Imidazopyridines and imidazopyrimidines, and methods of using same

Abstract

The disclosure provides a method of treating, ameliorating, and / or preventing retinal degenerations, such as but not limited to anterior segment ocular disorders and / or age-related macular degeneration (AMD), in a subject. In certain embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound of the disclosure. In certain embodiments, the compound of the disclosure prevents and / or minimizes cellular assault, such as oxidative stress-related cellular assault, and / or promote cell viability.

Description

[0001]Attorney Docket No.047162-7485WO1(02576) TITLE Imidazopyridines and Imidazopyrimidines, and Methods of Using Same CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No.63 / 567,289, filed March 19, 2024, which is hereby incorporated by reference in its entirety. BACKGROUND Retinal degenerations are a leading cause of untreatable blindness worldwide. There are many forms of this disease, including retinitis pigmentosa (RP), which is known to be caused by around 200 different gene defects; choroideremia; retinal ganglion cell atrophy in glaucoma; and age-related macular degeneration (AMD), which is the leading cause of blindness in elderly patients. Given the large number of patients with retinal degenerations, and the rapid increase in the aging population, the number of patients affected by these disorders is expected to increase in the future. Aside from vitamins and antioxidants recommended by the Age-Related Eye Disease Study, there is no effective therapy for 90% of AMD patients with “dry” or atrophic AMD. Likewise, other retinal degenerations have no known treatments. Therapies are needed to slow or retard the development and progression of retinal disorders. The retinal pigment epithelial (RPE) cells are vital for a proper functioning neurosensory retina. The cells make up a portion of the RPE-Bruch’s membrane-choroid complex and perform critical functions for maintaining vision, including phagocytosis of photoreceptor outer segments, processing of retinoids, and polarized secretion of factors such as vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF). Age-related changes in RPE cells are a hallmark of early AMD and contribute to pathology and visual morbidity associated with advanced AMD. Oxidative stress is a contributing factor to these changes and has been implicated in other diseases in which aging is a risk factor, including Alzheimer’s disease and Parkinson’s disease. In addition, Mendelian disorders, such as most forms of RP, can be accelerated by the presence of oxidative stress leading to the degeneration of the neurosensory retina, e.g. photoreceptors. In vitro and in vivo studies demonstrate that oxidative stress can accelerate cone photoreceptor death in animal models of RP. Diseases of the anterior segment including the cornea, lens, and trabecular meshwork, -1- 55240579.2 Attorney Docket No.047162-7485WO1(02576) and ocular surface disease (dry eye) are leading causes of blindness and virtual impairment worldwide. Oxidative stress, inflammation, and mitochondrial dysfunction have been implicated in these anterior segment diseases, including but not limited to Fuchs endothelial corneal dystrophy (FECD), ocular surface disease, cataracts, glaucoma, and keratoconus. Age-related changes in cornea endothelial cells are a hallmark of FECD and contribute to pathology and visual morbidity. FECD is a progressive, bilateral disease characterized by a gradual loss of corneal endothelial cells (CECs). Loss of CECs impairs the ability of the cornea to maintain hydration, and results in a progressive decline in corneal transparency and hence a decline in vision. FECD is estimated to affect about 4% of the population, mostly in their forties and fifties. CECs are a highly metabolic cell type, exposure to sunlight and the lack of a significant capacity for natural regeneration of CECs make them susceptible to mitochondrial dysfunction and oxidative damage. Increased oxidative stress in the FECD cornea contributes to endothelial oxidative DNA damage, morphological modification, and CEC apoptosis. Age-related cataracts are a leading cause of loss of vision among elderly individuals affecting approximately 46% of 180 million visually disabled people worldwide. Age-related changes in lens epithelial cells are a hallmark of cataract formation and contributes to pathology and visual morbidity. Increased oxidative stress is caused by factors such as ultraviolet light and hydrogen peroxide, and both are risk factors for cataract development. At present, the only effective treatment is extraction of cataractous lens followed by implantation of an artificial intraocular lens (IOL). However, this surgery carries some inherent risks of post-operative complications such as stimulation of chronic inflammation, cystoid macular edema, corneal edema, endophthalmitis, retinal detachment, vitreous hemorrhage, and other disorders. Moreover, inadequate surgical facilities and the high cost of artificial IOLs can be major limitations to treatment in developing countries. Keratoconus is a leading cause of corneal transplantation in younger individuals, accounting for approximately 25% of all transplants. Chronic keratocyte apoptosis, particularly of the anterior stromal keratocytes, can lead to stromal thinning in keratoconus. Oxidative stress is one of the key factors that contributes to keratoconus pathogenesis. Oxidative stress, including oxidative damage to trabecular meshwork cells, has been implicated in the pathogenesis of glaucoma and / or ocular surface disease. There is a statistically significant correlation between oxidative DNA damage and daily mean, minimum, and maximum intraocular pressure (IOP) values. Thus, there is a need for early interventions that protect or rescue RPE cells. As such -2- 55240579.2 Attorney Docket No.047162-7485WO1(02576) an intervention would be beneficial and treat, ameliorate, and / or prevent disease progression. Further, there is a need for compositions and methods for treating, ameliorating, and / or preventing anterior segment disorders, such as but not limited to FECD, cataracts, ocular surface disease, glaucoma, and / or keratoconus. There is a need to develop effective strategies to limit the progression of geographic atrophy (GA) and to prevent progression from dry to wet AMD. The present disclosure addresses this need. SUMMARY In one aspect, described herein is a compound of formula (I): , wherein: X1is N or CR1; selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, F, Cl, Br, I, and Y, with the proviso that at least one of R1(if present), R2, R3, and R4is Y; Y is -(CH2)m-G; m is 1, 2, 3, 4, 5, or 6; G is selected from the group consisting ; n is 0, 1, 2, 3, or 4; one of the following applies: X2is CR7, X3is CR8, and X4is CR13, or X2is N, X3is CR8, and X4is CR13, or X2is CR7, X3is N, and X4is CR13, or X2is CR7, X3is CR8, and X4is N; R5, R6, R7, R8, R9, R10, R11, R12, and R13(if present) are independently selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, F, Cl, Br, and I; R14and R15are independently H or C1-C6alkyl; or a salt, solvate, tautomer, and / or stereoisomer thereof. In another aspect, described herein is a method of treating, ameliorating, and / or preventing retinal degeneration in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound as described herein. -3- 55240579.2 Attorney Docket No.047162-7485WO1(02576) In another aspect, described herein is a method of treating, ameliorating, and / or preventing cell death, and / or promoting cell viability, in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound as described herein. In another aspect, described herein is a method of treating, ameliorating, and / or preventing blue light damage in a subject’s lens epithelial cell, the method comprising administering to the subject a therapeutically effective amount of a compound as described herein. In another aspect, described herein is a pharmaceutical composition comprising a compound as described herein and at least one pharmaceutically acceptable excipient. BRIEF DESCRIPTION OF THE DRAWINGS The following detailed description of illustrative embodiments of the disclosure will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the disclosure, specific embodiments are shown in the drawings. It should be understood, however, that the disclosure is not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawings. FIG.1 shows DH464A protects human retinal pigment epithelial (RPE) cells from oxidative stress-induced cell death. Human RPE cells were preincubated with 3 µM or 6 µM DH464A for 24 hours and then exposed to 300 µM tert-butyl hydroperoxide (TBHP) to induce cell death for 24 hours. Protective effects on human RPE cells treated with 3 µM or 6 µM of DH464A. ****p < 0.001. EC50= 2.09μM. TBHP, tertbutyl hydroperoxide. FIG.2 shows DH404AF and DH476A protect human retinal pigment epithelial (RPE) cells from oxidative stress-induced cell death. Human RPE cells were preincubated with 2.5 µM DH404AF or DH476A for 24 hours and then exposed to 250 µM tert-butyl hydroperoxide (TBHP) to induce cell death for 24 hours. Protective effects on human RPE cells treated with 2.5 µM of DH404AF or DH476A. **p < 0.05, ****p < 0.001. tert-butyl hydroperoxide (TBHP). FIG.3 shows structure activity relationship studies for imidazopyrimidines and pyridines. Imidazopyrimidines and pyridine 5,6 core compounds active after exposure to tert- butyl hydroperoxide-induced ferroptotic cell death. Data suggest binding to a biological enzyme or receptor. FIG.4 shows prevention of RSL3-induced ferroptosis by GPX4 activator DH464A in ARPE-19 cells. DH464A prevented cell death with a lethal concentration of RSL3 (10 nM). -4- 55240579.2 Attorney Docket No.047162-7485WO1(02576) Human RPE cells were preincubated with 10 nM RSL3 alone or RSL3 + 10 nM compound C325-0414 for 24 hours and then analyzed with viability assay. ****p < 0.001. FIG.5A shows iron chelating ability of Ciclopirox (10, 50, and 100^M) monitored by the absorbance at 592nm. Results shown represent the mean standard deviation (s.d.) (n=3). Ciclopirox (10, 50, and 100^M) show ability to chelate iron at 100^M FIG.5B shows iron chelating ability of Compound DH464A (10, 50, and 100^M), and C325-0414 were monitored for iron chelating ability monitored by the absorbance at 592nm. Results shown represent the mean standard deviation (s.d.) (n=3). FIG.5C shows iron chelating ability of C325-0414 (10, 50, and 100^M) were negative for their ability to chelate iron in a dose dependent manner. Results shown represent the mean standard deviation (s.d.) (n=3). FIG.6 shows the predicted binding mode of DH464A. The hydrogen bonds between DH464A (green) and GPX4 (pale cyan, PDB entry 2OBI (18)) are shown as dashed orange lines. FIG.7 shows surface plasmon resonance (SPR) experiments using DH476A for GPX4 target identification. Compound was tested using Cayman GPX4 (Cayman Chemical, Ann Arbor, MI; item number 26906). The CM5 sensor Chip was used and GPX4 was immobilized using standard amine coupling.10μg / ml GPX4 diluted in acetate buffer pH 4.5 was used.1x phosphate buffer saline (PBS-P; Cytiva Life Sciences; Marlborough, MA) was used as running buffer. Compounds were diluted to get 5% dimethyl sulfoxide (DMSO; Cytiva Life Sciences) in 1x PBS-P buffer. The compound was tested at the following concentrations (μM): 0, 0.78, 1.56, 3.125, 6.25, 12.5, 25, 50, 100, 200, 400. The SPR curves and the fitted data to get dissociation constant (Kd) values for each channel are shown. FIG.8 shows surface plasmon resonance (SPR) experiments using DH404AF for GPX4 target identification. Compound was tested using Cayman GPX4 (Cayman Chemical, Ann Arbor, MI; item number 26906). The CM5 sensor Chip was used and GPX4 was immobilized using standard amine coupling.10μg / ml GPX4 diluted in acetate buffer pH 4.5 was used.1x phosphate buffer saline (PBS-P; Cytiva Life Sciences; Marlborough, MA) was used as running buffer. Compounds were diluted to get 5% dimethyl sulfoxide (DMSO; Cytiva Life Sciences) in 1x PBS-P buffer. The compound was tested at the following concentrations (μM): 0, 0.78, 1.56, 3.125, 6.25, 12.5, 25, 50, 100, 200, 400. The SPR curves and the fitted data to get dissociation constant (Kd) values for each channel are shown. FIG.9 shows surface plasmon resonance (SPR) experiments using DH464A for -5- 55240579.2 Attorney Docket No.047162-7485WO1(02576) GPX4 target identification. Compound was tested using Cayman GPX4 (Cayman Chemical, Ann Arbor, MI; item number 26906). The CM5 sensor Chip was used and GPX4 was immobilized using standard amine coupling.10μg / ml GPX4 diluted in acetate buffer pH 4.5 was used.1x phosphate buffer saline (PBS-P; Cytiva Life Sciences; Marlborough, MA) was used as running buffer. Compounds were diluted to get 5% dimethyl sulfoxide (DMSO; Cytiva Life Sciences) in 1x PBS-P buffer. The compound was tested at the following concentrations (μM): 0, 0.78, 1.56, 3.125, 6.25, 12.5, 25, 50, 100, 200, 400. The SPR curves and the fitted data to get dissociation constant (Kd) values for each channel are shown. DETAILED DESCRIPTION Definitions Reference will now be made in detail to certain embodiments of the disclosed subject matter, examples of which are illustrated in part in the accompanying drawings. While the disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that the exemplified subject matter is not intended to limit the claims to the disclosed subject matter. In the methods described herein, the acts can be carried out in any order, except when a temporal or operational sequence is explicitly recited. Furthermore, specified acts can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, a claimed act of doing X and a claimed act of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process. Throughout this document, values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a range of “about 0.1% to about 5%” or “about 0.1% to 5%” should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. The statement “about X to Y” has the same meaning as “about X to about Y,” unless indicated otherwise. Likewise, the statement “about X, Y, or about Z” has the same meaning as “about X, about Y, or about Z,” unless indicated otherwise. In this document, the terms “a,” “an,” or “the” are used to include one or more than one unless the context clearly dictates otherwise. The term “or” is used to refer to a -6- 55240579.2 Attorney Docket No.047162-7485WO1(02576) nonexclusive “or” unless otherwise indicated. The statement “at least one of A and B” or “at least one of A or B” has the same meaning as “A, B, or A and B.” In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting; information that is relevant to a section heading may occur within or outside of that particular section. All publications, patents, and patent documents referred to in this document are incorporated by reference herein in their entirety, as though individually incorporated by reference. “About” as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20% or ±10%, more preferably ±5%, even more preferably ±1%, and still more preferably ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods. The term “alkyl” as used herein refers to straight chain and branched alkyl groups and cycloalkyl groups having from 1 to 40 carbon atoms, 1 to about 20 carbon atoms, 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms. Examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. As used herein, the term “alkyl” encompasses n- alkyl, isoalkyl, and anteisoalkyl groups as well as other branched chain forms of alkyl. Representative substituted alkyl groups can be substituted one or more times with any of the groups listed herein, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term “alkenyl” as used herein refers to straight and branched chain and cyclic alkyl groups as defined herein, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to 40 carbon atoms, or 2 to about 20 carbon atoms, or 2 to 12 carbon atoms or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to vinyl, -CH=C=CCH2, -CH=CH(CH3), - CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others. A disease or disorder is “alleviated” if the severity of a symptom of the disease or disorder, the frequency with which such a symptom is experienced by a patient, or both, is reduced. As used herein, “C325-0414” or “YU162779” refers to the compound 4-bromo-2- -7- 55240579.2 Attorney Docket No.047162-7485WO1(02576) (3-((2-ethyl-6-methylphenyl)amino)imidazo[1,2-a]pyrimidin-2-yl)phenol, or a salt and / or solvate thereof having the formula: . As used herein, the term composition” refers to a mixture of at least one compound with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic (including but not limited to topical, subconjunctival, sub-Tenon’s, suprachoroidal, intravitreal, or subretinal), pulmonary and topical administration. As used herein, “Compound 434” or “YU162787” refers to the compound 4- bromo-2-(3-((2-ethyl-6-methylphenyl)amino)-5,7-dimethylimidazo[1,2-a]pyrimidin-2- yl)phenol, or a salt and / or solvate thereof, having the formula: . As used herein, the term 4” corresponds to 4-bromo-2-(3- (pyridin-2-ylamino)imidazo[1,2-a]pyrimidin-2-yl)phenol, or a salt and / or solvate thereof, having the formula: HO NNBr . As used herein, to the compound 4-bromo-2-(7- ((dimethylamino)methyl)-3-((2,6-dimethylphenyl)amino)imidazo[1,2-a]pyridin-2- yl)phenol, or a salt and / or solvate thereof, having the formula: -8- 55240579.2 Attorney Docket No.047162-7485WO1(02576) . A “disease” is a state the animal cannot maintain homeostasis, and wherein if then the animal’s health continues to deteriorate. In contrast, a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health. As used herein, the terms “effective amount,” “pharmaceutically effective amount” and “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation. As used herein, “Erastin” refers to the compound 2-[1-[4-[2-(4- Chlorophenoxy)acetyl]-1-piperazinyl]ethyl]-3-(2-ethoxyphenyl)-4(3H)-quinazolinone, or a salt and / or solvate thereof, having the formula: . The term selected from the group consisting of” as used herein refers to referenced groups being the same, different, or a mixture thereof, unless the context clearly indicates otherwise. Thus, under this definition, the phrase “X1, X2, and X3are independently selected from noble gases” would include the -9- 55240579.2 Attorney Docket No.047162-7485WO1(02576) scenario where, for example, X1, X2, and X3are all the same, where X1, X2, and X3are all different, where X1and X2are the same but X3is different, and other analogous permutations. The terms “patient,” “subject,” “individual,” and the like are used interchangeably herein, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein. In certain non-limiting embodiments, the patient, subject or individual is a human. As used herein, the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained. As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, substrate, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the disclosure within or to the patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the disclosure, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. As used herein, “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the disclosure and are physiologically acceptable to the patient. -10- 55240579.2 Attorney Docket No.047162-7485WO1(02576) Supplementary active compounds may also be incorporated into the compositions. The “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within the disclosure. Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the disclosure are known in the art and described, for example in Remington’s Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference. As used herein, the language “pharmaceutically acceptable salt” refers to a salt of the administered compounds prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids or bases, organic acids or bases, solvates, hydrates, or clathrates thereof. Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric (including sulfate and hydrogen sulfate), and phosphoric acids (including hydrogen phosphate and dihydrogen phosphate). Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, malonic, saccharin, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2- hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric, salicylic, galactaric and galacturonic acid. Suitable pharmaceutically acceptable base addition salts of compounds described herein include, for example, ammonium salts, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N’-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared from the corresponding compound by reacting, for example, the appropriate acid or base with the compound. As used herein, “RSL3” refers to the compound methyl (1S,3R)-2-(2-chloroacetyl)- 1-(4-(methoxycarbonyl)phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate or a salt and / or solvate thereof, having the formula: -11- 55240579.2 Attorney Docket No.047162-7485WO1(02576) . The term “solvent” as that can dissolve a solid, liquid, or gas. Non-limiting examples of are compounds, water, alcohols, ionic liquids, and supercritical fluids. The term “substantially” as used herein refers to a majority of, or mostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. The term “substantially free of” as used herein can mean having none or having a trivial amount of, such that the amount of material present does not affect the material properties of the composition including the material, such that the composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less. The term “substantially free of” can mean having a trivial amount of, such that a composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less, or about 0 wt%. The term “substituent” or “functional group” as used herein refers to a group that can be or is substituted onto a molecule or onto an organic group. Examples of substituents or functional groups include, but are not limited to, a halogen (e.g., F, Cl, Br, and I); an oxygen atom in groups such as hydroxy groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxyamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups. Non-limiting examples of substituents that can be bonded to a substituted carbon (or other) atom include F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO, NO2, ONO2, azido, CF3, OCF3, R, O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, -12- 55240579.2 Attorney Docket No.047162-7485WO1(02576) C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2)0-2N(R)C(O)R, (CH2)0-2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, and C(=NOR)R, wherein R can be hydrogen or a carbon-based moiety; for example, R can be hydrogen, (C1-C100)hydrocarbyl, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl; or wherein two R groups bonded to a nitrogen atom or to adjacent nitrogen atoms can together with the nitrogen atom or atoms form a heterocyclyl. The term “substituted” as used herein in conjunction with a molecule or an organic group as defined herein refers to the state in which one or more hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms. The substitution can be direct substitution, whereby the hydrogen atom is replaced by a functional group or substituent, or an indirect substitution, whereby an intervening linker group replaces the hydrogen atom, and the substituent or functional group is bonded to the intervening linker group. A non-limiting example of direct substitution is: RR-H ^ RR-Cl, wherein RR is an organic moiety / fragment / molecule. A example of indirect substitution is: RR-H ^ RR- (LL)zz-Cl, wherein RR is an organic moiety / fragment / molecule, LL is an linker group, and ‘zz’ is an integer from 0 to 100 inclusive. When zz is 0, LL is absent, and direct substitution results. The intervening linker group LL is at each occurrence independently selected from the group consisting of -H, -O-, -OR, -S-, -S(=O)-, -S(=O)2-, -SR, -N(R)-, - NR2, -CR=, -C^^^-CH2-, -CHR-, -CR2-, -CH3, -C(=O)-, -C(=NR)-, and combinations thereof. (LL)zzcan be linear, branched, cyclic, acyclic, and combinations thereof. A “therapeutic” treatment is a treatment administered to a subject who exhibits signs of pathology, for the purpose of diminishing or eliminating those signs. Ranges: throughout this disclosure, various aspects of the disclosure can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, and so forth, as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless -13- 55240579.2 Attorney Docket No.047162-7485WO1(02576) of the breadth of the range. Description In its various aspects and embodiments, the disclosure provides compounds and methods for the treatment, prevention, and / or amelioration of retinal degeneration, including but not limited to AMD. In its various aspects and embodiments, the disclosure provides compounds and methods for the treatment, prevention, and / or amelioration of anterior segment ocular disorders, such as but not limited to Fuchs endothelial corneal dystrophy (FECD), cataracts, ocular surface disease (dry eye), glaucoma, and / or keratoconus. Without wishing to be limited by theory, in certain embodiments these compounds protect retinal cells, such as RPE cells, from cell death, in a non-limiting example oxidative stress-induced cell death. In other embodiments, these compounds protect retinal cells, such as RPE cells, from cell death on damaged extracellular matrix. In yet other embodiments, these compounds increase cell viability, wherein the cell is for example a lens epithelial cell. In other embodiments, these compounds protect retinal cells, such as RPE cells, from blue light damage. Administration of compounds of the disclosure can induce expression of oxidative stress and anti-apoptotic related genes, thereby treating, ameliorating, and / or preventing retinal degenerations, including but not limited to AMD, including but not limited to “dry” AMD. The disclosure herein should not be construed to be limited to AMD and / or oxidative stress-induced cell death. Oxidative stress is associated with a wide range of retinal degenerations, and oxidative stress has been shown to decrease photoreceptor / neuronal survival human diseases, including age-related macular degeneration (AMD), atherosclerosis, Alzheimer’s disease and others. Oxidative stress is a general mechanism in which cells and tissues undergo damage in high oxygen environments. Mechanisms will vary depending on disease process, but include mitochondrial damage and dysfunction, peroxide production, free radical formation, and other mechanisms. Without loss of generality, drugs that prevent or reverse effects of tissue damage from oxidative stress are useful for slowing or reversing the progression of human disease. Non-limiting examples of such diseases include heart failure and other cardiovascular such as atherosclerosis; retinal degenerations such as age- related macular degeneration; pulmonary fibrosis; kidney (renal) disease; diabetic macular edema and retinopathies; neurodegenerations such as Alzheimer’s disease; certain skeletal muscle disorders such as mitochondrial myopathy and Barth’s syndrome; ocular disorders -14- 55240579.2 Attorney Docket No.047162-7485WO1(02576) and diseases such as cataract and glaucoma; and liver disease. As described herein, exemplary compounds of the disclosure were found to mitigate risk of oxidative damage in tissue culture models of disease. For example, compounds of the disclosure were shown to protect human retinal pigment epithelial (RPE) cells from oxidative stress-induced cell death and are beneficial to treat, ameliorate, and / or prevent diseases contemplated herein. In non-limiting embodiments, compounds of the disclosure enhance metabolic function, such as adenosine triphosphate (ATP) production, basal respiration, maximal respiration, and / or spare respiration in RPE cells. In non-limiting embodiments, compounds of the disclosure have good solubility in aqueous buffers (from 1-20 mg / mL) and can be formulated for administration to any section of the eye of a subject in need thereof. In some embodiments, the compounds of the disclosure have a solubility of at least 0.1 mg / mL in an aqueous buffer and / or water, such as in an aqueous pharmaceutical composition suitable for ocular delivery. In some embodiments, the compounds of the disclosure have a solubility of at least 1 mg / mL in an aqueous buffer and / or water, such as in an aqueous pharmaceutical composition suitable for ocular delivery. Research suggests that GPX4 plays a crucial role in protecting retinal cells from oxidative stress and lipid peroxidation, which are believed to contribute to the development and progression of AMD. Oxidative stress occurs when there is an imbalance between the production of reactive oxygen species (ROS) and the body's ability to neutralize them with antioxidants. In the retina, which is highly metabolically active and exposed to light, oxidative stress can lead to damage to retinal cells, including those in the macula. Lipid peroxidation is a process in which reactive oxygen species attack and damage lipids (fatty acids) in cell membranes. This process can disrupt the integrity and function of retinal cells, including those in the macula, leading to cell death and the development of AMD. GPX4 is an enzyme that helps protect cells from oxidative damage by reducing lipid peroxides, the harmful byproducts of lipid peroxidation. It accomplishes this by using the antioxidant glutathione to neutralize lipid peroxides and prevent their damaging effects on cells.In the context of AMD, the activity of GPX4 may be compromised or insufficient, leading to increased oxidative stress and lipid peroxidation in the retina. This oxidative damage can contribute to the degeneration of retinal cells, including those in the macula, and the subsequent development and progression of AMD. GPX4 acts as a potent antioxidant enzyme that directly reduces lipid hydroperoxides, preventing their accumulation and subsequent oxidative damage. By utilizing glutathione as a cofactor, GPX4converts lipid hydroperoxides into their corresponding alcohols, thereby -15- 55240579.2 Attorney Docket No.047162-7485WO1(02576) neutralizing their harmful effects. This enzymatic activity of GPX4 is crucial in preventing ferroptosis. For instance, studies have shown that genetic or pharmacological inhibition of GPX4 leads to increased lipid peroxidation and subsequent ferroptotic cell death in various cell types. Iron plays a central role in ferroptosis, as it catalyzes the formation of lipid hydroperoxides through the Fenton reaction. GPX4 activation is closely linked to iron metabolism, as it can sequester and utilize free iron ions to catalyze the reduction of lipid hydroperoxides. By efficiently utilizing iron, GPX4 prevents its accumulation and subsequent lipid peroxidation, thereby protecting cells from ferroptotic death. This interplay between GPX4 and iron metabolism highlights the importance of GPX4 activation in preventing ferroptosis. In addition to its direct antioxidant activity, GPX4 also plays a crucial role in lipid repair. Lipid peroxidation can lead to the generation of highly reactive lipid species, such as 4-hydroxynonenal (4-HNE), which can further propagate oxidative damage. GPX4 activation helps in the removal of these reactive lipid species, preventing their detrimental effects on cellular membranes. This lipid repair function of GPX4 is essential for maintaining membrane integrity and preventing ferroptotic cell death. The activation of GPX4 is a critical factor in preventing ferroptotic cell death. Through its antioxidant activity, GPX4 efficiently reduces lipid hydroperoxides, preventing their accumulation and subsequent oxidative damage. Moreover, GPX4's role in iron metabolism and lipid repair further emphasizes its significance in safeguarding cellular integrity. Compounds In certain embodiments, the disclosure provides a compound of formula (I), or a salt, solvate, tautomer, and / or stereoisomer thereof (such as, but not limited to, a geometric isomer and / or enantiomer and / or diastereoisomer thereof): -16- 55240579.2 Attorney Docket No.047162-7485WO1(02576) (I), wherein: X1is N or CR1; R1(if present), R2, R3, and R4are independently selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, F, Cl, Br, I, and Y, with the proviso that at least one of R1(if present), R2, R3, and R4is Y; Y is -(CH2)m-G; m is 1, 2, 3, 4, 5, or 6; G is selected from the group consisting of: ; n is 0, 1, 2, 3, one of the X2is CR7, X3is CR8, and X4is CR13, or X2is N, X3is CR8, and X4is CR13, or X2is CR7, X3is N, and X4is CR13, or X2is CR7, X3is CR8, and X4is N; R5, R6, R7, R8, R9, R10, R11, R12, and R13(if present) are independently selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, F, Cl, Br, and I; R14and R15are independently H or C1-C6alkyl. In certain embodiments, X1is N. In certain embodiments, X1is CR1. In certain embodiments, X2is CR7, X3is CR8, and X4is CR13. In certain embodiments, X2is N, X3is CR7, and X4is CR8. In certain embodiments, X2is CR7, X3is N, and X4is CR8. In certain embodiments, X2is CR7, X3is CR8, and X4is N. In certain embodiments, R1is H. In certain embodiments, R1is CH3. In certain embodiments, R1is CH2CH3. In certain embodiments, R1is CH2CH2CH3. In certain embodiments, R1is CH(CH3)2. In certain embodiments, R1is F. In certain embodiments, R1is Cl. In certain embodiments, R1is Br. In certain embodiments, R1is I. In certain embodiments, R1is Y. -17- 55240579.2 Attorney Docket No.047162-7485WO1(02576) In certain embodiments, R2is H. In certain embodiments, R2is CH3. In certain embodiments, R2is CH2CH3. In certain embodiments, R2is CH2CH2CH3. In certain embodiments, R2is CH(CH3)2. In certain embodiments, R2is F. In certain embodiments, R2is Cl. In certain embodiments, R2is Br. In certain embodiments, R2is I. In certain embodiments, R2is Y. In certain embodiments, R3is H. In certain embodiments, R3is CH3. In certain embodiments, R3is CH2CH3. In certain embodiments, R3is CH2CH2CH3. In certain embodiments, R3is CH(CH3)2. In certain embodiments, R3is F. In certain embodiments, R3is Cl. In certain embodiments, R3is Br. In certain embodiments, R3is I. In certain embodiments, R3is Y. In certain embodiments, R4is H. In certain embodiments, R4is CH3. In certain embodiments, R4is CH2CH3. In certain embodiments, R4is CH2CH2CH3. In certain embodiments, R4is CH(CH3)2. In certain embodiments, R4is F. In certain embodiments, R4is Cl. In certain embodiments, R4is Br. In certain embodiments, R4is I. In certain embodiments, R4is Y. In certain embodiments, R5is H. In certain embodiments, R5is CH3. In certain embodiments, R5is CH2CH3. In certain embodiments, R5is CH2CH2CH3. In certain embodiments, R5is CH(CH3)2. In certain embodiments, R5is F. In certain embodiments, R5is Cl. In certain embodiments, R5is Br. In certain embodiments, R5is I. In certain embodiments, R6is H. In certain embodiments, R6is CH3. In certain embodiments, R6is CH2CH3. In certain embodiments, R6is CH2CH2CH3. In certain embodiments, R6is CH(CH3)2. In certain embodiments, R6is F. In certain embodiments, R6is Cl. In certain embodiments, R6is Br. In certain embodiments, R6is I. In certain embodiments, R7is H. In certain embodiments, R7is CH3. In certain embodiments, R7is CH2CH3. In certain embodiments, R7is CH2CH2CH3. In certain embodiments, R7is CH(CH3)2. In certain embodiments, R7is F. In certain embodiments, R7is Cl. In certain embodiments, R7is Br. In certain embodiments, R7is I. In certain embodiments, R8is H. In certain embodiments, R8is CH3. In certain embodiments, R8is CH2CH3. In certain embodiments, R8is CH2CH2CH3. In certain embodiments, R8is CH(CH3)2. In certain embodiments, R8is F. In certain embodiments, R8is Cl. In certain embodiments, R8is Br. In certain embodiments, R8is I. In certain embodiments, R9is H. In certain embodiments, R9is CH3. In certain embodiments, R9is CH2CH3. In certain embodiments, R9is CH2CH2CH3. In certain embodiments, R9is CH(CH3)2. In certain embodiments, R9is F. In certain embodiments, R9-18- 55240579.2 Attorney Docket No.047162-7485WO1(02576) is Cl. In certain embodiments, R9is Br. In certain embodiments, R9is I. In certain embodiments, R10is H. In certain embodiments, R10is CH3. In certain embodiments, R10is CH2CH3. In certain embodiments, R10is CH2CH2CH3. In certain embodiments, R10is CH(CH3)2. In certain embodiments, R10is F. In certain embodiments, R10is Cl. In certain embodiments, R10is Br. In certain embodiments, R10is I. In certain embodiments, R11is H. In certain embodiments, R11is CH3. In certain embodiments, R11is CH2CH3. In certain embodiments, R11is CH2CH2CH3. In certain embodiments, R11is CH(CH3)2. In certain embodiments, R11is F. In certain embodiments, R11is Cl. In certain embodiments, R11is Br. In certain embodiments, R11is I. In certain embodiments, R12is H. In certain embodiments, R12is CH3. In certain embodiments, R12is CH2CH3. In certain embodiments, R12is CH2CH2CH3. In certain embodiments, R12is CH(CH3)2. In certain embodiments, R12is F. In certain embodiments, R12is Cl. In certain embodiments, R12is Br. In certain embodiments, R12is I. In certain embodiments, R13is H. In certain embodiments, R13is CH3. In certain embodiments, R13is CH2CH3. In certain embodiments, R13is CH2CH2CH3. In certain embodiments, R13is CH(CH3)2. In certain embodiments, R13is F. In certain embodiments, R13is Cl. In certain embodiments, R13is Br. In certain embodiments, R13is I. In certain embodiments, X4is CR13, and R5and R13are not H. In certain embodiments, X4is N, and R5is not H. In certain embodiments, R14is H. In certain embodiments, R14is C1-C6 alkyl. In certain embodiments, R15is H. In certain embodiments, R15is C1-C6alkyl. In certain embodiments, Y is -(CH2)-G. In certain embodiments, Y is -(CH2)2-G. In certain embodiments, Y is -(CH2)3-G. In certain embodiments, Y is -(CH2)4-G. In certain embodiments, Y is -(CH2)5-G. In certain embodiments, Y is -(CH2)6-G. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5. In certain embodiments, m is 6. In certain embodiments, G is -N(R14)(R15). In certain embodiments, G is -OR14. In certain embodiments, G is . In certain embodiments, G is . In certain embodiments, G . In certain embodiments, G . In certain embodiments, . In certain -19- 55240579.2 Attorney Docket No.047162-7485WO1(02576) .In certain In certain embodiments, G is n is 0. In certain embodiments, n is 1. In certain n embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, the compound of formula (I) is a compound of formula (Ia): . In certain is a compound of formula (Ib): . In certain is selected from the group consisting of: , -20- 55240579.2 Attorney Docket No.047162-7485WO1(02576) . In group consisting . (Ic): . In -21- 55240579.2 Attorney Docket No.047162-7485WO1(02576) or In of: , stereocenter can exist independently in either the (R) or (S) configuration. In certain embodiments, compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds described herein encompass racemic, optically-active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the -22- 55240579.2 Attorney Docket No.047162-7485WO1(02576) therapeutically useful properties described herein. Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In certain embodiments, a mixture of one or more isomer is utilized as the therapeutic compound described herein. In other embodiments, compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis and / or separation of a mixture of enantiomers and / or diastereomers. Resolution of compounds and isomers thereof is achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography. The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and / or pharmaceutically acceptable salts of compounds having the structure of any compound(s) described herein, as well as metabolites and active metabolites of these compounds having the same type of activity. Solvates include water, ether (e.g., tetrahydrofuran, methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetates and the like. In certain embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, and ethanol. In other embodiments, the compounds described herein exist in unsolvated form. In certain embodiments, the compound(s) described herein can exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In certain embodiments, sites on, for example, the aromatic ring portion of compound(s) described herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the aromatic ring structures may reduce, minimize or eliminate this metabolic pathway. In certain embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a deuterium, a halogen, or an alkyl group. Compounds described herein also include isotopically-labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include and are not limited to2H,3H,11C,13C,14C,36Cl,18F,123I,125I,13N,15N,15O,17O,18O,32P, and35S. In certain embodiments, isotopically-labeled compounds are useful in drug and / or substrate -23- 55240579.2 Attorney Docket No.047162-7485WO1(02576) tissue distribution studies. In other embodiments, substitution with heavier isotopes such as deuterium affords greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements). In yet other embodiments, substitution with positron emitting isotopes, such as11C,18F,15O, and13N, is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. In certain embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. The compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein and as described, for example, in Fieser & Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4thEd., (Wiley 1992); Carey & Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000,2001), and Green & Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compound as described herein are modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formula as provided herein. Compounds described herein are synthesized using any suitable procedures starting from compounds that are available from commercial sources or are prepared using procedures described herein. In a non-limiting example, compounds of the disclosure can be prepared using illustrative procedures exemplified herein. In certain embodiments, an amine (which can be an optionally substituted 2-amino pyridine or an optionally substituted 2-amino pyrimidine, each of which can be commercially available or prepared according to methods known in the art) can be contacted with an optionally substituted 2-hydroxy benzaldehyde (which can be commercially available or prepared according to methods known in the art) in the presence of an acid (such as but not limited to formic acid, acetic acid, propionic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like) or a base (such as but not limited -24- 55240579.2 Attorney Docket No.047162-7485WO1(02576) to sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, Hunig’s base, pyridine, and the like) in a suitable solvent (such as but not limited to methanol, ethanol, (iso)propanol, acetonitrile, tetrahydrofuran, dimethylsulfoxide, chloroform, dichloromethane, and the like) to generate the corresponding imine. The imine can be purified from the reaction mixture or used as-is in the next reaction step. The imine can then be contacted with an optionally substituted phenyl isocyanide, optionally substituted 2-pyridine isocyanide, optionally substituted 3-pyridine isocyanide, or optionally substituted 4-pyridine isocyanide (each of which can be commercially available or prepared according to methods known in the art) in a suitable solvent (such as but not limited to methanol, ethanol, (iso)propanol, acetonitrile, tetrahydrofuran, dimethylsulfoxide, chloroform, dichloromethane, and the like) in the optional presence of an acid (such as but not limited to formic acid, acetic acid, propionic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like) or the optional presence of a base (such as but not limited to sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, Hunig’s base, pyridine, and the like), so as to generate the desired product, or an intermediate, analogue, or protected from thereof. In certain embodiments, an amine (an optionally substituted 2-amino pyridine or an optionally substituted 2-amino pyrimidine), an optionally substituted 2-hydroxy benzaldehyde, and an optionally substituted aromatic isocyanide can be reacted in a single pot reaction so as to generate the desired product, or an intermediate, analogue, or protected from thereof. with an aniline in the optional presence of an acid (such as but not limited to formic acid, acetic acid, propionic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, -25- 55240579.2 Attorney Docket No.047162-7485WO1(02576) phosphoric acid, and the like) and / or the optional presence of a base (such as but not limited to sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, Hunig’s base, pyridine, and the like) in a suitable solvent (such as but not limited to methanol, ethanol, (iso)propanol, acetonitrile, tetrahydrofuran, dimethylsulfoxide, chloroform, dichloromethane, and the like) to generate the corresponding alpha-anilino aromatic ketone, which can be reacted with a 2-amino pyridine or 2-amino pyrimidine in presence of an oxidant (such as but not limited to oxygen gas) and a Lewis acid (such as but not limited to zinc iodide) to generate the desired product, or an intermediate, analogue, or protected from thereof. See also Han et al., Synthesis 2016, 48, 351-356 (incorporated herein in its entirety by reference). The desired product can be isolated from the reaction mixture by (partial) removal of solvent from the reaction mixture, addition of water and / or any other suitable solvent to the reaction mixture, seeding, or any chemical / chromatographic method known in the art. In certain embodiments, reactive functional groups, such as hydroxyl, amino, imino, thio or carboxy groups, are protected in order to avoid their unwanted participation in reactions. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. In other embodiments, each protective group is removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal. In certain embodiments, protective groups are removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and / or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and are used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected -26- 55240579.2 Attorney Docket No.047162-7485WO1(02576) with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moieties are blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl, in the presence of amines that are blocked with acid labile groups, such as t-butyl carbamate, or with carbamates that are both acid and base stable but hydrolytically removable. In certain embodiments, carboxylic acid and hydroxy reactive moieties are blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids are blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties are protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or are blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while co- existing amino groups are blocked with fluoride labile silyl carbamates. Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and are subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid is deprotected with a palladium-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate is attached. As long as the residue is attached to the resin, that functional group is blocked and does not react. Once released from the resin, the functional group is available to react. Typically blocking / protecting groups may be selected from: -27- 55240579.2 Attorney Docket No.047162-7485WO1(02576) creation of protecting groups and their removal are described in Greene & Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosure. A skilled person will recognize that in various embodiments it can be advantageous to incorporate the compound into the pharmaceutical composition as a salt. Various counterions will be desirable for when employing different formulations and methods of administration and all pharmaceutically acceptable salts are contemplated for use with the present disclosure. In various embodiments, the pharmaceutical composition is formulated for ocular administration. Methods In one aspect, the disclosure provides a method of treating, ameliorating, and / or preventing AMD (such as, but not limited to, “dry” AMD) in a subject. In certain embodiments, the method comprises administering of a subject (such as a subject in need thereof) a therapeutically effective amount of a compound contemplated herein. In one aspect, the disclosure provides a method of treating, ameliorating, and / or preventing an anterior segment ocular disorder (such as but not limited to Fuchs endothelial corneal dystrophy (FECD), cataracts, ocular surface disease, glaucoma, and / or keratoconus). In certain embodiments, the method comprises administering of a subject (such as a subject in need thereof) a therapeutically effective amount of a compound contemplated herein. In one aspect, the disclosure provides a method of treating, ameliorating, and / or preventing blue light damage in a subject’s lens epithelial cell. In certain embodiments, the method comprises administering of a subject (such as a subject in need thereof) a therapeutically effective amount of a compound contemplated herein. Despite advancements in the understanding of the pathophysiology of atrophic AMD, approved therapies remain elusive for this form of the disease. The atrophic or “dry” form of AMD is characterized by loss of RPE cells with loss of photoreceptors and the choriocapillaris. While the etiology of AMD is not fully understood, it is clear that risk factors such as advanced age, cigarette smoking, diet, and genetic differences (including but not limited to race) play a role in the development of the disease. RPE cells are susceptible to oxidative stress and factors such as intense illumination into the eye or toxins in cigarettes contribute to the cumulative damage caused by this process. Moreover, antioxidant capacity decreases and the efficiency of reparative systems becomes impaired. Age-related damage to -28- 55240579.2 Attorney Docket No.047162-7485WO1(02576) Bruch’s membrane (BM) caused by risk factors such as cigarette smoking is also associated with aberrant RPE cell behavior. These changes are a hallmark of AMD and result in retinal dysfunction and cell loss seen in atrophic AMD. The presence of hydrogen peroxide in RPE cells catalyzes oxidation reactions and creates reactive oxygen species (ROS) which cause irreversible damage to cells. As people age, the ability of these cells to protect against ROS is compromised. Given the observation that mitochondrial DNA damage and repair in RPE is associated with aging and AMD, reducing oxidative stress is a viable therapeutic target. In certain embodiments, compounds of the disclosure prevent or minimize cell death caused by any cellular assault, which includes oxidative stress-related cellular assault or any other forms of cellular assault. Tert-butyl hydroperoxide (TBHP) exposure has been demonstrated to disrupt junctional integrity of the RPE and cause lipid peroxidation of the membrane bilayer as well as the oxidation of glutathione, endoplasmic reticulum Ca2+release, increased intracellular calcium ([Ca2+]), and increased mitochondrial inner membrane permeability. UV-B light damage has been shown to target mitochondrial DNA damage and produce reactive oxygen species. Chronic nitric oxide production and subsequent nitrite exposure by cigarette smoking is a risk factor strongly associated with AMD. These changes contribute to the cumulative damage to the BM and result in the age-related collagen cross linking, a decline in collagen solubility, and subsequent membrane damage. In the examples below, treatment with one or more of the compounds of the disclosure promotes cell survival as measured by a cell viability assay when challenged with tert-butyl hydroperoxide causing oxidative stress-induced cellular dysfunction and death. In certain embodiments, compounds of the disclosure can exhibit protective effects by enhancing mitochondrial respiration. In certain embodiments, enhancing metabolic activity is a valid target for degenerative diseases such as AMD. In certain non-limiting embodiments, the compounds described herein act as selective agonists of GPX4 and / or prevent iron-dependent ferroptosis. The activation of GPX4, and / or enhancement of GPX4’s activity, by the compounds described herein reduces oxidative stress and lipid peroxidation in the retina, protecting retinal cells and slowing down the progression of AMD. Moreover, the activation of GPX4 by the compounds described herein can serve therapeutic benefit with other diseases associated with ferroptosis and oxidative damage including acute kidney injury, cancer, cardiovascular diseases, neurodegenerative diseases, and / or hepatic diseases. -29- 55240579.2 Attorney Docket No.047162-7485WO1(02576) Administration / Dosage / Formulations The regimen of administration may affect what constitutes an effective amount. The therapeutic formulations may be administered to the subject either prior to or after the onset of a disease and / or disorder contemplated herein. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation. Administration of the compositions of the present disclosure to a patient, preferably a mammal, more preferably a human, may be carried out using known procedures, at dosages and for periods of time effective to treat disease in the patient. An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the state of the disease or disorder in the patient; the age, sex, and weight of the patient; and the ability of the therapeutic compound to treat a disease and / or disorder contemplated herein in the patient. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily, or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A non-limiting example of an effective dose range for a therapeutic compound of the disclosure is from about 1 and 5,000 mg / kg of body weight / per day. One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation. Actual dosage levels of the active ingredients in the pharmaceutical compositions of this disclosure may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. In particular, the selected dosage level depends upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts. A medical doctor, e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of -30- 55240579.2 Attorney Docket No.047162-7485WO1(02576) the disclosure employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In particular embodiments, it is especially advantageous to formulate the compound in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. The dosage unit forms of the disclosure are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding / formulating such a therapeutic compound for the treatment of a disease and / or disorder contemplated herein in a patient. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. In certain embodiments, the compositions of the disclosure are administered to the patient in dosages that range from one to five times per day or more. In other embodiments, the compositions of the disclosure are administered to the patient in range of dosages that include, but are not limited to, once every day, every two, days, every three days to once a week, once every two weeks, once every three weeks, once per month, once every 2 months, once every 3 months, and / or once every 1-12 weeks. It is readily apparent to one skilled in the art that the frequency of administration of the various combination compositions of the disclosure varies from individual to individual depending on many factors including, but not limited to, age, disease or disorder to be treated, gender, overall health, and other factors. Thus, the disclosure should not be construed to be limited to any particular dosage regime and the precise dosage and composition to be administered to any patient is determined by the attending physical taking all other factors about the patient into account. Compounds of the disclosure for administration may be in the range of from about 1 µg to about 10,000 mg, about 20 µg to about 9,500 mg, about 40 µg to about 9,000 mg, about 75 µg to about 8,500 mg, about 150 µg to about 7,500 mg, about 200 µg to about 7,000 mg, about 350 µg to about 6,000 mg, about 500 µg to about 5,000 mg, about 750 µg to about 4,000 mg, about 1 mg to about 3,000 mg, about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 30 mg to about 1,000 mg, about 40 -31- 55240579.2 Attorney Docket No.047162-7485WO1(02576) mg to about 900 mg, about 50 mg to about 800 mg, about 60 mg to about 750 mg, about 70 mg to about 600 mg, about 80 mg to about 500 mg, and any and all whole or partial increments therein between. In some embodiments, the dose of a compound of the disclosure is from about 1 mg and about 2,500 mg. In some embodiments, a dose of a compound of the disclosure used in compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, a dose of a second compound as described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof. In certain embodiments, the compounds of the disclosure can be administered ophthalmically, for example via intraocular or periocular injection. In other embodiments, the compounds are administered in a gel or a pegylated material. In other embodiments, the compounds themselves are pegylated or conjugated to a long-lasting biological molecule. In yet other embodiments, the compounds are formulated for slow delivery to the eye, for example using contact lenses comprising a polymer that releases the drug slowly, using punctual plugs, and / or using any delivery methodology that is known in the art and compatible with the present compounds. In certain embodiments, the present disclosure is directed to a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound of the disclosure, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat, prevent, or reduce one or more symptoms of a disease and / or disorder contemplated herein in a patient. Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art. The pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, -32- 55240579.2 Attorney Docket No.047162-7485WO1(02576) emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and / or aromatic substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic agents. Routes of administration of any of the compositions of the disclosure include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual, intraocular, or topical. The compounds for use in the disclosure may be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, topical administration, and ophthalmic(including but not limited to topical, subconjunctival, subTenon’s, suprachoroidal, intravitreal, or subretinal), Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions that would be useful in the present disclosure are not limited to the particular formulations and compositions that are described herein. Oral Administration For oral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gelcaps. The compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. The tablets may be uncoated, or they may be coated by known techniques for elegance or to delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent. The present disclosure also includes a multi-layer tablet comprising a layer providing for the delayed release of one or more compounds of the disclosure, and a further layer providing for the immediate release of a medication for treatment of certain diseases or -33- 55240579.2 Attorney Docket No.047162-7485WO1(02576) disorders. Using a wax / pH-sensitive polymer mix, a gastric insoluble composition may be obtained in which the active ingredient is entrapped, ensuring its delayed release. Parenteral Administration For parenteral administration, the compounds of the disclosure may be formulated for injection or infusion, for example, intravenous, intramuscular, or subcutaneous injection or infusion, or for administration in a bolus dose and / or continuous infusion. Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and / or dispersing agents may be used. Ophthalmological Administrations The disclosure contemplates administering to the eye the compounds useful within the disclosure. Any ophthalmological formulations can be useful within the present disclosure, as well as they allow for application of the compounds useful within the disclosure to the eye. In a non-limiting example, the compositions of the disclosure may be in the form of a suspension or solution can then be stirred for a period of time (for example, 1 hour) after which the pH is adjusted to about 5-8, preferably about 6.5-7.5. The suspension or solution can be allowed to stir for up to about 24 hours after which it is used directly, diluted with buffer to a desired concentration, and / or lyophilized to provide a powder for reconstitution. The lyophilized powder can be suspended in an amount of water that will not dissolve the powder completely but will provide a fine suspension. This suspension can then be further formulated with a thickening agent to improve adherence to the eye. Thickening agents include, but are not limited to, carboxymethylcellulose, hydroxymethylcellulose (for example, at a concentration of about 0.05-5%), or other approved agents. In some embodiments, the thickening agent includes hydroxymethylcellulose. In some embodiments, the thickening agent includes carboxymethylcellulose. In some embodiments, the compound is in a dispersion formulation. In some embodiments, the dispersion formulation is aqueous. In some embodiments, the dispersion formulation is a suspension, colloid, or solution. In some embodiments, the dispersion formulation is a solid. In some embodiments, the dispersion formulation comprises a thickening agent. In some embodiments, the dispersion formulation comprises hydroxymethylcellulose. In some embodiments, the dispersion formulation comprises microcrystalline cellulose, methylcellulose, ethylcellulose, carboxymethylcellulose, ethylhydroxyethylcellulose, ethylmethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, -34- 55240579.2 Attorney Docket No.047162-7485WO1(02576) hydroxymethylcellulose. Additional Administration Forms Additional dosage forms of this disclosure include dosage forms as described in U.S. Patents Nos.6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790. Additional dosage forms of this disclosure also include dosage forms as described in U.S. Patent Applications Nos.20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820. Additional dosage forms of this disclosure also include dosage forms as described in PCT Applications Nos. WO 03 / 35041; WO 03 / 35040; WO 03 / 35029; WO 03 / 35177; WO 03 / 35039; WO 02 / 96404; WO 02 / 32416; WO 01 / 97783; WO 01 / 56544; WO 01 / 32217; WO 98 / 55107; WO 98 / 11879; WO 97 / 47285; WO 93 / 18755; and WO 90 / 11757. Controlled Release Formulations and Drug Delivery Systems In certain embodiments, the formulations of the present disclosure may be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release and pulsatile release formulations. The term sustained release is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially constant blood levels of a drug over an extended time period. The period of time may be as long as a month or more and should be a release which is longer than the same amount of agent administered in bolus form. For sustained release, the compounds may be formulated with a suitable polymer or hydrophobic material which provides sustained release properties to the compounds. As such, the compounds for use within the methods of the disclosure may be administered in the form of microparticles, for example, by injection or in the form of wafers or discs by implantation. In certain embodiments, compounds of the disclosure are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation. The term delayed release is used herein in its conventional sense to refer to a drug formulation that provides for an initial release of the drug after some delay following drug administration and that mat, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours. The term pulsatile release is used herein in its conventional sense to refer to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma profiles of the drug after drug administration. -35- 55240579.2 Attorney Docket No.047162-7485WO1(02576) The term immediate release is used in its conventional sense to refer to a drug formulation that provides for release of the drug immediately after drug administration. As used herein, short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes and any or all whole or partial increments thereof after drug administration after drug administration. As used herein, rapid-offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all whole or partial increments thereof after drug administration. Dosing The therapeutically effective amount or dose of a compound of the present disclosure depends on the age, sex and weight of the patient, the current medical condition of the patient and the progression of AMD in the patient being treated. The skilled artisan is able to determine appropriate dosages depending on these and other factors. A suitable dose of a compound of the present disclosure may be in the range of from about 0.01 mg to about 5,000 mg per day, such as from about 0.1 mg to about 1,000 mg, for example, from about 1 mg to about 500 mg, such as about 5 mg to about 250 mg per day. The dose may be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day. When multiple dosages are used, the amount of each dosage may be the same or different. For example, a dose of 1 mg per day may be administered as two 0.5 mg doses, with about a 12-hour interval between doses. It is understood that the amount of compound dosed per day may be administered, in non-limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, with every other day administration, a 5 mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on. In the case wherein the patient’s status does improve, upon the doctor’s discretion the administration of the inhibitor of the disclosure is optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”). The length of the drug holiday optionally varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 -36- 55240579.2 Attorney Docket No.047162-7485WO1(02576) days, 320 days, 350 days, or 365 days. The dose reduction during a drug holiday includes from 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. Once improvement of the patient’s conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, is reduced, as a function of the viral load, to a level at which the improved disease is retained. In certain embodiments, patients require intermittent treatment on a long-term basis upon any recurrence of symptoms and / or infection. The compounds for use in the method of the disclosure may be formulated in unit dosage form. The term “unit dosage form” refers to physically discrete units suitable as unitary dosage for patients undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose. Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in cell cultures or experimental animals, including, but not limited to, the determination of the LD50(the dose lethal to 50% of the population) and the ED50(the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD50and ED50. The data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents were considered to be within the scope of this disclosure and covered by the claims appended hereto. For example, it should be understood, that modifications in reaction conditions, including but not limited to reaction times, reaction size / volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing / oxidizing agents, with art- recognized alternatives and using no more than routine experimentation, are within the scope -37- 55240579.2 Attorney Docket No.047162-7485WO1(02576) of the present application. It is to be understood that wherever values and ranges are provided herein, all values and ranges encompassed by these values and ranges, are meant to be encompassed within the scope of the present disclosure. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application. EXPERIMENTAL EXAMPLES The disclosure is further described in detail by reference to the following experimental examples. These examples are provided for purposes of illustration only and are not intended to be limiting unless otherwise specified. Thus, the disclosure should in no way be construed as being limited to the following examples, but rather, should be construed to encompass any and all variations which become evident as a result of the teaching provided herein. Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the compounds of the present disclosure and practice the claimed methods. The following working examples thus specifically point out the preferred embodiments of the present disclosure, and are not to be construed as limiting in any way the remainder of the disclosure. The materials and methods employed in practicing the following examples are here described: Human retinal pigment epithelial (RPE) cell culture Immortalized human RPE cells (ARPE-19) obtained from the American Type Culture Collection (ATCC, Manassas, VA, USA) were cultured in Dulbecco’s modified Eagle’s medium (DMEM; Thermo Fisher Scientific, Waltham, MA) containing 10% fetal bovine serum (FBS), 100 IU / mL penicillin, 100 μg / mL streptomycin, 100 μg / mL gentamicin, and 2.5 μg / mL amphotericin B (Thermo Fisher Scientific). Induction of oxidative stress using tert-butyl hydroperoxide Human ARPE-19 cells were plated in 96-well plates for 24 hours in DMEM supplemented with FBS and antibiotics. ARPE-19 cells were preincubated with either ciclopirox olamine (Sigma), compound C325-0414 (Chemical Diversity, San Diego, CA), -38- 55240579.2 Attorney Docket No.047162-7485WO1(02576) compound 434 (Chemical Diversity) or no compound for 24 hours and then exposed to varying concentrations of tert-butyl hydroperoxide (TBHP; Sigma-Aldrich, St. Louis, MO) the next day for 24 hours. Cell viability was measured the following day by RealTime-Glo™ MT cell viability assay (Promega, Madison, WI) using a BioTek FLx800™ fluorescence reader (BioTek, Winooski, VT). Nitrite modification of the extracellular matrix (ECM) Immortalized human RPE (ARPE-19) cells were obtained from the ATCC, cultured, and maintained in DMEM (Invitrogen-Gibco, Life Technologies) containing 10% FBS, 100 IU / mL penicillin, 100 μg / mL streptomycin, and 100 μg / mL gentamicin (Invitrogen-Gibco, Life Technologies). These cells were incubated in a humidified atmosphere of 5% CO2 and 95% air at 37°C. ARPE-19 cells were grown on 24-well Transwell®permeable supports (Corning, Inc.) in 12-well plates or flat bottom 24-well plates for 6–8 weeks to allow the ECM to form. ARPE-19 cells were then removed by the addition of 20 mM ammonium hydroxide buffer for 20 min, and the ECM was washed with phosphate buffered saline (PBS). PBS was removed from the RPE-ECM plates and dried. Subsequently, 100 mM sodium nitrite was added to the ECM and incubated at 37°C for 7 days. Plates were then washed with PBS and incubated with PBS for 4 hours. Finally, plates were washed with PBS to completely remove the nitrite. Cells are preincubated with drug for 24 hours and then seeded on nitrite-modified ECM for 24 hours. Cell viability was measured using RealTime-Glo MT assays (Promega) with a BioTek FLx800 fluorescence reader (Bio Tek, Winooski, VT). Induction of oxidative stress using blue light damage Human ARPE-19 cells were plated in 96-well plates for 24 hours in DMEM supplemented with FBS and antibiotics. The cells were preincubated with drug for 24 hours and then exposed to blue light (156.7 LUX for 36 hours). Cell viability was measured after 36 hours of blue light exposure using RealTime-Glo MT assays (Promega) with a BioTek FLx800 fluorescence reader (Bio Tek, Winooski, VT). Induction of ferroptosis in human RPE cells using RSL3 ((1S, 3R)-RSL3) or Erastin Human ARPE-19 cells were plated in 96-well plates for 24 hours in DMEM supplemented with FBS and antibiotics. The cells were preincubated with drug for 24 hours and then either 10nM RSL3 or 5 μM Erastin. Cell viability was measured after 36 hours of -39- 55240579.2 Attorney Docket No.047162-7485WO1(02576) exposure to RSL3 or Erastin using RealTime-Glo MT assays (Promega) with a BioTek FLx800 fluorescence reader (Bio Tek, Winooski, VT). Iron chelating ability assay The Ferrous Iron Chelating (FIC) assay was used for the testing (AmsBio, Cambridge, MA). Ciclopirox, C325-0414, DH464A, and EDTA were used as the positive control; test compound dissolved in DMSO (1 mM) was added to 50 μL of FeSO4and incubated for 10 min. After incubation, Ferrozine was added and the absorbance at 562nm was recorded with a BioTek Cytation 5 Cell Imaging Multimode Reader. Cellular thermal shift assay (CETSA) This experiment was performed according to the general CETSA protocol (Pelago Biosciences, Solna, Sweden; Martinez Molina et al. Science 2013) with detection by liquid chromatography–mass spectrometry (LC-MS) method and with implementation of a different concentration CETSA MS profiling strategy in the compressed format. The experiment includes protein stability assessment in cells treated with compound at up to four different concentrations, relative to the vehicle control. Treated cells were aliquoted and subjected to a heat challenge at 12 different temperatures, after which individual samples from all temperature points were pooled for each test condition. Aggregated proteins were removed using centrifugation and soluble protein amounts were measured using LC-MS. Activation of GPX4 in a Cell-Free Assay By coupling the oxidation of NADPH to NADP+by oxidized glutathione in the presence of glutathione reductase, the GPX4 activity was assessed by measuring the decrease in NADPH fluorescence emission at 460 nm (excitation at 335 nm). To evaluate the effects of imidazole C325-0414 on GPX4 activity, the compound was first preincubated with recombinant GPX4 (item no.26906; Cayman Chemical, Ann Arbor, MI) in the assay buffer of the glutathione peroxidase assay (item no.703102; Cayman Chemical). Each compound was dissolved in DMSO at a final concentration of 5%, which did not perturb the assay. Fluorescence signals were recorded on a plate reader (Synergy, BioTek). Control experiments were also conducted to confirm that the compounds were not glutathione reductase activators or inhibitors. Surface plasmon resonance (SPR) of GPX4 ligands -40- 55240579.2 Attorney Docket No.047162-7485WO1(02576) DH476A (FIG.7), DH404-AF (FIG.8), and DH464 (FIG.9) were tested using Cayman GPX4 to validate the binding of compounds to GPX4. Results show good binding of each compound to GPX4. DH464 shows the highest affinity among the group of compounds tested. Molecular Modeling Molecular docking was conducted using Molsoft software (Molsoft, LLC, San Diego, CA). PDB structure 6ELW was loaded into ICM-chemist pro and ICM Pocket Finder run to identify the major surface binding site. This site corresponded to that reported in the literature for GPX4 (Li et al., 2019). DH464A (FRX-002) was docked into this site via ICM Docking and the lowest energy pose reported. Statistical analysis All experiments were conducted at least three times with triplicates. Independent, two-tailed t tests were performed using Prism (GraphPad Software, Inc., La Jolla, CA). A criterion of α = 0.05 was adopted. General Methods: The solvents were purified according to the standard procedures. All other starting materials were purchased from commercial sources. Analytical TLC was performed using Polychrom SI F254 plates. Column chromatography was performed using Kieselgel Merck 60 (230–400 mesh) as the stationary phase.1H NMR spectra were recorded on a Varian Gemini 2000 spectrometer. was used as internal standard. Mass spectra were recorded on an Agilent 1100 LCMSD SL instrument [electrospray ionization (ESI)]. Example 1: Chemical Synthesis Synthesis of 4-Bromo-2-(7-((dimethylamino)methyl)-3-((2,6- dimethylphenyl)amino)imidazo-[1,2-a]pyridin-2-yl)phenol (DH464A). -41- 55240579.2 Attorney Docket No.047162-7485WO1(02576) of 4- ((dimethylamino)methyl)pyridin-2-amine(1) (1.20g, 7.9 mmol) in 1,4-dioxane (10 ml) in a sealed vial. The vial was flushed with argon and sealed with a Teflon cap. The reaction mixture was allowed to stir at 110 °C for 2 hours. The reaction was monitored by thin layer chromatography (TLC). After completion of the reaction, the reaction mixture was cooled to room temperature. After achieving the room temperature, solvent was evaporated under vacuum.100 mL of NaHCO3 (10% aqueous) were added to the mixture, which was then extracted with DCM (3 x 100 mL). The organic layer was dried over anhydrous sodium sulfate. The organic layer was concentrated under vacuum. The product was purified by the column chromatography over silica gel (DCM / MeOH = 20 / 1 v / v). Yield: 0.9650 g (26%). LCMS (Agilent 1200 LC / MSD SL, Rapid Resolution HT Cartridge 4.6x50mm, 1.8-Micron, Zorbx SB-C18 separation column) m / z = 466.8.1H NMR (δ, ppm): 13.25 (1.07H), 7.99 (1.06H), 7.81 (0.99H), 7.56 (1.00H), 7.30 (0.98H), 7.22 (0.98H), 7.04 (1.02H), 6.94 (1.95H), 6.84 (0.89H), 6.74 (0.99H), 3.48 (2.14H), 2.19 (5.75H), 1.90 (5.80H). Synthesis of -(7-((Dimethylamino)methyl)-3-((2,6-dimethylphenyl)amino)imidazo[1,2- a]pyridin-2-yl)-5-fluorophenol (4) (DH404AF) 1,3- dimethylbenzene(3) 0.8933g (6.81 mmol) were added to the solution of 4- ((dimethylamino)methyl)pyridin-2-amine(1) 1.03g (6.81 mmol) in MeOH (20ml) and 1ml -42- 55240579.2 Attorney Docket No.047162-7485WO1(02576) AcOH in sealed vial. The reaction mixture was stirred for 7 days at 20oC. The precipitate was filtered and washed with MeOH twice. Yield: 0.8g (29%). LCMS (Agilent 1200 LC / MSD SL, Rapid Resolution HT Cartridge 4.6x50mm, 1.8-Micron, Zorbx SB-C18 separation column) m / z = 405.0.1H NMR (δ, ppm): 13.59 (0.46H), 7.96 (1.03H), 7.77 (1.03H), 7.54 (1.00H), 7.22 (0.46H), 6.91 (3.06H), 6.71 (2.00H), 6.59 (1.06H), 3.45 (2.02H), 2.18 (6.07H), 1.89 (6.14H). Synthesis of 2-(7-(Azetidin-1-ylmethyl)-3-((2,6-dimethylphenyl)amino)imidazo[1,2- a]pyridin-2-yl)-4-bromophenol (DH476A) 1,3- dimethylbenzene(3) 0.7792g (5.94 mmol) were added to the solution of 4-(azetidin-1- ylmethyl)pyridin-2-amine (1) 0.97g (5.94 mmol) in MeOH (20ml) and 1ml AcOH in a sealed vial. The reaction mixture was stirred for 1 week at room temperature. The resulting mixture was purified with HPLC. Eluent: MeCN / H2O / HCOOH = 18 / 82 / 0.1. Yield: 0.83g (29%). LCMS (Agilent 1200 LC / MSD SL, Rapid Resolution HT Cartridge 4.6x50mm, 1.8-Micron, Zorbx SB-C18 separation column) m / z = 476.9.1H NMR (δ, ppm): 8.77 (0.98H), 8.06 (2.00H), 7.55 (1.00H), 7.17 (0.99H), 7.12 (0.99H), 6.82 (2.05H), 6.69 (2.12H), 4.65 (2.01H), 4.28 (4.00H), 3.29 (2.06H), 2.01 (6.14). General Synthesis of Imidazopyrimidines Imidazopyrimidines can be prepared via a three component coupling as shown below. -43- 55240579.2 Attorney Docket No.047162-7485WO1(02576) Imidazopyrimidines have added polar surface area versus imidazopyridine on the molecular surface versus and thus can increase solubility in aqueous solutions. Increased aqueous solubility may provide other additional benefits when administered to subjects for therapeutic purposes. Example 2: Protection of human retinal pigment epithelial (RPE) cells from oxidative stress-induced cell death As illustrated in FIG.1, a compound of the disclosure (DH464) was found to protect human retinal pigment epithelial (RPE) cells from oxidative stress-induced cell death. Human RPE cells were preincubated with 3 µM or 6 µM DH464A for 24 hours and then exposed to 300 µM tert-butyl hydroperoxide (TBHP) to induce cell death for 24 hours. Protective effects on human RPE cells treated with 3 µM or 6 µM of DH464A. ****p < 0.001. EC50= 2.09μM. TBHP, tertbutyl hydroperoxide. Enumerated Embodiments The following exemplary embodiments are provided, the numbering of which is not to be construed as designating levels of importance: Embodiment 1: A compound of formula (I): from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, F, Cl, Br, I, and Y, with the proviso that at least one of R1(if present), R2, R3, and R4is Y; Y is -(CH2)m-G; m is 1, 2, 3, 4, 5, or 6; -44- 55240579.2 Attorney Docket No.047162-7485WO1(02576) G is selected from the group consisting , ; n is 0, one of applies: X2is CR7, X3is CR8, and X4is CR13, or X2is N, X3is CR8, and X4is CR13, or X2is CR7, X3is N, and X4is CR13, or X2is CR7, X3is CR8, and X4is N; R5, R6, R7, R8, R9, R10, R11, R12, and R13(if present) are independently selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, F, Cl, Br, and I; R14and R15are independently H or C1-C6alkyl; or a salt, solvate, tautomer, and / or stereoisomer thereof. Embodiment 2: The compound of embodiment 1, wherein X1is N. Embodiment 3: The compound of embodiment 1, wherein X1is CR1. Embodiment 4: The compound of any one of embodiments 1-3, wherein X2is CR7, X3is CR8, and X4is CR13. Embodiment 5: The compound of any one of embodiments 1-3, wherein X2is N, X3is CR8, and X4is CR13. Embodiment 6: The compound of any one of embodiments 1-3, wherein X2is CR7, X3is N, and X4is CR13. Embodiment 7: The compound of any one of embodiments 1-3, wherein X2is CR7, X3is CR8, and X4is N. Embodiment 8: The compound of any one of embodiments 1-7, wherein R10is Br and / or wherein R11is Br or F. Embodiment 9: The compound of any one of embodiments 1-8, wherein R5, R6, R7, and R8(if present) are H. Embodiment 10: The compound of any one of embodiments 1-9, which is: -45- 55240579.2 Attorney Docket No.047162-7485WO1(02576) . which is selected , , -46- 55240579.2 Attorney Docket No.047162-7485WO1(02576) is selected , degeneration in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-12. Embodiment 14: The method of embodiment 13, wherein the retinal degeneration comprises age-related macular degeneration (AMD). Embodiment 15: The method of embodiment 13, wherein the retinal degeneration -47- 55240579.2 Attorney Docket No.047162-7485WO1(02576) comprises ‘dry’ AMD. Embodiment 16: A method of treating, ameliorating, and / or preventing an anterior segment ocular disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-12. Embodiment 17: The method of embodiment 16, wherein the disorder comprises at least one selected from the group consisting of Fuchs Endothelial Corneal Dystrophy, cataracts, ocular surface disease, glaucoma, and keratoconus. Embodiment 18: The method of treating, ameliorating, and / or preventing cell death, and / or promoting cell viability, in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-12. Embodiment 19: The method of embodiment 18, wherein the cell death comprises oxidative stress-induced cell death. Embodiment 20: The method of embodiment 18, wherein the cell comprises a lens epithelial cell. Embodiment 21: The method of embodiment 18, wherein the cell death is associated with at least one disease selected from the group consisting of heart failure and other cardiovascular; pulmonary fibrosis, kidney disease, diabetic macular edema and retinopathies, neurodegeneration, mitochondrial myopathy, Barth’s syndrome, and liver disease. Embodiment 22: A method of treating, ameliorating, and / or preventing blue light damage in a subject’s lens epithelial cell, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-12 Embodiment 23: The method of any one of embodiments 13-22, wherein the compound is formulated in a pharmaceutically acceptable composition further comprising at least one pharmaceutically acceptable excipient. Embodiment 24: The method of any of embodiments 13-20 and 22-23, wherein the compound is administered ocularly to the subject. Embodiment 25: The method of any one of embodiments 13-24, wherein the compound is one of the , -48- 55240579.2 Attorney Docket No.047162-7485WO1(02576) , of embodiments 1-12 and at least one pharmaceutically acceptable excipient. Embodiment 27: The pharmaceutical composition of embodiment 26, which is formulated for ocular administration. Embodiment 28: The pharmaceutical composition of any one of embodiments 26-27, which has pH of about 5-8. Embodiment 29: The pharmaceutical composition of any one of embodiments 26-28, which is lyophilized. Embodiment 30: The pharmaceutical composition of any one of embodiments 26-29, which further comprises a thickening agent. Embodiment 31: The pharmaceutical composition of any one of claims 26-30, wherein the pharmaceutical composition is a solid formulation. Embodiment 32: The pharmaceutical composition of 31, wherein the solid formulation comprises hydroxymethylcellulose. The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety. While this disclosure has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this disclosure may be devised by others skilled in the art without departing from the true spirit and scope of the disclosure. The -49- 55240579.2 Attorney Docket No.047162-7485WO1(02576) appended claims are intended to be construed to include all such embodiments and equivalent variations. -50- 55240579.2

Claims

Attorney Docket No.047162-7485WO1(02576) CLAIMS What is claimed is:

1. A compound of formula (I): wherein: 1X is N or R1(if present), R2, R3, and R4are independently selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, F, Cl, Br, I, and Y, with the proviso that at least one of R1(if present), R2, R3, and R4is Y; Y is -(CH2)m-G; m is 1, 2, 3, 4, 5, or 6; G is selected from the group consisting of: ; n is 0, 1, 2, 3,one of the following applies: X2is CR7, X3is CR8, and X4is CR13, or X2is N, X3is CR8, and X4is CR13, or X2is CR7, X3is N, and X4is CR13, or X2is CR7, X3is CR8, and X4is N; R5, R6, R7, R8, R9, R10, R11, R12, and R13(if present) are independently selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, F, Cl, Br, and I; -51- 55240579.2Attorney Docket No.047162-7485WO1(02576) R14and R15are independently H or C1-C6 alkyl; or a salt, solvate, tautomer, and / or stereoisomer thereof.

2. The compound of claim 1, wherein X1is N.

3. The compound of claim 1, wherein X1is CR1.

4. The compound of any one of claims 1-3, wherein X2is CR7, X3is CR8, and X4is CR13.

5. The compound of any one of claims 1-3, wherein X2is N, X3is CR8, and X4is CR13.

6. The compound of any one of claims 1-3, wherein X2is CR7, X3is N, and X4is CR13.

7. The compound of any one of claims 1-3, wherein X2is CR7, X3is CR8, and X4is N.

8. The compound of any one of claims 1-7, wherein R10is Br and / or wherein R11is Br or F.

9. The compound of any one of claims 1-8, wherein R5, R6, R7, and R8(if present) are H.

10. The compound of any one of claims 1-9, which is: .

11. The compound of any one of claims 1-10, which is selected from the group consisting of: -52- 55240579.2Attorney Docket No.047162-7485WO1(02576) .

12. The compound of any one of claims 1-11, which is selected from the group consisting of: -53- 55240579.2Attorney Docket No.047162-7485WO1(02576) ,13. A method of treating, ameliorating, and / or preventing retinal degeneration in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-12.

14. The method of claim 13, wherein the retinal degeneration comprises age-related macular degeneration (AMD).

15. The method of claim 13, wherein the retinal degeneration comprises ‘dry’ AMD.

16. A method of treating, ameliorating, and / or preventing an anterior segment ocular disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-12.

17. The method of claim 16, wherein the disorder comprises at least one selected from the group consisting of Fuchs Endothelial Corneal Dystrophy, cataracts, ocular surface disease, glaucoma, and keratoconus.

18. A method of treating, ameliorating, and / or preventing cell death, and / or promoting -54- 55240579.2Attorney Docket No.047162-7485WO1(02576) cell viability, in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-12.

19. The method of claim 18, wherein the cell death comprises oxidative stress-induced cell death.

20. The method of claim 18, wherein the cell comprises a lens epithelial cell.

21. The method of claim 18, wherein the cell death is associated with at least one disease selected from the group consisting of heart failure and other cardiovascular; pulmonary fibrosis, kidney disease, diabetic macular edema and retinopathies, neurodegeneration, mitochondrial myopathy, Barth’s syndrome, and liver disease.

22. A method of treating, ameliorating, and / or preventing blue light damage in a subject’s lens epithelial cell, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-12.

23. The method of any one of claims 13-22, wherein the compound is formulated in a pharmaceutically acceptable composition further comprising at least one pharmaceutically acceptable excipient.

24. The method of any of claims 13-20 and 22-23, wherein the compound is administered ocularly to the subject.

25. The method of any one of claims 13-24, wherein the compound is one of the following: ,-55- 55240579.2Attorney Docket No.047162-7485WO1(02576) , .

26. A claims 1-12 and at least one pharmaceutically acceptable excipient.

27. The pharmaceutical composition of claim 26, which is formulated for ocular administration.

28. The pharmaceutical composition of any one of claims 26-27, which has pH of about 5-8.

29. The pharmaceutical composition of any one of claims 26-28, which is lyophilized.

30. The pharmaceutical composition of any one of claims 26-29, which further comprises a thickening agent.

31. The pharmaceutical composition of any one of claims 26-30, wherein the pharmaceutical composition is a solid formulation.

32. The pharmaceutical composition of claim 31, wherein the solid formulation comprises hydroxymethylcellulose. -56- 55240579.2

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