Short acting visual cycle modulators

Abstract

A short-acting, ester-containing visual cycle modulator (VSM) includes a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), a pharmaceutically acceptable salt thereof, or a solvate thereof.

Description

PATENT SHORT ACTING VISUAL CYCLE MODULATORS RELATED APPLICATION

[0001] This application claims priority from U. S. Provisional ApplicationNo. 63 / 779,421, filed March 28, 2025, the subject matter of which is incorporated herein by reference in its entirety.GOVERNMENT FUNDING

[0002] This invention was made with government support under I01BX004939 awarded by the Department of Veterans Affairs, and 1904530 awarded by the National Science Foundation. The government has certain rights in the invention.BACKGROUND

[0003] In the retina, there is a need to maintain a delicate balance between absorbance of visible light photons with minimal light-induced (photic) retinal damage. Shifting this equilibrium towards photodamage can result in severe and irreversible vision loss. At the molecular level, this equilibrium leans on the flux of retinoids in the retina, which are the key chemicals at the base of sight. Both genetic and environmental (e.g., surgical lights) factors implicate the retinoid (visual) cycle in degenerative processes. This multi-enzymatic process is a dominant metabolic pathway in the retina that synthesizes the visual chromophore essential for vision, 11- cri-retinal (11cRAL) bound to visual pigment opsins.

[0004] Stargardt disease (STGD1) is an example of inherited retinal disease associated with a dysfunctional visual cycle. Specifically, mutations affecting the ABCA4 transporter lead to the accumulation of retinoid-based metabolic products in the photoreceptors after the photoactivation of visual pigment. These metabolic products drive the formation of toxic bisretinoids that are enriched in lipofuscin granules. Experimental evidence indicates that STGD1 is driven by visual cycle activity per se, independently from exposing the eye to visible light which accelerates the disease progression. Presently, no approved treatment is available for STGD1.

[0005] Light itself can induce retinal damage in healthy subjects with different mechanisms. Among these, Nodi’ s type of photic retinal damage was first reported to occur in response to long-duration exposures (8 h) to constant fluorescent white light. This photic damage is specific to photoreceptors and retinal pigment epithelium (RPE) cells and requireseffective visual cycle activity in the retina to occur. Specifically, it was shown that it is the rhodopsin photobleaching and its continuous biosynthesis that cause retinal degeneration. Full protection was achieved by ablation of Rho, the mediator of damage, and by knocking out Rpe65, which removed the RPE-specific enzyme named RPE65 catalyzing the obligatory all-trans to 11-cis-isomerization for the regeneration of photobleached visual pigments.

[0006] Considering the above, the concept and the first tools for therapeutic modulation of the visual cycle were established with the aim of providing treatment. The rationale is the following: a pharmacological intervention capable of slowing visual cycle activity shall protect the retina from the consequences of an aberrant flux of retinoids. There are different types of visual cycle modulators (VCMs), some of which are being evaluated as treatments for STGD1 (e.g., NCT05949593, NCT03845582, and NCT05244304). Among those tested in humans, emixustat is the VCM best characterized. Emixustat is a non-retinoid, small drug molecule for targeted inhibition of RPE65. In mice, emixustat treatment protects the retina from damage induced by prolonged exposure to white light. In humans, oral administration of emixustat suppresses the scotopic electroretinogram (ERG), and prolonged administration does not cause significant extra-ocular side effects highlighting the safety of this treatment. However, emixustat therapy is associated with unwanted adverse events that are visual in nature. These visual disturbances are due to the suboptimal pharmacological properties of emixustat, specifically its prolonged duration of action (days) despite having a short plasma half-life (4-6 h).

[0007] Ultimately, this unusual pharmacology of emixustat makes it difficult to dose because it does not allow a drug-free period in which the visual cycle can operate at a normal rate, thereby eliminating problematic visual side effects. This is a significant practical limitation to translate this molecule into a life-long treatment for retinopathies, such as STGD1, in which visual function is already compromised or for applications in which shortterm prevention of retinal phototoxicity is the goal, such as during ocular surgeries.SUMMARY

[0008] Embodiments described herein relate to compounds for use as short- acting visual cycle modulators (saVCMs), and, particularly, to ester-containing saVCMs that are susceptible to hydrolytic clearance in the eye, and their use in treating and / or preventing ocular disorders and / or photic retinal damage. We developed saVCMs capable of shortacting RPE65 inhibition by introduction of an ester functionality within the scaffold of aVCM that confers susceptibility to metabolism by non-selective esterases, including those found within the RPE. We show that the ester-containing saVCMs are cleaved by one such esterase at a rate that is governed by the steric bulk of the ester substituent. The ester functionality allows hydrolytic depletion of compound stores while preserving high-affinity RPE65 active site targeting. This novel metabolic susceptibility manifested in vivo as an ability to therapeutically suppress the visual cycle but with a shorter duration of action. Advantageously, ester-containing RPE65 inhibitors or saVCMs described herein can combine a very rapid onset of the pharmacological effect (minutes) with a tunable duration of action (hours), allowing the recovery of visual cycle activity during drug-free periods.

[0009] In some embodiments, the saVCMs described herein can have strategically incorporated deuterium and / or fluorine to modulate the saVCMs’ potency and metabolism. Previously, we showed that selective fluorination of emixustat could be used to abrogate phase-I hydroxylation events. Moreover, these studies partially addressed the metabolic liability of emixustat by deuterating the carbon a to the primary amine, but did not ablate it.

[0010] Regioselective incorporation of fluorine can impact pKa modulation; alter target selectivity through conformational variations or changes in specific hydrophobic interactions; and alter tissue-specific penetration (e.g., central nervous system (CNS)), through modification of lipophilicity. These effects of fluorination are in addition to the well-established strategy of replacing metabolically labile hydrogens with C-F bonds.Regioselective incorporation of deuterium can be used to attenuate amine oxidation and rapid metabolic elimination via engineering a localized primary isotope effect. Collectively, the saVCMs with the incorporated deuterium or fluorine can have improved potency, absorption, selectivity, and metabolism to mitigate the toxicity of retinal diseases associated with visual cycle activity.

[0011] In some embodiments, the ester-containing saVCMs described herein can be used for treating and / or preventing retinopathies associated with visual cycle activity.Populations that can be treated with the saVCMs include those affected by genetically inherited conditions that predispose the retina to an enhanced risk of photic damage, such as STGD1. The saVCMs described herein were found to exhibit protective effects against light damage in a mouse model of STGD1. Beyond their suitability to treat STGD1, these metabolically-labile saVCMs can be used for indications where transient visual cyclesuppression could be indicated; for example, in situations where the retina is susceptible to light damage.

[0012] Our findings show that ester-containing saVCMs can be employed as a standard of care whenever there is a potential for photic retinal injury. In our experiments, we attributed the success of the ester-containing saVCMs in preventing phototoxic retinal damage to a transitory blockage of the visual cycle, which increased the tolerance threshold of the retina to the toxicity caused by continuous photobleaching and biosynthesis of visual pigments. We showed the efficacy of ester-containing saVCMs in preserving retinal integrity in BALB / cJ albino mice which are notoriously susceptible to phototoxic retinal damage. Therefore, the ester-containing saVCMs can be used as a way to augment the success of ocular surgeries, much like the use of vasoconstrictors improves the outcome of chemosurgery for retinoblastoma.

[0013] Other vulnerable populations that can benefit from treatment with saVCMs include those with albinism. Albinism is associated with significant abnormalities in the human visual system. A consistent trend with an accelerated age-related loss of retinal function has been reported in the albino population that was attributed to phototoxic retinal damage. Indeed, albinism is associated with an increased susceptibility to phototoxic retinal damage in several species. Moreover, the intraocular surgeries in subjects affected by albinism are notoriously challenging, leading to poorer outcomes compared to pigmented individuals. Therefore, the favorable pharmacological properties of ester-containing saVCMs may translate into a treatment for accelerated vision loss in patients affected by albinism and improve surgical outcomes in this vulnerable population.

[0014] In some embodiments, a saVCM can include a compound of formula (I):OHr5 r6(i) or a pharmaceutically acceptable salt or solvate thereof, wherein:* denotes a chiral center;R1is an alkyl optionally substituted with one or more F, an alkenyl optionally substituted with one or more F, or an aryl optionally substituted with one or more alkyl, F, or fluoroalkyl;R2is H or F;R3and R4are each independently H, D, or an alkyl, which is optionally substituted with one or more D or F; andR5and R6are each independently H or D.

[0015] In some embodiments, R1is a C1-C12 alkyl optionally substituted with one or more F, a C2-C12 alkenyl optionally substituted with one or more F, or a C6-C12 aryl optionally substituted with one or more alkyl, F, or fluoroalkyl.

[0016] In some embodiments, R1is a branched C3-C10 alkyl optionally substituted with one or more F or a C3-C10 cycloalkyl optionally substituted with one or more F, C1-C3 alkyl, or C1-C3 fluoroalkyl.

[0017] In some embodiments, R1is a branched C3-C8 alkyl optionally substituted with one or more F.

[0018] In other embodiments, R1is C3-C10 cycloalkyl optionally substituted with one or more F, -CH3, or -CF3.

[0019] In some embodiments, R1is a branched C3-C10 alkenyl optionally substituted with one or more F or a C4-C8 cycloalkenyl optionally substituted with one or more F, C1-C3 alkyl, or C1-C3 fluoroalkyl.

[0020] In some embodiments, R1is a branched C3-C8 alkenyl optionally substituted with one or more F.

[0021] In some embodiments, R1is a C4-C8 cycloalkenyl optionally substituted with one or more -CH3, F, or -CF3.

[0022] In some embodiments, R1is a Ce-Cio aryl optionally substituted with one or more F, C1-C3 alkyl, or C1-C3 fluoroalkyl.

[0023] In some embodiments, R1is a phenyl optionally substituted with one or more F, -CH3, or -CF3.

[0024] In other embodiments, R1is selected from:or fluoro substituted derivatives thereof.

[0025] In some embodiments, R2is H.

[0026] In other embodiments, R2is F.

[0027] In some embodiments, at least one of R3or R4is an alkyl optionally substituted with one or more D or F.

[0028] In some embodiments, at least one of R3or R4is Ci-Ce alkyl optionally substituted with one or more D or F.

[0029] In some embodiments, at least one of R3or R4is Ci-Cs alkyl substituted with one or more D or F.

[0030] In some embodiments, both R3and R4are C1-C6 alkyl substituted with one or more D or F.

[0031] In some embodiments, at least one of R3or R4is methyl substituted with one or more D or F.

[0032] In some embodiments, both R3and R4are methyl substituted with one or more D or F.

[0033] In some embodiments, at least one of R3or R4is -CD3 or -CF3.

[0034] In some embodiments, both R3and R4are -CD3 or -CF3.

[0035] In some embodiments, at least one of R3or R4is H.

[0036] In some embodiments, both R3and R4are H.

[0037] In some embodiments, at least one of R3or R4is D.

[0038] In some embodiments, both R3and R4are D.

[0039] In some embodiments, R2is F or at least one of R3or R4is an alkyl optionally substituted with one or more D or F.

[0040] In some embodiments, at least one of R5or R6is D.

[0041] In some embodiments, both R5and R6are D.

[0042] In some embodiments, both R5and R6are H.

[0043] In some embodiments, the compound of formula (I), pharmaceutically acceptable salt, or solvate thereof is an (R)-OH isomer.

[0044] In other embodiments, the compound of formula (I), pharmaceutically acceptable salt, or solvate thereof is an (S)-OH isomer.

[0045] Other embodiments described herein relate to a compound selected from:OH D D; OH D DOH; OHOH; OHOH; OHOHpharmaceutically acceptable salt, or solvate thereof.

[0046] Still other embodiments relate to a pharmaceutical composition that includes a compound, pharmaceutically acceptable salt, or solvate thereof as described herein and a pharmaceutically acceptable carrier.

[0047] Other embodiments relate to a method of treating and / or preventing phototoxic retinal damage in a subject in need thereof. The method includes administering to the subject a therapeutically effective amount of a compound, pharmaceutically acceptable salt, or solvate thereof or a pharmaceutical composition as described herein.

[0048] Other embodiments relate to a method of treating and / or preventing an iatrogenic photic retinopathy in a subject in need thereof. The method includes administering to the subject a therapeutically effective amount of a compound, pharmaceutically acceptable salt, or solvate thereof or a pharmaceutical composition as described herein.

[0049] In some embodiments, the subject is treated by intraocular or ocular surgery requiring illumination of the eye.

[0050] In some embodiments, the illumination of the eye is effective to cause phototoxic retinal damage or iatrogenic photic retinopathy.

[0051] In some embodiments, the surgery can include cataract surgery.

[0052] In some embodiments, the compound, pharmaceutically acceptable salt, or solvate thereof or the pharmaceutical composition is administered to the subject prior to surgery.

[0053] In some embodiments, the subject has a genetically inherited condition that predisposes the subject to enhanced risk of photodamage.

[0054] In some embodiments, the subject has Stargardt disease or albinism.

[0055] Other embodiments relate to a method of treating and / or preventing an ocular disorder in a subject in need thereof. The method includes administering to the subject a therapeutically effective amount of a compound, pharmaceutically acceptable salt, or solvate thereof or a pharmaceutical composition as described herein.

[0056] In some embodiments, the ocular disorder includes at least one of light-induced retinal degeneration, macular degeneration, Stargardt disease, geographic atrophy, or retinitis pigmentosa.

[0057] In some embodiments, the pharmacokinetics of the compound, pharmaceutically acceptable salt, or solvate thereof upon administration to the subject is such that the compound, pharmaceutically acceptable salt, or solvate thereof does not promote night blindness when administered daily.

[0058] In some embodiments, the compound, pharmaceutically acceptable salt, or solvate thereof transiently inhibits RPE65 enzymatic activity in the subject.

[0059] In some embodiments, the compound, pharmaceutically acceptable salt, or solvate thereof inhibits RPE65 enzymatic activity in the subject prior to hydrolytic cleavage by esterase-mediated metabolism but does not inhibit RPE65 enzymatic activity after hydrolytic cleavage.

[0060] In some embodiments, the compound, pharmaceutically acceptable salt, or solvate thereof or the pharmaceutical composition is administered by oral, intravenous, intraocular, or intravitreal administration.

[0061] Other embodiments relate to a unit dosage form of a formulation comprising a compound, pharmaceutically acceptable salt, or solvate thereof as described herein.

[0062] In some embodiments, the unit dosage formulation is an oral preparation.BRIEF DESCRIPTION OF THE DRAWINGS

[0063] Figs. 1(A-B) illustrate: (A) Scheme shows the strategy utilized to achieve shortacting RPE65 inhibition. (B) Plots showing time courses of loss of test compound in the presence of porcine liver esterase; data are plotted as mean (solid lines) and 95% confidence interval (dotted lines), n = 3 replicates per point. The data obtained from the hydrolytic cleavage of test compounds were fit to either a linear or exponential decay function using GraphPad Prism. The values of the initial rate of VCM loss are given in Table 1.

[0064] Fig. 2 illustrates a plot showing time courses of loss of test compounds in the presence of porcine liver esterase of EYE-004 - EYE-006. EYE-002 is shown for reference, n = 3 replicates per point.

[0065] Figs. 3(A-B) illustrate ester derivatives of emixustat inhibit RPE65 and are metabolized by esterases. (A) Schematic of chemical structure of test compounds. (B) Plots showing dose-response curves for RPE65 inhibition. Data are plotted as mean ± SD and represent n = 3 replicates per point. IC50 values are given in Table 1.

[0066] Fig. 4 illustrates plots showing RPE65 Inhibition data of EYE-004 - EYE-006.

[0067] Fig. 5 illustrates plots showing RPE65 inhibition data of methylated EYE-001 - EYE-003.

[0068] Fig. 6 illustrates plots showing shelf-life (Thermal Stability) of ester-based VCMs.

[0069] Fig. 7 illustrates plots showing time courses of auto-lysis of test compounds in PBS at 37°C; data are plotted as mean (solid lines) ± 95% confidence interval (dotted lines), n = 3 replicates per time point. Note that lines for EYE-005 and EYE-006 are superimposed due to identical stability. The graph was generated with GraphPad Prism.

[0070] Figs. 8(A-B) illustrate schematics showing the crystal structure of EYE-002 in a complex with RPE65. (A) Illustration of RPE65 residues within 4.5 Å from the bound ligands. The corresponding omit 2Fo- Fcelectron density map, contoured at 1 RMSD, is shown as a blue mesh within 2 A of the bound ligands (PDB accession code 9DQA). (B) Comparison of the binding orientations between EYE-002, emixustat (PDB accession code 4RSC), and MB-004 (PDB accession code 5UL5) in the RPE65 active site.

[0071] Figs. 9(A-F) illustrate plots and graphs showing ester analogs of emixustat are short-acting RPE65 inhibitors. (A) Representative HPLC chromatograms showing the effects of vehicle or test compounds on the retinoid extracted from whole mouse eye homogenates. Dark-adapted, 6-8 weeks old mice received a single IP injection of vehicle or test compounds in the dark. 30 min after the IP injection, the mice were photobleached and then housed in the dark for 2 h before HPLC analysis. The peaks corresponding to atREs (b) and 11cRAL oxime (syn) (a) are indicated by solid black lines and their UV-Vis spectra is shown in the insets. (B and C) Absolute 11cRAL and atREs quantification from the screening of test compounds. ANOVA showed a significant effect of the test compounds (p < 0.0001).Dunnctt’ s multiple comparison test showed a significant effect of emixustat, EYE-002 andEYE-003 in reducing 11cRAL and augmenting atREs, respectively, compared to the vehicle (*p < 0.05,s< 0.0001). Data represent mean ± SD, n = 3 animals. (D) Raw HPLC chromatograms from mouse eye retinoid extracts illustrating short-acting RPE65 inhibition by EYE-002 and EYE-003. Dark- adapted, 6-8 weeks old mice were administered a single IP injection of vehicle or test compounds in the dark. At different points in time after the IP injection (0.5-4 h), the mice were photobleached and then housed in the dark for 2 h before HPLC analysis. (E and F) Absolute quantification of 11cRAL synthesis and atREs clearance at different points in time after IP injection of vehicle or test compounds. ANOVA analysis showed a significant effect for the test compounds (p < 0.0001). The results of Dunnett’s multiple comparison test are reported in the figure. (*p < 0.05,#p < 0.01,< 0.001, < 0.0001).

[0072] Figs. 10(A-H) illustrate images, plots, and graphs showing a single administration of EYE-002 prevents photic retinal damage in BALBc / J mice. (A) SLO images illustrating the effect of vehicle or test compounds on retinal autofluorescence. Dark-adapted, 6-8 weeks old mice received an IP injection in the dark. 30 min later the mice were photobleached for 8 h (15,000 lux) and then housed one week in regular light / dark cycles before assessment. Scale bars 500 pm. (B) Corresponding retinal OCT images. Test compounds maintain an intact ONL (black brackets). The white arrows indicate the optic nerve head. Scale bars 200 pm. (C) ONL thickness as measured in OCT images at 500 pm from the optic nerve head. Data represent means ± SEM, and circles individual eyes, n = 12. ANOVA analysis showed a significant effect of test compounds (p < 0.0001). The results of Dunnett’s test are reported in the figure. (D) Images of retinal cross sections stained with H& E; scale bars 100 pm. The white arrows indicate the optic nerve head. The white rectangles correspond to the area magnified in the insets; scale bars 50 pm. Abbreviations: retinal ganglion cell layer (RGC); inner nuclear layer (INL). (E) Spider plot showing the thickness of ONL. Data represent means ± SEM, n = 10. ANOVA analysis showed that emixustat and EYE-002 have a significant effect (p < 0.0001). The results of Dunnett’s test are shown in the figure. (F) Corresponding scotopic ERG swipes. The black arrowheads indicate the timing of test flash delivery. (G and H) Quantification of scotopic a-wave and b-wave amplitudes, respectively. ANOVA analysis showed a significant effect of the compounds on the amplitude of a- (p = 0.0005) and b- (p = 0.0016) waves. The results ofDunnett’s multiple comparisons are reported in the figure (*p < 0.05,#p < 0.01,< 0.001, p < 0.0001).

[0073] Figs. 11(A-F) illustrate images, a graph, and plots showing oral administration of EYE-003 prevents retina degeneration in a mouse model of STGD1. (A) SLO images illustrating the effect of vehicle or EYE-003 on retinal autofluorescence. Light- adapted, 6-8 weeks old Abca4⁻ / ⁻Rdh8⁻ / ⁻7' mice received a single oral or IP dose of vehicle or EYE-003 (5 mg / kg). 30 min after the administration of the vehicle or EYE-003, the mice were photobleached for 30 min (10,000 lux) and then housed in regular light / dark cycles for one week before assessment. Scale bars 500 pm. (B) Corresponding retinal OCT images. EYE-003 maintains the ONL (black brackets). The white arrows indicate the optic nerve head. Scale bars 200 pm. (C) ONL thickness as measured in OCT images at 500 pm from the optic nerve head. Data represented as means ± SEM, the individual data points represent single eyes, n = 6 or more eyes per group. ANOVA analysis showed a significant effect of EYE-003 administration (p < 0.0001). Dunnett’s multiple comparison test shows that EYE-003 has a significant effect when dosed by IP injection (10 mg / kg) and orally at doses of 20 and 50 mg / kg (§p < 0.0001). (D, E, and F) Quantification of ERG b-wave amplitudes from the rods, S-cones, and M-cones, respectively. ANOVA analysis showed a significant effect of EYE-003 dosing on the ERG b-wave amplitude of rods (p = 0.0002), S-cones (p = 0.002), and M-cones (p = 0.0199). The results of Dunnett’s multiple comparisons test are reported in the figure (*p < 0.05,#p < 0.01,< 0.001,< 0.0001).

[0074] Figs. 12(A-B) illustrate graphs showing oral administration of short-acting VCMs inhibits the scotopic ERG. (A and B) Quantification of scotopic ERG a- and b-wave amplitudes after a single oral administration of cither vehicle or test compounds (10 mg / kg). Dark-adapted, 6-8 weeks old BALBc / . T mice were administered a single IP of vehicle or test compounds in the dark. 30 min after the IP, the mice were photobleached and then housed in the dark for 2 h before recording the scotopic ERG using a single flash intensity of 0.5 cd’s / m2. Data are shown as Mean ± SE, each data point corresponds to one eye. ANOVA analysis showed a significant effect of test compounds on both the a- [34.88 (3.000, 24.59), p < 0.0001] and b- [51.06 (3.000, 19.87), p < 0.0001]. The results of Donnett’ s multiple comparison are shown in the graph (*p < 0.05,#p < 0.01, *p < 0.001,7p < 0.0001). EYE-002 treatment suppressed significantly the scotopic a-wave but not the b-wave compared to thevehicle treatment. Instead, EYE-003 treatment suppressed significantly both the scotopic a-and b- wave.

[0075] Figs. 13(A-C) illustrate a plot and graphs showing esters analogs of emixustat allow fast recovery of rod- specific ERG responses. (A) Representative scotopic ERG swipes illustrating the effect of vehicle or test compounds on rod dark adaptation after a photobleach. Dark-adapted, 6-8 weeks old BALBc / . T mice were administered a single IP of vehicle or test compounds in the dark. 30 min after the IP, the mice were photobleached and then housed in the dark. Scotopic ERG was recorded at different time points after the photobleach (0.5-8 h). The black arrows indicate the timing of test flash delivery. (B and C) Quantification of scotopic a- and b-wave amplitudes, respectively. Data represent mean ± SEM, each data point corresponds to one eye. ANOVA analysis showed a statistically significant difference between the groups (p < 0.0001). The results of Dunnett’s test are reported as *p < 0.05,#p < 0.01, *p < 0.001,§p < 0.0001).

[0076] Figs. 14(A-B) illustrate plots showing oral delivery of EYE-005 allows recovery of rod-specific ERG responses while emixustat does not. A. ERG a-wave (oral 10 mg / kg): EYE-005 delivers strong suppression with near-baseline recovery by 24 h, whereas emixustat at the same dose remains suppressed >24 h. B. ERG b-wave (oral 10 mg / kg): The b-wave mirrors the a-wave: EYE-005 recovers by ~24 h, while emixustat shows prolonged suppression at the same dose.DETAILED DESCRIPTION

[0077] While the following terms are believed to be well understood by one of ordinary skill in the art, the following definitions are set forth to facilitate explanation of the presently disclosed subject matter.

[0078] As used herein, the verb “comprise” as is used in this description and in the claims and its conjugations are used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded. The present invention may suitably “comprise”, “consist of’, or “consist essentially of', the steps, elements, and / or reagents described in the claims.

[0079] It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as "solely", "only" and the like in connection with the recitation of claim elements, or the use of a "negative" limitation.

[0080] The term "chiral" refers to molecules that have the property of non-superimposability of the mirror image partner, while the term "achiral" refers to molecules which are superimposable on their mirror image partner.

[0081] The term "stereoisomers" refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0082] The term "enantiomers" refers to two stereoisomers of a compound.

[0083] The terms "crystal polymorphs" or "polymorphs" or "crystal forms" means crystal structures in which a compound (or salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectral, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Crystal polymorphs of the compounds can be prepared by crystallization under different conditions.

[0084] The term "derivative", refers to compounds that have a common core structure, and are substituted with various groups as described herein. For example, all of the compounds represented by formula I have formula I as a common core.

[0085] The term "bioisostere" refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms. The objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound. The bioisosteric replacement may be physiochemically or topologically based. Examples of carboxylic acid bioisosteres include acyl sulfonimides, tctrazolcs, sulfonates, and phosphonatcs. Sec, e.g., Patani and LaVoic, Chcm. Rev. 96, 3147-3176 (1996).

[0086] When an atom or a chemical moiety is followed by a subscripted numeric range (e.g., Cue), the invention is meant to encompass each number within the range as well as all intermediate ranges. For example, " Ci-6 alkyl" is meant to include alkyl groups with 1, 2, 3, 4, 5, 6, 1-6, 1-5, 1-4, 1-3, 1-2, 2-6, 2-5, 2-4, 2-3, 3-6, 3-5, 3-4. 4-6, 4-5, and 5-6 carbons.

[0087] “Alkyl” or “alkyl group” refers to a fully saturated, straight or branched, or cyclic hydrocarbon chain radical having from one to twelve carbon atoms, and which is attached to the rest of the molecule by a single bond. Alkyls comprising any number of carbon atoms from 1 to 12 arc included. An alkyl comprising up to 12 carbon atoms is a Ci-C12 alkyl, an alkyl comprising up to 10 carbon atoms is a C1-C10 alkyl, an alkyl comprising up to 6 carbon atoms is a Ci-Ce alkyl and an alkyl comprising up to 5 carbon atoms is a C1-C5 alkyl. A C1-C5 alkyl includes C5 alkyls, C4 alkyls, C3 alkyls, C2 alkyls and Ci alkyl (i.e., methyl). A Ci-Ce alkyl includes all moieties described above for C1-C5 alkyls but also includes Ce alkyls. A C1-C10 alkyl includes all moieties described above for C1-C5 alkyls and Ci-Ce alkyls, but also includes C7, Cs, C9 and C10 alkyls. Similarly, a C1-C12 alkyl includes all the foregoing moieties, but also includes C11 and C12 alkyls. Non-limiting examples of C1-C12 alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.

[0088] “Alkenyl” or “alkenyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Each alkenyl group is attached to the rest of the molecule by a single bond. Alkenyl group comprising any number of carbon atoms from 2 to 12 are included. An alkenyl group comprising up to 12 carbon atoms is a C2-C12 alkenyl, an alkenyl comprising up to 10 carbon atoms is a C2-C10 alkenyl, an alkenyl group comprising up to 6 carbon atoms is a C2-C6 alkenyl and an alkenyl comprising up to 5 carbon atoms is a C2-C5 alkenyl. A C2-C5 alkenyl includes C5 alkenyls, C4 alkenyls, C3 alkenyls, and C2 alkenyls. A C2-C6 alkenyl includes all moieties described above for C2-C5 alkenyls but also includes Ce alkenyls. A C2-C10 alkenyl includes all moieties described above for C2-C5 alkenyls and C2-C6 alkenyls, but also includes C7, Cs, C9 and C10 alkenyls. Similarly, a C2-C12 alkenyl includes all the foregoing moieties, but also includes Cn and C12 alkenyls. Non-limiting examples of C2-C12 alkenyl include ethenyl (vinyl), 1 -propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1 -heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1 -decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1 -undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1 -dodecenyl, 2-dodcccnyl, 3-dodcccnyl, 4-dodcccnyl, 5-dodcccnyl, 6-dodcccnyl, 7-dodcccnyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, and 11 -dodecenyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.

[0089] “Aryl” refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring. For purposes of this invention, the aryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from phenyl (benzene), aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, chrysene, fluoranthene, fluorene, av-indacene,.v-indacenc. indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, the term “aryl” is meant to include aryl radicals that are optionally substituted.

[0090] “Carbocyclyl,” “carbocyclic ring” or “carbocycle” refers to a ring structure, wherein the atoms which form the ring are each carbon. Carbocyclic rings can comprise from 3 to 20 carbon atoms in the ring. Carbocyclic rings include aryls and cycloalkyl.Cycloalkenyl and cycloalkynyl as defined herein. Unless stated otherwise specifically in the specification, a carbocyclyl group can be optionally substituted.

[0091] “Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, which can include fused, bridged, or spiral ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl, dccalinyl,7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group can be optionally substituted.

[0092] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl,1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group can be optionally substituted.

[0093] “Haloalkenyl” refers to an alkenyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., 1-fluoropropenyl, 1,1-difluorobutenyl,and the like. Unless stated otherwise specifically in the specification, a haloalkenyl group can be optionally substituted.

[0094] As used herein, "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo. " Counterion" is used to represent a small, negatively charged species such as fluoride, chloride, bromide, iodide, hydroxide, acetate, and sulfate.

[0095] Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation, and as appropriate, purification from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0096] " Free compound" is used herein to describe a compound in the unbound state.

[0097] The term “substituted” used herein means any of the above groups (e.g., alkyl, alkenyl, aryl, carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, etc.) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atoms such as, but not limited to: a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. “Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom, such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. For example, “substituted” includes any of the above groups in which one or more hydrogen atoms are replaced with -NRgRh, -NRgC(=O)Rh. -NRgC(=O)NRgRh, -NRgC(=O)ORh, -NRgSO2Rh, -OC(=O)NRgRh, -ORg, -SRg. -SORg. -SO2Rg, -OSO2Rg, -SO2ORg, =NSO2Rg, and -SO2NRgRh. “Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced with -C(=O)Rg, -C(=O)ORg, -C(=O)NRgRh, -CH2SO2Rg, -CH2SO2NRgRh. In the foregoing, Rgand Rh are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, 7V-heterocyclyl, heterocyclylalkyl, heteroaryl, 7V-heteroaryl and / or heteroarylalkyl. “Substituted” further means any of the above groups in which one or more hydrogen atoms arc replaced by a bondto an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, A-heterocyclyl, heterocyclylalkyl, heteroaryl, / V-heteroaryl and / or heteroarylalkyl group. In addition, each of the foregoing substituents can also be optionally substituted with one or more of the above substituents.

[0098] As used herein, the symbol “ ” (hereinafter can be referred to as “a point of attachment bond”) denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which is not depicted as being attached to the point of attachment bond. Forexample,AH ” indicates that the chemical entity “A” is bonded to another chemical entity via the point of attachment bond. Furthermore, the specific point of attachment to the non-depicted chemical entity can be specified by inference. For example, the compoundwherein X isAH ” infers that the point of attachment bond is the bond by which X is depicted as being attached to the phenyl ring at the ortho position relative to fluorine.

[0099] The phrases "parenteral administration" and "administered parenterally" refer to modes of administration other than enteral and topical administration, such as injections, and include, without limitation, intravenous, intramuscular, intrapleural, intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra- articular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.

[0100] The term "treating" refers to inhibiting a disease, disorder or condition in a subject, e.g., impeding its progress; and relieving the disease, disorder or condition, e.g., causing regression of the disease, disorder and / or condition. Treating the disease or condition includes ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected.

[0101] The term "preventing" refers to stopping a disease, disorder or condition from occurring in a subject, which may be predisposed to the disease, disorder and / or condition buthas not yet been diagnosed as having it. Preventing a condition related to a disease includes stopping the condition from occurring after the disease has been diagnosed but before the condition has been diagnosed.

[0102] The term a "pharmaceutical composition" refers to a formulation containing the disclosed compounds in a form suitable for administration to a subject. The pharmaceutical composition can be in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler, or a vial. The quantity of active ingredient (e.g., a formulation of the disclosed compound or salts thereof) in a unit dose of composition is an effective amount and varies according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including ocular, oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal, and the like. Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In a preferred embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.

[0103] The phrase "pharmaceutically acceptable" refers to compositions, polymers and other materials and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0104] The phrase "pharmaceutically acceptable carrier" refers to pharmaceutically acceptable materials, compositions or vehicles, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any subject composition from one organ, or portion of the body, to another organ, or portion of the body. Each earner must be "acceptable" in the sense of being compatible with the other ingredients of a subject composition and not injurious to the patient. In certain embodiments, a pharmaceutically acceptable carrier is non-pyrogenic. Some examples of materials which may serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose,glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0105] The compounds of the application are capable of further forming salts. All of these forms are also contemplated within the scope of the claims.

[0106] The term “pharmaceutically acceptable salts” include those obtained by reacting the active compound functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. Those skilled in the art will further recognize that acid addition salts may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. The term “pharmaceutically acceptable salts” also includes those obtained by reacting the active compound functioning as an acid, with an inorganic or organic base to form a salt, for example salts of ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N, N’-dibcnzylcthylcncdiaminc, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris-(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, and the like. Non limiting examples of inorganic or metal salts include lithium, sodium, calcium, potassium, magnesium salts and the like.

[0107] It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt.

[0108] Additionally, the salts of the compounds described herein can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0109] The term "solvates" refers to solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds tend to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate: when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H2O, such a combination being able to form one or more hydrates.

[0110] The term "analog" refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound.

[0111] A "patient," "subject," or "host" to be treated by the compounds or methods described herein may mean either a human or non-human animal, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one aspect, the subject is a mammal. A patient refers to a subject afflicted with a disease or disorder.

[0112] The term "prophylactic or therapeutic" treatment refers to the administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, i.e., it protects the host against developing the unwanted condition, whereas if it is administered after manifestation of the unwantedcondition, the treatment is therapeutic (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).

[0113] The terms "therapeutic agent", "drug", "medicament" and "bioactive substance" refer to molecules and other agents that are biologically, physiologically, or pharmacologically active substances that act locally or systemically in a patient or subject to treat a disease or condition, such as retinal degeneration or other forms of retinal disease whose etiology involves elevated levels of all trans-retinal in the ocular tissue of a subject. The terms include without limitation pharmaceutically acceptable salts thereof and prodmgs. Such agents may be acidic, basic, or salts; they may be neutral molecules, polar molecules, or molecular complexes capable of hydrogen bonding; they may be prodrugs in the form of ethers, esters, amides and the like that are biologically activated when administered into a patient or subject.

[0114] The phrase "therapeutically effective amount" is an art-recognized term. In certain embodiments, the term refers to an amount of a therapeutic agent that produces some desired effect at a reasonable benefit / risk ratio applicable to any medical treatment. In certain embodiments, the term refers to that amount necessary or sufficient to eliminate, reduce or maintain a target of a particular therapeutic regimen. The effective amount may vary depending on such factors as the disease or condition being treated, the particular targeted constructs being administered, the size of the subject or the severity of the disease or condition. One of ordinary skill in the art may empirically determine the effective amount of a particular compound without necessitating undue experimentation.

[0115] With respect to any chemical compounds, the present application is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include C-13 and C-14.

[0116] In the specification, the singular forms also include the plural, unless the context clearly dictates otherwise. Throughout the description, where compositions are described as having, including, or comprising, specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, itshould be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0117] Small molecule" refers to a molecule, which has a molecular weight of less than about 2000 amu, or less than about 1000 amu, and even less than about 500 amu.

[0118] All percentages and ratios used herein, unless otherwise indicated, are by weight.

[0119] The term "retina" refers to a region of the central nervous system with approximately 150 million neurons. It is located at the back of the eye where it rests upon a specialized epithelial tissue called retinal pigment epithelium or RPE. The retina initiates the first stage of visual processing by transducing visual stimuli in specialized neurons called "photoreceptors". Their synaptic outputs are processed by elaborate neural networks in the retina and then transmitted to the brain. The retina has evolved two specialized classes of photoreceptors to operate under a wide range of light conditions. " Rod" photoreceptors transduce visual images under low light conditions and mediate achromatic vision. " Cone" photoreceptors transduce visual images in dim to bright light conditions and mediate both color vision and high acuity vision.

[0120] Every photoreceptor is compartmentalized into two regions called the "outer" and "inner" segment. The inner segment is the neuronal cell body containing the cell nucleus. The inner segment survives for a lifetime in the absence of retinal disease. The outer segment is the region where the light sensitive visual pigment molecules are concentrated in a dense array of stacked membrane structures. Part of the outer segment is routinely shed and rcgrown in a diurnal process called outer segment renewal. Shed outer segments are ingested and metabolized by RPE cells.

[0121] The term "macula" refers to the central region of the retina, which contains the fovea where visual images are processed by long slender cones in high spatial detail ("visual acuity"). " Macular degeneration" is a form of retinal neurodegeneration, which attacks the macula and destroys high acuity vision in the center of the visual field. AMD can be in a "dry form" characterized by residual lysosomal granules called lipofuscin in RPE cells, and by extracellular deposits called "drusen". Drusen contain cellular waste products excreted by RPE cells. " Lipofuscin" and drusen can be detected clinically by ophthalmologists andquantified using fluorescence techniques. They can be the first clinical signs of macular degeneration.

[0122] Lipofuscin contains aggregations of A2E. Lipofuscin accumulates in RPE cells and poisons them by multiple known mechanisms. As RPE cells become poisoned, their biochemical activities decline and photoreceptors begin to degenerate. Extracellular drusen may further compromise RPE cells by interfering with their supply of vascular nutrients. Drusen also trigger inflammatory processes, which leads to choroidal neovascular invasions of the macula in one patient in ten who progresses to wet form AMD. Both the dry form and wet form progress to blindness.

[0123] The term " ERG" is an acronym for electroretinogram, which is the measurement of the electric field potential emitted by retinal neurons during their response to an experimentally defined light stimulus. ERG is a non-invasive measurement, which can be performed on either living subjects (human or animal) or a hemisected eye in solution that has been removed surgically from a living animal.

[0124] Embodiments described herein relate to compounds for use as short-acting visual cycle modulators (saVCMs), and, particularly, to ester-containing saVCMs that are susceptible to hydrolytic clearance in the eye, and their use in treating and / or preventing ocular disorders and / or photic retinal damage. We developed saVCMs capable of shortacting RPE65 inhibition by introduction of an ester functionality within the scaffold of a VCM that confers susceptibility to metabolism by non-selective esterases, including those found within the RPE. We show that the ester-containing saVCMs are cleaved by one such esterase at a rate that is governed by the steric bulk of the ester substituent. The ester functionality allows hydrolytic depletion of compound stores while preserving high-affinity RPE65 active site targeting. This novel metabolic susceptibility manifested in vivo as an ability to therapeutically suppress the visual cycle but with a shorter duration of action. Notably, a single dose of an ester-containing saVCM described herein protected the retina from damage induced by prolonged exposure to white light. Crystallographic analysis revealed how the ester functionality is accommodated within the RPE65 active site. These data elucidate a new concept in VCM design where a shorter attenuation of the visual cycle can therapeutically intervene in retinal disease processes while avoiding problematic side effects on visual function. Advantageously, ester-containing RPE65 inhibitors or saVCMs described herein can combine a very rapid onset of the pharmacological effect (minutes) witha tunable duration of action (hours), allowing the recovery of visual cycle activity during drug -free periods.

[0125] In some embodiments, the saVCMs described herein can have strategically incorporated deuterium and / or fluorine to modulate the saVCMs’ potency and metabolism. Previously, we showed that selective fluorination of emixustat could be used to abrogate phase-I hydroxylation events. Moreover, these studies partially addressed the metabolic liability of emixustat by deuterating the carbon a to the primary amine, but did not ablate it.

[0126] Regioselective incorporation of fluorine can impact pKa modulation; alter target selectivity through conformational variations or changes in specific hydrophobic interactions; and alter tissue-specific penetration (e.g., central nervous system (CNS)), through modification of lipophilicity. These effects of fluorination are in addition to the well-established strategy of replacing metabolically labile hydrogens with C-F bonds.Regioselective incorporation of deuterium can be used to attenuate amine oxidation and rapid metabolic elimination via engineering a localized primary isotope effect. Collectively, the saVCMs with the incorporated deuterium or fluorine can have improved potency, absorption, selectivity, and metabolism to mitigate the toxicity of all-trans-retinal in retinal diseases associated with visual cycle activity.

[0127] In some embodiments, the ester-containing saVCMs described herein can be used for treating and / or preventing retinopathies associated with visual cycle activity.Populations that can be treated with the saVCMs include those affected by genetically inherited conditions that predispose the retina to an enhanced risk of photic damage, such as STGD1. The saVCMs described herein were found to exhibit protective effects against light damage in a mouse model of STGD1. Beyond their suitability to treat STGD1, these metabolically-labile saVCMs can be used for indications where transient visual cycle suppression could be indicated; for example, in situations where the retina is susceptible to light damage.

[0128] For example, we conducted experiments in the context of photic retinal damage induced by aberrant visual cycle activity in response to prolonged illumination with white FED light at an intensity (15,000 lux) equivalent to that of an ophthalmic surgical microscope. Retinal damage induced by continuous photobleaching of visual pigments is relevant to several real-world scenarios. Surgeons are familiar with the delicate tradeoff between bright illumination of the field of operation and retinal safety, as highlighted by thehistory of vision loss caused by surgical illumination. Surgical procedures allow for light to bypass the natural filters of the ocular tissues and impinge on the retina without the protection of blinking and pupillary constriction, thus exceeding the limits of irradiances tolerated by the retina. It is documented that threshold lesions go unnoticed without routine postoperative retina imaging, and there is little incentive for clinicians to report a well-known problem.

[0129] Our findings show that ester-containing saVCMs should be employed as a standard of care whenever there is a potential for photic retinal injury. In our experiments, we attributed the success of the ester-containing saVCMs in preventing phototoxic retinal damage to a transitory blockage of the visual cycle, which increased the tolerance threshold of the retina to the toxicity caused by continuous photobleaching and biosynthesis of visual pigments. We showed the efficacy of ester-containing saVCMs in preserving retinal integrity in BALB / cJ albino mice which are notoriously susceptible to phototoxic retinal damage. Therefore, the ester-containing saVCMs can be used as a way to augment the success of ocular surgeries, much like the use of vasoconstrictors improves the outcome of chemosurgery for retinoblastoma.

[0130] Advantageously, saVCMs described herein can be dispensed even in the most minimalistic clinical setting and their therapeutic effect synergizes with the protection provided by the 3D visualization systems. The advantages of ester-containing saVCM treatment become obvious when considering that cataract surgery is the most performed elective surgery worldwide with more than 28 million surgeries conducted annually, and the incidence of its adverse surgical outcomes strongly correlate with the socioeconomic status of the country. Moreover, there are 1.8 million vitrectomies performed each year worldwide of which 225,000 in the United States alone. Lastly, we considered the growing interest in ocular gene therapies, where the eye may be exposed to light for extended periods of time (hours). Presently, there are more than 30 gene therapy trials for retinal diseases actively recruiting or enrolling, several of which require vitrectomy for delivery.

[0131] Other vulnerable populations that can benefit from treatment with short-acting VCMs include those with albinism. Albinism is associated with significant abnormalities in the human visual system. A consistent trend with an accelerated age-related loss of retinal function has been report in the albino population that was attributed to phototoxic retinal damage. Indeed, albinism is associated with an increased susceptibility to phototoxic retinal damage in several species. Moreover, the intraocular surgeries in subjects affected byalbinism are notoriously challenging, leading to poorer outcomes compared to pigmented individuals. Therefore, the favorable pharmacological properties of ester-containing saVCMs may translate into a treatment for accelerated vision loss in patients affected by albinism and improve surgical outcomes in this vulnerable population.

[0132] In some embodiments, a saVCM can include a compound of formula (I):R i - N(I) or a pharmaceutically acceptable salt or solvate thereof, wherein:* denotes a chiral center;R1is an alkyl optionally substituted with one or more F, an alkenyl optionally substituted with one or more F, or an aryl optionally substituted with one or more alkyl, F, or fluoroalkyl;R2is H or F;R3and R4are each independently H, D, or an alkyl, which is optionally substituted with one or more D or F; andR5and R6are each independently H or D.

[0133] In some embodiments, R1is a C1-C12 alkyl optionally substituted with one or more F, a C2-C12 alkenyl optionally substituted with one or more F, or a C6-C12 aryl optionally substituted with one or more alkyl, F, or fluoroalkyl.

[0134] In some embodiments, R1is a branched C3-C10 alkyl optionally substituted with one or more F or a C3-C10 cycloalkyl optionally substituted with one or more F, -CH3, or - CF3.

[0135] In some embodiments, R1is a branched C3-C8 alkyl optionally substituted with one or more F.

[0136] Examples of branched C3-C8 alkyls optionally substituted with one or more Fcan includesubstituted derivatives thereof.

[0137] In some embodiments, R1is a C3-C10 cycloalkyl optionally substituted with one or more F, C1-C3 alkyl, or C1-C3 fluoroalkyl.

[0138] Examples of C3-C6 cycloalkyls optionally substituted with one or more F, C1-C3 alkyl, or C1-C3 fluoroalkyl can include, or fluoro substituted derivative thereof.

[0139] In other embodiments, R1is a C7-C10 bicyclic or polycyclic cycloalkyl optionally substituted with one or more F, -CH3, or -CF3.

[0140] Examples of C7-C10 bicyclic or polycyclic cycloalkyls optionally substituted with one or more F, -CH3, or -CF3 can include:or fluoro substituted derivatives thereof.

[0141] In some embodiments, R1is a branched C3-C10 alkenyl optionally substituted with one or more F or a C4-C8 cycloalkenyl optionally substituted with one or more F, -CH3, or -CF3.

[0142] In other embodiments, R1is a branched C3-C8 alkenyl optionally substituted with one or more F.

[0143] In some embodiments, R1is a C4-C8 cycloalkenyl optionally substituted with one or more -CH3, F, or -CF3.

[0144] An example of a C4-C8 cycloalkenyl optionally substituted with one or more -CH3, F, or -CF3 can includeor fluoro substituted derivatives thereof.

[0145] In some embodiments, R1is a phenyl optionally substituted with one or more F, C1-C3 alkyl, or C1-C3 fluoroalkyl.

[0146] In some embodiments, R1is a phenyl optionally substituted with one or more F, -CH3, or -CF3.

[0147] Examples of a phenyl optionally substituted with one or more F, -CH3, or -CF3 can include:, or fluoro substituted derivatives thereof.

[0148] In other embodiments, R1is selected from:substituted derivatives thereof.

[0149] In some embodiments, R2is H.

[0150] In other embodiments, R2is F.

[0151] In some embodiments, at least one of R3or R4is an alkyl optionally substituted with one or more D or F.

[0152] In some embodiments, at least one of R3or R4is Ci-Cg alkyl optionally substituted with one or more D or F.

[0153] In some embodiments, at least one of R3or R4is Ci-Ce alkyl substituted with one or more D or F.

[0154] In some embodiments, both R3and R4are Ci-Ce alkyl substituted with one or more D or F.

[0155] In some embodiments, at least one of R3or R4is methyl substituted with one or more D or F.

[0156] In some embodiments, both R3and R4are methyl substituted with one or more D or F.

[0157] In some embodiments, at least one of R3or R4is -CD3 or -CF3.

[0158] In some embodiments, both R3and R4are -CD3 or -CF3.

[0159] In some embodiments, at least one of R3or R4is H.

[0160] In some embodiments, both R3and R4are H.

[0161] In some embodiments, at least one of R3or R4is D.

[0162] In some embodiments, both R3and R4are D.

[0163] In some embodiments, R2is F or at least one of R3or R4is an alkyl optionally substituted with one or more D or F.

[0164] In some embodiments, at least one of R5or R6is D.

[0165] In some embodiments, both R5and R6are D.

[0166] In some embodiments, both R5and R6are H.

[0167] In some embodiments, the compound of formula (I), pharmaceutically acceptable salt, or solvate thereof is an (R)-OH isomer.

[0168] In other embodiments, the compound of formula (I), pharmaceutically acceptable salt, or solvate thereof is an (S)-OH isomer.

[0169] In other embodiments, a saVCM can include a compound of formula (II):R I N OH R5aR'(II) or a pharmaceutically acceptable salt or solvate thereof, wherein:* denotes a chiral center;R2ais H or F;R3aand R4aare each independently H, D, or an alkyl, which is optionally substituted with one or more D or F; andR5aand R6aare each independently H or D.

[0170] In some embodiments, R2ais H.

[0171] In other embodiments, R2ais F.

[0172] In some embodiments, at least one of R3aor R4ais an alkyl optionally substituted with one or more D or F.

[0173] In some embodiments, at least one of R3aor R4ais Ci-Ce alkyl optionally substituted with one or more D or F.

[0174] In some embodiments, at least one of R3aor R4ais Ci-Ce alkyl substituted with one or more D or F.

[0175] In some embodiments, both R3aand R4aare Ci-Ce alkyl substituted with one or more D or F.

[0176] In some embodiments, at least one of R3aor R4ais methyl substituted with one or more D or F.

[0177] In some embodiments, both R3aand R4aare methyl substituted with one or more D or F.

[0178] In some embodiments, at least one of R3aor R4ais -CD3 or -CF3.

[0179] In some embodiments, both R3aand R4aare -CD3 or -CF3.

[0180] In some embodiments, at least one of R3aor R4ais H.

[0181] In some embodiments, both R3aand R4aare H.

[0182] In some embodiments, at least one of R3aor R4ais D.

[0183] In some embodiments, both R3aand R4aare D.

[0184] In some embodiments, R2ais F or at least one of R3aor R4ais an alkyl optionally substituted with one or more D or F.

[0185] In some embodiments, at least one of R5aor R6ais D.

[0186] In some embodiments, both R5aand R6aare D.

[0187] In some embodiments, both R5aand R6aare H.

[0188] In some embodiments, the compound of formula (II), pharmaceutically acceptable salt, or solvate thereof is an (R)-OH isomer.

[0189] In other embodiments, the compound of formula (II), pharmaceutically acceptable salt, or solvate thereof is an (S)-OH isomer.

[0190] In some embodiments, a saVCM of formula (II) is selected from:pharmaceutically acceptable salt, or solvate thereof.

[0191] In other embodiments, a saVCM can include a compound of formula (III):R3b1OH R4bR (III) or a pharmaceutically acceptable salt or solvate thereof, wherein:* denotes a chiral center;R2bis H or F;R3band R4bare each independently H, D, or an alkyl, which is optionally substituted with one or more D or F; andR5band R6bare each independently H or D.

[0192] In some embodiments, R2bis H.

[0193] In other embodiments, R2bis F.

[0194] In some embodiments, at least one of R3bor R4bis an alkyl optionally substituted with one or more D or F.

[0195] In some embodiments, at least one of R3bor R4bis Ci-Ce alkyl optionally substituted with one or more D or F.

[0196] In some embodiments, at least one of R3bor R4bis Ci-Ce alkyl substituted with one or more D or F.

[0197] In some embodiments, both R3band R4bare Ci-Ce alkyl substituted with one or more D or F.

[0198] In some embodiments, at least one of R3bor R4bis methyl substituted with one or more D or F.

[0199] In some embodiments, both R3band R4bare methyl substituted with one or more D or F.

[0200] In some embodiments, at least one of R3bor R4bis -CD3 or -CF3.

[0201] In some embodiments, both R3band R4bare -CD3 or -CF3.

[0202] In some embodiments, at least one of R3bor R4bis H.

[0203] In some embodiments, both R3band R4bare H.

[0204] In some embodiments, at least one of R3bor R4bis D.

[0205] In some embodiments, both R3band R4bare D.

[0206] In some embodiments, R2bis F or at least one of R3bor R4bis an alkyl optionally substituted with one or more D or F.

[0207] In some embodiments, at least one of R5bor R6bis D.

[0208] In some embodiments, both R5band R6bare D.

[0209] In some embodiments, both R5band R6bare H.

[0210] In some embodiments, the compound of formula (III), pharmaceutically acceptable salt, or solvate thereof is an (R)-OH isomer.

[0211] In other embodiments, the compound of formula (III), pharmaceutically acceptable salt, or solvate thereof is an (S)-OH isomer.

[0212] In some embodiments, a saVCM of formula (III) is selected from:pharmaceutically acceptable salt, or solvate thereof.

[0213] In other embodiments, a saVCM can include a compound of formula (IV):(IV) or a pharmaceutically acceptable salt or solvate thereof, wherein:* denotes a chiral center;R2CIS H or F;R3Cand R4Care each independently H, D, or an alkyl, which is optionally substituted with one or more D or F; andR5Cand R6Care each independently H or D.

[0214] In some embodiments, R2cis H.

[0215] In other embodiments, R2cis F.

[0216] In some embodiments, at least one of R3cor R4cis an alkyl optionally substituted with one or more D or F.

[0217] In some embodiments, at least one of R3cor R4cis Ci-Ce alkyl optionally substituted with one or more D or F.

[0218] In some embodiments, at least one of R3cor R4cis Ci-Ce alkyl substituted with one or more D or F.

[0219] In some embodiments, both R3cand R4care Ci-Ce alkyl substituted with one or more D or F.

[0220] In some embodiments, at least one of R3cor R4cis methyl substituted with one or more D or F.

[0221] In some embodiments, both R3cand R4care methyl substituted with one or more D or F.

[0222] In some embodiments, at least one of R3cor R4cis -CD3 or -CF3.

[0223] In some embodiments, both R3cand R4care -CD3 or -CF3.

[0224] In some embodiments, at least one of R3cor R4cis H.

[0225] In some embodiments, both R3cand R4care H.

[0226] In some embodiments, at least one of R3cor R4cis D.

[0227] In some embodiments, both R3cand R4care D.

[0228] In some embodiments, R2cis F or at least one of R3cor R4cis an alkyl optionally substituted with one or more D or F.

[0229] In some embodiments, at least one of R5cor R6cis D.

[0230] In some embodiments, both R5cand R6care D.

[0231] In some embodiments, both R5cand R6care H.

[0232] In some embodiments, the compound of formula (IV), pharmaceutically acceptable salt, or solvate thereof is an (R)-OH isomer.

[0233] In other embodiments, the compound of formula (IV), pharmaceutically acceptable salt, or solvate thereof is an (S)-OH isomer.

[0234] In some embodiments, a saVCM of formula (IV) is selected fromor a pharmaceutically acceptable salt, or solvate thereof.

[0235] In other embodiments, a saVCM can include a compound of formula (V):(V) or a pharmaceutically acceptable salt or solvate thereof, wherein:* denotes a chiral center;R2dis H or F;R3dand R4dare each independently H, D, or an alkyl, which is optionally substituted with one or more D or F; andR5dand R6dare each independently H or D.

[0236] In some embodiments, R2dis H.

[0237] In other embodiments, R2dis F.

[0238] In some embodiments, at least one of R3dor R4dis an alkyl optionally substituted with one or more D or F.

[0239] In some embodiments, at least one of R3dor R4dis Ci-Ce alkyl optionally substituted with one or more D or F.

[0240] In some embodiments, at least one of R3dor R4dis Ci-Ce alkyl substituted with one or more D or F.

[0241] In some embodiments, both R3dand R4dare Ci-Ce alkyl substituted with one or more D or F.

[0242] In some embodiments, at least one of R3dor R4dis methyl substituted with one or more D or F.

[0243] In some embodiments, both R3dand R4dare methyl substituted with one or more D or F.

[0244] In some embodiments, at least one of R3dor R4dis -CD3 or -CF3.

[0245] In some embodiments, both R3dand R4dare -CD3 or -CF3.

[0246] In some embodiments, at least one of R3dor R4dis H.

[0247] In some embodiments, both R3dand R4dare H.

[0248] In some embodiments, at least one of R3dor R4dis D.

[0249] In some embodiments, both R3dand R4dare D.

[0250] In some embodiments, R2dis F or at least one of R3dor R4dis an alkyl optionally substituted with one or more D or F.

[0251] In some embodiments, at least one of R5dor R6dis D.

[0252] In some embodiments, both R5dand R6dare D.

[0253] In some embodiments, both R5dand R6dare H.

[0254] In some embodiments, the compound of formula (V), pharmaceutically acceptable salt, or solvate thereof is an (R)-OH isomer.

[0255] In other embodiments, the compound of formula (V), pharmaceutically acceptable salt, or solvate thereof is an (S)-OH isomer.

[0256] In some embodiments, a saVCM of formula (V) is selected from:or a pharmaceutically acceptable salt, or solvate thereof.

[0257] In other embodiments, a saVCM can include a compound of formula (VI):(VI) or a pharmaceutically acceptable salt or solvate thereof, wherein:* denotes a chiral center;R2eis H or F;R3eand R4eare each independently H, D, or an alkyl, which is optionally substituted with one or more D or F; andR5eand R6eare each independently H or D.

[0258] In some embodiments, R2eis H.

[0259] In other embodiments, R2eis F.

[0260] In some embodiments, at least one of R3eor R4eis an alkyl optionally substituted with one or more D or F.

[0261] In some embodiments, at least one of R3eor R4eis Ci-Ce alkyl optionally substituted with one or more D or F.

[0262] In some embodiments, at least one of R3eor R4eis Ci-Ce alkyl substituted with one or more D or F.

[0263] In some embodiments, both R3eand R4eare Ci-Ce alkyl substituted with one or more D or F.

[0264] In some embodiments, at least one of R3eor R4eis methyl substituted with one or more D or F.

[0265] In some embodiments, both R3eand R4eare methyl substituted with one or more D or F.

[0266] In some embodiments, at least one of R3eor R4eis -CD3 or -CF3.

[0267] In some embodiments, both R3eand R4eare -CD3 or -CF3.

[0268] In some embodiments, at least one of R3eor R4eis H.

[0269] In some embodiments, both R3eand R4eare H.

[0270] In some embodiments, at least one of R3eor R4eis D.

[0271] In some embodiments, both R3eand R4eare D.

[0272] In some embodiments, R2eis F or at least one of R3eor R4eis an alkyl optionally substituted with one or more D or F.

[0273] In some embodiments, at least one of R5eor R6eis D.

[0274] In some embodiments, both R5eand R6eare D.

[0275] In some embodiments, both R5eand R6eare H.

[0276] In some embodiments, the compound of formula (VI), pharmaceutically acceptable salt, or solvate thereof is an (R)-OH isomer.

[0277] In other embodiments, the compound of formula (VI), pharmaceutically acceptable salt, or solvate thereof is an (S)-OH isomer.

[0278] In some embodiments, a saVCM of formula (VI) is selected from:OHor a pharmaceutically acceptable salt, or solvate thereof.

[0279] In other embodiments, a saVCM can include a compound of formula (VII):(VII) or a pharmaceutically acceptable salt or solvate thereof, wherein:* denotes a chiral center;R2fis H or F;R3fand R4fare each independently H, D, or an alkyl, which is optionally substituted with one or more D or F; andR5fand R6fare each independently H or D.

[0280] In some embodiments, R2fis H.

[0281] In other embodiments, R2fis F.

[0282] In some embodiments, at least one of R3for R4fis an alkyl optionally substituted with one or more D or F.

[0283] In some embodiments, at least one of R3for R4fis Ci-Ce alkyl optionally substituted with one or more D or F.

[0284] In some embodiments, at least one of R3for R4fis Ci-Ce alkyl substituted with one or more D or F.

[0285] In some embodiments, both R3fand R4fare Ci-Ce alkyl substituted with one or more D or F.

[0286] In some embodiments, at least one of R3for R4fis methyl substituted with one or more D or F.

[0287] In some embodiments, both R3fand R4fare methyl substituted with one or more D or F.

[0288] In some embodiments, at least one of R3for R4fis -CD3 or -CF3.

[0289] In some embodiments, both R3fand R4fare -CD3 or -CF3.

[0290] In some embodiments, at least one of R3for R4fis H.

[0291] In some embodiments, both R3fand R4fare H.

[0292] In some embodiments, at least one of R3for R4fis D.

[0293] In some embodiments, both R3fand R4fare D.

[0294] In some embodiments, R2fis F or at least one of R3for R4fis an alkyl optionally substituted with one or more D or F.

[0295] In some embodiments, at least one of R5for R6fis D.

[0296] In some embodiments, both R5fand R6fare D.

[0297] In some embodiments, both R5fand R6fare H.

[0298] In some embodiments, the compound of formula (VII), pharmaceutically acceptable salt, or solvate thereof is an (R)-OH isomer.

[0299] In other embodiments, the compound of formula (VII), pharmaceutically acceptable salt, or solvate thereof is an (S)-OH isomer.

[0300] In some embodiments, a saVCM of formula (VII) is selected from:or a pharmaceutically acceptable salt, or solvate thereof.

[0301] In other embodiments, a saVCM can include a compound of formula (VIII):(VIII) or a pharmaceutically acceptable salt or solvate thereof, wherein:* denotes a chiral center;R2gis H or F;R3gand R4gare each independently H, D, or an alkyl, which is optionally substituted with one or more D or F; andR5gand R6gare each independently H or D.

[0302] In some embodiments, R2gis H.

[0303] In other embodiments, R2gis F.

[0304] In some embodiments, at least one of R3gor R4gis an alkyl optionally substituted with one or more D or F.

[0305] In some embodiments, at least one of R3gor R4gis Ci-Ce alkyl optionally substituted with one or more D or F.

[0306] In some embodiments, at least one of R3gor R4gis Ci-Ce alkyl substituted with one or more D or F.

[0307] In some embodiments, both R3gand R4gare Ci-Ce alkyl substituted with one or more D or F.

[0308] In some embodiments, at least one of R3gor R4gis methyl substituted with one or more D or F.

[0309] In some embodiments, both R3gand R4gare methyl substituted with one or more D or F.

[0310] In some embodiments, at least one of R3gor R4gis -CD3 or -CF3.

[0311] In some embodiments, both R3gand R4gare -CD3 or -CF3.

[0312] In some embodiments, at least one of R3gor R4gis H.

[0313] In some embodiments, both R3gand R4gare H.

[0314] In some embodiments, at least one of R3gor R4gis D.

[0315] In some embodiments, both R3gand R4gare D.

[0316] In some embodiments, R2gis F or at least one of R3gor R4gis an alkyl optionally substituted with one or more D or F.

[0317] In some embodiments, at least one of R5gor R6gis D.

[0318] In some embodiments, both R5gand R6gare D.

[0319] In some embodiments, both R5gand R6gare H.

[0320] In some embodiments, the compound of formula (VIII), pharmaceutically acceptable salt, or solvate thereof is an (R)-OH isomer.

[0321] In other embodiments, the compound of formula (VIII), pharmaceutically acceptable salt, or solvate thereof is an (S)-OH isomer.

[0322] In some embodiments, a saVCM of formula (VIII) is selected from:or a pharmaceutically acceptable salt, or solvate thereof.

[0323] In other embodiments, a saVCM can include a compound of formula (IX):(IX) or a pharmaceutically acceptable salt or solvate thereof, wherein:* denotes a chiral center;R2his H or F;Rhand R411are each independently H, D, or an alkyl, which is optionally substituted with one or more D or F; andR5hand R6hare each independently H or D.

[0324] In some embodiments, R2his H.

[0325] In other embodiments, R2his F.

[0326] In some embodiments, at least one of R311or R4his an alkyl optionally substituted with one or more D or F.

[0327] In some embodiments, at least one of R3bor R4his C i-Ce alkyl optionally substituted with one or more D or F.

[0328] In some embodiments, at least one of R311or R4his Ci-Ce alkyl substituted with one or more D or F.

[0329] In some embodiments, both R311and R4hare Ci-Ce alkyl substituted with one or more D or F.

[0330] In some embodiments, at least one of R3bor R4his methyl substituted with one or more D or F.

[0331] In some embodiments, both R311and R411are methyl substituted with one or more D or F.

[0332] In some embodiments, at least one of R3bor R4his -CD3 or -CF3.

[0333] In some embodiments, both R3band R4hare -CD3 or -CF3.

[0334] In some embodiments, at least one of R311or R4his H.

[0335] In some embodiments, both R311and R4hare H.

[0336] In some embodiments, at least one of R3bor R4his D.

[0337] In some embodiments, both R3band R4hare D.

[0338] In some embodiments, R2his F or at least one of R3bor R4his an alkyl optionally substituted with one or more D or F.

[0339] In some embodiments, at least one of R5hor R6his D.

[0340] In some embodiments, both R5hand R6harc D.

[0341] In some embodiments, both R5hand R6hare H.

[0342] In some embodiments, the compound of formula (IX), pharmaceutically acceptable salt, or solvate thereof is an (R)-OH isomer.

[0343] In other embodiments, the compound of formula (IX), pharmaceutically acceptable salt, or solvate thereof is an (S)-OH isomer.

[0344] In some embodiments, a saVCM of formula (IX) is selected from:or a pharmaceutically acceptable salt, or solvate thereof.

[0345] In other embodiments, a saVCM can include a compound of formula (X):(X) or a pharmaceutically acceptable salt or solvate thereof, wherein:* denotes a chiral center;R21is H or F;R31and R41are each independently H, D, or an alkyl, which is optionally substituted with one or more D or F; andR31and R61are each independently H or D.

[0346] In some embodiments, R21is H.

[0347] In other embodiments, R21is F.

[0348] In some embodiments, at least one of R31or R41is an alkyl optionally substituted with one or more D or F.

[0349] In some embodiments, at least one of R31or R41is Ci-Ce alkyl optionally substituted with one or more D or F.

[0350] In some embodiments, at least one of R31or R41is Ci-Ce alkyl substituted with one or more D or F.

[0351] In some embodiments, both R31and R41are Ci-Ce alkyl substituted with one or more D or F.

[0352] In some embodiments, at least one of R31or R41is methyl substituted with one or more D or F.

[0353] In some embodiments, both R31and R41are methyl substituted with one or more D or F.

[0354] In some embodiments, at least one of R31or R41is -CD3 or -CF3.

[0355] In some embodiments, both R31and R41are -CD3 or -CF3.

[0356] In some embodiments, at least one of R31or R41is H.

[0357] In some embodiments, both R31and R41are H.

[0358] In some embodiments, at least one of R31or R41is D.

[0359] In some embodiments, both R31and R41are D.

[0360] In some embodiments, R21is F or at least one of R31or R41is an alkyl optionally substituted with one or more D or F.

[0361] In some embodiments, at least one of R51or R61is D.

[0362] In some embodiments, both R51and R61are D.

[0363] In some embodiments, both R51and R61are H.

[0364] In some embodiments, the compound of formula (X), pharmaceutically acceptable salt, or solvate thereof is an (R)-OH isomer.

[0365] In other embodiments, the compound of formula (X), pharmaceutically acceptable salt, or solvate thereof is an (S)-OH isomer.

[0366] In some embodiments, a saVCM of formula (X) is selected from:or a pharmaceutically acceptable salt, or solvate thereof.

[0367] In other embodiments, a saVCM can include a compound of formula (XI):(XI) or a pharmaceutically acceptable salt or solvate thereof, wherein:* denotes a chiral center;R2Jis H or F;R3’ and R4Jare each independently H, D, or an alkyl, which is optionally substituted with one or more D or F; andR5' and R6Jare each independently H or D.

[0368] In some embodiments, R2Jis H.

[0369] In other embodiments, R2jis F.

[0370] In some embodiments, at least one of R3Jor R4Jis an alkyl optionally substituted with one or more D or F.

[0371] In some embodiments, at least one of R3Jor R4’ is Ci-G, alkyl optionally substituted with one or more D or F.

[0372] In some embodiments, at least one of R3Jor R4Jis Ci-Ce alkyl substituted with one or more D or F.

[0373] In some embodiments, both R3' and R4' are Ci-Ce alkyl substituted with one or more D or F.

[0374] In some embodiments, at least one of R3Jor R4Jis methyl substituted with one or more D or F.

[0375] In some embodiments, both R3' and R4Jare methyl substituted with one or more D or F.

[0376] In some embodiments, at least one of R3Jor R4jis -CD3 or -CF3.

[0377] In some embodiments, both R3' and R4Jare -CD3 or -CF3.

[0378] In some embodiments, at least one of R3' or R4Jis H.

[0379] In some embodiments, both R3Jand R4Jarc H.

[0380] In some embodiments, at least one of R3' or R4jis D.

[0381] In some embodiments, both R3Jand R4Jare D.

[0382] In some embodiments, R2Jis F or at least one of R3Jor R4Jis an alkyl optionally substituted with one or more D or F.

[0383] In some embodiments, at least one of R5jor R6jis D.

[0384] In some embodiments, both R5Jand R6Jare D.

[0385] In some embodiments, both R5Jand R6Jare H.

[0386] In some embodiments, the compound of formula (XI), pharmaceutically acceptable salt, or solvate thereof is an (R)-OH isomer.

[0387] In other embodiments, the compound of formula (XI), pharmaceutically acceptable salt, or solvate thereof is an (S)-OH isomer.

[0388] In some embodiments, a saVCM of formula (XI) is selected from:or a pharmaceutically acceptable salt, or solvate thereof.

[0389] In other embodiments, a saVCM can include a compound of formula (XII):(XII) or a pharmaceutically acceptable salt or solvate thereof, wherein:* denotes a chiral center;R2kis H or F;R3kand R4kare each independently H, D, or an alkyl, which is optionally substituted with one or more D or F: andR5kand R6kare each independently H or D.

[0390] In some embodiments, R2kis H.

[0391] In other embodiments, R2kis F.

[0392] In some embodiments, at least one of R3kor R4kis an alkyl optionally substituted with one or more D or F.

[0393] In some embodiments, at least one of R3kor R4kis Ci-Ce alkyl optionally substituted with one or more D or F.

[0394] In some embodiments, at least one of R3kor R4kis Ci-Ce alkyl substituted with one or more D or F.

[0395] In some embodiments, both R3kand R4kare Ci-Ce alkyl substituted with one or more D or F.

[0396] In some embodiments, at least one of R3kor R4kis methyl substituted with one or more D or F.

[0397] In some embodiments, both R3kand R4kare methyl substituted with one or more D or F.

[0398] In some embodiments, at least one of R3kor R4kis -CD3 or -CF3.

[0399] In some embodiments, both R3kand R4kare -CD3 or -CF3.

[0400] In some embodiments, at least one of R3kor R4kis H.

[0401] In some embodiments, both R3kand R4kare H.

[0402] In some embodiments, at least one of R3kor R4kis D.

[0403] In some embodiments, both R3kand R4kare D.

[0404] In some embodiments, R2kis F or at least one of R3kor R4kis an alkyl optionally substituted with one or more D or F.

[0405] In some embodiments, at least one of R5kor R6kis D.

[0406] In some embodiments, both R5kand R6kare D.

[0407] In some embodiments, both R5kand R6kare H.

[0408] In some embodiments, the compound of formula (XII), pharmaceutically acceptable salt, or solvate thereof is an (R)-OH isomer.

[0409] In other embodiments, the compound of formula (XII), pharmaceutically acceptable salt, or solvate thereof is an (S)-OH isomer.

[0410] In some embodiments, a saVCM of formula (XII) is selected from:or a pharmaceutically acceptable salt, or solvate thereof.

[0411] In other embodiments, a saVCM can include a compound of formula (XIII):(XIII) or a pharmaceutically acceptable salt or solvate thereof, wherein:* denotes a chiral center;R21is H or F;R31and R41are each independently H, D, or an alkyl, which is optionally substituted with one or more D or F; andR51and R61are each independently H or D.

[0412] In some embodiments, R21is H.

[0413] In other embodiments, R21is F.

[0414] In some embodiments, at least one of R31or R41is an alkyl optionally substituted with one or more D or F.

[0415] In some embodiments, at least one of R31or R41is Ci-Ce alkyl optionally substituted with one or more D or F.

[0416] In some embodiments, at least one of R31or R41is Ci-Ce alkyl substituted with one or more D or F.

[0417] In some embodiments, both R31and R41are Ci-Ce alkyl substituted with one or more D or F.

[0418] In some embodiments, at least one of R31or R41is methyl substituted with one or more D or F.

[0419] In some embodiments, both R31and R41are methyl substituted with one or more D or F.

[0420] In some embodiments, at least one of R31or R41is -CD3 or -CF3.

[0421] In some embodiments, both R31and R41are -CD3 or -CF3.

[0422] In some embodiments, at least one of R31or R41is H.

[0423] In some embodiments, both R31and R41are H.

[0424] In some embodiments, at least one of R31or R41is D.

[0425] In some embodiments, both R31and R41are D.

[0426] In some embodiments, R21is F or at least one of R31or R41is an alkyl optionally substituted with one or more D or F.

[0427] In some embodiments, at least one of R51or R61is D.

[0428] In some embodiments, both R51and R61are D.

[0429] In some embodiments, both R51and R61are H.

[0430] In some embodiments, the compound of formula (XIII), pharmaceutically acceptable salt, or solvate thereof is an (R)-OH isomer.

[0431] In other embodiments, the compound of formula (XIII), pharmaceutically acceptable salt, or solvate thereof is an (S)-OH isomer.

[0432] In some embodiments, a saVCM of formula (XIII) is selected from:or a pharmaceutically acceptable salt, or solvate thereof.

[0433] In other embodiments, a saVCM can include a compound of formula (XIV):(XIV) or a pharmaceutically acceptable salt or solvate thereof, wherein:* denotes a chiral center;R2mis H or F;R3mand R4mare each independently H, D, or an alkyl, which is optionally substituted with one or more D or F; andR5mand R6mare each independently H or D.

[0434] In some embodiments, R2mis H.

[0435] In other embodiments, R2mis F.

[0436] In some embodiments, at least one of R3mor R4mis an alkyl optionally substituted with one or more D or F.

[0437] In some embodiments, at least one of R3mor R4mis Ci-Ce alkyl optionally substituted with one or more D or F.

[0438] In some embodiments, at least one of R3mor R4mis Ci-Ce alkyl substituted with one or more D or F.

[0439] In some embodiments, both R3mand R4mare Ci-Ce alkyl substituted with one or more D or F.

[0440] In some embodiments, at least one of R3mor R4mis methyl substituted with one or more D or F.

[0441] In some embodiments, both R3mand R4mare methyl substituted with one or more D or F.

[0442] In some embodiments, at least one of R3mor R4mis -CD3 or -CF3.

[0443] In some embodiments, both R3mand R4mare -CD3 or -CF3.

[0444] In some embodiments, at least one of R3mor R4mis H.

[0445] In some embodiments, both R3mand R4marc H.

[0446] In some embodiments, at least one of R3mor R4mis D.

[0447] In some embodiments, both R3mand R4mare D.

[0448] In some embodiments, R2mis F or at least one of R3mor R4mis an alkyl optionally substituted with one or more D or F.

[0449] In some embodiments, at least one of R5mor R6mis D.

[0450] In some embodiments, both R5mand R6mare D.

[0451] In some embodiments, both Rl" and R6mare H.

[0452] In some embodiments, the compound of formula (XIV), pharmaceutically acceptable salt, or solvate thereof is an (R)-OH isomer.

[0453] In other embodiments, the compound of formula (XIV), pharmaceutically acceptable salt, or solvate thereof is an (S)-OH isomer.

[0454] In some embodiments, a saVCM of formula (XIV) is selected from:or a pharmaceutically acceptable salt, or solvate thereof.

[0455] In other embodiments, a saVCM can include a compound of formula (XV):(XV) or a pharmaceutically acceptable salt or solvate thereof, wherein:* denotes a chiral center;R2nis H or F;R3nand R4nare each independently H, D, or an alkyl, which is optionally substituted with one or more D or F: andR5nand R6nare each independently H or D.

[0456] In some embodiments, R2nis H.

[0457] In other embodiments, R2nis F.

[0458] In some embodiments, at least one of R3nor R4nis an alkyl optionally substituted with one or more D or F.

[0459] In some embodiments, at least one of R3nor R4nis Ci-Ce alkyl optionally substituted with one or more D or F.

[0460] In some embodiments, at least one of R3nor R4nis Ci-Ce alkyl substituted with one or more D or F.

[0461] In some embodiments, both R3nand R4nare Ci-Ce alkyl substituted with one or more D or F.

[0462] In some embodiments, at least one of R3nor R4nis methyl substituted with one or more D or F.

[0463] In some embodiments, both R3nand R4nare methyl substituted with one or more D or F.

[0464] In some embodiments, at least one of R3nor R4nis -CD3 or -CF3.

[0465] In some embodiments, both R3nand R4nare -CD3 or -CF3.

[0466] In some embodiments, at least one of R3nor R4nis H.

[0467] In some embodiments, both R3nand R4nare H.

[0468] In some embodiments, at least one of R3nor R4nis D.

[0469] In some embodiments, both R3nand R4nare D.

[0470] In some embodiments, R2nis F or at least one of R3nor R4nis an alkyl optionally substituted with one or more D or F.

[0471] In some embodiments, at least one of R5nor R6nis D.

[0472] In some embodiments, both R5nand R6nare D.

[0473] In some embodiments, both R5nand R6nare H.

[0474] In some embodiments, the compound of formula (XV), pharmaceutically acceptable salt, or solvate thereof is an (R)-OH isomer.

[0475] In other embodiments, the compound of formula (XV), pharmaceutically acceptable salt, or solvate thereof is an (S)-OH isomer.

[0476] In some embodiments, a saVCM of formula (XV) is selected from:or a pharmaceutically acceptable salt, or solvate thereof.

[0477] In other embodiments, a saVCM can include a compound of formula (XVI):(XVI) or a pharmaceutically acceptable salt or solvate thereof, wherein:* denotes a chiral center;R2° is H or F;R3° and R4° are each independently H, D, or an alkyl, which is optionally substituted with one or more D or F; andR30and R6° are each independently H or D.

[0478] In some embodiments, R2° is H.

[0479] In other embodiments, R2° is F.

[0480] In some embodiments, at least one of R30or R4° is an alkyl optionally substituted with one or more D or F.

[0481] In some embodiments, at least one of R3° or R4° is Ci-Ce alkyl optionally substituted with one or more D or F.

[0482] In some embodiments, at least one of R30or R4° is Ci-Ce alkyl substituted with one or more D or F.

[0483] In some embodiments, both R3° and R4° are Ci-Ce alkyl substituted with one or more D or F.

[0484] In some embodiments, at least one of R3° or R4° is methyl substituted with one or more D or F.

[0485] In some embodiments, both R3° and R4° are methyl substituted with one or more D or F.

[0486] In some embodiments, at least one of R3° or R4ois -CD3 or -CF3.

[0487] In some embodiments, both R30and R4° are -CD3 or -CF3.

[0488] In some embodiments, at least one of R30or R4° is H.

[0489] In some embodiments, both R3° and R4° are H.

[0490] In some embodiments, at least one of R3° or R4° is D.

[0491] In some embodiments, both R3° and R4° are D.

[0492] In some embodiments, R2° is F or at least one of R3° or R4° is an alkyl optionally substituted with one or more D or F.

[0493] In some embodiments, at least one of R5° or R6° is D.

[0494] In some embodiments, both R5° and R6° are D.

[0495] In some embodiments, both R50and R6° are H.

[0496] In some embodiments, the compound of formula (XVI), pharmaceutically acceptable salt, or solvate thereof is an (R)-OH isomer.

[0497] In other embodiments, the compound of formula (XVI), pharmaceutically acceptable salt, or solvate thereof is an (S)-OH isomer.

[0498] In some embodiments, a saVCM of formula (XVI) is selected from:pharmaceutically acceptable salt, or solvate thereof.

[0499] Other embodiments described herein relate to a compound selected from:-71-a pharmaceutically acceptable salt, or solvate thereof.

[0500] In some embodiments, a compound, pharmaceutically acceptable salt, or solvate thereof as described herein, which inhibits retinal degeneration upon administration to a subject, can be selected using an in vitro assays that measure the ability of a compound to inhibit retinoid isomerase activity in the ocular tissue and in vivo assays that measure chromophore regeneration and ERG as well as the optical coherence tomography score of retinas of Rdh8- / -Abca4- / -mice exposed to intense light-induced retinal degeneration.

[0501] In some embodiments, a compound, pharmaceutically acceptable salt, or solvate thereof as described herein can inhibit the enzymatic activity of bovine RPE65 microsomes at an IC50 of less than 1 pM, at an IC50 of less than 950 nM, at an IC50 of less than 900 nM, at an IC50 of less than 850 nM, at an IC50 of less than 800 nM, at an IC50 of less than 750 nM, at an IC50 of less than 700 nM, at an IC50 of less than 650 nM, at an IC50 of less than 600 nM, at an IC50 of less than 550 nM, at an IC50 of less than 500 nM, at an IC50 of less than 450 nM, at an IC50 of less than 400 nM, at an IC50 of less than 350 nM, at an IC50 of less than 300 nM, at an IC50 of less than 250 nM, at an IC50 of less than 200 nM, at an IC50 of less than 150 nM, or at an IC50 of less than 100 nM, or at an IC50 of less than 50 nM, preferably at an IC50 of about 10 nM to about 200 nM, or more preferably at an IC50 about 10 nM to about 100 nM.

[0502] In certain embodiments, a compound, pharmaceutically acceptable salt, or solvate thereof as described herein, which inhibit retinal degeneration upon administration to a subject, at least partially inhibist RPE65 activity in a subject’s ocular tissue. In some embodiments, the compounds when administered to a Rdh8- / -Abca4- / -mouse increase the optical coherence tomography score of the mouse in comparison to untreated control animal.In other embodiments, therapeutic efficacy of the compound, pharmaceutically acceptable salt, or solvate thereof as described herein can be determined using an in vitro assay that measures the ability of a compound to improve viability of RPE cells treated with retinal.

[0503] In some embodiments, a compound, pharmaceutically acceptable salt, or solvate thereof as described herein may be formulated in a conventional manner with one or more pharmaceutically acceptable carriers, additives, diluents, or excipients to provide a pharmaceutical composition. Formulation of pharmaceutical compositions for use in modes of administration are described, for example, in Remington’s Pharmaceutical Sciences (18th edition), ed. A. Gennaro, 1990, Mack Publishing Company, Easton, Pa. (also see, e.g., M. J. Rathbone, ed., Oral Mucosal Drug Delivery, Drugs and the Pharmaceutical Sciences Series, Marcel Dekker, Inc., N. Y., U. S. A., 1996; M. J. Rathbone et al., eds., Modified-Release Drug Delivery Technology, Drugs and the Pharmaceutical Sciences Series, Marcel Dekker, Inc., N. Y., U. S. A., 2003; Ghosh et al., eds., Drug Delivery to the Oral Cavity, Drags and the Pharmaceutical Sciences Series, Marcel Dekker, Inc., N. Y. U. S. A., 1999.

[0504] Pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as prolamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, poly acrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0505] Pharmaceutical compositions as described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally.

[0506] Pharmaceutical compositions as described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers which are commonlyused include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried com starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0507] In other embodiments, a compound, pharmaceutically acceptable salt, or solvate thereof as described herein can be provided in an ophthalmic preparation that can be administered to the subject’s eye. The ophthalmic preparation can contain the compound in a pharmaceutically acceptable solution, suspension or ointment. Some variations in concentration will necessarily occur, depending on the particular compound employed, the condition of the subject to be treated and the like, and the person responsible for treatment will determine the most suitable concentration for the individual subject. The ophthalmic preparation can be in the form of a sterile aqueous solution containing, if desired, additional ingredients, for example, preservatives, buffers, tonicity agents, antioxidants, stabilizers, nonionic wetting or clarifying agents, and viscosity increasing agents.

[0508] Examples of preservatives for use in such a solution include benzalkonium chloride, benzethonium chloride, chlorobutanol, thimerosal and the like. Examples of buffers include boric acid, sodium and potassium bicarbonate, sodium and potassium borates, sodium and potassium carbonate, sodium acetate, and sodium biphosphate, in amounts sufficient to maintain the pH at between about pH 6 and about pH 8, and for example, between about pH 7 and about pH 7.5. Examples of tonicity agents are dextran 40, dextran 70, dextrose, glycerin, potassium chloride, propylene glycol, and sodium chloride.

[0509] Examples of antioxidants and stabilizers include sodium bisulfite, sodium metabisulfite, sodium thiosulfite, and thiourea. Examples of wetting and clarifying agents include polysorbate 80, polysorbate 20, poloxamer 282 and tyloxapol. Examples of viscosity-increasing agents include gelatin, glycerin, hydroxyethylcellulose, hydroxymethylpropylcellulose, lanolin, methylcellulose, petrolatum, polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, and carboxymethylcellulose. The ophthalmic preparation will be administered topically to the eye of the subject in need of treatment by conventional methods, for example, in the form of drops or by bathing the eye in the ophthalmic solution.

[0510] In some embodiments, a compound, pharmaceutically acceptable salt, or solvate thereof or a pharmaceutical composition as described herein can be used in a method of treating and / or preventing an ocular disorder in a subject in need thereof. The method can includes administering to the subject a therapeutically effective amount of the compound, pharmaceutically acceptable salt, or solvate thereof or the pharmaceutical composition as described herein.

[0511] In some embodiments, the ocular disorder can include, for example, retinal degeneration, macular degeneration, including age-related macular degeneration, such as the dry form and the wet form of age related macular degeneration, Stargardt disease, Stargardt macular degeneration, fundus flavimaculatus, geographic atrophy, retinitis pigmentosa, ABCA4 mutation related retinal dystrophies, vitelliform (or Best) macular degeneration, adult onset form of vitelliform macular dystrophy, Sorsby's fundus dystrophy, Malattia leventinese (Doyne honeycomb or dominant radial drusen), diabetic retinopathy, diabetic maculopathy, diabetic macular edema, retinopathy that is or presents geographic atrophy and / or photoreceptor degeneration, retinopathy that is a lipofuscin-based retinal degeneration, aberrant modulation of lecithin-retinol acyltransferase in an eye, Leber’s congenital amaurosis, retinal detachment, hemorrhagic retinopathy, hypertensive retinopathy, hereditary or non-hereditary optic neuropathy, inflammatory retinal disease, retinal blood vessel occlusion, retinopathy of prematurity, ischemia reperfusion related retinal injury, proliferative vitreoretinopathy, retinal dystrophy, uveitis, retinal disorders associated with Alzheimer's disease, retinal disorders associated with multiple sclerosis, retinal disorders associated with Parkinson's disease, retinal disorders associated with viral infection (cytomegalovirus or herpes simplex virus), retinal disorders related to light overexposure or myopia, retinal disorders associated with AIDS, glaucoma, genetic retinal dystrophies, traumatic injuries to the optic nerve, such as by physical injury, excessive light exposure, or laser light, neuropathies due to a toxic agent or caused by adverse drug reactions or vitamin deficiency, progressive retinal atrophy or degeneration, retinal diseases or disorders resulting from mechanical injury, chemical or drug-induced injury, thermal injury, radiation injury, light injury, or laser injury, hereditary and non-hereditary retinal dystrophy, ophthalmic injuries from environmental factors, such as light-induced oxidative retinal damage, laser-induced retinal damage, "flash bomb injury," or "light dazzle", refractive errors including but not limited to myopia, and retinal diseases related to A2E accumulation including RDS / PHRP2-related macular degeneration, Batten disease (juvenile neuronal ceroid lipofuscinosis), and central serous chorioretinopathy.

[0512] In some embodiments, the ocular disorder includes at least one of light-induced retinal degeneration, macular degeneration, Stargardt disease, geographic atrophy, or retinitis pigmentosa.

[0513] In other embodiments, a compound, pharmaceutically acceptable salt, or solvate thereof or a pharmaceutical composition as described herein can be used in a method of treating and / or preventing phototoxic retinal damage in a subject in need thereof. The method includes administering to the subject a therapeutically effective amount of a compound, pharmaceutically acceptable salt, or solvate thereof or a pharmaceutical composition as described herein.

[0514] In still other embodiments, a compound, pharmaceutically acceptable salt, or solvate thereof or a pharmaceutical composition as described herein can be used in a method of treating and / or preventing an iatrogenic photic retinopathy in a subject in need thereof. The method includes administering to the subject a therapeutically effective amount of a compound, pharmaceutically acceptable salt, or solvate thereof or a pharmaceutical composition as described herein.

[0515] In some embodiments, the subject is treated by intraocular or ocular surgery requiring illumination of the eye.

[0516] In some embodiments, the illumination of the eye is effective to cause phototoxic retinal damage or iatrogenic photic retinopathy.

[0517] In some embodiments, the surgery can include cataract surgery.

[0518] In some embodiments, the compound, pharmaceutically acceptable salt, or solvate thereof or the pharmaceutical composition is administered to the subject prior to surgery.

[0519] In some embodiments, the subject has a genetically inherited condition that predisposes the subject to enhanced risk of photodamage.

[0520] In some embodiments, the subject has Stargardt disease or albinism.

[0521] In some embodiments, the pharmacokinetics of the compound, pharmaceutically acceptable salt, or solvate thereof upon administration to the subject is such that the compound, pharmaceutically acceptable salt, or solvate thereof does not promote night blindness when administered daily.

[0522] In some embodiments, the compound, pharmaceutically acceptable salt, or solvate thereof transiently inhibits RPE65 enzymatic activity in the subject.

[0523] In some embodiments, the compound, pharmaceutically acceptable salt, or solvate thereof inhibits RPE65 enzymatic activity in the subject prior to hydrolytic cleavage by esterase-mediated metabolism but does not inhibit RPE65 enzymatic activity after hydrolytic cleavage.

[0524] In some embodiments, the compound, pharmaceutically acceptable salt, or solvate thereof as described herein can inhibit RPE65 enzymatic activity involved in retinoid metabolism in the eye of the subject.

[0525] In certain embodiments, the compound, pharmaceutically acceptable salt, or solvate thereof as described herein for use in a method described herein can inhibit or at least partially inhibit RPE65 but does not cause delayed dark adaptation (i.e., night blindness) in a subject.

[0526] In other embodiments, the compound, pharmaceutically acceptable salt, or solvate thereof as described herein is not deaminated by VAP-1 enzyme.

[0527] The compound, pharmaceutically acceptable salt, or solvate thereof as described herein used in the methods described herein can be administered to the subject to treat the ocular disorder (e.g., macular degeneration or Stargardt disease) using standard delivery methods including, for example, ophthalmic, topical, parenteral, subcutaneous, intravenous, intraarticular, intrathecal, intramuscular, intraperitoneal, intradermal injections, or by transdermal, enteral, buccal, oromucosal, oral routes or via inhalation. Preferably, the compounds described herein can be administered enterally, such as orally. The particular approach and dosage used for a particular subject depends on several factors including, for example, the general health, weight, and age of the subject. Based on factors such as these, a medical practitioner can select an appropriate approach to treatment.

[0528] Generally, the effective amount of the compound, pharmaceutically acceptable salt, or solvate thereof as described herein may be in the range of about 1 to about 1,000 mg in the oral administration. Examples of dose ranges can include from a minimum dose of about 0.01, 0.10, 0.50, 1, 5, 10, 25, 50, 100, 125, 150, 200, or 250 mg to a maximum dose of about 300, 400, 500, 600, 700, 800, 900, or 1000 mg, wherein the dose range can include from any one of the foregoing minimum doses to any one of the foregoing maximum doses. Specific examples of particular effective amounts contemplated via oral administration caninclude about 0.02, 0.03, 0.04, 0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17. 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33. 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585. 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700, 705, 710, 715, 720, 725, 730, 735, 740, 745, 750, 755, 760, 765, 770, 775, 780, 785, 790, 795, 800, 805, 810, 820, 825, 830, 835, 840, 845, 850, 855, 860, 865, 870, 875, 880, 885, 890, 895, 900, 905, 910, 915, 920, 925, 930, 935, 940, 945, 950, 955, 960, 965, 970, 975, 980, 985, 990, 995, 1000 mg or more. The oral dose can be administered once daily, twice daily, three times daily, or more frequently.

[0529] Generally, the daily dosage for adults is in the range of about 0.1 to about 5,000 mg, preferably about 1 to about 1,000 mg but cannot be determined uniformly because it depends on age, sex, body weight and the physical condition of the patients to be treated. The formulation may be administered once a day or several times a day with a divided dose.

[0530] Treatment according to the method described herein can be altered, stopped, or re -initiated in a subject depending on the status of ocular disorder. Treatment can be carried out as intervals determined to be appropriate by those skilled in the art. For example, the administration can be carried out 1, 2, 3, or 4 times a day. In another embodiment, the compound can be administered after induction of macular degeneration has occurred.

[0531] The treatment methods can include administering to the subject a therapeutically effective amount of the compound, pharmaceutically acceptable salt, or solvate thereof as described herein. Determination of a therapeutically effective amount is within the capability of those skilled in the art. The exact formulation, route of administration, and dosage can be chosen by the individual physician in view of the subject’s condition.

[0532] As discussed above, the compounds may be administered to a subject in order to treat or prevent ocular disorders associated aberrant visual cycle activity and / or photic retinal damage in a subject. Other diseases, disorders, or conditions characterized by associated aberrant visual cycle activity and / or photic retinal damage, such as increased or excessive all-trans-retinal in ocular tissue may be similarly treated.

[0533] In one embodiment, a subject is diagnosed as having symptoms of macular degeneration, and then a disclosed compound is administered. In another embodiment, a subject may be identified as being at risk for developing macular degeneration (risk factors include a history of smoking, age, female gender, and family history), and then a disclosed compound is administered. In another embodiment, a subject may have dry AMD in both eye, and then a disclosed compound is administered. In another embodiment, a subject may have wet AMD in one eye but dry AMD in the other eye, and then a disclosed compound is administered. In yet another embodiment, a subject may be diagnosed as having Stargardt disease and then a disclosed compound is administered. In another embodiment, a subject is diagnosed as having symptoms of other forms of retinal disease whose etiology involves aberrant visual cycle activity and / or photic retinal damage in ocular tissue of a subject, and then the compound is administered. In another embodiment, a subject may be identified as being at risk for developing other forms of retinal disease whose etiology involves aberrant visual cycle activity and / or photic retinal damage in ocular tissue, and then the disclosed compound is administered. In some embodiments, a compound is administered prophylactically. In some embodiments, a subject has been diagnosed as having the disease before retinal damage is apparent. In some embodiments, a human subject may know that he or she is in need of the macular degeneration treatment or prevention.

[0534] In some embodiments, a subject may be monitored for the extent of macular degeneration. A subject may be monitored in a variety of ways, such as by eye examination, dilated eye examination, fundoscopic examination, visual acuity test, and / or biopsy.Monitoring can be performed at a variety of times. For example, a subject may be monitored after a compound is administered. The monitoring can occur, for example, one day, one week, two weeks, one month, two months, six months, one year, two years, five years, or any other time period after the first administration of a compound. A subject can be repeatedly monitored. In some embodiments, the dose of a compound may be altered in response to monitoring.

[0535] In some embodiments, the disclosed methods may be combined with other methods for treating or preventing ocular disorders or other forms of retinal disease whose etiology involves aberrant visual cycle activity, such as increased all-trans-retinal accumulation, and / or photic retinal damage in ocular tissue, such as photodynamic therapy. For example, a patient may be treated with more than one therapy for one or more diseases or disorders. For example, a patient may have one eye afflicted with dry form AMD, which is treated with a compound described herein, and the other eye afflicted with wet form AMD, which is treated with, e.g., photodynamic therapy.

[0536] In yet another embodiment, the compound described herein can be administered as part of a combinatorial therapy with additional therapeutic agents. The phrase “combinatorial therapy’’ or “combination therapy’’ embraces the administration of a compound, and one or more therapeutic agents as part of a specific treatment regimen intended to provide beneficial effect from the co-action of these therapeutic agents.Administration of these therapeutic agents in combination typically is carried out over a defined period (usually minutes, hours, days or weeks depending upon the combination selected). “Combinatorial therapy” or “combination therapy” is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example by administering to the subject an individual dose having a fixed ratio of each therapeutic agent or in multiple, individual doses for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissue. The therapeutic agents can be administered by the same route or by different routes. The sequence in which the therapeutic agents are administered is not narrowly critical.

[0537] The invention is further illustrated by the following examples, which are not intended to limit the scope of the claims.Example

[0538] This Example presents data on rationally designed short-acting Visual Cycle Modulators (saVCM) obtained by an ether-to-ester substitution of emixustat analogues thatrenders these new saVCMs susceptible to inactivation via esterase cleavage. We demonstrate that single doses of the saVCMs, prevented retinal damage induced by visual cycle activity in wild-type and Abca4 ' Rdh8~ ' mice. Our data indicate that ester-based saVCMs retain desirable properties of emixustat analogues in selectively targeting RPE65 but feature a strategically limited duration of action. The limited duration of action of ester-based saVCMs allows a daily period during which the visual cycle can operate at a normal rate thereby minimizing disturbances of visual perception.saVCMsOH HCOO- Methyl-EYE-003EYE-004 Dimethyl-EYE-001EYE-004.5 Dimethyl-EYE-002EYE-005 Dimethyl-EYE-003F-EYE-005EYE-006Materials and MethodsQuantification and statistical analysis

[0539] No statistical methods were applied to predetermine sample size. The ages of mice used for experiments are given in figure legends. The experiments were not randomized, and the investigators were not blinded to allocation prior to data analysis.Statistical analyses and graph generation were carried out using GraphPad Prism. Statistical methods and details of descriptive statistics are provided in the figure legends. A p value of less than 0.05 was considered significant.Animal study approvals

[0540] All animal procedures were approved by the Institutional Animal Care and Use Committees (IACUC) at the University of California Irvine (AUP-22-140) and the Tibor Rubin VA Long Beach Medical Center. All experimental protocols were conducted following the NIH Guide for the Care and Use of Laboratory Animals, the recommendations of the American Veterinary Medical Association Panel on Euthanasia, and the Association for Research in Vision and Ophthalmology (ARVO) Statement for the Use of Animals in Ophthalmic and Visual Research.Sex as a biological variable

[0541] Our study examined male and female animals, and similar findings were reported for both sexes.Animal husbandry

[0542] BALB / cJ mice (Jackson, strain #000651) and Abca4^ Rdh8 '' were housed in a standard 12 / 12-h light / dark cycle environment, fed a standard soy protein-free rodent chow diet (Envigo Teklad 2020X), provided water ad libitum, and housed in plastic cages with standard corncob rodent bedding and 6 g nestlets (Ancare). The spectral information of the white, fluorescent lights in our vivarium are shown in Figure S2.RPE microsomal preparations

[0543] Bovine RPE microsomes were isolated from RPE homogenates by differential centrifugation as previously described. The resulting microsomal precipitate was resuspended in 10 mM Bis-Tris propane / HCl buffer, pH 7.4, to achieve a total protein concentration of approximately 5 mg / mL. Then, the mixture was placed into a quartz cuvetteand irradiated for 6 minutes at 4°C with a ChromatoUVE transilluminator (model TM-15; UVP) to eliminate residual retinoids. After irradiation, DTT was added to the RPE microsomal mixture to achieve a final concentration of 5 mMIn vitro RPE65 activity assay

[0544] Synthesized EYE compounds and emixustat (2 pL in DMF, with the final concentration ranging between 0.1 and 10 pM) were added to 10 mM Bis-Tris propane / HCl buffer, pH 7.4, containing 150 pg RPE microsomes, 1% BSA, 1 mM disodium pyrophosphate, and 20 pM aporetinaldehyde-binding protein 1 (CRALBP). The resulting mixture was preincubated at room temperature for 5 minutes. Then, all-trans-retinol (1 pL in DMF, at a final concentration of 20 pM) was added. The resulting mixture was incubated at 37°C for 1 h. The reaction was quenched by adding 300 pL methanol, and products were extracted with 300 pL hexanes. Production of 11-cis-retinol was quantified by normal-phase HPLC with 10% (v / v) EtOAc in hexanes as the eluent at a flow rate of 1.4 mL / minute.Retinoids were detected by monitoring absorbance at 325 nm and quantified based on a standard curve representing the relationship between the amount of synthetic 11 -cis-retinol standard and the area under the corresponding chromatographic peak. IC50 and relative SD were obtained by fitting the results from each inhibitor using the [Inhibitor] vs normalized response - variable slope function of GraphPad Prism software.Shelf-life of ester-based VCMs

[0545] 10 mg of ester-based VCMs and 10 mg of acetaminophen (internal standard) were dissolved in 25 mL of PBS. This solution was dispatched in 1 ml aliquots into an autosampler vial and capped. The vials were incubated at 37°C. Three vials were analyzed at each time point (0-16 days) by injecting 50 pL of the solution from individual vials in an HPLC equipped with a Cl 8 column. The flowrate was 1 mL / min and the esters were detected at 265 nm. The test compounds were eluted with a mixture of water and methanol supplemented with 0.1% formic. The elution gradient was the following: 0 min, 100 % A; 10 min, 50 % A; 15 min, 0% A; 22 min, 0% A: 22.01 min, 100% A; 29 min, 100% A. The area under the peak of the VCMs was normalized with the area under the peak of the acetaminophen and the ratio was converted in % of VCM by normalizing to the time 0 min.In vitro esterase susceptibility assay

[0546] Esterase from the porcine liver (E3019-20KU, Sigma) was dissolved in DPBS (SH30028.02, Cytiva) to achieve the concentration of 20 mU / mL. 500 p L aliquots of the enzyme solution were pre-warmed to 37°C for 10 min prior to adding 5 pL of 10 mM test compound in DMF. The sample was mixed and then incubated at 37°C with 300 rpm shaking in an Eppendorf Thermomixer. 100 pL samples were taken at 0, 5, 15, 30, 60 min after the initiation of the reaction. At each time point, the reactions were immediately quenched with 100 pL of ice-cold methanol, vortexed for 3 s, and stored at -20°C. Next, the solvent of each sample was evaporated in a Speed Vac vacuum concentrator. Each dried sample was reconstituted in 100 pL in 0.1% (v / v) trifluoroacetic acid in water, centrifuged to remove particulates, and then transferred to an HPLC vial. 50 pL of the sample was analyzed on an Agilent 1260 Infinity series HPLC equipped with a Proshell EC- 18 column (Agilent) and a diode array detector. The sample was separated using a mobile phase consisting of 0.1% (v / v) trifluoroacetic acid in H2O (A) and acetonitrile (B) at the following ratios and time intervals: B was increased from 0 to 50% between 0-10 min followed by a gradient to 100% B over 5 min; and then a gradient from 100 to 0% B over 5 min. The disappearance of the reaction substrates was assessed by monitoring absorbance at 265 and 275 nm. Test compounds were eluted at ~ 11.75 min. Results were normalized by dividing the results by the value obtained at 0 min. Results were fit using the one-phase decay slope function of GraphPad Prism software.HPLC analysis of retinoid extracts from whole mouse eve homogenates

[0547] For retinoid analysis, both eyes from each animal were homogenized in 1 mL of 10 mM sodium phosphate buffer, pH 8.0, containing 50% v / v methanol (Sigma-Aldrich; 34860- 1L-R) and 100 mM hydroxylamine, pH = 8 (Sigma- Aldrich; 159417-100G). After a 15 min incubation at room temperature, 2 mL of 3 M sodium chloride were added to the homogenate. The resulting sample was extracted twice with 3 mL of ethyl acetate (Fisher Scientific; El 95-4). The combined organic phase was dried in vacuo and reconstituted in 450 pL hexane. Retinoids extracts (100 pL) were analyzed with an Agilent 1260 Infinity II HPLC system equipped with a diode array detector (DAD) and a Zorbax Sil column (5 pm; 4.6 mm x 250 mm; Agilent Technologies). The mobile phase consisted of 0.6% v / v ethyl acetate in hexanes (Fisher Scientific; H302-4) flowing at 1.4 mL / min for 17 min followed bya step increase to 10% v / v ethyl acetate in hexanes flowing at 1.4mL / min for an additional 25 min. Retinoids were detected by monitoring absorbance at 325 nm and 360 nm with continuous spectral recording. Peaks were identified based on their absorbance spectra and retention times relative to authentic standards. Absolute quantification of retinoids was conducted by peak integration with reference to authentic retinoid standards.Extent and duration of EYE compound effects on visual chromophore recovery in BALBc / J mice

[0548] Six to eight- week-old BALBc / J Mice were dark adapted for 24 h prior experiments. All drug administration procedures were performed under dim red light. The mice were administered 50 pL of vehicle (DMSO) or test compounds (emixustat, EYE-001, EYE-002, EYE-003, AHPP) at doses of 10 mg / kg by IP injection. Next, the pupils of the animals were dilated by topical administration of 1 % tropicamide ophthalmic solution (Akorn; 17478-102-12) and 10% phenylephrine ophthalmic solution (MWI Animal Health #054243). 30 min after IP injection, the mice were placed in a cage with a light-reflective white coating. Each cage was divided into four equal compartments with transparent Plexiglas separators. To prevent grouping and consequent light shielding, single animals were placed into their own compartment for the duration of the experiment. Then exposed to 10,000 lux white LED light for 10 min to bleach their visual pigment. Next, the animals were allowed to recover in the dark for 2 h before euthanasia, eye collection, and retinoid analysis by HPLC. To study the drug duration effect of EYE-002 and EYE-003, the same procedure of above was carried out with only one difference: the mice were left in the dark for different amounts of time (0.5-4 h) between the IP administration and the photobleach. After the photobleach, the mice were dark-adapted for 2 h before euthanasia, eye collection, and retinoid analysis by HPLC.In vivo ERG measurement of rod dark adaptation

[0549] BALBc / J mice were dark-adapted for 24 h. Under a red safety light, the mice were administered test compounds a single IP injection or gavaged with a single dose of vehicle or test compounds (10 mg / kg). 30 min later the animals were placed in a white cage and exposed to 10,000 lux white light for 10 min and then housed in the dark. Rod-driven ERG responses were recorded between 0.5-8 h after the bright light exposure to track thedark adaptation process. In the experiments using oral gavage as the method of drug administration, dark adaptation was assessed 2 h after the photobleach.

[0550] The scotopic ERG was measured as follows: mice were anesthetized by isoflurane inhalation and their pupils were dilated with topical administration of 1 % tropicamide ophthalmic solution (Akorn; 17478-102-12) and 10% phenylephrine ophthalmic solution (MWI Animal Health #054243), followed by 0.3% hypromellose (Akorn; 9050-1) to maintain corneal hydration. Anesthetized mice were placed on a heated pad set to 37 °C to prevent hypothermia. ERG responses were measured using a Diagnosys Celeris rodent-ERG device (Diagnosys LCC, Lowell, MA, USA). Ocular stimulator electrodes were placed on the corneas, the reference electrode was positioned subdermally between the ears, and a ground electrode was placed in the rear leg. The eyes were subjected to a green-light stimulus (peak emission 544 nm, bandwidth ~160 nm) of 0.5 cd-s / m2, which exclusively excites rod photoresponses. The responses obtained from 5 consecutive stimuli with an interstimulus interval of 30 s were averaged, and the a- and b-wave amplitudes were acquired from the averaged ERG waveform. Data were analyzed with Espion V6 software (Diagnosys LLC).Induction of retinal phototoxicity in mice

[0551] Six to eight-week-old BALBc / . T mice were dark-adapted for 24 h prior to the experiment, and all drug administration procedures were performed under dim red light. Animals were administered 50 pL of vehicle or test compounds (emixustat or EYE-002) dissolved in DMSO at a dose of 10 mg / kg in DMSO vehicle by IP injection. Pupils were dilated by the application of a drop of 1% atropine sulfate to the eye (Ophthalmics Inc.). The mice were placed in a cage with a light- reflective white coating. Each cage was divided into four equal compartments with transparent Plexiglas separators. To prevent grouping and consequent light shielding, single animals were placed into their own compartment for the duration of the experiment. Mice were exposed to broad-spectrum 15,000 lux white light emitted by clusters of LEDs placed on top of each white cage for 8 h. The animals had full access to food and water during light exposure. During the light exposure, atropine sulfate was applied to mouse eyes every 2 h to maintain mydriasis. After light exposure, animals were returned to their normal cages and kept under standard lighting conditions for one week before SLO and OCT imaging and ERG.

[0552] The same procedure of above was used to induced photic retinal damage in Abca4'7' Rdh.8'7' mice with minor modifications. Abca4'~ Rdh.8'7' mice were adapted to the vivarium light conditions. Next, these mice were administered either 50 pL of vehicle (DMSO) or EYE-003 dissolved in DMSO (10 mg / kg) by IP injection or 100 pL of an emulsion containing 10% DMSO - soybean oil by oral gavage. For the oral administration, EYE-003 was dosed at 10, 20 or 50 mg / kg and compared to the 10% DMSO - soybean oil without test compound. Next, their pupils were dilated as mentioned above. 30 min after the IP injection or oral administration, the mice were placed in the same cage with a light-reflective white coating used for inducing retinal damage in BALBc / J and photobleached at 10,000 lux for 30 min. After the photobleach, the Abca4'7' Rdh87' mice were returned to their normal cages and kept under standard lighting conditions for one week before SLO and OCT imaging and ERG.In vivo retinal imaging

[0553] Mice were anesthetized by an IP injection of ketamine (100 mg / kg) and xylazine (8.75 mg / kg) and pupils were dilated with 1% tropicamide and 10% phenylephrine before imaging. Ultrahigh-resolution spectral domain OCT (Bioptigen, Research Triangle Park, NC) was performed for cross-sectional imaging of mouse retinas as described previously. Briefly, five frames of OCT images were first acquired in the B-mode in two orthogonal directions and then averaged. Images were then analyzed using ImageJ software. Briefly, for each animal, the images collected from each eye were used to measure the thickness of the outer nuclear layer (ONL) in the four retinal quadrants at 0.5 mm from the optic nerve head. The values from the right and left eye of the same animal were averaged. During the same session, the fundus was imaged by scanning laser ophthalmoscopy (SLO) (Heidelberg Engineering, Heidelberg, Germany) in autofluorescence mode as previously described.In vivo ERG scotopic intensity-response measurements after light damage

[0554] One week after induction of retinal damage induced by light, mice were dark-adapted overnight for rod ERG recordings. All procedures were performed like described above for the measurement of rod dark- adaptation with the difference that several intensities of green-light stimulus were assessed (0.002 to 100 cd-s / m2). The responses obtained from consecutive stimuli were averaged, and the a- and b-wavc amplitudes were acquired from the averaged ERG waveform. Data were analyzed with Espion V6 software (Diagnosys LLC).In vivo ERG photopic intensity-response measurements after light damage

[0555] The eyes of mice were stimulated with a green light-emitting diode (LED) (peak 544 nm, bandwidth 160 nm) as steady rod-suppressing background light. To measure M-cone and S-cone function, stimulation was performed with alternating green and UV light at increasing intensities. Green light stimulation (peak emission 544 nm, bandwidth 160 nm) had intensity increments of 0.3, 0.5, 1, 3, 10, 30, 100 cd-s / m2. UV light stimulation (peak emission 370 nm, bandwidth 50 nm) had intensity increments of 0.03, 0.05, 0.1, 0.3, 0.5, 1, 3, 10, 30 log cd- s / m2. The responses for 20-25 stimuli were averaged together, and the a- and b-wave responses were acquired from the averaged ERG waveform. The ERGs were analyzed with the Espion V6 software (Diagnosys LLC).Histology

[0556] The enucleated mouse eyes were kept in Hartman’s fixative (Millipore Sigma) for 24 h at RT, transferred to 70% ethanol, and embedded in paraffin. Sagittally cut 6-pm paraffin sections spanning the optic nerve head (ONH) were stained with hematoxylin and eosin (H& E) and imaged with light microscopy with BZ-X800 (Keyence) instruments.Manual counting of photoreceptor nuclei per row, every 500 pm starting from the edge of the ONH along both superior and inferior directions, was performed manually. Average values of ONL nuclei counts for each animal group represent data obtained from 6 eyes.RPE65 crystallization and structure determination

[0557] Crystals of RPE65 in the complex with EYE-002 were obtained using previously described procedures. Briefly, isolated bovine RPE membranes were incubated with 2.5 mM EYE-002 (delivered in DMF) for 15 min before solubilization with 24 mM hexaethylene glycol mono-octyl ether (C8E6). After anion-exchange chromatography, purified RPE65 was concentrated to 10—15 rng / mL and EYE-002 was added again to a concentration of 2.5 mM before crystallization. Crystals were grown by the hanging-drop vapor diffusion method by mixing 2 pL of a 10 mg / mL RPE65 sample with 2 pL of crystallization solution consisting of 30% v / v PEG 400, 100 mM CAPS, pH 10.5, 500 mM (NH4)2SO4, and 10% v / v glycerol. After incubation for 1-2 weeks at 8°C, crystals of ~ 100 x 100 x 300 pm3in size were observed. Mature crystals were harvested directly into liquid nitrogen for X-ray data collection. X-ray diffraction data were collected at the APS NE-CAT 24-ID-E beamlines. Data were processed using XDS, and the initial model was obtained bydirect refinement using published RPE65 coordinates in which ligands had been removed (PDB accession code: 4RSC). The structure was refined by alternating reciprocal space refinement in REFMAC and manual building and adjustments in Coot. Ligand coordinates and geometry dictionary files were generated using the Grade server (http: / / grade.globalphasing.org / cgi-bin / grade / server). The models were validated using MolProbity and the wwPDB validation server.In vivo ERG measurement of rod dark adaptation

[0558] 4-6 weeks old BALBc / . T mice were dark-adapted for 24 h. Under a red safety light, the mice were administered a single dose of test compounds (10 mg / kg) by gavage. 30 min later the animals were placed in a white cage and exposed to 10,000 lux white light for 10 min and then housed in the dark. Rod-driven ERG responses were recorded between 8-32 h after the bright light exposure to track the dark adaptation process.

[0559] The scotopic ERG was measured as follows: mice were anesthetized by isoflurane inhalation and their pupils were dilated with topical administration of 1 % tropicamide ophthalmic solution (Akorn; 17478-102-12) and 10% phenylephrine ophthalmic solution (MWI Animal Health #054243), followed by 0.3% hypromellose (Akorn; 9050-1) to maintain corneal hydration. Anesthetized mice were placed on a heated pad set to 37°C to prevent hypothermia. ERG responses were measured using a Diagnosys Celeris rodent-ERG device (Diagnosys LCC, Lowell, MA, USA). Ocular stimulator electrodes were placed on the corneas, the reference electrode was positioned subdermally between the ears, and a ground electrode was placed in the rear leg. The eyes were subjected to a green-light stimulus (peak emission 544 nm, bandwidth -160 nm) of 0.1 cd-s / m2, which exclusively excites rod photoresponses. The responses obtained from 5 consecutive stimuli with an interstimulus interval of 30 s were averaged, and the a- and b-wave amplitudes were acquired from the averaged ERG waveform. Data were analyzed with Espion V6 software (Diagnosys LLC).Chemical Synthesis

[0560] Abbreviations: 1,3-Bis(diphenylphosphino)propane (DPPP);Bis(dibenzylideneacetone)palladium(0) (Pd(DBA)2); N, N-Diisopropylethylamine (DIPEA); molecular sieve (MS); 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC); acid chloride(RC0C1); Palladium on carbon (Pd / C); Dimethylformamide (DMF); Methanol (MeOH); Tetrahydrofuran (THF).Scheme 1: Synthetic Scheme to Obtain EYE-001 - EYE-003RCOCf, DIPEA Of f - * OCT 4 Jl, RCOjH, EDC HCi, DiPEA, y DPPP. PdiDBAj-'. PyrroficRne, (j THF DIPEA. DMF. 4A MS y3a R = R. EYE-001 R = R;3b R ~ R?EYE-S02 3c R =• RaEYE-003 R = Ro.Scheme 2: Synthetic Scheme to Obtain EYE-004 - EYE-006.Pd / C, H2, MeOH, r.t., 2d then HCOOHSynthetic Scheme 3 to Obtain Methylated and Dimethylated EYE-001 - EYE-006(COCiiy DMSCt{-bzXt3En a mine Heck Reaction: H?, Pti / C 2. HCOOH R )wH of Me R2~ Cy. t-Bu, ethylfeistyl. t-methyP1> Bthyibutyi or pf-opyipentylCH?O, HCOOHTable 1 - Values of half-maximal inhibitory concentrations and rates of esterase-mediated hydrolysis measured in vitro.Test IC50 towards Initial rate of VCM losscompound RPE65 (pM) (% compound / min)Emixustat 0.126 + 0.016 0.069AHPP > 10 Not testedEYE-001 0.081 ± 0.023 5.611EYE-002 0.099 + 0.022 1.512EYE-003 0.102 + 0.037 0.440Table 2: X-ray diffraction data collection, processing, and refinement Data collection and processingCrystal RPE65- EYE-002vX-ray source SSRL 12-2 Wavelength (A) 0.979460Space group P65Unit cell lengths (A) a = 175.81, c = 86.46 Resolution (A) 50.0 - 2.10 (2.22 - 2.10)* Unique reflections 87,750 (12,591) Multiplicity 10.0 (4.7) Completeness (%) 98.8 (92.6)< / / (j / > 8.5 (0.8) / ?merge / (%) 15.3 (202.5)CCl / 2(%) 99.7 (29.8)Wilson B factor (A2) 50Resolution (A) 47.9 - 2.1No reflections 83,253 (4,497)* ^work / ^free (%) 18.0 / 20.9No atoms 9,396Protein 8,333Metal 2 FE2Water 987Ligand 36 V2W, 38 PLM< B-factor> (A2) 52.7Protein 51.5Metal 43.9Water 61.6Ligand 75.4 V2W, 67.6 PLMRMS deviationsBond lengths (A) 0.002Bond angles (°) 0.914Ramachandran plot (%97.7 / 0favored / outliers)*All-atom clashscore (%) 1.69 (100thpercentile)PDB accession code 9DQAvFinal data set obtained by merging data from three isomorphous crystals ' Values in parentheses are for the highest resolution shell of data * Value in parentheses indicates the number of reflections used for cross- validationGeneral Synthetic Methods

[0561] All reactions were performed in oven-dried glassware under inert atmosphere. The reagents were purchased from various vendors (Sigma- Aldrich, Fisher, Oakwood, Combi Blocks, and AA Blocks) and were used as supplied without purification. Thin-layer chromatography (TLC) was performed on 0.25 mm glass-backed EMD Millipore 60 F254 plates. Visualization of TLC plates was accomplished with UV light (254 nm) and final amines were stained with permanganate (KMnO4). Purification of all intermediates was achieved by use of the CombiFlash Nextgen 100 (Teledyne Isco). All final target amines were purified manually by forced air-flow on silica gel (Merck, 230 - 400 mesh) using eluting solvents (reported as V / V ratio mixture) that were dried with sodium sulfate, filtered and evaporated under reduced pressure. The1H,13C NMR nuclear magnetic resonance (NMR) spectra were recorded at 25 °C on Bruker AVANCE NMR spectrometer operating at 500 MHz. Chemical shifts were reported in 5 units, part per million, with reference to the residual solvent peak CDCL (57.26), DMSO- e (52.50), and methanol-^ (53.33) for ’ll and CDCL (577.3) and methanol-dk (549.5) for13C NMR spectra. NMR data are presented in the following order: chemical shift, peak multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublet, dt = doublet of triplet, ddd = doublet of doublet of doublet, dq = doublet of quartet), coupling constant (in Hz). Analytical HPLC analysis of final targets was carried out on an Agilent 1260 series system consisting of a G4204A quaternary pump, a G4226A AES auto-sampler, and a G1316C column compartment. The separation was performed on a Shimadzu Premier C18 (5 pm, 100 mm x 4.5mm) column using a mobile phase consisting of 0.1% formic acid in water (A) and 0.1% formic acid in acetonitrile (B) at a flow rate of 1 mL / min, and the mobile-phase gradients and time course were as follows: 0 - 5 min, 95% A / 5% B; 5 - 10 min, 95-5% A / 5-95% B; 10 -20 min, 5% A / 95% B; 20 - 25 min, 5-95% A / 95-5% B; 25 - 30 min, 95% A / 5% B. The finalbiologically tested compounds displayed >95% purity. The synthesis of the precursors and target esters is detailed in the Supporting Information together with the NMR spectra for all compounds, and HPLC traces of final targets.Synthesized moleculesbenzyl (3-(3-hydroxyphenyl)-3-oxopropyl)carbamate (Compound 2)

[0562] To a dried flask was added benzyl (3-oxopropyl)carbamate (0.500 g, 2.4 mmol), Pd(DBA)2(0.037 g, 0.04 mmol), DPPP (0.034 g, 0.06 mmol), 4A molecular sieve (2.0 g) and DMT (8 mL), followed by pyrrolidine (0.2 mL, 2.4 mmol) and DIPEA (2mL). After the mixture turned yellow, a solution of 3-iodophenol (0.440 g, 2.0 mmol) in DMF (5mL) was injected. Then the reaction was stirred at 115 °C for 2 days. After cooling, the mixture was diluted with EA (250mL), washed with water (2 x 200 mL) and brine (lOOmL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was further purified by column chromatography (hexanes / EA = 4 / 1 to 1 / 1) and concentrated in vacuo to give a product as a deep yellow liquid (0.200 g, 33%). ’ll NMR (500 MHz, CDC13) 57.43 (s, 1H, Ar-H), 7.43 (d, J = 10.2 Hz, 1H, Ar-H), 7.34 - 7.26 (m, 5H, Ar-H), 7.26 (t, J = 8.3 Hz), 7.06 (dd, J= 8.3, 3.1 Hz, 1H, Ar-H), 5.57 (t, J = 6.4 Hz, 1H, N-H), 5.08 (s, 2H, CH2), 3.58 (dt, J = 6.4, 5.7 Hz, 2H, CH2), 3.15 (t, J = 5.7 Hz, 2H, CH2)..13C NMR (126 MHz, CDCL) 5 199.4, 157.0. 156.8, 137.7, 136.2, 130.0, 128.6, 128.2, 128.1, 121.1, 120.2, 114.7, 67.1, 38.5, 36.1.3-( 3-( ((benzyloxy)carbonyl)amino)propanoyl)phenyl cyclohexanecarboxylate ( Compound 3a)

[0563] To a dried flask was added benzyl (3-(3-hydroxyphenyl)-3-oxopropyl)carbamate (0.400 g, 1.34 mmol), cyclohexanecarboxylic acid (0.192 g, 1.50 mmol), EDC-HC1 (0.326 g, 1.70 mmol), DMAP (0.208 g, 1.70 mmol), THF (25mL) and DCM (lOmL), then stirred at r.t. overnight. The reaction was directly concentrated under reduced pressure, purified by column chromatography (hexanes / EA = 4 / 1) and concentrated in vacuo to give a product as a yellow viscous liquid (0.370 g, 68%).1H NMR (500 MHz, CDC13) 57.80 (d, J = 7.8 Hz,1H, Ar-H), 7.65 (t, J= 2.6 Hz, 1H, Ar-H), 7.47 (t, J = 8.0 Hz, 1H, Ar-H), 7.38 - 7.31 (m, 5H, Ar-H), 7.30 (dd, J= 8.0, 2.6 Hz, 1H, Ar-H), 5.50 (t, J= 6.4 Hz, 1H, N-H), 5.10 (s, 2H, CH2), 3.61 (dt, J= 6.4, 5.7 Hz, 2H, CH2), 3.21 (t, J= 5.7 Hz, 2H, CH2), 2.64 - 2.55 (m, 1H, CH), 2.12 - 2.04 (m, 2H, CH2), 1.89 - 1.80 (m, 2H, CH2), 1.75 - 1.68 (m, 1H, CH2), 1.67 - 1.55 (m, 2H, CH2), 1.44 - 1.25 (m, 3H, CH3).13C NMR (126 MHz, CDCh) 5 198.1, 174.3, 156.4, 151.2, 137.9, 136.6, 129.7, 128.5, 128.1, 128.0, 126.8, 125.3, 121.2, 66.6, 43.1, 38.7, 35.9, 28.9, 25.7, 25.3.3-( 3-( ((benzyloxy)c.arbonyl)amino)propanoyl)phenyl 2-ethylbutanoate ( Compound 3b)

[0564] To a dried flask was added benzyl (3-(3-hydroxyphenyl)-3-oxopropyl)carbamate (0.500 g, 1.67 mmol) and THF (15 mL), followed by 2-ethylbutyryl chloride (0.25 mL, 1.80 mmol). The mixture was stirred under 0°C and NIL (1 mL) was injected. After stirring for 15 minutes, the reaction was allowed to warm to r.t. and stirred overnight. The reaction was directly concentrated under reduced pressure, purified by column chromatography (hexanes / EA = 4 / 1) and concentrated in vacuo to give a product as a yellow viscous liquid (0.450 g, 68%). ’ll NMR (500 MHz, CDC13) 57.69 (d, J = 8.0 Hz, 1H, Ar-H), 7.53 (t, J = 2.0 Hz, III, Ar-H), 7.36 (t, 7 = 8.9 Hz, HI, Ar-H), 7.26 - 7.19 (m, 511, Ar-H), 7.19 (dd, 7 = 8.0, 2.0 Hz, 1H, Ar-H), 5.39 (t, 7= 6.5 Hz, 1H, N-H), 4.98 (s, 2H, CH2), 3.50 (dt, 7= 6.5, 5.7 Hz, 2H, CH2), 3.09 (t, 7= 5.7 Hz, 2H, CH2), 2.42 - 2.35 (m, 1H, CH), 1.74 - 1.54 (m, 4H, CH2), 0.94 (t, 7 = 7.4 Hz, 6H, CH3).13C NMR (126 MHz, CDC13) 5 198.1, 174.5, 156.4, 151.1, 137.9, 136.5, 129.7, 128.5, 128.1, 128.0, 126.9, 125.4, 121.2, 66.6, 48.9, 38.7, 35.9, 25.0, 11.9.3-(3-(((benzyloxy)carbonyl)amino)propanoyl)phenyl 2-propylpentanoate (Compound 3c)

[0565] To a dried flask was added benzyl (3-(3-hydroxyphenyl)-3-oxopropyl)carbamate (0.393 g, 1.31 mmol), valproic acid (0.23 mL, 1.40 mmol), EDC HC1 (0.345 g, 1.80 mmol), DMAP (0.220 g, 1.80 mmol), THF (25mL) and DCM (lOmL), then stirred at r.t. overnight. The reaction was directly concentrated under reduced pressure, purified by columnchromatography (hexanes / EA = 4 / 1) and concentrated in vacuo to give a product as a yellow viscous liquid (0.309 g, 56%). 'H NMR (500 MHz. CDC13) 57.66 (d, J= 7.9 Hz, 1H, Ar-H), 7.51 (t. 7 = 2.1 Hz. 1H, Ar-H). 7.33 (t, 7 = 7.9 Hz. 1H, Ar-H). 7.22 - 7.17 (m. 5H, Ar-H). 7.16 (dd, 7 = 7.9, 2.1 Hz, 1H, Ar-H), 5.48 (t, 7= 6.4 Hz, 1H, N-H), 4.96 (s, 2H, CH2), 3.46 (dt, 7 = 6.4, 5.7 Hz, 2H, CH2), 3.06 (t, 7= 5.7 Hz, 2H, CH2), 2.56 - 2.48 (m, 1H, CH), 1.69 - 1.60 (m, 2H, CH2), 1.49 - 1.40 (m, 2H, CH2), 1.38 - 1.28 (m, 4H, CH2), 0.87 (t, 7 = 7.3 Hz, 6H, CH3).13C NMR (126 MHz, CDCh) 5 198.1, 174.8, 156.5, 151.1, 137.9, 136.6, 129.7, 128.5, 128.1, 128.0, 126.9, 125.4, 121.2, 66.6, 45.3, 38.7, 35.9, 34.6, 20.8, 14.1.3 -(3 -amino- 1 -hydroxypropyl )phenol ( Compound named AHPP )OH

[0566] To a sealed tube was added 3-hydroxy-3-(3-hydroxyphenyl)propanenitrile (1.292 g, 7.9 mmol), tetrahydrofuran (60 mL). Then 1 M of lithium aluminum hydride solution in tetrahydrofuran (16 mL) was added by drop, then stirred at 50°C overnight. The reaction mixture was quenched by MeOH, concentrated under reduced pressure, purified by column chromatography (EA / MeOH / NIR IhO = 6 / 1 / 0.4) and concentrated in vacuo to give a product as a light yellow solid (0.765 g, 58%). ’ll NMR (500 MHz, CD3OD) 57.13 (t, J = 7.85 Hz, 1H, Ar-H), 6.82 (s, 1H, Ar-H). 6.80 (t. J = 7.3 Hz. 1H, Ar-H). 6.68 (dd, J = 8.0, 1.8 Hz, 1H, Ar-H), 4.65 (dd, J = 8.1, 5.2 Hz, 1H, HOCH), 3.35 (s, 1H, OH), 2.74 (m, 2H, CH2), 1.93 (s, 2H, NH2), 1.86 (m, 2H, CH2).13C NMR (126 MHz, CD3OD) 5 159.1, 147.8, 130.3, 117.1, 115.4, 114.0, 73.4, 41.9, 39.5. HRMS (ES): (m / z) calculated for C9H13NO2 [M]+168.1024; found 168.1024.benzyl (3-hydroxypropyl)(methyl)carbamate, 20010O

[0567] To a dried flask was added 3-(methylamino)propan-l-ol (5.1 mL, 56 mmol) and N, N-Diisopropylethylamine (10.9 mL, 62.5 mmol). Under ice water bath, benzyl carbonochloridate (8.1 mL, 57.5 mmol) was added to the mixture by drop. After 30 minutes, the ice water bath was removed and the reaction mixture was stirred at r.t. for 1 day. The reaction was concentrated under reduced pressure, purified by column chromatography (hexanes / EA = 7 / 3 to 3 / 7) and concentrated in vacuo to give a product as a colorless liquid(8.65 g, 69%).1H NMR (500 MHz, CD3OD) 57.38 - 7.26 (m, 5H, Ar-H), 5.10 (s, 2H, CH2), 3.55 (t,. / = 8.6 Hz, 2H, CH2), 3.38 (t, J= 6.6 Hz, 2H, CH2), 2.93 (s, 3H, CH3), 1.75 (m, 2H, CH2);13C NMR (126 MHz, CD3OD) 5 158.1. 158.0, 138.2, 129.5, 129.0, 128.8, 68.2, 60.3, 60.2, 47.2, 47.0, 35.1, 34.6, 32.0, 31.3.benzyl methyl(3-oxopropyl)carbamate, 20020O

[0568] To a dried flask was added dichloromethane (100 mL) and oxalyl chloride (5 mL, 58.1 mmol). After stirring under acetone - dry ice bath for 5 minutes, a solution of dimethyl sulfoxide (8.23 mL, 116 mmol) in dichloromethane (50 mL) was added into the mixture. After 10 minutes, a solution of benzyl (3-hydroxypropyl)(methyl)carbamate (8.65 g, 38.7 mmol) in dichloromethane (50 mL) was added by drop. After 15 minutes, tri ethylamine (24 mL, 174 mmol) was injected by drop. Then the dry ice bath was removed and the reaction mixture was stirred at room temperature for 5 hours. After reaction, the mixture was washed with 200 mL water twice and dried by sodium sulfate. Then the solution was concentrated under reduced pressure, purified by column chromatography (hexanes / EA = 7 / 3 to 1 / 1) and concentrated in vacuo to give a product as a light yellow liquid (4.38 g, 51%). ’ll NMR (500 MHz, CDCL) 59.81 / 9.75 (2 x s, 1H, CHO), 7.39 - 7.28 (m, 5H, Ar-H), 5.11 (s, 2H, CH2), 3.61 / 3.60 (2 x t, J = 6.5 Hz, 2H, CH2), 2.95 (s, 3H, CH3), 2.75 / 2.68 (2 x t, 7= 6.3 Hz, 2H, CH2);13C NMR (126 MHz, CDCI3) 5201.0, 200.5, 156.3, 156.1, 136.8, 136.7, 128.6, 128.2, 128.1, 128.0, 67.4, 67.3, 43.4, 43.0, 42.6, 35.3, 34.9.benzyl (3-(3-hydroxyphenyl)-3-oxopropyl)(methyl)carbamate, 20030

[0569] To a dried flask was added benzyl methyl(3-oxopropyl)carbamate (4.38 g, 19.8 mmol), Pd(DBA)2 (0.3 g, 0.33 mmol), DPPP (0.27 g, 0.49 mmol), 4A molecular sieve (15 g) and DMF (45 mL), followed by pyrrolidine (1.7 mL, 19.8 mmol) and DIPEA (16.9 mL). After the mixture turned yellow, a solution of 3-iodophenol (3.63 g, 16.5 mmol) in DMF (15mL) was injected. Then the reaction was stirred at 115°C for 2 days. After cooling, the mixture was diluted with EA (300mL), washed with water (2 x 250 mL) and brine (lOOmL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was further purified by column chromatography (hexanes / EA = 4 / 1 to 7 / 3 to 1 / 1) and concentrated in vacuo to give a product as a brown liquid (2.23 g, 43%).XH NMR (500 MHz, CDCE) 57.43 (m, 2H, Ar-H), 7.37 - 7.26 (m, 5H, Ar-H), 7.23 (m, 1H, Ar-H), 7.06 (m, 1H, Ar-H), 5.13 (s, 2H, CH2), 3.69 / 3.67 (2 x t, J= 6.8 Hz, 2H, CH2), 3.22 / 3.15 (2 x t, J = 6.9 Hz, 2H, CH2), 2.98 / 2.97 (2 x s, 3H, CH3);13C NMR (126 MHz, CDCE) 8 199.1, 199.0, 157.1, 157.0, 156.8, 156.5, 137.9, 136.4, 129.9, 128.6, 128.2, 128.1, 127.9, 121.1, 121.0, 120.1, 114.8, 114.6, 67.6, 67.5, 45.6, 45.0, 37.4, 37.1, 35.5, 35.4.3-(3-((( benzyloxy)carbonyl)( methyl)amino)propanoyl)phenyl cyclohexanecarboxylate, 20044

[0570] To a dried flask was added benzyl (3-(3-hydroxyphenyl)-3-oxopropyl)(methyl)carbamate (0.743 g, 2.37 mmol), cyclohexanecarboxylic acid (0.321 g, 2.5 mmol), EDC HC1 (0.575 g, 3.0 mmol), DMAP (0.367 g, 3.0 mmol), THF (10 mL) and DCM (30 mL), then stirred at r.t. for 1 day. The reaction was directly concentrated under reduced pressure, purified by column chromatography (hexanes / EA = 4 / 1) and concentrated in vacuo to give a product as an orange liquid (0.699 g, 70%).1H NMR (500 MHz, CDCI3) 8 7.75 (m, 1H, Ar-H), 7.63 (m, 1H, Ar-H), 7.47 - 7.23 (m, 7H, Ar-H), 5.12 (s, 2H, CH2), 3.68 (t, J = 7.0 Hz, 2H, CH2), 3.26 / 3.16 (2 x t, J = 7.0 Hz, 2H, CH2), 2.97 (s, 3H, CH3), 2.57 (m, 1H, CH), 2.06 (m, 2H, CH2), 1.81 (m, 2H, CH2), 1.69 (m, 1H, CH2), 1.59 (m, 2H, CH2), 1.35 (m, 3H, CH2);13C NMR (126 MHz, CDCI3) 8 197.7, 197.4, 174.2, 156.2, 156.0, 151.2, 138.0, 137.9, 136.7, 129.6, 128.5, 128.4, 128.0, 127.9, 127.8, 126.7, 126.6, 125.4, 125.3, 121.2, 121.1, 67.1, 67.0, 45.2, 44.5, 43.1, 37.5, 37.1, 35.3, 28.9, 25.7, 25.3.3-(3-((cyclohexanecarbonyl)oxy)phenyl)-3-hydroxy-N-methylpropan-l-aminium formate, Methyl EYE-001

[0571] To a flask was added 3-(3-(((benzyloxy)carbonyl)(methyl)amino)propanoyl)phenyl cyclohexanecarboxylate (0.699 g, 1.65 mmol), 10% Pd / C (0.07 g) and MeOH (25 mL). The flask was put into a high pressure reactor, evacuated and back-filled the flask with H2 (150 Psi), stirred at r.t. for 2 days. The Pd / C was filtered and the reaction was concentrated under reduced pressure, purified by column chromatography (EA / MeOH / NPh fTO = 12 / 1 / 0.4). The product solution was combined and formic acid (1 mL) was added. After ammonium formate precipitated, the solution was concentrated by rotavap, dried with sodium sulfate and filtered into a smaller flask. Then the solution was concentrated in vacuo to give a product as an orange liquid (0.273 g, 49%).1H NMR (500 MHz, CD3OD) 5 8.55 (s, 1H, HCOO ), 7.38 (m, 1H, Ar-H), 7.26 (m, 1H, Ar-H), 7.13 (m, 1H, Ar-H), 6.98 (m, 1H, Ar-H), 4.84 (dd, J = 4.1, 8.5 Hz, 1H, HOCH), 3.10 (m, 2H, CH2), 2.66 (s, 3H, CH3), 2.60 (m, 1H, CH), 2.04 (m, 4H, CH2), 1.82 (m, 2H, CH2), 1.70 (m. 1H, CH2), 1.58 (m, 2H, CH2), 1.37 (m, 3H, CH2);13C NMR (126 MHz, CD3OD) 5 176.0, 170.4, 152.5, 147.6, 130.5, 124.0, 121.7, 120.0, 72.3, 48.2, 44.2, 35.9, 33.7, 30.1, 26.8, 26.4.3-(3-( ( (benzyloxy)carbonyl)(methyl)amino)propanoyl)phenyl 2-ethylbutanoate, 20045

[0572] To a dried flask was added benzyl (3-(3-hydroxyphenyl)-3-oxopropyl)(methyl)carbamate (0.743 g, 2.37 mmol) and THF (10 mL) and DCM (30 mL), followed by 2-ethylbutyryl chloride (0.35 mL, 2.5 mmol). The mixture was stirred under 0°C and NEt3 (1 mL) was injected. After stirring for 15 minutes, the reaction was allowed to warm to r.t. and stirred for 1 day. The reaction was directly concentrated under reduced pressure, purified by column chromatography (hexanes / EA = 4 / 1) and concentrated in vacuoto give a product as a yellow viscous liquid (0.653 g, 67%).1H NMR (500 MHz, CDCh) 5 7.76 (m, 1H, Ar-H), 7.63 (m, 1H, Ar-H), 7.50 - 7.24 (m, 7H, Ar-H), 5.12 (s, 2H, CH2), 3.69 (t, J= 6.9 Hz, 2H, CH2), 3.28 / 3.17 (2 x t, J= 6.9 Hz, 2H, CH2), 2.99 (s, 3H, CH3), 2.48 (m, 1H, CH), 1.73 (m, 4H, CH2), 1.03 (t, J = 7.5 Hz, 6H, CH3);13C NMR (126 MHz, CDCh) 8 197.8, 197.5, 174.5, 156.3, 156.1, 151.2, 138.1, 138.0, 136.8, 129.7, 128.6, 128.5, 128.1, 128.0, 127.9, 126.8, 126.7, 125.5, 125.4, 121.2, 121.1, 67.2, 67.1, 48.9, 45.3, 44.6, 37.5, 37.2, 35.4, 25.1, 11.9.3-(3-amino-l -hydroxypropyl)phenyl cyclohexanecarboxylate formate ( EYE-001 )

[0573] To a flask was added 3-(3-(((benzyloxy)carbonyl)amino)propanoyl)phenyl cyclohexanecarboxylate (0.370 g, 0.904 mmol), 10% Pd / C (0.056 g) and MeOH (25 mL). The flask was put into a high pressure reactor, evacuated and back-filled the flask with H2(150 Psi), stirred at r.t. for 2 days. The Pd / C was filtered and the reaction was concentrated under reduced pressure, purified by column chromatography (EA / MeOH / NH3H2O = 12 / 1 / 0.4). After concentrated by rotavap, formic acid (0.17 mL) in EA (15 mL) was added. Then it was concentrated in vacuo to give a product as a yellow viscous liquid (0.149 g, 51%). ’H NMR (500 MHz, CDC13) 58.54 (s, 1H, HCO2), 7.40 (t, 7= 7.9 Hz, 1H, Ar-H), 7.28 (d, J = 7.6 Hz, 1H, Ar-H), 7.14 (s, 1H, Ar-H), 6.99 (dd, J = 7.9, 1.9 Hz, 1H, Ar-H), 4.87 (dd, J= 8.6, 4.2 Hz, 1H, HOCH), 3.15 - 3.02 (m, 2H, CH2), 3.65 - 3.57 (m, 1H, CH), 2.12 -1.94 (m, 4H, CH2), 1.87 - 1.80 (m, 2H, CH2), 1.75 - 1.68 (m, 1H, CH2), 1.65 - 1.54 (m, 2H, CII2), 1.48 - 1.28 (m, 311, CII2). This fll NMR spectra is shown in Fig. S15.13C NMR (126 MHz, CDCh) 5 176.1, 152.5, 147.6, 130.5, 124.0. 121.7, 119.9, 72.4, 44.2, 38.4, 37.1, 30.1, 26.8. 26.3. HRMS (ES): m / z) calculated for Ci6H23NO3[M]+278.1756; found 278.1746. 3-( 3-amino-l -hydroxypropyl)phenyl 2-ethylbutanoate formate (EYE-002 )

[0574] To a flask was added 3-(3-(((benzyloxy)carbonyl)amino)propanoyl)phenyl 2-ethylbutanoate (0.534 g, 1.34 mmol), 10% Pd / C (0.053 g) and MeOH (25 mL). The flask was put into a high pressure reactor, evacuated and back-filled the flask with H2(150 Psi),stirred at r.t. for 2 days. The Pd / C was filtered and the reaction was concentrated under reduced pressure, purified by column chromatography (EA / MeOH / NH3H2O = 12 / 1 / 0.4). After concentrated by rotavap, formic acid (0.3 mL) in EA (20 mL) was added. Then it was concentrated in vacuo to give a product as a yellow viscous liquid (0.309 g, 74%).XH NMR (500 MHz, CDC13) 58.56 (s, 1H, HCO2), 7.41 (t, 7= 7.9 Hz, 1H, Ar-H), 7.29 (d, 7 = 7.8 Hz, 1H, Ar-H), 7.15 (s, 1H, Ar-H), 7.00 (dd, 7 = 8.0, 1.6 Hz, 1H, Ar-H), 4.88 (dd, 7= 8.7, 4.1 Hz, 1H, HOCH), 3.16 - 3.04 (m, 2H, CH2), 3.53 - 3.45 (m, 1H, CH), 2.11 - 1.97 (m, 2H, CH2).1.83 - 1.65 (m, 4H, CH2), 1.05 (t, 7= 7.4 Hz, 6H, CH3).13C NMR (126 MHz, CDCI3) 8 176.3, 170.3, 152.4, 147.8, 130.5, 124.1, 121.7, 119.9, 72.3, 50.1, 38.4, 37.2, 26.2, 12.2. HRMS (ES): (m / z) calculated for Ci5II23NO3[M]+288.1576; found 288.1577.3 -(3 -amino- 1 -hydroxypropyl)phenyl 2-propylpentanoate formate (EYE-003 )

[0575] To a flask was added 3-(3-(((benzyloxy)carbonyl)amino)propanoyl)phenyl 2-propylpentanoate (0.309 g, 0.726 mmol), 10% Pd / C (0.036 g) and MeOH (18 mL). The flask was put into a high pressure reactor, evacuated and back-filled the flask with H2(150 Psi), stirred at r.t. for 2 days. The Pd / C was filtered and the reaction was concentrated under reduced pressure, purified by column chromatography (EA / MeOH / NH3H2O = 12 / 1 / 0.4). Formic acid (0.3 mL) in EA (15 mL) was added. The precipitate was filtered and the filtrate was concentrated in vacuo to give a product as a light yellow viscous liquid (0.159 g, 75%). ’ll NMR (500 MHz, CDC13) 88.42 (s, 1H, HCO2), 7.28 (t, J = 7.9 Hz, 1H, Ar-H), 7.16 (d, J = 7.9 Hz, 1H, Ar-H), 7.00 (s, 1H, Ar-H), 6.85 (dd, J = 8.1, 3.2 Hz, 1H, Ar-H), 4.75 (dd, J = 8.7, 4.0 Hz, 1H, HOCH), 3.02 - 2.90 (m, 2H, CH2), 2.56 - 2.49 (m, 1H, CH), 1.98 - 1.81 (m, 2H, CH2), 1.67 - 1.57 (m, 2H, CH2), 1.51 - 1.43 (m, 2H, CH2), 1.39 - 1.29 (m, 4H, CH2), 0.88 (t, J = 7.3 Hz, 6H, CH3).13C NMR (126 MHz, CDC13) 8 176.6, 170.2, 152.4, 147.8, 130.6, 124.2, 121.7, 119.9, 72.4, 46.5, 38.5, 37.2, 35.9, 21.8. 14.4. HRMS (ES): (m / z) calculated for Ci7H27NO3[M]+294.2069; found 294.2066.3-(3-((2-ethylbutanoyl)oxy)phenyl)-3-hydroxy-N-inethylpropan-l-aminium formate, (Methyl EYE-002)

[0576] To a flask was added 3-(3-(((benzyloxy)carbonyl)(methyl)amino)propanoyl)phenyl 2-ethylbutanoate (0.653 g, 1.59 mmol), 10% Pd / C (0.065 g) and MeOH (25 mL). The flask was put into a high pressure reactor, evacuated and back-filled the flask with H2 (150 Psi), stirred at r.t. for 2 days. The Pd / C was filtered and the reaction was concentrated under reduced pressure, purified by column chromatography (EA / MeOH / NH3 H2O = 12 / 1 / 0.4). The product solution was combined and formic acid (1 mL) was added. After ammonium formate precipitated, the solution was concentrated by rotavap, dried with sodium sulfate and filtered into a smaller flask. Then the solution was concentrated in vacuo to give a product as an orange liquid (0.423 g, 82%).1H NMR (500 MHz, CD3OD) 5 8.55 (s, 1H, HCOO ), 7.39 (m, 1H, Ar-H), 7.27 (m, 1H, Ar-H), 7.14 (m, 1H, Ar-H), 6.98 (m, 1H, Ar-H), 4.85 (dd, J = 4.1, 8.7 Hz, 1H, HOCH), 3.11 (m, 2H, CH2), 2.66 (s, 3H, CH3), 2.48 (m, 1H, CH), 2.04 (m, 2H, CH2), 1.72 (m, 4H, CH2), 1.03 (t, J= 7.5 Hz, 6H, CH3);13C NMR (126 MHz, CD3OD) 5 176.2, 170.3, 152.4, 147.7, 130.6, 124.1, 121.7, 120.0, 72.2, 50.1, 48.1. 35.9, 33.6, 26.2, 12.2.3-( 3-( ((benzyloxy)carbonyl)(methyl)amino)propanoyl)phenyl 2-propylpentanoate, 20046

[0577] To a dried flask was added benzyl (3-(3-hydroxyphenyl)-3-oxopropyl)(methyl)carbamate (0.743 g, 2.37 mmol), valproic acid (0.40 mL, 2.5 mmol), EDC HC1 (0.575 g, 3.0 mmol), DMAP (0.367 g, 3.0 mmol), THF (10 mL) and DCM (30 mL), then stirred at r.t. for 1 day. The reaction was directly concentrated under reduced pressure, purified by column chromatography (hexanes / EA = 4 / 1) and concentrated in vacuo to give a product as an orange liquid (0.650 g, 62%). ’ll NMR (500 MHz, CDC13) 57.82 -7.56 (m, 2H, Ar-H), 7.45 - 7.20 (m, 7H, Ar-H), 5.10 (s, 2H, CH2), 3.66 (t, J= 8.6 Hz, 2H,CH2), 3.24 / 3.14 (2 x t, J = 8.6 Hz, 2H, CH2), 2.95 (s, 3H, CH3), 2.62 (m, 1H, CH), 1.75 (m, 2H, CH2), 1.55 (m, 2H, CH2), 1.43 (m, 4H, CH2), 0.97 (t, J = 7.4, 6H, CH3);13C NMR (126 MHz, CDCh) 5 197.4, 197.0, 174.3, 155.9, 155.7, 150.9, 137.8, 137.7, 136.6, 129.4. 128.3, 128.2, 127.7, 127.6, 127.5, 126.4, 125.2, 125.1, 120.9, 120.7, 66.8, 66.7, 45.0, 44.3, 37.2, 36.9, 35.0, 34.3, 20.5, 13.8.3-hydroxy-N-methyl-3-(3-((2-propylpentanoyl)oxy)phenyl)propan-1-aminium formate, (Methyl EYE-003)

[0578] To a flask was added 3-(3- (((benzyloxy)carbonyl)(methyl)amino)propanoyl)phenyl 2-propylpentanoate (0.650 g, 1.48 mmol), 10% Pd / C (0.066 g) and MeOH (25 mL). The flask was put into a high pressure reactor, evacuated and back-filled the flask with H2 (150 Psi), stirred at r.t. for 2 days. The Pd / C was filtered and the reaction was concentrated under reduced pressure, purified by column chromatography (EA / MeOH / NH3H2O = 12 / 1 / 0.4). The product solution was combined and formic acid (1 mL) was added. After ammonium formate precipitated, the solution was concentrated by rotavap, dried with sodium sulfate and filtered into a smaller flask. Then the solution was concentrated in vacuo to give a product as an orange liquid (0.394 g, 75%).1H NMR (500 MHz, CD3OD) 5 8.53 (s, 1H, HCOO ), 7.39 (m, 1H, Ar-H), 7.27 (m, 1H, Ar-H), 7.13 (m, 1H, Ar-H), 6.97 (m, 1H, Ar-H), 4.85 (dd, 7 = 4.0, 8.7 Hz, 1H, HOCH), 3.11 (m, 211, CII2), 2.65 (s, 311, CII3), 2.64 (m, III, CH), 2.04 (m, 211, CII2), 1.73 (m, 2H, CH2), 1.58 (m, 2H, CH2), 1.46 (m, 4H, CH2), 0.99 (t, 7 = 7.3 Hz, 6H, CH3);13C NMR (126 MHz, CD3OD) 5 176.4, 170.1, 152.3, 147.7, 130.5, 124.1, 121.6, 119.9, 72.1, 48.1, 46.4, 35.9, 35.8, 33.6, 21.7, 14.4.3 -(3-((cyclohexanecarbonyl)oxy)phenyl)-3-hydroxy-N, N-dimethylpropan-l -aminium formate, (Dimethyl EYE-001 )1NHHCOO'

[0579] After hydrogenation with the same condition for 12034, the mixture was filtered to remove Pd / C and concentrated under reduced pressure. To the concentrated intermediate was added paraformaldehyde (0.09 g, 3 mmol), formic acid (0.22mL, 6 mmol) and N, N-dimethylformaldehyde (20 mL). The mixture was stirred at 100°C overnight. After reaction, the solution was diluted by ethyl acetate (100 mL), washed with sodium carbonate solution (30 mL) and water (60 mL). Then the solution was concentrated under reduced pressure, purified by column chromatography (EA / MeOH / NH3H2O = 16 / 1 / 0.4). The product solution was combined and formic acid (0.3 mL) was added. After ammonium formate precipitated, the solution was concentrated by rotavap, dried with sodium sulfate and filtered into a smaller flask. Then the solution was concentrated in vacuo to give a product as a colorless liquid (0.11 g, 31%). ’ll NMR (500 MHz, CD3OD) 58.55 (s, 1H, HCOO ), 7.37 (m, 1H, Ar-H), 7.25 (m, 1H, Ar-H), 7.11 (m, 1H, Ar-H), 6.97 (m, 1H, Ar-H), 4.77 (dd, 7 = 6.3, 6.4 Hz, 1H, HOCH), 2.84 (m, 2H, CH2), 2.60 (m, 1H, CH), 2.54 (s, 6H, CH3), 2.05 (m, 2H, CH2), 1.98 (m, 2H, CH2), 1.82 (dt,. / = 4.0, 13.3 Hz, 2H, CH2), 1.70 (m, 1H, CH2), 1.57 (m, 2H, CH2), 1.38 (m, 3H, CH2);13C NMR (126 MHz, CD3OD) 5 176.1, 170.4, 152.5, 147.8, 130.4, 124.1, 121.6, 120.1, 72.7. 57.1, 44.4, 44.2, 35.7, 30.1, 26.8, 26.4.3-(3-( ( 2-ethylbutanoyl)oxy)phenyl)-3-hydroxy-N, N-dimethylpropan-l -aminium formate, (Dimethyl EYE-002)

[0580] After hydrogenation with the same condition for 12035, the mixture was filtered to remove Pd / C and concentrated under reduced pressure. To the concentrated intermediate was added paraformaldehyde (0.18 g, 6 mmol), formic acid (0.45mL, 12 mmol) and N, N-dimethylformaldehyde (20 mL). The mixture was stirred at 100°C overnight. After reaction, the solution was diluted by ethyl acetate (120 mL), washed with sodium carbonate solution (30 mL) and water (60 mL). Then the solution was concentrated under reduced pressure, purified by column chromatography (EA / MeOH / NH3-H2O = 16 / 1 / 0.4). The product solution was combined and formic acid (2 mL) was added. After ammonium formate precipitated, the solution was concentrated by rotavap, dried with sodium sulfate and filtered into a smaller flask. Then the solution was concentrated in vacuo to give a product as an orange liquid(0.616 g, 65%).1H NMR (500 MHz, CD3OD) 5 8.38 (s, 1H, HCOO ), 7.40 (m, 1H, Ar-H), 7.29 (m, 1H, Ar-H), 7.16 (m, 1H, Ar-H), 6.99 (m, 1H, Ar-H), 4.83 (dd, J = 4.3, 8.1 Hz, 1H, HOCH), 3.22 (m, 2H, CH2). 2.82 (s, 6H, CH3), 2.48 (m, 1H, CH), 2.09 (m, 2H, CH2), 1.72 (m, 4H, CH2), 1.03 (t,.1 = 7.5 Hz, 6H, CH3);13C NMR (126 MHz, CD3OD) 8 176.2, 168.0, 152.3, 147.5, 130.6, 124.2, 121.8, 120.0, 71.7, 56.5, 50.0, 43.4, 34.4, 26.1, 12.2.3-hydroxy-N,N-dimethyl-3-(3-((2-propylpentanoyl)oxy)phenyl)propan-1-aminium formate, Dimethyl EYE-003

[0581] After hydrogenation with the same condition for 12036, the mixture was filtered to remove Pd / C and concentrated under reduced pressure. To the concentrated intermediate was added paraformaldehyde (0.09 g, 3 mmol), formic acid (0.22mL, 6 mmol) and N, N-dimethylformaldehyde (20 mL). The mixture was stirred at 100°C overnight. After reaction, the solution was diluted by ethyl acetate (100 mL), washed with sodium carbonate solution (30 mL) and water (60 mL). Then the solution was concentrated under reduced pressure, purified by column chromatography (EA / MeOH / NH3H2O = 16 / 1 / 0.4). The product solution was combined and formic acid ( 1 mL) was added. After ammonium formate precipitated, the solution was concentrated by rotavap, dried with sodium sulfate and filtered into a smaller flask. Then the solution was concentrated in vacuo to give a product as a colorless liquid (0.299 g, 64%).111 NMR (500 MHz, CD3OD) 8 8.50 (s, 1H, HCOO ), 7.36 (m, 1H, Ar-H), 7.24 (m, III, Ar-H), 7.10 (m, III, Ar-H), 6.93 (m, III, Ar-H), 4.78 (dd, 7 = 4.5, 8.3 IIz, III, HOCH), 3.15 (m, 2H, CH2), 2.76 (s, 6H, CH3), 2.60 (m, 1H, CH), 2.04 (m, 2H, CH2), 1.70 (m, 2H, CH2), 1.55 (m, 2H, CH2), 1.43 (m, 4H, CH2), 0.96 (t, J = 7.3 Hz, 6H, CH3);13C NMR (126 MHz, CD3OD) 8 176.5, 170.2, 152.4, 147.6, 130.6, 124.2, 121.7, 120.0, 71.9, 56.7, 46.5, 43.5, 35.8, 34.6, 21.7, 14.4.3-(3-(((benzyloxy)carbonyl)amino)propanoyl)phenyl pivalate, 12029

[0582] To a dried flask was added benzyl (3-(3-hydroxyphenyl)-3-oxopropyl)carbamate (0.68 g, 2.27 mmol), pivalic acid (0.26 g, 2.5 mmol), EDC HC1 (0.58 g, 3 mmol), DMAP (0.37 g, 3 mmol), THF (10 mL) and DCM (15 mL), then stirred at r.t. overnight. The reaction was directly concentrated under reduced pressure, purified by column chromatography (hexanes / EA = 4 / 1) and concentrated in vacuo to give a product as a yellow viscous liquid (0.677 g, 78%). ’ll NMR (500 MHz, CDC13) 57.73 (m, 1H, Ar-H), 7.61 (m, 1H, Ar-H), 7.40 (m, 1H, Ar-H), 7.32 - 7.21 (m, 6H, Ar-H), 5.63 (t, J= 6.4 Hz, 1H, N-H), 5.05 (s, 2H, CH2), 3.54 (dt,. / = 5.9, 6.0 Hz, 2H, CH2), 3.13 (t, J = 5.9 Hz, 2H, CH2), 1.35 (s, 9H, CH3);13C NMR (126 MHz, CDCI3) 5 197.8, 176.6, 156.3, 151.2, 137.7, 136.5, 129.5, 128.3, 127.8, 126.5, 125.1, 120.9, 66.4, 38.9, 38.4, 35.7, 26.9.3-hydroxy-3-(3-(pivaloyloxy)phenyl)propan-l-aminium formate, (EYE-004)HCOO'

[0583] To a flask was added 3-(3-(((benzyloxy)carbonyl)amino)propanoyl)phenyl pivalate (0.677 g, 1.77 mmol), 10% Pd / C (0.095 g) and MeOH (15 mL). The flask was put into a high pressure reactor, evacuated and back-filled the flask with H2 (180 Psi), stirred at r.t. for 2 days. The Pd / C was filtered and the reaction was concentrated under reduced pressure, purified by column chromatography (EA / MeOH / NH -H2O = 15 / 1 / 0.4). Formic acid (0.8 mL) in EA (15 mL) was added. The precipitate was filtered and the filtrate was concentrated in vacuo to give a product as a light yellow viscous liquid (0.128 g, 24%). ’ll NMR (500 MHz, CD3OD) 58.55 (s, 1H, HCOO ), 7.39 (m, 1H, Ar-H), 7.26 (m, 1H, Ar-H), 7.11 (m, 1H, Ar-H), 6.97 (m, 1H, Ar-H), 4.86 (dd, J = 4.2, 8.6 Hz, 1H, HOCH), 3.07 (m, 2H, CH2), 2.02 (m, 2H, CH2), 1.36 (s, 9H, CH3);13C NMR (126 MHz, CD3OD) 5 178.6, 170.4, 152.7, 147.7, 130.5, 124.0, 121.6, 119.9, 72.5, 40.0, 38.5, 37.2, 27.5.3-(3-(((benzyloxy)carbonyl)amino)propanoyl)phenyl 2-ethyl-2-methylbutanoate, 12028

[0584] To a dried flask was added benzyl (3-(3-hydroxyphenyl)-3-oxopropyl)carbamate (1.325 g, 4.43 mmol), 2-ethyl-2-methylbutanoic acid (0.62 g, 4.8 mmol), EDC-HC1 (1.07 g, 5.6 mmol), DMAP (0.68 g, 5.6 mmol), THE (20 mL) and DCM (20 mL), then stirred at r.t. overnight. The reaction was directly concentrated under reduced pressure, purified by column chromatography (hexanes / EA = 4 / 1) and concentrated in vacuo to give a product as a yellow viscous liquid (0.901 g, 49%). ’ll NMR (500 MHz, CDC13) 87.79 (m, 1H, Ar-H), 7.60 (m, 1H, Ar-H), 7.48 (m, 1H, Ar-H), 7.37 - 7.26 (m, 6H, Ar-H), 5.37 (t, J = 6.3 Hz, 1H, N-H), 5.08 (s, 2H, CH2), 3.62 (dt, J= 5.6, 6.3 Hz, 2H, CH2), 3.22 (t, J= 5.6 Hz, 2H, CH2), 1.85 (m, 2H, CH2), 1.62 (m, 2H, CH2), 1.25 (s, 3H, CH3), 0.97 (t, J = 7.5 Hz, 6H, CH3);13C NMR (126 MHz, CDCb) 8 198.3, 176.0, 156.5, 151.5, 138.0, 136.6, 129.8, 128.6, 128.3, 128.2, 127.1, 125.4, 121.3, 66.8, 47.2, 38.8, 35.9, 31.7, 20.3, 9.2.3-( 3-( ( 2-ethyl-2-methylbutanoyl)oxy)phenyl)-3-hydroxypropan-l-aminium formate, (EYE-005)NH

[0585] To a flask was added 3-(3-(((benzyloxy)carbonyl)amino)propanoyl)phenyl 2-ethyl-2-methylbutanoate (0.901 g, 2.19 mmol), 10% Pd / C (0.09 g) and MeOH (20 mL). The flask was put into a high pressure reactor, evacuated and back-filled the flask with H2 (180 Psi), stirred at r.t. for 2 days. The Pd / C was filtered and the reaction was concentrated under reduced pressure, purified by column chromatography (EA / MeOH / NH3 H2O = 15 / 1 / 0.4). Formic acid (0.8 mL) in EA (15 mL) was added. The precipitate was filtered and the filtrate was concentrated in vacuo to give a product as a light yellow viscous liquid (0.130 g, 18%). 'H NMR (500 MHz, CD3OD) 88.55 (s, 1H, HCOO ), 7.39 (m, 1H, Ar-H), 7.26 (m, 1H, Ar-H), 7.10 (m, 1H, Ar-H), 6.95 (m, 1H, Ar-H), 4.86 (dd,. / = 4.1, 8.6 Hz, 1H, HOCH), 3.07 (m, 2H, CH2), 2.00 (m, 2H, CH2), 1.86 (m, 2H, CH2), 1.62 (m, 2H, CH2), 1.23 (s, 3H, CH3), 0.98(t, J= 1.6 Hz, 6H, CH3);13C NMR (126 MHz, CD3OD) 5 177.5, 170.4, 152.6, 147.8, 130.6, 124.1, 121.7, 119.9, 72.4, 48.2, 38.5, 37.3, 32.8. 20.5, 9.4.3-(3-(((benzyloxy)carbonyl)amino)propanoyl)phenyl 2-methyl-2-propylpentanoate, 120261

[0586] To a dried flask was added benzyl (3-(3-hydroxyphenyl)-3-oxopropyl)carbamate (0.714 g, 2.39 mmol), 2-methyl-2-propylpentanoic acid (0.25 g, 1.58 mmol), EDC-HC1 (0.38 g, 2 mmol), DMAP (0.24 g, 2 mmol), THF (10 mL) and DCM (25 mL), then stirred at r.t. overnight. The reaction was directly concentrated under reduced pressure, purified by column chromatography (hexanes / EA = 4 / 1) and concentrated in vacuo to give a product as a yellow viscous liquid (0.330 g, 48%).1H NMR (500 MHz, CDCh) 57.75 (m, 1H, Ar-H), 7.57 (m, 1H, Ar-H), 7.42 (m, 1H, Ar-H), 7.34 - 7.21 (m, 6H, Ar-H), 5.50 (t,. / = 6.4 Hz, 1H, N-H), 5.05 (s, 2H, CH2), 3.56 (dt, J = 5.7, 6.4 Hz, 2H, CH2), 3.16 (t, J= 5.7 Hz, 2H, CH2), 1.75 (m, 2H, CH2), 1.52 (m, 2H, CH2), 1.41 (m, 2H, CH2), 1.30 (m, 2H, CH2), 1.24 (s, 3H, CH3), 0.95 (t, J = 7.3 Hz, 6H, CH3);13C NMR (126 MHz, CDC13) 3 198.1, 176.0, 156.4, 151.3, 137.8, 136.5, 129.7, 128.5, 128.1, 128.0, 126.9, 125.3, 121.1, 66.6, 46.4, 41.7, 38.6, 35.8, 21.1, 18.0, 14.7.3-hydroxy-3-(3-((2-methyl-2-propylpentanoyl)oxy)phenyl)propan- 1 -aminium formate, (EYE-006)

[0587] To a flask was added 3-(3-(((benzyloxy)carbonyl)amino)propanoyl)phenyl 2-methyl-2-propylpentanoate (0.330 g, 0.75 mmol), 10% Pd / C (0.08 g) and MeOH (20 mL). The flask was put into a high pressure reactor, evacuated and back-filled the flask with H2 (175 Psi), stirred at r.t. for 2 days. The Pd / C was filtered and the reaction was concentrated under reduced pressure, purified by column chromatography (EA / MeOH / NH3H2O = 15 / 1 / 0.4). Formic acid (0.4 mL) in EA (8 mL) was added. The precipitate was filtered and the filtrate was concentrated in vacuo to give a product as a light yellow viscous liquid (0.171g, 64%). ’ll NMR (500 MHz, CD3OD) 58.54 (s, 1H, HCOO ), 7.40 (m, 1H, Ar-H), 7.26 (m, 1H, Ar-H), 7.07 (m, 1H, Ar-H), 6.93 (m, 1H, Ar-H), 4.86 (dd, J = 4.1, 8.7 Hz, 1H, HOCH), 3.07 (m, 2H, CH2), 1.99 (m, 2H, CH2), 1.78 (m, 2H, CH2), 1.55 (m, 2H, CH2), 1.45 (m, 2H, CH2), 1.33 (m, 2H, CH2), 1.23 (s, 3H, CH3), 0.98 (1, J = 7.6 Hz, 6H, CH3);13C NMR (126 MHz, CD3OD) 5 177.7, 170.8, 152.7, 147.8, 130.7, 124.1, 121.8, 119.9, 72.6, 47.5, 43.1, 38.6, 37.2, 21.5, 19.1, 15.0.3-( 3-( ((benzyloxy)carbonyl)amino)propanoyl)phenyl 2,2-dimethylbutanoate, 120211

[0588] To a dried flask was added benzyl (3-(3-hydroxyphenyl)-3-oxopropyl)carbamate (0.827 g, 2.77 mmol), 2,2-dimethylbutanoic acid (0.38 mL, 3 mmol), EDC-HC1 (0.77 g, 4 mmol), DMAP (0.49 g, 4 mmol), THF (15 mL) and DCM (20 mL), then stirred at r.t. overnight. The reaction was directly concentrated under reduced pressure, purified by column chromatography (hexanes / EA = 7 / 3) and concentrated in vacuo to give a product as an orange viscous liquid (0.731 g, 66%). ’ll NMR (500 MHz, CDCI3) 37.79 (m, 1H, Ar-H), 7.61 (m, 1H, Ar-H), 7.48 (m, 1H, Ar-H), 7.36 - 7.26 (m, 6H, Ar-H), 5.36 (t, J = 6.8 Hz, 1H, N-H), 5.08 (s, 2H, CH2), 3.62 (dt, J= 5.7, 6.8 Hz, 2H, CH2), 3.22 (t, J= 5.7 Hz, 2H, CH2), 1.74 (q, 7 = 7.6 Hz, 2H, CH2), 1.32 (s, 6H, CH3), 0.99 (t, J = 7.6 Hz, 3H, CH3);13C NMR (126 MHz, CDCh) 8 198.3, 176.5, 156.5, 151.5, 138.0, 136.6, 129.8, 128.6, 128.3, 128.2, 127.0, 125.4, 121.3, 66.8, 43.2, 38.8, 35.9, 33.5, 24.8, 9.5.3-(3-((2, 2 -dimethylbutanoyl )oxy)phenyl)-3-hydroxypropan-l -aminium formate, (EYE-004.5 )

[0589] To a flask was added 3-(3-(((benzyloxy)carbonyl)amino)propanoyl)phenyl 2,2-dimethylbutanoate (0.73 g, 1.8 mmol), 10% Pd / C (0.1 g) and MeOH (20 mL). The flask was put into a high pressure reactor, evacuated and back-filled the flask with H2 (200 Psi), stirred at r.t. for 2 days. The Pd / C was filtered and the reaction was concentrated under reduced pressure, purified by column chromatography (EA / MeOH / NH3 H2O = 15 / 1 / 0.4). Formicacid (0.8 mL) in EA (15 mL) was added. The precipitate was filtered and the filtrate was concentrated in vacuo to give a product as a yellow viscous liquid (0.429 g, 73%).1H NMR (500 MHz, CD3OD) 58.45 (s, 1H, HCOO ), 7.40 (m, 1H, Ar-H), 7.27 (m, 1H, Ar-H), 7.10 (m, 1H, Ar-H), 6.96 (m, 1H, Ar-H), 4.85 (dd, J = 4.2, 8.6 Hz, 1H, HOCH), 3.07 (m, 2H, CH2), 2.01 (m, 2H, CH2), 1.74 (q, J= 7.6 Hz, 2H, CH2), 1.31 (s, 6H, CH3), 0.98 (t, 7= 7.6 Hz, 3H, CH3);13C NMR (126 MHZ, CD3OD) δ 178.1, 169.1, 152.7, 147.7, 130.6, 124.0, 121.8, 119.9, 72.6. 44.1, 38.6, 37.2, 34.4, 25.1, 9.7.3-(3-((2-ethyl-2-methylbutanoyl)oxy)-4-fluorophenyl)-3-hydroxypropan-l-aminium formate, F-EYE-005

[0590] To a flask was added 5-(3-(((benzyloxy)carbonyl)amino)propanoyl)-2-fhiorophcnyl 2-cthyl-2-mcthylbutanoatc (0.064 g, 0.15 mmol), 10% Pd / C (0.04 g) and McOH (20 mL). The flask was put into a high pressure reactor, evacuated and back-filled the flask with H2 (200 Psi), stirred at r.t. for 2 days. The Pd / C was filtered and the reaction was concentrated under reduced pressure, purified by column chromatography (EA / MeOH / NH3H2O = 15 / 1 / 0.4 to 9 / 1 / 0.4). Formic acid (0.2 mL) in EA (3 mL) was added. The precipitate was filtered and the filtrate was concentrated in vacuo to give a product as a colorless liquid (0.005 g, 10%) mixed with 650% mol of ammonium formate, ’ll NMR (500 MHz, CD3OD) δ 8.47 (s, 1H, HCOO ), 7.28 (m, 1H, Ar-H), 7.21 (m, 1H, Ar-H), 7.16 (m, 1H, Ar-H), 4.83 (dd, J = 4.1, 8.8 Hz, 1H, HOCH), 3.07 (m, 2H, CH2), 1.99 (m, 2H, CH2), 1.86 (m, 2H, CH2), 1.63 (m, 2H, CH2), 1.24 (s, 3H, CH3), 0.98 (t, J = 7.5 Hz, 6H, CH3);13C NMR (126 MHz, CD3OD) δ 176.3, 169.4, 155.7, 153.8, 143.1, 143.0, 139.7, 125.4, 125.3, 122.2, 117.5, 117.4, 72.0, 48.4. 38.5, 37.2, 32.8, 20.5, 9.2.ResultsMedicinal chemistry

[0591] We used ester derivatization to limit the duration of action of lead molecules. Importantly, there are several esterases in the RPE, our target tissue of interest, that could act to limit ester-based emixustat derivative activity (Fig. 1). The challenge in the synthesis ofester-containing VCMs is that, based on the emixustat pharmacophore, they must contain a primary or secondary y-amino-a-aryl alcohol. While necessary for potent RPE65 inhibition, the amine group was incompatible with most ester synthetic methods due to the autoreactivity with the ester functional group. To overcome this conflict, we utilized an enamine-based Heck coupling, which used a commercially-available benzyl chloroformate (Cbz)-protected 3 -aminopropionaldehyde and 3 -iodophenol to synthesize the Cbz-protected phenol in one step (Scheme 1). Conversion of the phenol to an ester was attained via direct reaction with the acyl chloride or activation of the corresponding carboxylic acid with l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC). The collection of carboxylic acids used for the synthesis were chosen to either mimic emixustat through a methyl cyclohexyl ester (EYE-001) or another potent VCM, MB -004, in the form of a diethylacetate ester (EYE-002) or a valproate ester (EYE-003), Fig. 3B. The choices of the ester functional groups were based on defined SAR with the corresponding ether derivatives, but also on the lack of toxicity displayed by the carboxylic acid cleavage products at doses -30-50 times higher (-300-500 mg / kg) than the dose we planned to use in this study (10 mg / kg).In vitro characterization of short- acting VCMs

[0592] We tested the ability of EYE-001, EYE-002, and EYE-003 to inhibit RPE65 in vitro using bovine RPE microsomes as an enzyme source Fig. 3B. All three compounds displayed dose-dependent RPE65 inhibition with IC50 values (-70-164 nM) comparable to that of emixustat (-98 nM). Importantly, the amine-containing product of ester hydrolysis, 4, did not significantly inhibit RPE65. Next, we measured the susceptibility of the ester derivatives to porcine liver esterase-catalyzed hydrolysis (Fig. IB). Equal concentrations of EYE-001, EYE-002, and EYE-003 and emixustat (negative control) were incubated with the esterase, and the time course of the reaction was followed for 60 min by HPLC. EYE-001, EYE-002, and EYE-003 showed time-dependent enzymatic hydrolysis, with the hydrolytic rate being correlated with the degree of steric hindrance exerted by the ester group substituents (Table 1). EYE-001 with its conformationally restricted cyclohexyl group, was hydrolyzed most rapidly. EYE-002 and EYE-003 exhibited greater stability with ~4-fold and - 13-fold slower initial rates of hydrolysis. This greater stability can be attributed in part to their more conformationally flexible diethyl acetate and valproate esters, which can adopt conformations that sterically protect the carbonyl group from nucleophilic attack during theesterase-catalyzed reaction. Non-enzymatic aminolysis also showed that EYE-001 is substantially less stable compared to EYE-002 and EYE-003 (Fig. 6).

[0593] To gain an understanding of how the ester functionality can be accommodated in the RPE65 active site, we determined the crystal structure of RPE65 in complex with EYE-002 (Table 2). Crystals of the RPE65 / EYE-002 complex were obtained by cocrystallization. The unbiased omit electron density maps revealed characteristic density for the y-amino-a-aryl alcohol VCM core together with a bound palmitate molecule as observed in other RPE65 crystal structures (Fig. 8A). The diethylacetate tail of the molecule was well defined but appeared to adopt different conformations in the two different chains in the asymmetric unit. Flexibility in this region of the molecule was due to a smaller number of stabilizing interactions in the membrane -proximal region of the active site and is consistent with the variability seen in the tail region in published RPE65-ligand complexes.Comparison of the mode of EYE-002 active-site binding to that of emixustat and MB-004 revealed an overall similar docking location but with some small shifts in orientation (Fig. 8B).In vivo pharmacodynamic properties of short- acting VCM

[0594] Next, we examined the inhibitory effects of EYE-001, EYE-002, and EYE-003 on visual chromophore regeneration in unanesthetized mice following a light exposure that bleached >90% of the visual pigment. In this experiment, dark-adapted BALB / cJ mice received a single intraperitoneal (IP) injection of either vehicle (DMSO) or test compounds (10 mg / kg) in the dark. Thirty minutes later, the animals were subjected to a 10 min, 10,000 lux photobleach and then placed back in darkness for 2 h to allow visual pigment regeneration. Afterward, the animals were euthanized, and their eyes collected for retinoid analysis by HPLC. The spectral properties of the white LED cluster used for the photobleach and those of the fluorescent white light in our vivarium are shown in Fig. 13. EYE-002 (red trace) and EYE-003 (blue trace) reproduced the retinoid pattern observed after emixustat treatment (purple trace), featuring a buildup of atREs (a) and minimal levels of 11cRAL (b) (Fig. 9A). By contrast, EYE-001 (green trace), like 4 (grey trace), led to the same pattern as vehicle treatment (black trace), with minimal atREs and high 11cRAL levels, respectively. The absolute quantification of these retinoids is shown in Fig. 9B, C. Emixustat led to a 93% reduction of 11cRAL synthesis while EYE-002 and EYE-003 led to a 78% and 71% reduction, respectively. This result demonstrated that the new ester chemistry wascompatible with RPE65 inhibition in vivo. The lack of RPE65 inhibition by EYE-001 was attributed to faster hydrolysis based on the results from the in vitro esterase assay (Fig. IB).

[0595] Next, we examined the duration of RPE65 inhibition following single doses of EYE-002 and EYE-003. In this experiment, dark-adapted mice received a single IP injection of either vehicle or the test compounds (10 mg / kg) and were housed in the dark for different periods of time (0.5-4 h) before being subjected to a deep photobleach. Following a 2 h dark recovery period, the animals were euthanized and their ocular retinoids quantified by HPLC. Fig. 9D shows the raw chromatograms obtained from this experiment. After a period of 4 h in the dark, the treatment with EYE-002 (red traces) and EYE-003 (blue traces) led to the recovery of 11cRAL and a / Riis levels comparable to those obtained with vehicle treatment (black traces) (Fig. 9E, F). By contrast, emixustat treatment (purple trace) led to significant RPE65 inhibition after 4 h. Importantly, this result confirmed that EYE-002 and EYE-003 were short-acting RPE65 inhibitors.

[0596] Electrophysiological measurements of rod function confirmed the short-acting effect of EYE-002 (Fig. 13). The mice were administered either vehicle or test compounds (emixustat or EYE-002) via a single IP injection (10 mg / kg) in the dark. 30 min later, the animals were photobleached, and the course of dark adaptation was monitored between 0.5 -8 h after photobleach (Fig. 13A). After 4 h of dark adaptation, the animals treated with vehicle (black trace) showed a similar ERG pattern compared to dark-adapted animals (grey trace). As expected, emixustat treatment (purple trace) abolished the a- and b-waves after 8 h of dark-adaptation. Conversely, treatment with EYE-002 (red traces) featured timed recovery of both a- and b-wave amplitudes. After 8 h of dark adaptation, the mice treated with EYE-002 recovered ~ 80% of the a- and b-wavc amplitudes that were measured in the vehicle group (Fig. 13B and C).Systemic administration of EYE-002 protects the retina from light-induced retinal damage

[0597] Here, we explored whether EYE-002 reproduced the effect of emixustat in protecting the retina of BALB / cJ mice from damage induced by a prolonged exposure to white light. First, dark-adapted animals received a single IP dose of either vehicle or test compounds ( 10 mg / kg) in the dark. 30 min later, the mice were illuminated with 15,000 lux of constant white LED light for 8 h. Next, the animals were moved back to the standard light / dark cycle for 7 days after which their retinal structure was assessed by optical coherence tomography (OCT) and scanning laser ophthalmoscopy (SLO) and retinal functionassessed by scotopic ERG. Eventually, the animals were sacrificed, their eyes processed for histological analysis, and the number of rod nuclei across the thickness of the outer nuclear layer (ONL) was counted at fixed distances from the optic nerve.

[0598] SLO analysis (Fig. 10 A) showed that vehicle treatment was associated with the presence of auto-fluorescent puncta distributed across the whole mouse retina. By contrast, EYE-002 and emixustat treatments were associated with rare auto-fluorescent puncta. These auto-fluorescent puncta were attributed to lesions in the neurovascular tissue. OCT analysis (Fig. 10B) revealed that vehicle treatment did not prevent the ablation of the ONL between ± 750 pm from the optic nerve head. Instead, EYE-002 and emixustat treatments preserved the thickness of the ONL (black brackets). The thickness of the ONL was quantified as shown in Fig. 10C, showcasing an equivalent efficacy between emixustat and EYE-002in preventing retinal damage induced by prolonged exposure to bright light.

[0599] Consistent with the data gathered by live imaging techniques, histological analysis of retinal cross-sections (Fig. 10D) showed the presence and absence of retinal damage in the retina treated with vehicle or test compounds, respectively. Notably, ablation of the ONL was found in an area within ± 1.5 mm from the optic nerve head (Fig. 10E), suggesting that the phototoxicity affects the retinal regions where light is directly focused on the retina.

[0600] Next, we investigated whether these structural changes translated to a loss of rod function as measured by scotopic ERG (Fig. 1 OF). In this experiment, the mice were dark-adapted for 24 h before recording scotopic ERG. Vehicle treatment (black traces) did not afford the protective effect on the amplitude of scotopic ERG responses because they were largely reduced compared to EYE-002 (red traces) and emixustat (purple traces) treatment. Quantification of the scotopic a- (Fig. 10G) and b- (Fig. 10H) waves showed significant differences between the vehicle and treatment groups, highlighting that the observed structural damage translated into a diminished capability of the retina to respond to light.

[0601] Together, these results demonstrated that the efficacy of a single systemic administration of EYE-002 is equal to that of emixustat in the prevention of photic retinal damage in albino BALB / c.1 mice, which are vulnerable to photic retinal damage.Oral administration of compound EYE-003 protects a STGD1 mouse model from retinal damage

[0602] Scotopic ERG was also used to measure the effect of enterally EYE-002 and EYE-003 in BALBc / J mice. Vehicle or test compounds (emixustat, EYE-002, and EYE-003) (10 mg / kg) were administered to dark-adapted mice by oral gavage. After 30 min, the mice were exposed to a 10 min, 10,000 lux photobleach and housed in the dark for 2 h before measuring the scotopic ERG. As expected, the vehicle treatment (black) led to a complete recovery of the scotopic ERG response while emixustat (purple) suppressed it (Figs. 12A and B). Compounds EYE-002 (red) and EYE-003 (blue) suppressed significantly the scotopic ERG a- wave but only EYE-003 suppressed also the b-wave amplitude to about ~ 50% that of the vehicle treatment. This result was expected (Fig. 3A and Table 1) and attributed to the slower hydrolysis of the ester bond of EYE-003 before absorption into the systemic circulation. Consequently, EYE-003 was selected to test the efficacy of short-acting RPE65 inhibitors in preventing the retinal degeneration associated with the dysfunctional visual cycle of the Abca^' Rdh^' mouse model of STGD 1.

[0603] Next, EYE-003 and the vehicle control were administered by either IP injection or by oral gavage to light-adapted Abca^' Rdh.8 ^ mice. Thirty min after the administration, the mice were illuminated with white LED light (10,000 lux) for 30 minutes and then housed under normal vivarium lighting for one week before assessing the structure and function of their retinas (Fig. 11). SLO analysis showed the presence of auto-fluorescent puncta in the retina of vehicle-treated Abca4' / ' Rdh^' mice (Fig. 11 A) that were like those observed previously in BALB / cJ mice (Fig. 10A) In addition, Abcad' ' Rdh ‘' mice displayed large areas of homogeneous auto-fluorescent signal in the background arising from lipofuscin of which bisretinoids are a major component. Instead, a single IP injection of EYE-003 (10 mg / kg) prevented the development of these auto-fluorescent signals. However, oral administration of EYE-003 at doses of 10, 20, and 50 mg / kg did not afford complete protection and both fluorescent signals were detected by SLO.

[0604] OCT analysis (Fig. 1 IB) revealed that the vehicle treatment did not afford protection against light-induced ONL thinning and retinal detachment. Instead, the ONL remained intact in the group treated with a single IP dose of EYE-003 (black bracket).Notably, oral treatment with EYE-003 provided a dose-dependent preservation of the ONL layer. The measurement of the ONL thickness (Fig. 11C) showed that the effect of oraladministration of EYE-003 was significant starting from 20 mg / kg, which was twice the dose administered by IP injection, although the efficacy of 50 mg / kg treatment was less than 50% of that achieved with the IP control.

[0605] The function of rods was measured by scotopic ERG and that of S-cones and M-cones was measured by photopic ERG. As expected, Rod-specific ERG recordings (Fig. 1 ID) showed that the vehicle treatment (black rhombs) did not afford the preservation of rod ERG responses while the IP administration of EYE-003 (red hexagons) had a significant effect in maintaining rod function. The oral administration of EYE-003 led to a dose -dependent preservation of rod ERG b-wave amplitudes although the significance of these responses was not consistent throughout the whole range of flash intensities tested. A similar trend was observed for S-cone (Fig. 1 IE) and M-cone (Fig. 1 IF) b-wave amplitudes. However, cones are resilient to the damage induced by prolonged exposure to bright light, and this property contributed to the lack of consistent significance of the drug effect explored in this study.

[0606] These data, on one hand, confirmed that EYE-003 protected the retina of Abca4' / _Rdh.8' ' mice from photic damage and, on the other hand, it demonstrated that the inferior efficacy of the oral treatment was likely due to the suboptimal oral bioavailability of EYE-003. Altogether, these results indicated that the oral administration of 50 mg / kg of EYE-003 preserved the soma of a significant number of rod photoreceptors in the ONL of a STGD1 mouse model, the function of these rods was partially impaired while that of cones was maintained.

[0607] While EYE-003 was active when given orally, it required a five-fold higher dose and exerted only partial visual cycle suppressive activity compared to IP administration. Thus, we investigated further optimization of the ester chemistry to balance oral bioavailability with an ideal duration of action. As shown in Figs. 14(A-B), EYE-005 exhibits strong ERG suppressive activity after an oral dose with a duration of action much shorter than emixustat given orally at an equal dose.

[0608] Based on our findings, we argue that ester-containing, short-acting RPE65 inhibitors hold significant potential for use in the treatment and prevention of retinopathies associated with visual cycle activity. The foremost among these is STGD1, which currently lacks effective therapies but is among the most common recessive Mendelian disorders affecting retinal structure and function. The emixustat ester derivatives exhibited protectiveeffects against light damage in a mouse model of STGD1, providing proof of concept for the therapeutic properties of these molecules. Beyond their suitability to treat STGD1, these metabolically-labile RPE65 inhibitors would be ideal for indications where transient visual cycle suppression could be indicated; for example, in situations where the retina is susceptible to light damage, as demonstrated by our light damage protection studies in albino BALB / cJ mice. Ocular surgeons are aware of the delicate tradeoff between bright illumination of the field of operation and retinal safety, as highlighted by the history of vision loss caused by surgical illumination. Although iatrogenic retinal damage with surgical lights is now a rare event, there appear to be vulnerable individuals that may benefit from the prophylactic administration of a short-acting RPE65 inhibitor before ocular surgery. Our proposition considers the growing interest in ocular gene therapies, where the eye may be exposed to light for extended periods of time (hours). Indeed, there are more than 30 gene therapy trials for retinal diseases actively recruiting or enrolling, several of which require vitrectomy for delivery. Although there are 3D visualization systems for ocular surgery that reduce the amount of illumination needed for the operation, we foresee that the combined use of 3D visualization systems and saVCMs could offer an opportunity for ophthalmologists to create safer protocols for ocular surgeries and ocular gene therapy administration.

[0609] The key advantage of using ester-containing RPE65 inhibitors is that they combine a very rapid onset of the pharmacological effect (minutes) with a tunable duration of action (hours), allowing the recovery of visual cycle activity during drug-free periods. By contrast, the effectiveness of RBP4 antagonists relies on sustained RBP4 depletion, which is achieved with a delay of at least 4-6 h from the time of administration. Furthermore, physiological levels of RBP4 cannot recover for days or even weeks after treatment cessation. These pharmacodynamic properties of RBP4 antagonists limit the range of applications compared to that of short-acting RPE65 inhibitors.

[0610] From the above description of the invention, those skilled in the art will perceive improvements, changes and modifications. Such improvements, changes and modifications within the skill of the art are intended to be covered by the appended claims. All references, publications, and patents cited in the present application are herein incorporated by reference in their entirety.

Claims

1. Having described the invention, we claim:

1. A compound of formula (1):or a pharmaceutically acceptable salt or solvate thereof, wherein:* denotes a chiral center;R1is an alkyl optionally substituted with one or more F, an alkenyl optionally substituted with one or more F, or an aryl optionally substituted with one or more alkyl, F, or fluoroalkyl;R2is H or F;R and R4are each independently H, D, or an alkyl, which is optionally substituted with one or more D or F; andR5and R6are each independently H or D.

2. The compound, pharmaceutically acceptable salt, or solvate thereof of claim 1, wherein R1is a C1-C12 alkyl optionally substituted with one or more F, a C2-C12 alkenyl optionally substituted with one or more F, or a C6-C12 aryl optionally substituted with one or more alkyl, F, or fluoroalkyl3. The compound, pharmaceutically acceptable salt, or solvate thereof of claim 1 or claim 2, wherein R1is a branched C3-C10 alkyl optionally substituted with one or more F or a C3-C10 cycloalkyl optionally substituted with one or more F, -CH3, or -CF3.

4. The compound, pharmaceutically acceptable salt, or solvate thereof of any of claims 1 to 3, wherein R1is a branched C3-C8 alkyl optionally substituted with one or more F.

5. The compound, pharmaceutically acceptable salt, or solvate thereof of any of claims 1 to 3, wherein R1is C3-C10 cycloalkyl optionally substituted with one or more F, -CH3, or -CF3.

6. The compound, pharmaceutically acceptable salt, or solvate thereof of claim 1 or claim 2, wherein R1is a branched C3-C10 alkenyl optionally substituted with one or more F or a C4-C8 cycloalkenyl optionally substituted with one or more F, -CH3, or -CF3.

7. The compound, pharmaceutically acceptable salt, or solvate thereof of claim 1, claim 2, or claim 6, wherein R1is a branched Cs-Cs alkenyl optionally substituted with one or more F.

8. The compound, pharmaceutically acceptable salt, or solvate thereof of claim 1, claim 6, wherein R1is a C4-C8 cycloalkenyl optionally substituted with one or more -CII3, F, or -CF3.

9. The compound, pharmaceutically acceptable salt, or solvate thereof of claim 1 or claim 2, wherein R1is a Ce-Cio aryl optionally substituted with one or more F, C1-C3 alkyl, or C1-C3 fluoroalkyl.

10. The compound, pharmaceutically acceptable salt, or solvate thereof of claim 1, claim 2, or claim 9, wherein R1is a phenyl optionally substituted with one or more F, -CH3, or -CF3.

11. The compound, pharmaceutically acceptable salt, or solvate thereof of any of claims 1 to 2, wherein R1is selected fromOb > o o o oderivatives thereof.

12. The compound, pharmaceutically acceptable salt, or solvate thereof of any of claims 1 to 11, wherein R2is H.

13. The compound, pharmaceutically acceptable salt, or solvate thereof of any of claims 1 to 11, wherein R2is F.

14. The compound, pharmaceutically acceptable salt, or solvate thereof of any of claims 1 to 13, wherein at least one of R3or R4is an alkyl optionally substituted with one or more D or F.

15. The compound, pharmaceutically acceptable salt, or solvate thereof of any of claims 1 to 14, wherein at least one of R3or R4is Ci-Ce alkyl optionally substituted with one or more D or F.

16. The compound, pharmaceutically acceptable salt, or solvate thereof of any of claims 1 to 15, wherein at least one of R3or R4is Ci-Ce alkyl substituted with one or more D or F.

17. The compound, pharmaceutically acceptable salt, or solvate thereof of any of claims 1 to 16, wherein both of R3and R4are Ci-Ce alkyl substituted with one or more D or F.

18. The compound, pharmaceutically acceptable salt, or solvate thereof of any of claims 1 to 15, wherein at least one of R3or R4is methyl substituted with one or more D or F.

19. The compound, pharmaceutically acceptable salt, or solvate thereof of any of claims 1 to 15, wherein both of R3and R4are methyl substituted with one or more D or F.

20. The compound, pharmaceutically acceptable salt, or solvate thereof of any of claims 1 to 15, wherein at least one of R3or R4is -CD3 or -CF3.

21. The compound, pharmaceutically acceptable salt, or solvate thereof of any of claims 1 to 15, wherein both of R3and R4are -CD3 or -CF3.

22. The compound, pharmaceutically acceptable salt, or solvate thereof of any of claims 1 to 11, wherein at least one of R3or R4is H.

23. The compound, pharmaceutically acceptable salt, or solvate thereof of claim 11, wherein both R3and R4are H.

23. The compound, pharmaceutically acceptable salt, or solvate thereof of any of claims 1 to 11, wherein at least one of R3or R4is D.

24. The compound, pharmaceutically acceptable salt, or solvate thereof of claim 11, wherein both R3and R4are D.

25. The compound, pharmaceutically acceptable salt, or solvate thereof of any of claims 1 to 11, wherein R2is F or at least one of R3or R4is an alkyl optionally substituted with one or more D or F.

26. The compound, pharmaceutically acceptable salt, or solvate thereof of any of claims 1 to 25, wherein at least one of R5or R6is D.

27. The compound, pharmaceutically acceptable salt, or solvate thereof of any of claims 1 to 26, wherein both R5and R6are D.

28. The compound, pharmaceutically acceptable salt, or solvate thereof of any of claims 1 to 25, wherein both R5and R6are H.

29. The compound, pharmaceutically acceptable salt, or solvate thereof of any of claims 1 to 28, comprising an (R)-OH isomer.

30. The compound, pharmaceutically acceptable salt, or solvate thereof of any of claims 1 to 28, comprising an (S)-OH isomer.or a pharmaceutically acceptable salt, or solvate thereof.

32. A pharmaceutical composition comprising a compound, pharmaceutically acceptable salt, or solvate thereof of any of claims 1 to 31 and a pharmaceutically acceptable carrier.

33. A method of treating and / or preventing phototoxic retinal damage in a subject in need thereof, the method comprising:administering to the subject a therapeutically effective amount of a compound, pharmaceutically acceptable salt, or solvate thereof of any of claims 1 to 31 or a pharmaceutical composition of claim 32.

34. A method of treating and / or preventing an iatrogenic photic retinopathy in a subject in need thereof, the method comprising:administering to the subject a therapeutically effective amount of a compound, pharmaceutically acceptable salt, or solvate thereof of any of claims 1 to 31 or a pharmaceutical composition of claim 22.

35. The method of claim 33 or 34, wherein the subject is treated by intraocular or ocular surgery requiring illumination of the eye.

36. The method of claim 35, wherein the illumination of the eye is effective to cause phototoxic retinal damage or iatrogenic photic retinopathy.

37. The method of claim 35 or 36, wherein the surgery is cataract surgery.

38. The method of any of claims 35 to 37, wherein the compound, pharmaceutically acceptable salt, or solvate thereof or the pharmaceutical composition is administered to the subject prior to surgery.

39. The method of any of claims 34 to 38, wherein the subject has a genetically inherited condition that predisposes the subject to enhanced risk of photodamage.

40. The method of claim 39, wherein the subject has Stargardt disease or albinism.

41. A method of treating and / or preventing an ocular disorder in a subject in need thereof, the method comprising:administering to the subject a therapeutically effective amount of a compound, pharmaceutically acceptable salt, or solvate thereof of any of claims 1 to 31 or a pharmaceutical composition of claim 32.

42. The method of claim 41, wherein the ocular disorder comprises at least one of light induced retinal degeneration, macular degeneration, Stargardt disease, geographic atrophy, and retinitis pigmentosa.

43. The method of any of claims 33 to 42, wherein the pharmacokinetics of the compound, pharmaceutically acceptable salt, or solvate thereof upon administration to the subject is such that the compound, pharmaceutically acceptable salt, or solvate thereof does not promote night blindness when administered daily.

44. The method of any of claims 33 to 43, wherein the compound, pharmaceutically acceptable salt, or solvate thereof transiently inhibits RPE65 enzymatic activity in the subject.

45. The method of any of claims 33 to 44, wherein the compound, pharmaceutically acceptable salt, or solvate thereof inhibits RPE65 enzymatic activity in the subject prior to hydrolytic cleavage by esterase mediated metabolism but does not inhibit RPE65 enzymatic activity after hydrolytic cleavage.

46. The method of any of claims 33 to 45, wherein the compound, pharmaceutically acceptable salt, or solvate thereof or the pharmaceutical composition is administered by oral, intravenous, intraocular, or intravitreal administration.

47. A unit dosage form of a formulation comprising a compound, pharmaceutically acceptable salt, or solvate thereof of any of claims 1 to 31.

48. The unit dosage formulation of claim 47, comprising an oral preparation.

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