula II or IIA, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof.

[0177] In any or all of the embodiments described above, the compound has a structure according to formula II or IIA, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or tautomer thereof, R B teeth, [ka] [ka] Selected from.

[0178] In any or all of the embodiments described above, the compound is [ka] Alternatively, it may be a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof.

[0179] In any or all of the embodiments described above, the compound has a structure according to formulas IIIA to IIID, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof. [ka]

[0180] In any or all of the embodiments described above, the compound is R' is selected from halo, -CN;-CF3;-OCF3;alkyl;heteroalkyl containing one or more nitrogen atoms, one or more oxygen atoms, one or more sulfur atoms, or a combination thereof; or aminoaryl. R'' is a halogen, alkoxy, or -NR a’ R b’ Selected from, R a’ and R b’ Each of these is independently selected from alkyl, heteroalkyl, benzyl, acyl, and sulfonyl. R''' is a halogen, alkoxy, or -NR a’ R b’ Selected from, R a’ and R b’ Each of these is independently selected from alkyl, heteroalkyl, benzyl, acyl, or sulfonyl, p and q are integers independently selected from 0, 1, 2, 3, or 4. r is 0 or 1. It has a structure according to formula III or IIIA-IIID, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof.

[0181] In any or all of the embodiments described above, the compound is R' [ka] Selected from, R'' and R''' are independent of -NR a’ Rb’ And R a’ and R b’ One of them is H, and the other is, [ka] [ka] Selected from, It has a structure according to formula III or IIIA-IIID, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof.

[0182] In any or all of the embodiments described above, the compound is [ka] [ka] Alternatively, a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof may be selected.

[0183] In any or all of the embodiments described above, the compound is [ka] Selected from.

[0184] Furthermore, embodiments of compositions comprising a therapeutically effective amount of any or all of the compounds described above for use in the treatment of the target retinal degeneration are disclosed herein.

[0185] In any or all of the embodiments described above, the composition is formulated for oral administration.

[0186] In any or all of the embodiments described above, the composition is included in the dosage form.

[0187] In any or all of the embodiments described above, the composition is formulated for topical administration to the eye.

[0188] In any or all of the embodiments described above, the composition is formulated for intravitreous administration.

[0189] In any or all of the embodiments described above, the composition further comprises therapeutically acceptable excipients.

[0190] Furthermore, this specification provides embodiments of compositions comprising a therapeutically effective amount of a compound for use in any one or all of the embodiments described above, wherein the compound is 3-(dibutylamino)-1-(1,3-dichloro-6-(trifluoromethyl)phenanthren-9-yl)propan-1-ol hydrochloride, or another pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate or tautomer, or a compound having a structure according to a formula selected from formulas I, II or III. [ka] Alternatively, embodiments of the composition are disclosed, selected from pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or tautomers thereof. [In the formula, Regarding equation I, R 1 It is heterolipid, R 2 is OR 5 or NR 6 R 7 And R 5 , R 6 , and R 7 Each of these is independently selected from aliphatic, hydrogen, aromatic, or organic functional groups. R 3 These are selected from aliphatic, aromatic, acyl, or sulfonyl compounds. R 4 These are selected from acyl, aliphatic, aromatic, or sulfonyl compounds. n is an integer selected from 0 to 4. Regarding Equation II, R A These are selected from halogens, heteroaliphatic, haloaliphatic, or organic functional groups. R B It is an aromatic compound, R C and R D Each of these is independently selected from hydrogen, aliphatic, or heteroaliphatic. m is an integer selected from 0 to 4. Regarding Equation III, R' is selected from aliphatic, aromatic, halogen, heteroaliphatic, haloaliphatic, or organic functional groups. Each R'' is independently selected from halogen, heteroaliphatic, or amino. Each R''' is independently selected from halogen, heteroaliphatic, or amino. p is an integer selected from 0 to 4. q is an integer selected from 0 to 4. r is an integer selected from 0 or 1. [Examples]

[0191] VII. Examples This disclosure is illustrated by the following non-limiting embodiments.

[0192] (Example 1) Ether analogs are prepared by Williamson ether synthesis, from the reaction of alkyl halides with 100 under basic conditions (1). Acyl-functionalized analogs are synthesized from the reaction of 100 with carboxylic acids under coupling reagent (3) or the corresponding acyl chloride (2). Sulfonyl analogs are produced from the reaction of 100 with the corresponding sulfonyl chloride (4). [ka]

[0193] In a specific example, methyl ester 100 is dissolved in toluene, and then R 4I and Ag2O are added, and the resulting mixture is heated in an oil bath at 80°C for 6 to 12 hours, after which most of the starting material 100 is converted. Next, the product is filtered, the filtrate is collected, concentrated, and purified using the CombiFlash® purification system. [ka]

[0194] Methyl reserpate 100 and DIPEA are dissolved in DCM, and the resulting mixture is cooled in an ice bath at 4°C. The acyl halogenated reagent (obtained either from a commercial source or by preparation according to procedures known in the art) is added dropwise over 5 minutes (as a DCM solution). The reaction mixture is then heated to room temperature for 1 to 5 hours. Once the reaction is complete (monitored by LC-MS to ensure all starting materials have been converted), it is filtered to remove insoluble salts, the filtrate is collected, concentrated, and purified using the CombiFlash® purification system. [ka]

[0195] Add methyl resorbate 100 to a DCM solution of carboxylic acid, coupling reagents (DCC, EDC), DIPEA, and DPAM, cooled to 4°C in an ice bath. Next, warm the reaction mixture to room temperature for 12-24 hours. Once the reaction is complete (monitored by ensuring all starting materials have been converted), filter the mixture to remove insoluble salts, collect the filtrate, concentrate it, and purify it using the CombiFlash® purification system. [ka]

[0196] Methyl reserpate 100 and DIPEA are dissolved in DCM, and the resulting mixture is cooled in an ice bath at 4°C. A solution of sulfonyl chloride reagent (obtained from a commercial source or by preparation according to procedures known in the art) in DCM is added dropwise over 5 minutes. The reaction mixture is heated to room temperature for 1 to 5 hours. Once the reaction is complete (monitored by ensuring that all starting materials have been converted), it is filtered to remove insoluble salts, the filtrate is collected, concentrated, and purified using a CombiFlash® purification system.

[0197] (Example 2) [ka] LiOH is added to a solution of the precursor (102, 104, or 106) dissolved in MeOH / H2O. The resulting mixture is stirred at room temperature for 20-48 hours until most of the starting material is converted. The mixture is concentrated, dissolved in DCM / water, acidified with HCl, then the organic phase is collected, dried over Na2SO4, filtered, concentrated, dried under high vacuum, and prepared for use in the next step without further purification. The above scheme shows a method for preparing the corresponding ester products (110, 112, and 114), but alcohol reagents (R 5 OH) is used as an amine reagent (for example, R 6 R 7 The amide can also be prepared by substituting NH) and DIPEA and benzotriazole-1-yloxytripyrrolidinophosphonium hexafluorophosphate (or "PyBOP").

[0198] (Example 3) In this example, compounds according to formula II are prepared. In some examples, precursor 200 is used in a Suzuki coupling with boronic acid 208, the boronic acid being commercially available or can be prepared using methods known to those skilled in the art who benefit from this disclosure. Cs2CO3 and boronic acid 208 are added to precursor 200 in dioxane / H2O=10:1, degassed by nitrogen gas aeration, and Pd(PPh3)4 is added. The reaction mixture is capped and irradiated with microwaves at 80°C for 1 hour. The resulting solution is filtered, concentrated, and purified using a CombiFlash® purification system to provide product 210. Aldehyde reagent and NaBH(OAc)3 are added to a DCE solution of 210. The resulting mixture is stirred for 12-24 hours and monitored by LCMS. The mixture is concentrated and purified using a CombiFlash® purification system to provide product 212. [ka]

[0199] (Example 4) In this example, the compound of formula III is prepared. In some examples, precursor 318 can be converted to product 320 (where R is as enumerated herein for scheme 3A). The "RONa" reagent can be purchased commercially or prepared by reacting the corresponding alcohol with Na or NaOH. Next, RONa is added to the dioxane solution of precursor 318, the reaction vessel is capped, and the reaction mixture is heated at 100-120°C for 10-24 hours. The reaction mixture is concentrated and then purified using the CombiFlash® purification system to provide product 320. [ka]

[0200] In some further examples, compounds such as compound 310 of the amine-functionalized scheme (Scheme 3A) can be prepared using the method shown in Scheme 3A. In some examples, K2CO3 and the desired amine reagent are added to a DMF solution of starting material 318. The reaction vessel is capped, and the reaction mixture is heated at 100-120°C for 10-24 hours. The reaction mixture is concentrated and then purified using the CombiFlash® purification system to provide a product according to formula 310 of Scheme 3A.

[0201] In some other examples, HCl dissolved in dioxane and the desired amine reagent are added to the EtOH solution of starting material 318. The reaction vessel is capped, and the reaction mixture is heated at 100-120°C for 10-24 hours. The reaction mixture is concentrated and then purified using the CombiFlash® purification system to provide a product according to formula 310 of scheme 3A.

[0202] In a further example, Cs2CO3 and an arylamine coupling partner are added to a solution of starting material 318 in dioxane. The reaction vessel is degassed by venting with nitrogen gas, and then Pd(OAc)2 and xanthophos are added. The reaction vessel is then capped and irradiated with microwaves at 80°C for 1 hour. The reaction mixture is filtered, concentrated, and then purified using the CombiFlash® purification system to provide a product according to formula 312 of scheme 3A.

[0203] (Example 5) In this embodiment, a compound according to Scheme 3B is prepared. In a specific embodiment, the compound having formula 316 (Scheme 3B) is prepared by providing a solution of acridine-3,6-diamine and DIPEA dissolved in DCM and cooling it to 4°C in an ice bath. Next, the desired acyl chloride or sulfonyl chloride is added dropwise over 5 minutes. The reaction mixture is heated to room temperature and stirred for a further 1 to 3 hours. The reaction mixture is filtered to remove insoluble salts, the filtrate is collected and concentrated, and then purified to the product compound according to formula 316 of Scheme 3B using the CombiFlash® purification system. In these embodiments, compound 316 is a symmetric amine. [ka]

[0204] Asymmetric amines can be prepared by using different coupling partners, as shown in the following scheme. [ka]

[0205] The sulfonyl-containing compound is prepared as follows. In a specific embodiment, a solution of acridine-3,6-diamine and DIPEA dissolved in DCM is cooled to 4°C in an ice bath, and the sulfonate is added dropwise over 5 minutes. The reaction mixture is heated to room temperature and stirred for a further 1 to 3 hours. The reaction mixture is filtered to remove insoluble salts, the filtrate is collected and concentrated, and then purified using the CombiFlash® purification system to provide the sulfonyl-containing product. [ka]

[0206] In further examples, other amine compounds can be prepared by mixing a solution of acridine-3,6-diamine and NaHCO3 dissolved in THF / water with Boc2O. The resulting mixture is stirred overnight and extracted to provide crude Boc-protected acridine-3,6-diamine. Deprotonation is performed using NaH, and the desired R is obtained. a’ or R b’ The group is added. Next, the Boc protecting group is removed using TFA. [ka]

[0207] (Example 6) Neuroretina organoids derived from induced pluripotent stem cells (iPSCs) targeting CEP290-LCA exhibit disease-associated defects. Leber congenital amaurosis (LCA) is an early-onset hereditary blindness disorder caused by defects in more than 20 different genes. Genetic defects associated with LCA can affect other tissues in addition to photoreceptor development and / or function, potentially leading to symptomatic clinical phenotypes. CEP290 is a ciliary-centrosome protein that is a crucial component of the transitional zone and likely controls ciliary protein transport. Defects in CEP290 can result in multiple symptomatic phenotypes that may lead LCA towards a milder spectrum.

[0208] Human pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and iPSCs, can differentiate into retinal organoids with laminar neural retina and photoreceptors with underdeveloped structures such as the outer segment. To investigate whether a human organoid culture system can reproduce disease-associated phenotypes observed in CEP290-LCA subjects, a family consisting of a phenotypically normal mother (control) and its two LCA offspring (LCA1 and LCA2) was recruited. iPSCs from both control and subject cells were reprogrammed from fibroblasts and differentiated into retinal organoids. Abnormal phenotypes were identified in the subject retinal organoids compared to the control. In control organoids, rhodopsin, a rod photoreceptor opsin, became apparent at differentiation day (D) 120, subsequently polarizing towards the apical end of the neural retina at day D150, and being transported to the outer segment region by day D200 (Figure 2A). However, in LCA1 organoids, rhodopsin was observed throughout development but was not delivered to the outer segment and remained mislocalized in the cell body. LCA2 organoids showed an even more severe phenotype, as indicated by the lack of robust rhodopsin expression. The cone opsins OPN1SW and OPN1MW were less robust compared to the control neuroretina, but no significant morphological differences in cone photoreceptors were observed between the control and target organoids. Immunostaining for the binding ciliary and ciliary axoneme marker ARL13B revealed that in the target organoids, ciliary defects in the photoreceptor led to abnormal photoreceptor development (Figure 2B). ARL13B staining was concentrated in the binding ciliary cilia of the control photoreceptor and elongated according to the differentiation process as the outer segment developed. In contrast, its photoreceptor consistently demonstrated abnormal binding ciliary development in both target organoids and lacked outer segment biosynthesis.

[0209] To understand the disease mechanism and evaluate effective treatments, control and target organoid samples were collected on days D67, D90, D120, and D150 to determine gene / signaling pathway signatures in CEP290-LCA target organoids, and transcriptome analysis was performed. Principal component analysis showed that the control and target organoid samples were broadly divided into two groups at different stages of differentiation, suggesting inconsistencies in the gene profiles between the control and target samples (Figure 2C). Differential expression analysis revealed the greatest inconsistencies between the control and target samples at days D90 and D120, with differentially expressed (DE) genes being 2026 and 1911, compared to 162 on day D67 and 190 on day D150, respectively (Figure 2D). To isolate DE genes caused by mutation rather than development, age-matched pairwise comparisons were performed between control and target transcriptomes to remove DE genes attributable to developmental stage (Figure 2E). Of these, 779 unique genes belonged to signaling pathways associated with protein metabolism, vesicle-mediated transport, membrane transport, translation, the citric acid cycle, and protein processing in the endoplasmic reticulum (Figure 2F). In particular, the expression of phototransduction genes important for photoreceptor function was largely downregulated in the target organoids (Figure 2G).

[0210] (Example 7) High-throughput phenotypic screening in mouse retinal organoids identified embodiments of compounds that maintain rod photoreceptor survival. A representative method for identifying embodiments of the compounds disclosed herein, particularly those useful for treating retinal degeneration, especially retinal ciliary-related diseases (including those associated with CEP290 deficiency), is shown in Figure 3. Since the pathogenesis of CEP290-related diseases is largely unknown, we decided to perform non-targeted high-throughput screening (HTS) to identify embodiments of compounds that maintain photoreceptor survival. Differentiation of human iPSCs into retinal organoids could not meet the large-scale cellular requirements for HTS due to technical difficulties. Since ciliary biosynthesis is conserved on a large scale between mice and humans (Soares et al., 2 Cells, 8, 2019), ), Nrl-GFP rd16 mouse (CEP290-LCA model (Chang et al., Retinal organoids derived from iPSCs (Hum Mol Genet, 15, 1847-57, 2006) A multiplexed HTS platform was established using [a specific method / tool]. These organoids could be efficiently produced from iPSCs with a comparatively much shorter differentiation time (Chen et al., Mol Vis, 22, 1077-1094, 2016). By GFP tagging under the control of the promoter of Nrl, a rod photoreceptor termination marker for the first mitosis (Akimoto et al., Proc Natl Acad Sci USA, 103, 3890-5, 2006), rod cells in organoid cultures were differentiated. We provided tools for monitoring the biosynthesis of [the compound]. Based on >30% lower GFP+ cells and >50% lower viability in retinal organoids derived from Nrl-GFP rd16 iPSCs, we developed a compound discovery pipeline for maintaining rod photoreceptor viability by screening to identify embodiments of compounds that increase the fluorescence intensity of GFP and nuclear staining 4',6-diamidino-2-phenylindole (DAPI), followed by validation of hits in mouse retinal organoids. These hits were further confirmed by transcriptome analysis, retinal organoids derived from target iPSCs, and in vivo by rd16 mouse retinas (Figure 3).

[0211] In the primary selection, rd16 retinal organoids on day D26, in which photoreceptor cilia had begun to grow and abnormal phenotypes could be observed, were dissociated into single cells (GFP+ cells that become rod photoreceptors) and seeded at a density of 4,000 cells / well in 1,536-well plates. On day D30, retinal organoids were also seeded as a positive control. After 24 hours, approximately 6,000 small molecules from the Sigma LOPAC library, FDA-approved drugs, and agonists and antagonists of major cellular signaling pathways were administered to cells at seven different concentrations using DMSO (solvent for small molecules) as a control. After 48 hours of incubation, the treated cells were fixed and stained with DAPI. By gated against the untreated group, approximately 100 compounds appeared to have a positive effect on GFP and DAPI signal intensity. To eliminate false-positive hits due to the autofluorescence of the compounds, these initial hits from the primary selection were applied to dissociated D26-day organoids differentiated from parental PSC-derived organoids lacking the GFP marker. Compounds with high autofluorescence signals were then excluded from subsequent experiments. After standardization with DMSO control, 14 embodiments of the compounds were selected based on their potency, calculated as the maximum half-molecule concentration derived from Hill's formula model.

[0212] (Example 8) Rhodopsin and S-opsin expression was increased in rd16 retinal organoids treated with embodiments of the compound. Next, embodiments of 14 compounds were tested in intact rd16 retinal organoid cultures at AC50 and half AC50 to evaluate their toxicity and effects. Small molecules that caused retinal organoid dissociation or photoreceptor death at 0.5 × AC50 could be removed from subsequent testing. The compounds were directly applied to the culture on day 22 and removed on day 25. Treated organoids were harvested 72 hours after compound removal on day 28 (Figure 4A). Embodiments of five compounds (NCGC0091250, reserpine; NCGC00253604, recimetol; NCGC00263128, CHEMBL39740; NCGC00015874, quinacrine dihydrochloride dihydrate; NCGC00166245, proflavin hemisulfate) demonstrated higher immunostaining of markers for rod and cone photoreceptors in rd16 organoid cultures. As shown in Figure 4B, immunostaining of rhodopsin in untreated rd16 photoreceptors was rather faint, and polarity was lost on the apical side of the neuroretina. Treatment with embodiments of these compounds improved rhodopsin expression and polarity with variable potency. In particular, cone photoreceptor biosynthesis was impaired even in WT organoids on day D28, but some embodiments of the compound, e.g., NCGC0091250, were able to increase S-opsin expression and polarization in cone photoreceptors, suggesting a similarly favorable effect on S cones. To account for the high variability of mouse retinal organoids, fluorescence intensities of rhodopsin and S-opsin staining in all untreated and treated neuroretina were quantified (Figure 4C) using an image processing algorithm that captured most pixels and avoided immunostaining background. Improvements for rod and / or cone photoreceptors in rd16 retinal organoids were confirmed with the selected embodiments of the compound. NCGC00253604 is a derivative of NCGC0091250, but is not as potent and only shows borderline improvement of rhodopsin staining in mouse retinal organoids.

[0213] (Example 9) The target iPSC-derived retinal organoids showed improved photoreceptor biosynthesis after treatment with the compound embodiments. To further validate the embodiments of the five compounds, LCA-targeted iPSCs were differentiated into retinal organoids and treated with selected small molecules. Transcriptome comparative analysis of the gene profiles of control and target retinal organoids showed the most dramatic divergence observed on day D120 (Figure 2D). Therefore, drug treatment was administered on days D110 and D135, each for 3 days, and retinal organoids were collected on days D125 and D150 for immunostaining evaluation of photoreceptor and ciliary biosynthesis (Figure 5A). Due to varying sensitivities of the small molecules and the inversion of the neural retinal structure between mouse and human retinal organoids, each compound from 5 to 40 μM was re-evaluated in the target organoids. One embodiment of the compound, NCGC00166245, demonstrated toxicity within this range in one of the target organoids, and it was excluded from further validation experiments. The remaining four compounds were applied to the target organoid cultures. The target organoids on day 150 had barely detectable rhodopsin and limited ciliary axoneme development, which improved with treatment of various small molecules (Figure 5B). Cone photoreceptors were not dramatically affected in the target organoids, but improvement in cone cells was observed in the target organoids with two small molecule treatments (NCGC0091250, NCGC0015874), which is consistent with their effects on mouse organoids (Figure 5C). Treatment with NCGC00253604, a derivative of NCGC009125, demonstrated a more potent effect on human rod photoreceptors compared to mice.

[0214] (Example 10) Intravitreal injection of the compound embodiment into rd16 mice maintained the thickness of the outer granular layer of photoreceptors. To validate the compound embodiment in vivo, intravitreal injection was performed to deliver the compound to the retina of Nrl-GFP rd16 mice, and the survival of photoreceptors in the outer granular layer (ONL) was assessed. Since the differences in the retinas of wild-type and rd16 mice appear as early as postnatal (P) day 6, the compound was delivered intravitreously on P4 day, with DMSO (control) administered to one eye and the candidate compound administered to the other. Both eyes were harvested on P21 day (Figure 6A). To systematically assess technical issues, including injection technique, compound concentration, and toxicity, the experiment was initiated with one compound, NCGC0091250, which revealed the most significant effects in mouse and human organoids. In two of the three injected animals, injection of 40 μM NCGC0091250 maintained ONL thickness on day P21 compared to the untreated control eye, as shown by GFP (rod cells) and DAPI (Figure 6B). Photoreceptor ciliary proteins, including rhodopsin (RHO) and cyclic GMP phosphodiesterase β (PDE6β), which are rod-specific proteins, were transported to the outer segment region. In the treated retina, more ciliary proteins were consistently located in longer outer segments compared to the untreated retina. No apparent toxicity was observed in any of the three injected mice.

[0215] (Example 11) Evaluation of drug effects on target retinal organoids. The timeline of drug treatment for CEP290-LCA (IVS26+1655A>G p.C998X; c.5668G>T p.G1890X) is shown in Figure 7A. Two treatment modules were evaluated using target induced pluripotent stem cell (iPSC)-derived retinal organoids: (1) intermittent high dose (20 μM and 30 μM) and (2) sustained low dose (10 μM). Abnormal phenotypes were observed in the target organoids 3 days after the start of treatment (D117), and organoids were collected on D150 for analysis. DMSO, the drug vehicle, was added as a control at a concentration of less than 1% (v / v). Figures 7B and 7C show Western blot analysis and quantification of rhodopsin levels in the target organoids, respectively. Data were expressed as the mean ± standard deviation from two experiments, each experiment containing at least two retinal organoids. Beta-actin (ACTB) was used as a loading control. As determined from the data, retinal organoids from both subjects had lower rhodopsin expression compared to those from familial controls (labeled "C" in Figures 7B and 7C), suggesting a defect in rod photoreceptors. Treatment with various concentrations of reserpine (labeled "R" in Figures 7A–7C) was able to improve rhodopsin staining. In this example, 30 μM reserpine showed a positive effect in subject 1, while 10 μM was sufficient for subject 2, which likely indicates variability in the subjects or cell lines. Images shown in Figures 7D and 7E confirm the Western blot results that reserpine improved both photoreceptors and ciliated axoneme in the subject organoids.

[0216] (Example 12) Evaluation of autophagy misregulation in the target organoids. Since the general pathway for all positive hits in rd16 organoid mice was autophagy inhibition, we assessed the autophagy levels of the target retinal organoids. Autophagy is a cellular homeostatic mechanism whose initiation can be induced by stress and may result in phosphorylation of ULK1 (see Figure 8A). p-ULK1, together with other autophagy components ATG101 and ATG13, induces the formation of an isolation membrane, which is a dilated endoplasmic reticulum membrane. p62, a crucial autophagy adapter, binds to ubiquitinated cellular components and delivers them to the isolation membrane, forming a sealed vesicle called an autophagosome. LC3-II, a standard marker for autophagosomes, is produced by the conjugation of phosphatidylethanolamine (PE) on the surface of nascent autophagosome LC3-II with cytoplasmic LC3-I. The cellular components of autophagosomes are degraded by fusion with lysosomes. To assess the overall autophagy state in the target organoids, several components of the process, including p-ULK1, ULK1, p62, and LC3, were evaluated. Figure 8B outlines the timeline used for evaluation in this example. Since ciliary biosynthesis and photoreceptor maturation begin around D90, control and target organoids were harvested at D60 and D120 to assess the effect of ciliary defects on cellular autophagy. Figures 8C and 8D–8G show Western blot analysis and quantification of autophagy components in the target organoids, respectively (data are expressed as mean ± standard deviation from two experiments, each experiment having at least three retinal organoids). Beta-actin (ACTB) was used as a loading control. At D60, no significant differences in the tested autophagy components were found between the control and target organoids. However, as demonstrated by the upregulation of p-ULK1, we were able to observe the initiation of enhanced autophagy in the target organoid.Significant downward regulation of p62 and upward regulation of LC3-II consistently indicated misregulation of autophagy flux in the subject organoids compared to the control.

[0217] (Example 13) Drug repurposing of autophagy inhibitors. To confirm the effect of autophagy inhibition on the rescue of target photoreceptors and to identify the key autophagy molecules involved in this process, various FDA-approved autophagy inhibitor drugs were used in the reported AC (Acceptance of Drug Repurposing). 50 and 2×AC 50 The compounds were applied to organoid cultures (overviewed in Figure 9A). MRT68921 and Lys05 inhibit ULK1 phosphorylation. Chloroquine (Q), hydroxychloroquine (HQ), and ROC-325 increase lysosome pH, preventing lysosome-autophagosome fusion. MRT68921 and Lys05 showed high toxicity even at 0.5 × AC50 (data not shown) and were therefore excluded from subsequent analysis. Figure 9B shows the results of immunohistochemical staining of rod (rhodopsin, green), S-cone (S-opsin, red), and L / M-cone (L / M-opsin, reddish-purple) photoreceptors. Immunohistochemical analysis revealed positive effects of all autophagy inhibitors on the target photoreceptors, albeit with varying degrees of efficacy, suggesting that autophagy inhibition plays a role in maintaining / improving photoreceptors in retinal degenerative diseases.

[0218] (Example 14) p62-mediated. In this example, the increase in p62 induced by reserpine in organoids of treated subjects was evaluated. Figures 10A and 10B show Western blot analysis and quantification of p62 and LC3-II, respectively. As can be seen from Figure 10B, LC3-II levels decreased in one subject but not in the other. In particular, a more significant change in p62 was observed in subjects that were more responsive to reserpine treatment. Figure 10C shows the results of immunostaining for p62 and acetylated tubulin (DM1T) in organoids of treated subjects, which was performed to confirm the increase in p62 in photoreceptors in organoids of subjects treated with reserpine and hydroxychloroquine (HQ). DM1T staining also showed more well-developed ciliated axial filaments in the photoreceptors of treated subjects. Figures 10D and 10E show Western blot analysis and quantification of HDAC6, the interaction partner of p62 and a key driver of ciliary degradation, as well as other ciliary regulatory proteins including IFT88 (intraflagellar transport), BBS6, and CEP164 (distal adnexal components for the initiation of ciliation) in treated organoids. Downregulation of HDAC6 and upregulation of CEP164 were observed in the organoids of the subject treated with reserpine. Since HDAC6 is a major driver for ciliary biosynthesis and CEP164 is located in the distal adnexa of preciliary vesicle docking for the initiation of ciliation, transmission electron microscopy (TEM) was performed to reveal further details of the photoreceptors in the untreated and treated organoids. Defects in preciliary vesicle docking and ciliary membrane formation have been reported as early phenotypes in retinal organoids targeted by CEP290-LCA, and these defects could be mitigated by reserpine treatment (see Figure 10F, upper panel). TEM analysis also revealed longer ciliary axonems in treated photoreceptors (see Figure 10F, lower panel).In particular, we were able to observe well-organized, disc-like structures, which are rare in organoid cultures, in the target organoids (see Figure 10G), suggesting a favorable effect of reserpine on the development of the outer segments (primary cilia of photoreceptors).

[0219] (Example 15) Improved photoreceptor morphology of induced pluripotent stem cell (iPSC)-derived retinal organoids of CEP290-LCA after short-term treatment. To evaluate the effect of reserpine on target organoids caused by various mutations, CEP290-LCA target organoids caused by homozygous IVS26+1655A>G p.C998X, the most common mutation of CEP290-LCA, were treated with short-term reserpine treatment. Figure 11A provides a schematic diagram showing the small molecule treatment paradigm for CEP290-LCA retinal organoids used in this example. Figure 11B shows images obtained from immunostaining of rod cells (green), S cones (red), and L / M cones (red-purple). The images confirm that homozygous CEP290-LCA retinal organoids for IVS26+1655A>G p.C998X exhibit defects in photoreceptor development, and that treatment with reserpine improved rod photoreceptors in the cultured tissue.

[0220] Given that the principles of this disclosure may be applied to many possible embodiments, it should be recognized that the embodiments shown are merely preferred examples and should not be construed as limiting the scope of this disclosure. Rather, the scope of this disclosure is defined by the following claims. Accordingly, the inventors claim all that falls within these claims and ideas as the present invention. In certain embodiments, for example, the following items are provided: (Item 1) A method for treating retinal degeneration of a subject, comprising the step of administering a therapeutically effective amount of a compound to the subject, thereby treating the retinal degeneration of the subject, wherein the compound has a structure according to a formula selected from formula I, II, or III. [ka] Alternatively, a pharmaceutically acceptable salt, prodrug, solvate, hydrate or tautomer thereof, or 3-(dibutylamino)-1-(1,3-dichloro-6-(trifluoromethyl)phenanthren-9-yl)propan-1-ol hydrochloride, or another pharmaceutically acceptable salt or a method selected from the prodrug, solvate, hydrate or tautomer thereof. [In the formula, (i) Regarding equation I, R 1 It is heterolipid, R 2 is OR 5 or NR 6 R 7 And R 5 , R 6 , and R 7 Each of these is independently selected from aliphatic, hydrogen, aromatic, or organic functional groups. R 3 These are selected from aliphatic, aromatic, acyl, or sulfonyl compounds. R 4 These are selected from acyl, aliphatic, aromatic, or sulfonyl compounds. n is an integer selected from 0 to 4. (ii) Regarding equation II, R A These are selected from halogens, heteroaliphatic, haloaliphatic, or organic functional groups. R B It is an aromatic compound, R C and R D Each of these is independently selected from hydrogen, aliphatic, or heteroaliphatic. m is an integer selected from 0 to 4. (iii) Regarding equation III, R' is selected from aliphatic, aromatic, halogen, heteroaliphatic, haloaliphatic, or organic functional groups. Each R'' is independently selected from halogen, heteroaliphatic, or amino. Each R''' is independently selected from halogen, heteroaliphatic, or amino. p is an integer selected from 0 to 4. q is an integer selected from 0 to 4. r is an integer selected from 0 or 1. (Item 2) The method according to item 1, wherein the subject has retinitis pigmentosa, LCA, Stargard macular dystrophy, cone-rod dystrophy, total choroidal atrophy, or age-related macular degeneration. (Item 3) The method according to item 1 or item 2, wherein the compound is administered orally. (Item 4) The method according to item 1 or item 2, wherein the compound is administered topically to the eye of the subject. (Item 5) The method according to item 4, wherein the compound is administered intravitreously to the eye of the subject. (Item 6) The method described in any one of items 1 to 5, wherein the subject is a human. (Item 7) The method according to any one of items 1 to 6, wherein the compound maintains the thickness of the granular layer of photoreceptors in the retina of the eye in question. (Item 8) The method according to any one of items 1 to 7, wherein the compound increases the expression of opsin in the retina of the subject. (Item 9) The method according to item 8, wherein the photoreceptor opsin is a phototransduction protein containing cone opsin, rhodopsin, or rod-cyclic GMP phosphodiesterase 6β (PDE6β). (Item 10) The method according to any one of items 1 to 9, wherein the compound increases the number of the target photoreceptor cells. (Item 11) The method according to any one of items 1 to 10, further comprising the step of evaluating the visual acuity of the subject. (Item 12) The method according to item 11, which includes the step of performing an electroretinography examination on the subject. (Item 13) The method according to any one of items 1 to 12, wherein the compound has a structure according to one of formulas IA, IC, or IE, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof. [ka] (Item 14) The aforementioned compound, R 1 However, it is an alkoxy, R 2 However, -OR 5 or -NR 6 R 7 And R 5 , R 6 , and R 7 Each of these is independently selected from alkyl, hydrogen, heteroaryl, or aryl. R 3 However, selected from alkyl, heteroaryl, aryl, sulfonyl, or acyl, R 4 However, selected from acyl, alkyl, heteroaryl, aryl, or sulfonyl, n is 0, 1, 2, 3, or 4. The method according to any one of items 1 to 13, having a structure according to formula I, IA, IC, or IE, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof. (Item 15) The aforementioned compound, R 4 but, [ka] [ka] Selected from, The method according to any one of items 1 to 14, having a structure according to formula I, IA, IC, or IE, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof. (Item 16) The aforementioned compound, [ka] [ka] Or the method described in any one of items 1 to 15, selected from pharmaceutically acceptable salts, prodrugs, solvates, hydrates or tautomers thereof. (Item 17) The aforementioned compound is of formula IIA, [ka] The method according to any one of items 1 to 12, having a structure according to a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof. (Item 18) The aforementioned compound, Each R A However, they can be independently selected from halogen, -OMe, -CN, or -CF3. R B However, selected from aryl; aryl containing one or more substituents selected from halogen, -CF3, -CN, -OH, alkyl, or alkoxy; heteroaryl; heteroaryl containing one or more substituents selected from halogen, -CF3, -CN, -OH, alkyl, or alkoxy, R C and R D Each of these is independently selected from hydrogen, alkyl, or amino. m is 0, 1, 2, 3, or 4. The method according to any one of items 1 to 12 or 17, having a structure according to formula II or IIA, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof. (Item 19) The compound has a structure according to formula II or IIA, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof, R B but, [ka] [ka] The method described in any one of items 1-12, 17, or 18, selected from the above. (Item 20) The aforementioned compound, [ka] The method described in any one of items 1-12 or 17-19, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof. (Item 21) The aforementioned compounds are given by formulas IIIA to IIID. [ka] The method according to any one of items 1 to 12, having a structure according to a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof. (Item 22) The aforementioned compound, R' is selected from halo, -CN;-CF3;-OCF3;alkyl;heteroalkyl containing one or more nitrogen atoms, one or more oxygen atoms, one or more sulfur atoms, or a combination thereof; or aminoaryl. R'' is a halogen, alkoxy, or -NR a’ R b’Selected from, R a’ and R b’ Each of these is independently selected from alkyl, heteroalkyl, benzyl, acyl, and sulfonyl. R''' is a halogen, alkoxy, or -NR a’ R b’ Selected from, R a’ and R b’ Each of these is independently selected from alkyl, heteroalkyl, benzyl, acyl, or sulfonyl, p and q are integers independently selected from 0, 1, 2, 3, or 4. r is 0 or 1. The method according to any one of items 1 to 12 or 21, having a structure according to formula III or IIIA to IIID, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or tautomer thereof. (Item 23) The aforementioned compound, R' [ka] [ka] Selected from, R'' and R''' are independent of -NR a’ R b’ And R a’ and R b’ One of them is H, and the other is, [ka] Selected from, The method according to any one of items 1-12, 21, or 22, having a structure according to formula III or IIIA-IIID, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or tautomer thereof. (Item 24) The aforementioned compound, [ka] [ka] Or the method described in any one of items 1-12 or 21-23, selected from pharmaceutically acceptable salts, prodrugs, solvates, hydrates or tautomers thereof. (Item 25) The aforementioned compound, [ka] The method described in item 1, selected from the options provided. (Item 26) A composition comprising a therapeutically effective amount of a compound as described in item 1 or any one of items 13-25, for use in the treatment of the target retinal degeneration. (Item 27) The composition described in item 26, formulated for oral administration. (Item 28) The composition described in item 27, which is included in the dosage form. (Item 29) The composition described in item 26, formulated for topical administration to the eye. (Item 30) The composition described in item 29, formulated for intravitreal administration. (Item 31) A composition according to any one of items 26 to 30, further comprising therapeutically acceptable excipients. (Item 32) A composition comprising a therapeutically effective amount of a compound for use in the method described in any one of items 1 to 25, wherein the compound has a structure according to a formula selected from formula I, II, or III. [ka] Or a composition selected from a pharmaceutically acceptable salt, prodrug, solvate, hydrate or tautomer thereof, or 3-(dibutylamino)-1-(1,3-dichloro-6-(trifluoromethyl)phenanthren-9-yl)propan-1-ol hydrochloride, or another pharmaceutically acceptable salt thereof, or a prodrug, solvate, hydrate or tautomer thereof. [In the formula, (i) Regarding equation I, R 1 It is heterolipid, R 2 is OR 5 or NR 6 R 7 And R 5 , R 6 , and R 7 Each of these is independently selected from aliphatic, hydrogen, aromatic, or organic functional groups. R 3 These are selected from aliphatic, aromatic, acyl, or sulfonyl compounds. R 4 These are selected from acyl, aliphatic, aromatic, or sulfonyl compounds. n is an integer selected from 0 to 4. (ii) Regarding equation II, R A These are selected from halogens, heteroaliphatic, haloaliphatic, or organic functional groups. R B It is an aromatic compound, R C and R D Each of these is independently selected from hydrogen, aliphatic, or heteroaliphatic. m is an integer selected from 0 to 4. (iii) Regarding equation III, R' is selected from aliphatic, aromatic, halogen, heteroaliphatic, haloaliphatic, or organic functional groups. Each R'' is independently selected from halogen, heteroaliphatic, or amino. Each R''' is independently selected from halogen, heteroaliphatic, or amino. p is an integer selected from 0 to 4. q is an integer selected from 0 to 4. r is an integer selected from 0 or 1. (Item 33) A compound for use as a pharmaceutical in a method for treating retinal degeneration of a subject, wherein the method comprises the step of administering a therapeutically effective amount of the compound to the subject, thereby treating the retinal degeneration of the subject, and the compound has a structure according to a formula selected from formulas I, II, or III. [ka] Or a pharmaceutically acceptable salt thereof, prodrug, solvate, hydrate or tautomer, or 3-(dibutylamino)-1-(1,3-dichloro-6-(trifluoromethyl)phenanthren-9-yl)propan-1-ol hydrochloride, or another pharmaceutically acceptable salt thereof, or a compound selected from a prodrug, solvate, hydrate or tautomer. [In the formula, (i) Regarding equation I, R 1 It is heterolipid, R 2 is OR 5 or NR 6 R 7 And R 5 , R 6 , and R 7 Each of these is independently selected from aliphatic, hydrogen, aromatic, or organic functional groups. R 3 These are selected from aliphatic, aromatic, acyl, or sulfonyl compounds. R 4 These are selected from acyl, aliphatic, aromatic, or sulfonyl compounds. n is an integer selected from 0 to 4. (ii) Regarding equation II, R A These are selected from halogens, heteroaliphatic, haloaliphatic, or organic functional groups. RB It is an aromatic compound, R C and R D Each of these is independently selected from hydrogen, aliphatic, or heteroaliphatic. m is an integer selected from 0 to 4. (iii) Regarding equation III, R' is selected from aliphatic, aromatic, halogen, heteroaliphatic, haloaliphatic, or organic functional groups. Each R'' is independently selected from halogen, heteroaliphatic, or amino. Each R''' is independently selected from halogen, heteroaliphatic, or amino. p is an integer selected from 0 to 4. q is an integer selected from 0 to 4. r is an integer selected from 0 or 1. (Item 34) A compound for use in a method for treating retinal degeneration of a subject, wherein the method comprises the step of administering a therapeutically effective amount of the compound to the subject, thereby treating the retinal degeneration of the subject, and the compound has a structure according to a formula selected from formulas I, II, or III. [ka] Or a pharmaceutically acceptable salt thereof, prodrug, solvate, hydrate or tautomer, or 3-(dibutylamino)-1-(1,3-dichloro-6-(trifluoromethyl)phenanthren-9-yl)propan-1-ol hydrochloride, or another pharmaceutically acceptable salt thereof, or a compound selected from a prodrug, solvate, hydrate or tautomer. [In the formula, (i) Regarding equation I, R 1 It is heterolipid, R 2 is OR 5 or NR 6 R 7 And R 5 , R6 , and R 7 Each of these is independently selected from aliphatic, hydrogen, aromatic, or organic functional groups. R 3 These are selected from aliphatic, aromatic, acyl, or sulfonyl compounds. R 4 These are selected from acyl, aliphatic, aromatic, or sulfonyl compounds. n is an integer selected from 0 to 4. (ii) Regarding equation II, R A These are selected from halogens, heteroaliphatic, haloaliphatic, or organic functional groups. R B It is an aromatic compound, R C and R D Each of these is independently selected from hydrogen, aliphatic, or heteroaliphatic. m is an integer selected from 0 to 4. (iii) Regarding equation III, R' is selected from aliphatic, aromatic, halogen, heteroaliphatic, haloaliphatic, or organic functional groups. Each R'' is independently selected from halogen, heteroaliphatic, or amino. Each R''' is independently selected from halogen, heteroaliphatic, or amino. p is an integer selected from 0 to 4. q is an integer selected from 0 to 4. r is an integer selected from 0 or 1.

Claims

1. A composition for use in a method for treating a target retinal degeneration, comprising a compound, the compound being (a) 3-(dibutylamino)-1-(1,3-dichloro-6-(trifluoromethyl)phenanthren-9-yl)propan-1-ol or pharmaceutically acceptable salts, prodrugs, solvates, hydrates or tautomers thereof; or (b) Formula II or III 【Chemistry 1】 Compounds having a structure according to a formula selected from, or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or tautomers thereof. Selected from, in the formula, (i) Regarding equation II, R A is selected from halogens, heteroaliphatic, haloaliphatic, or organic functional groups. R B is an aromatic compound, Each of R C and R D is independently selected from hydrogen, aliphatic, or heteroaliphatic. m is an integer selected from 0 to 4. (ii) Regarding formula III, R' is selected from aliphatic, aromatic, halogen, heteroaliphatic, haloaliphatic, or organic functional groups. Each R'' is independently selected from halogen, heteroaliphatic, or amino. Each R''' is independently selected from halogen, heteroaliphatic, or amino. p is an integer selected from 0 to 4. q is an integer selected from 0 to 4. r is an integer selected from 0 or 1. composition.

2. The composition according to claim 1, wherein the subject has retinitis pigmentosa, LCA, Stargard macular dystrophy, cone-rod dystrophy, total choroidal atrophy, or age-related macular degeneration, and the subject is optionally human.

3. The composition according to claim 1 or 2, wherein the composition is administered orally or locally to the eye of the subject using intravitreous injection or subconjunctival injection.

4. The composition according to any one of claims 1 to 3, wherein the compound maintains the thickness of the granular layer of photoreceptors in the retina of the eye in question.

5. The composition according to any one of claims 1 to 4, wherein the compound increases the expression of photoreceptor opsins in the retina of the target, or the compound increases the number of photoreceptor cells of the target.

6. The composition for use according to claim 5, wherein the photoreceptor opsin is a phototransduction protein comprising cone opsin, rhodopsin, or rod-cyclic GMP phosphodiesterase 6β (PDE6β).

7. The composition according to any one of claims 1 to 6, wherein the compound is 3-(dibutylamino)-1-(1,3-dichloro-6-(trifluoromethyl)phenanthren-9-yl)propan-1-ol hydrochloride.

8. The composition according to any one of claims 1 to 6, wherein the composition comprises a carrier selected as necessary from water, physiological saline, or equilibrium salt solution.

9. The composition according to any one of claims 1 to 6, wherein the compound is 3-(dibutylamino)-1-(1,3-dichloro-6-(trifluoromethyl)phenanthren-9-yl)propan-1-ol or 3-(dibutylamino)-1-(1,3-dichloro-6-(trifluoromethyl)phenanthren-9-yl)propan-1-ol hydrochloride, and the composition is formulated for intravitreous or subconjunctival administration.

10. The compound is of formula IIIA to IIID, 【Chemistry 2】 Or having a structure according to a pharmaceutically acceptable salt, prodrug, solvate, hydrate or tautomer thereof, in the formula, R' is selected from halo, -CN; -CF3; -OCF3; alkyl; heteroalkyl containing one or more nitrogen atoms, one or more oxygen atoms, one or more sulfur atoms, or a combination thereof; or aminoaryl. R'' is selected from halogens, alkoxys, or -NR a' R b', and each of R a' and R b' is independently selected from alkyl, heteroalkyl, benzyl, acyl, and sulfonyl. R''' is selected from halogens, alkoxys, or -NR a' R b', and each of R a' and R b' is independently selected from alkyl, heteroalkyl, benzyl, acyl, or sulfonyl. p and q are integers independently selected from 0, 1, 2, 3, or 4. r is either 0 or 1. The composition according to any one of claims 1 to 6.

11. The compound has a structure according to formula III or IIIA to IIID, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or tautomer thereof, and R' is 【Transformation 3】 Selected from R'' and R''' are independently -NR a' R b', where one of R a' and R b' is H and the other is 【Chemistry 4】 A composition according to any one of claims 1 to 6 or 10, selected from among them.

12. The compound is 【Chemistry 5-1】 【Chemistry 5-2】 The composition according to any one of claims 1 to 6, 10, or 11, or selected from pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or tautomers thereof.

13. The compound is of formula IIA, 【Transformation 6】 Or having a structure according to a pharmaceutically acceptable salt, prodrug, solvate, hydrate or tautomer thereof, in the formula, Each R A is independently selected from halogen, -OMe, -CN, or -CF3. R B is selected from aryl; aryl containing one or more substituents selected from halogen, -CF3, -CN, -OH, alkyl, or alkoxy; heteroaryl; heteroaryl containing one or more substituents selected from halogen, -CF3, -CN, -OH, alkyl, or alkoxy, Each of R C and R D is independently selected from hydrogen, alkyl, or amino. m is 0, 1, 2, 3, or 4, If necessary, the compound 【Transformation 7】 or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, The composition according to any one of claims 1 to 6.

14. The compound has a structure according to formula II or IIA, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or tautomer thereof, and R B is 【Transformation 8】 A composition according to any one of claims 1 to 6 or 13, selected from among them.

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