Substituted imidazopyridines and imidazopyrimidines, and their use for treating, ameliorating, and / or preventing retinal degeneration

Abstract

The present disclosure provides a method for treating, improving, and / or preventing retinal degeneration in a subject, such as, but not limited to, anterior segment ocular disorder and / or age-related macular degeneration (AMD).In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound of the present disclosure.In some embodiments, the compound of the present disclosure prevents and / or minimizes cell attack, such as oxidative stress-related cell attack, and / or promotes cell survival. TIFF2025516315000053.tif138128

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 63 / 338,264, filed May 4, 2022, and U.S. Provisional Patent Application No. 63 / 411,405, filed September 29, 2022, all of which are incorporated by reference in their entireties. [Background technology]

[0002] background Retinal degeneration is the leading cause of incurable blindness worldwide. There are many forms of the disease, including retinitis pigmentosa (RP), known to be caused by approximately 200 different genetic defects; choroideremia; retinal ganglion cell atrophy in glaucoma; and age-related macular degeneration (AMD), the leading cause of blindness in elderly patients, affecting more than 8 million people in the United States alone. Due to the large number of patients with retinal degeneration and the rapidly aging population, the number of patients affected by these disorders is expected to increase in the future.

[0003] With the exception of vitamins and antioxidants recommended by the Age-Related Eye Disease Study, there is no effective treatment for the 90% of AMD patients with "dry" or atrophic AMD. There are no known treatments for the other retinal degenerations mentioned above. There is a need for treatments to slow or delay the onset and progression of retinal damage. As a specific example, there is a need to develop effective strategies to limit the progression of geographic atrophy (GA) and prevent the progression of dry AMD to wet AMD. The AMD treatment market in the United States, United Kingdom, Germany, France, Spain, Italy, and Japan alone will double in value from $5.3 billion in 2015 to $10.1 billion in 2023.

[0004] Retinal pigment epithelial (RPE) cells are essential for a properly functioning neurosensory retina. These cells form part of the RPE-Bruch's membrane-choroid complex and perform important functions to maintain 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).

[0005] Age-related changes in RPE cells are a hallmark of early AMD and contribute to the pathology and visual morbidity associated with advanced AMD. Oxidative stress is a contributor to these changes and is involved in other diseases for which aging is a risk factor, including Alzheimer's and Parkinson's diseases. Furthermore, Mendelian genetic diseases, such as most forms of RP, can be accelerated by the presence of oxidative stress, leading to degeneration of the neurosensory retina, e.g., photoreceptors. In vitro and in vivo studies have shown that oxidative stress can accelerate cone photoreceptor death in animal models of RP.

[0006] Diseases of the anterior segment of the eye, including the cornea, lens, and trabecular meshwork, are the leading cause of blindness worldwide. Oxidative stress and mitochondrial function are involved in these anterior segment diseases, including but not limited to Fuchs endothelial corneal dystrophy (FECD), cataract, glaucoma, and keratoconus.

[0007] Age-related changes in corneal endothelial cells are a hallmark of FECD and contribute to pathology and visual morbidity. FECD is a progressive, bilateral disease characterized by the gradual loss of corneal endothelial cells (CECs). The loss of CECs impairs the cornea's ability to retain moisture, resulting in a gradual loss of corneal transparency and therefore impaired vision. FECD is estimated to affect approximately 4% of the population, primarily those in their 40s and 50s. CECs are a highly metabolic cell type that are susceptible to mitochondrial dysfunction and oxidative damage due to exposure to sunlight, and the lack of a significant capacity for natural renewal of CECs. Increased oxidative stress in FECD corneas contributes to endothelial oxidative DNA damage, morphological changes, and CEC apoptosis.

[0008] Age-related cataract is the leading cause of vision loss in the elderly, affecting approximately 46% of the 180 million visually impaired people worldwide. Age-related changes in lens epithelial cells are a hallmark of cataract formation and contribute to pathology and visual morbidity. Increased oxidative stress is caused by factors such as ultraviolet light and hydrogen peroxide, both of which are risk factors for cataract development. Currently, the only effective treatment is extraction of the cataractous lens followed by implantation of an artificial intraocular lens (IOL). However, this surgery has several inherent risks of postoperative complications, such as stimulation of chronic inflammation, cystoid macular edema, corneal edema, endophthalmitis, retinal detachment, vitreous hemorrhage, and other disorders. In addition, inadequate surgical facilities and the high cost of artificial IOLs may be major limitations to treatment in developing countries.

[0009] Keratoconus is the leading cause of corneal transplantation in young people, accounting for approximately 25% of all transplants. Chronic keratocyte apoptosis, especially of the anterior stromal keratocytes, can lead to stromal thinning in keratoconus. Oxidative stress is one of the important factors contributing to the pathogenesis of keratoconus.

[0010] Oxidative stress, including oxidative damage to trabecular meshwork cells, has been implicated in the pathogenesis of glaucoma. A statistically significant correlation has been demonstrated between oxidative DNA damage and daily mean, minimum, and maximum intraocular pressure (IOP) values.

[0011] Therefore, there is a need for early intervention to protect or save RPE, so that intervention is beneficial and treats, improves, and / or prevents disease progression.Furthermore, there is a need for compositions and methods for treating, improving, and / or preventing anterior ocular disorders, such as, but not limited to, FECD, cataract, glaucoma, and / or keratoconus.The present disclosure addresses this need. Summary of the Invention

[0012] overview In one aspect, the present disclosure provides compounds of formula (I) and compositions comprising same: Provide TIFF2025516315000002.tif53128, where the variable R 2 ~R 6 , R 9 ~R 12 , and X 1 ~X 4 is defined elsewhere herein.

[0013] In another aspect, the present disclosure provides a compound of formula (II) and compositions comprising same: Provide TIFF2025516315000003.tif59128, where the variable R 1 ~R 13 is defined elsewhere herein.

[0014] In yet another aspect, the present disclosure provides a method for treating, ameliorating, and / or preventing retinal degeneration in a subject. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound and / or composition of the present disclosure.

[0015] In yet another aspect, the present disclosure provides a method for treating, ameliorating, and / or preventing an anterior segment eye disorder in a subject. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound and / or composition of the present disclosure.

[0016] In yet another aspect, the present disclosure provides a method for treating, ameliorating, and / or preventing cell death and / or promoting cell survival. In some embodiments, the method comprises administering to a subject a therapeutically effective amount of a compound and / or composition of the present disclosure.

[0017] In yet another aspect, the present disclosure provides a method for treating, ameliorating, and / or preventing blue light damage in lens epithelial cells of a subject. In some embodiments, the method comprises administering to a subject a therapeutically effective amount of a compound and / or composition of the present disclosure. [Brief description of the drawings]

[0018] The following detailed description of illustrative embodiments of the present disclosure will be better understood when read in conjunction with the accompanying drawings. For the purpose of illustrating the present 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.

[0019] (Figure 1) DH381-2 (4-bromo-2-(3-(pyridin-2-ylamino)imidazo[1,2-a]pyrimidin-2-yl)phenol) and DH421 (4-bromo-2-(3-((2-ethyl-6-methylphenyl)amino)imidazo[1,2-a]pyridin-2-yl)phenol) protected human retinal pigment epithelial (RPE) cells from oxidative stress-induced cell death. Human ARPE-19 cells (CRL-2302; American Type Culture Collection) were preincubated with 0.9 μM DH381-2 and DH421 for 24 h and then exposed to 300 μM tert-butyl hydroperoxide (TBHP) for 24 h to induce cell death. DH381-2 and DH421 significantly increased cell survival of human ARPE-19 cells after exposure to TBHP. ****p<0.0001. TIFF2025516315000004.tif30128 (Figure 2) DH421 protected human retinal pigment epithelium (RPE) cells from oxidative stress-induced cell death. Human ARPE-19 cells (CRL-2302; American Type Culture Collection) were preincubated with 0.9 μM DH421 for 24 h and then exposed to 250 μM tert-butyl hydroperoxide (TBHP) for 24 h to induce cell death. DH421 significantly increased cell survival of human ARPE-19 cells after exposure to TBHP and had no effect on cell proliferation inhibition. ****p<0.0001. (Figure 3) DH421 and DH381-2 protected human retinal pigment epithelium (RPE) cells from oxidative stress-induced cell death. Human ARPE-19 cells (CRL-2302; American Type Culture Collection) were preincubated with 0.6 μM of compounds DH421 or DH381-2 for 24 hours and then exposed to 300 μM tert-butyl hydroperoxide (TBHP) for 24 hours to induce cell death. Protective effect on human ARPE-19 cells treated with DH421 and DH381-2. ****p<0.0001. (Figure 4) DH421 and DH381-2 protected human retinal pigment epithelium (RPE) cells from blue light damage. Human ARPE-19 cells (CRL-2302; American Type Culture Collection) were pre-incubated with 0.6 μM of compounds DH421 or DH381-2 for 24 hours and then exposed to blue light (156.7 LUX, 36 hours). Protective effect of compounds DH421 or DH381-2 on human ARPE-19 cells exposed to blue light (156.7 LUX, 36 hours). Control = no compound used. *p<0.05, ***p<0.01. (FIG. 5) Treatment with compounds DH421 or DH381-2 enhanced human retinal pigment epithelial (RPE) cell survival on nitrite-modified extracellular matrix (ECM). Human ARPE-19 cells (CRL-2302; American Type Culture Collection) were treated with compounds DH421 or DH381-2 at 1 μM, 3 μM, and 10 μM, and then plated on nitrite-modified ECM and untreated (normal) ECM for 24 hours. Protective effect of compounds DH421 or DH381-2 on human ARPE-19 cells plated on nitrite-modified ECM. *p<0.05, **p<0.01. (Figure 6) DH421 or DH381-2 protected human retinal pigment epithelium (RPE) cells from oxidative stress-induced cell death. Human RPE cells were preincubated with 0.6 μM of compounds DH421 or DH381-2 for 24 hours and then exposed to 300 μM tert-butyl hydroperoxide (TBHP) for 24 hours to induce cell death. Protective effect on human RPE cells treated with DH421 and DH381-2. ****p<0.0001. (Figure 7) DH421 and DH381-2 protected human retinal pigment epithelium (RPE) cells from blue light damage. Human RPE cells were pre-incubated with 0.6 μM of compounds DH421 or DH381-2 for 24 hours and then exposed to blue light (156.7 LUX, 36 hours). Protective effect of compounds DH421 or DH381-2 on human RPE cells exposed to blue light (156.7 LUX, 36 hours). Control = no compound. *p<0.05, ***p<0.01. (Figure 8) Treatment with compounds DH421 or DH381-2 enhanced human retinal pigment epithelium (RPE) cell survival on nitrite-modified extracellular matrix (ECM). Human RPE cells were treated with 1 μM of compounds DH421 or DH381-2 and then plated on nitrite-modified ECM and untreated (normal) ECM for 24 hours. Protective effect of compounds DH421 or DH381-2 on RPE cells plated on nitrite-modified ECM. *p<0.05. (FIG. 9A) DH381-2 and DH421 improved mitochondrial function after oxidative stress-induced cell death in human retinal pigment epithelial (RPE) cells. Human RPE cells were preincubated with 1 μM of compounds DH381-2 and DH421 for 18 h and then treated with 300 μM tert-butyl hydroperoxide (TBHP) for 24 h. Oxygen consumption rate (OCR) was determined by a Seahorse XF analyzer to measure mitochondrial function. ATP production was significantly decreased in TBHP-treated cells compared to the control, while treatment with compounds DH381-2 or DH421 increased ATP production when compared to the TBHP-treated group. **p<0.001. (Figure 9B) See the description of Figure 9A. (Figure 10) Cytotoxicity levels in human retinal pigment epithelium (RPE) cells were not affected after treatment with compounds DH381-2 and DH421. Human RPE cells were pre-incubated with 1 μM of compounds DH381-2 and DH421 for 24 hours. Cytotoxicity was measured by CellTox Green cytotoxicity assay in human RPE cells after treatment with TBHP and compounds DH381-2 and DH421. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] Detailed Description definition Reference will now be made in detail to certain aspects 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 is understood that the exemplified subject matter is not intended to limit the scope of the appended claims to the disclosed subject matter.

[0021] In the methods described herein, acts may be performed in any order unless a temporal or operational order is expressly recited. Moreover, certain acts may be performed simultaneously unless express claim language recites them being performed separately. For example, a claimed act X and a claimed act Y may be performed simultaneously in a single operation, and the resulting process would fall within the literal scope of the claimed process.

[0022] Throughout this document, values ​​expressed in range format should be interpreted flexibly to include not only the numerical values ​​expressly recited as the limits of the range, but also all individual numerical values ​​or subranges subsumed within the range as if each numerical value and subrange were expressly recited. For example, the range "about 0.1% to about 5%" or "about 0.1% to 5%" should be interpreted to include not only about 0.1% to about 5%, but also the individual values ​​(e.g., 1%, 2%, 3%, and 4%) and subranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the stated range. The statement "about X to Y" has the same meaning as "about X to about Y" unless otherwise specified. Similarly, the statement "about X, Y, or about Z" has the same meaning as "about X, about Y, or about Z" unless otherwise specified.

[0023] In this document, the terms "a", "an", or "the" are used to include one or more unless the context clearly dictates otherwise. The term "or" is used to refer to a non-exclusive "or" unless otherwise specified. The statements "at least one of A and B" or "at least one of A or B" have the same meaning as "A, B, or A and B". Furthermore, it is to be understood that expressions or terms used herein, unless otherwise defined, are for illustrative purposes only and not for limiting purposes. The use of section headings is intended to aid in the reading of this document and should not be construed as limiting; information associated with a section heading may appear within or outside that particular section. All publications, patents, and patent documents referenced in this document are incorporated herein by reference in their entirety as if each was individually incorporated by reference.

[0024] As used herein, "about" when referring to a measurable value, such as an amount, time period, 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 variations are appropriate for performing the disclosed methods.

[0025] A disease or disorder is "alleviated" if the severity of the symptoms of the disease or disorder, the frequency with which the patient experiences such symptoms, or both, are reduced.

[0026] As used herein, “compound 414” or “YU162779-01” refers to ChemDiv library compound number C325-0414, or a salt and / or solvate thereof, and has the formula: TIFF2025516315000005.tif31128

[0027] As used herein, “compound 434” or “YU162787-01” refers to ChemDiv library compound number C325-0434, or a salt and / or solvate thereof, and has the formula: TIFF2025516315000006.tif31128

[0028] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound useful within the present disclosure and a pharma- ceutical acceptable carrier. Pharmaceutical compositions facilitate the administration of compounds to patients or subjects. There are multiple techniques of administering compounds in the art, including, but not limited to, intravenous administration, oral administration, aerosol administration, parenteral administration, ophthalmic administration (including, but not limited to, topical, subconjunctival, subtenon, suprachoroidal, intravitreal, or subretinal), pulmonary administration, and topical administration.

[0029] A "disease" is a condition in the health of an animal in which the animal is unable to maintain homeostasis and the health of the animal continues to deteriorate if the disease is not ameliorated.

[0030] In contrast, a "disorder" in an animal is a health state in which the animal is able to maintain homeostasis, but the health state of the animal is less favorable than it would be in the absence of the disorder. When left untreated, the disorder does not necessarily result in a further deterioration of the animal's health state.

[0031] A disease or disorder is "alleviated" if the severity of the symptoms of the disease or disorder, the frequency with which the patient experiences such symptoms, or both, are reduced.

[0032] As used herein, the term "DH381-2" corresponds to 4-bromo-2-(3-(pyridin-2-ylamino)imidazo[1,2-a]pyrimidin-2-yl)phenol, or a salt and / or solvate thereof: TIFF2025516315000007.tif32128C 17 H 12 BrN 5 O, molecular mass 382.21, monoisotopic mass 381.022. Mass spectrum analysis: m / z = 381.

[0033] As used herein, the term "DH421" corresponds to 4-bromo-2-(3-((2-ethyl-6-methylphenyl)amino)imidazo[1,2-a]pyridin-2-yl)phenol, or a salt and / or solvate thereof: TIFF2025516315000008.tif32128C 22 H 20 BrN 3 , molecular mass 422.318, monoisotopic mass 421.079. Mass spectrum analysis: m / z [M+H]=422.

[0034] As used herein, the terms "effective amount," "pharmacologically effective amount," and "therapeutically effective amount" refer to a non-toxic but sufficient amount of an agent to provide a desired biological result. The 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. The appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[0035] As used herein, the terms "independently selected from" or "independently selected from the group consisting of" refer to the groups referenced being the same, different, or a mixture thereof, unless the context clearly dictates otherwise. Thus, under this definition, "X 1 , X 2 , and X 3 is independently selected from the noble gases" is intended to include, for example, 1 , X 2 , and X 3 A scenario where all are equal, X 1 , X 2 , and X 3 All are different scenarios, X 1 and X 2 is the same but X 3 This includes different scenarios, and other similar permutations.

[0036] The terms "patient," "subject," "individual," and the like are used interchangeably herein to refer to any animal or cells thereof suitable for the methods described herein, whether in vitro or in situ. In one non-limiting embodiment, the patient, subject, or individual is a human.

[0037] As used herein, the term "pharmacologically acceptable" refers to a material, such as a carrier or diluent, that does not abrogate the biological activity and 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.

[0038] As used herein, the term "pharmaceutical acceptable carrier" refers to a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersant, matrix, suspending agent, diluent, excipient, thickener, solvent or encapsulating material, involved in carrying or transporting a compound useful within the present disclosure into or to a patient so that it can perform its intended function. Typically, such constructs are carried or transported from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation containing the compound useful within the present disclosure and not harmful to the patient. Some examples of materials which may serve as pharma- ceutically 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 carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; 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; buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffers; and other non-toxic compatible substances used in pharmaceutical formulations. As used herein, "pharmacologically acceptable carriers" also include any and all coatings, antibacterial and antifungal agents, absorption delaying agents, and the like, that are compatible with the activity of the compounds useful within the disclosure and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. "Pharmaceutically acceptable carriers" may further include pharma- ceutically acceptable salts of the compounds useful within the disclosure.Other additional ingredients that may be included in pharmaceutical compositions used in the practice of the present 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.

[0039] As used herein, the phrase "pharmaceutically acceptable salt" refers to a salt, solvate, hydrate, or clathrate thereof of the administered compound prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids or bases, organic acids or bases.

[0040] Suitable pharma- ceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Examples of inorganic acids include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric (including sulfate and hydrogen sulfate), and phosphoric acid (including hydrogen phosphate and dihydrogen phosphate). Suitable organic acids can be selected from the aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids, examples of which include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, malonic acid, saccharin, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactaric acid, and galacturonic acid.

[0041] Suitable pharmaceutically acceptable base addition salts of the compounds described herein include metal salts, including, for example, ammonium salts, alkali metal salts, alkaline earth metal salts, and transition metal salts, such as calcium salts, magnesium salts, potassium salts, sodium salts, 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 these salts may be prepared from the corresponding compound, for example, by reacting the compound with an appropriate acid or base.

[0042] The term "solvent" as used herein refers to a liquid capable of dissolving a solid, liquid, or gas. Non-limiting examples of solvents are silicones, organic compounds, water, alcohols, ionic liquids, and supercritical fluids.

[0043] As used herein, the term "substantially" refers to a majority or majority, such as 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" as used herein can mean completely free, or having such an insignificant amount of the substance that the amount of the substance present does not affect the material properties of the composition including the substance, and the composition is from about 0 wt% to about 5 wt% of the substance, or from 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" can mean that the composition has an insignificant amount of a substance, such as about 0 wt% to about 5 wt%, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or 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 less than, equal to, or greater than about 0 wt%.

[0044] A "therapeutic" treatment is a treatment administered to a subject who exhibits signs of pathology with the intent of reducing or eliminating those signs.

[0045] Ranges: Throughout this disclosure, various aspects of the disclosure may 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. Thus, the description of a range should be considered to specifically disclose all possible subranges as well as individual numerical values ​​within that range. For example, the description of a range such as 1-6 should be considered to specifically disclose subranges such as 1-3, 1-4, 1-5, 2-4, 2-6, 3-6 as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0046] explanation In its various aspects and embodiments, the present disclosure provides compounds and methods for the treatment, prevention, and / or amelioration of retinal degeneration, including but not limited to AMD.

[0047] In its various aspects and embodiments, the present 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, glaucoma, and / or keratoconus.

[0048] Without wishing to be limited by theory, in some 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 survival, where the cell is, for example, lens epithelial cells. In other embodiments, these compounds protect retinal cells, such as RPE cells, from blue light damage. Administration of the compounds of the present disclosure can induce the expression of oxidative stress and anti-apoptosis-related genes, thereby treating, improving, and / or preventing retinal degeneration, including but not limited to AMD, including but not limited to "dry" AMD.

[0049] The disclosure herein should not be construed as 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 reduce photoreceptor / neuron survival human diseases, including age-related macular degeneration (AMD), atherosclerosis, Alzheimer's disease, and others. Oxidative stress is a common mechanism by which cells and tissues are damaged in hyperoxic environments. Mechanisms vary depending on the disease process, but include mitochondrial damage and dysfunction, peroxide generation, free radical formation, and other mechanisms. Without loss of generality, drugs that prevent or reverse the effects of tissue damage due to oxidative stress are useful in slowing or reversing the progression of human diseases. Non-limiting examples of such diseases include heart failure and other cardiovascular, such as atherosclerosis; retinal degeneration, such as age-related macular degeneration; pulmonary fibrosis; renal (kidney) disease; diabetic macular edema and retinopathy; neurodegeneration, such as Alzheimer's disease; certain skeletal muscle disorders, such as mitochondrial myopathies and Barth syndrome; eye disorders and diseases, such as cataracts and glaucoma; and liver disease.

[0050] As described herein, the exemplary compounds of the present disclosure have been found to reduce the risk of oxidative damage in tissue culture models of disease.For example, compounds of the present disclosure have been shown to protect human retinal pigment epithelium (RPE) cells from oxidative stress-induced cell death, and are beneficial for treating, improving, and / or preventing diseases as contemplated herein.In a non-limiting embodiment, compounds of the present disclosure enhance metabolic functions such as adenosine triphosphate (ATP) production, basal respiration, maximum respiration, and spare respiration in RPE cells.

[0051] compound In certain embodiments, the present disclosure relates to 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): Provide TIFF2025516315000009.tif51128, During the ceremony, X 1 is N or CR 1 and; below: X 2 is N and X 3 is CR 7 and X 4 is CR 8 or X 2 is CR 7 and X 3 is N and X 4 is CR 8 or X 2 is CR 7 and X 3 is CR 8 and X 4 is N One of the following is true; R 1 (if present), R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 , H, CH 3 , C.H. 2 CH 3 , C.H. 2 CH 2 CH 3 , CH(CH 3 ) 2 , F, Cl, Br, and I.

[0052] In one embodiment, X 1 is N.

[0053] In one embodiment, X 1 is CR 1 It is.

[0054] In one embodiment, X 2 is N and X 3 is CR 7 and X 4 is CR 8 It is.

[0055] In one embodiment, X 2 is CR 7 and X 3 is N and X 4 is CR 8 It is.

[0056] In one embodiment, X 2 is CR 7 and X 3 is CR 8 and X 4 is N.

[0057] In one embodiment, R 1 is H. In some embodiments, R 1 CH 3 In some embodiments, R 1 CH 2 CH 3 In some embodiments, R 1 CH 2 CH 2 CH 3 In some embodiments, R 1 is CH(CH 3 ) 2 In some embodiments, R 1 is F. In some embodiments, R 1 is Cl. In some embodiments, R 1 is Br. In some embodiments, R 1 is I.

[0058] In one embodiment, R 2 is H. In some embodiments, R 2 CH 3 In some embodiments, R 2 CH 2 CH 3 In some embodiments, R 2 CH2 CH 2 CH 3 In some embodiments, R 2 is CH(CH 3 ) 2 In some embodiments, R 2 is F. In some embodiments, R 2 is Cl. In some embodiments, R 2 is Br. In some embodiments, R 2 is I.

[0059] In one embodiment, R 3 is H. In some embodiments, R 3 CH 3 In some embodiments, R 3 CH 2 CH 3 In some embodiments, R 3 CH 2 CH 2 CH 3 In some embodiments, R 3 is CH(CH 3 ) 2 In some embodiments, R 3 is F. In some embodiments, R 3 is Cl. In some embodiments, R 3 is Br. In some embodiments, R 3 is I.

[0060] In one embodiment, R 4 is H. In some embodiments, R 4 CH 3 In some embodiments, R 4 CH 2 CH 3 In some embodiments, R 4 CH 2 CH 2 CH 3 In some embodiments, R 4 is CH(CH 3 ) 2 In some embodiments, R 4 is F. In some embodiments, R 4is Cl. In some embodiments, R 4 is Br. In some embodiments, R 4 is I.

[0061] In one embodiment, R 5 is H. In some embodiments, R 5 CH 3 In some embodiments, R 5 CH 2 CH 3 In some embodiments, R 5 CH 2 CH 2 CH 3 In some embodiments, R 5 is CH(CH 3 ) 2 In some embodiments, R 5 is F. In some embodiments, R 5 is Cl. In some embodiments, R 5 is Br. In some embodiments, R 5 is I.

[0062] In one embodiment, R 6 is H. In some embodiments, R 6 CH 3 In some embodiments, R 6 CH 2 CH 3 In some embodiments, R 6 CH 2 CH 2 CH 3 In some embodiments, R 6 is CH(CH 3 ) 2 In some embodiments, R 6 is F. In some embodiments, R 6 is Cl. In some embodiments, R 6 is Br. In some embodiments, R 6 is I.

[0063] In one embodiment, R 7 is H. In some embodiments, R 7 CH3 In some embodiments, R 7 CH 2 CH 3 In some embodiments, R 7 CH 2 CH 2 CH 3 In some embodiments, R 7 is CH(CH 3 ) 2 In some embodiments, R 7 is F. In some embodiments, R 7 is Cl. In some embodiments, R 7 is Br. In some embodiments, R 7 is I.

[0064] In one embodiment, R 8 is H. In some embodiments, R 8 CH 3 In some embodiments, R 8 CH 2 CH 3 In some embodiments, R 8 CH 2 CH 2 CH 3 In some embodiments, R 8 is CH(CH 3 ) 2 In some embodiments, R 8 is F. In some embodiments, R 8 is Cl. In some embodiments, R 8 is Br. In some embodiments, R 8 is I.

[0065] In one embodiment, R 9 is H. In some embodiments, R 9 CH 3 In some embodiments, R 9 CH 2 CH 3 In some embodiments, R 9 CH 2 CH 2 CH 3 In some embodiments, R9 is CH(CH 3 ) 2 In some embodiments, R 9 is F. In some embodiments, R 9 is Cl. In some embodiments, R 9 is Br. In some embodiments, R 9 is I.

[0066] In one embodiment, R 10 is H. In some embodiments, R 10 CH 3 In some embodiments, R 10 CH 2 CH 3 In some embodiments, R 10 CH 2 CH 2 CH 3 In some embodiments, R 10 is CH(CH 3 ) 2 In some embodiments, R 10 is F. In some embodiments, R 10 is Cl. In some embodiments, R 10 is Br. In some embodiments, R 10 is I.

[0067] In one embodiment, R 11 is H. In some embodiments, R 11 CH 3 In some embodiments, R 11 CH 2 CH 3 In some embodiments, R 11 CH 2 CH 2 CH 3 In some embodiments, R 11 is CH(CH 3 ) 2 In some embodiments, R 11 is F. In some embodiments, R 11 is Cl. In some embodiments, R 11 is Br. In some embodiments, R 11is I.

[0068] In one embodiment, R 12 is H. In some embodiments, R 12 CH 3 In some embodiments, R 12 CH 2 CH 3 In some embodiments, R 12 CH 2 CH 2 CH 3 In some embodiments, R 12 is CH(CH 3 ) 2 In some embodiments, R 12 is F. In some embodiments, R 12 is Cl. In some embodiments, R 12 is Br. In some embodiments, R 12 is I.

[0069] In some embodiments, the compound of formula (I) has the formula (Ia): The compound is TIFF2025516315000010.tif53128.

[0070] In some embodiments, the compound of formula (I) has the formula (Ib): The compound is TIFF2025516315000011.tif54128.

[0071] In some embodiments, the compound of formula (I) is TIFF2025516315000012.tif127142.

[0072] In some embodiments, the compound of formula (I) is TIFF2025516315000013.tif130142.

[0073] In one embodiment, the compound is The file is TIFF2025516315000014.tif30128.

[0074] In certain embodiments, the present disclosure provides a compound of formula (II), or a salt, solvate, tautomer, and / or stereoisomer (such as, but not limited to, a geometric isomer and / or enantiomer and / or diastereoisomer thereof): Provide TIFF2025516315000015.tif60128, During the ceremony, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 10 , R 11 , R 12 , and R 13 , H, CH 3 , C.H. 2 CH 3 , C.H. 2 CH 2 CH 3 , CH(CH 3 ) 2 , F, Cl, Br, and I; R 5 and R 9 is CH 3 , C.H. 2 CH 3 , C.H. 2 CH 2 CH 3 , CH(CH 3 ) 2 , F, Cl, Br, and I.

[0075] In one embodiment, R 1 is H. In some embodiments, R 1 CH 3 In some embodiments, R 1 CH 2 CH 3 In some embodiments, R 1 CH 2 CH 2 CH 3 In some embodiments, R 1is CH(CH 3 ) 2 In some embodiments, R 1 is F. In some embodiments, R 1 is Cl. In some embodiments, R 1 is Br. In some embodiments, R 1 is I.

[0076] In one embodiment, R 2 is H. In some embodiments, R 2 CH 3 In some embodiments, R 2 CH 2 CH 3 In some embodiments, R 2 CH 2 CH 2 CH 3 In some embodiments, R 2 is CH(CH 3 ) 2 In some embodiments, R 2 is F. In some embodiments, R 2 is Cl. In some embodiments, R 2 is Br. In some embodiments, R 2 is I.

[0077] In one embodiment, R 3 is H. In some embodiments, R 3 CH 3 In some embodiments, R 3 CH 2 CH 3 In some embodiments, R 3 CH 2 CH 2 CH 3 In some embodiments, R 3 is CH(CH 3 ) 2 In some embodiments, R 3 is F. In some embodiments, R 3 is Cl. In some embodiments, R 3 is Br. In some embodiments, R 3 is I.

[0078] In one embodiment, R 4 is H. In some embodiments, R 4 CH 3 In some embodiments, R 4 CH 2 CH 3 In some embodiments, R 4 CH 2 CH 2 CH 3 In some embodiments, R 4 is CH(CH 3 ) 2 In some embodiments, R 4 is F. In some embodiments, R 4 is Cl. In some embodiments, R 4 is Br. In some embodiments, R 4 is I.

[0079] In one embodiment, R 5 CH 3 In some embodiments, R 5 CH 2 CH 3 In some embodiments, R 5 CH 2 CH 2 CH 3 In some embodiments, R 5 is CH(CH 3 ) 2 In some embodiments, R 5 is F. In some embodiments, R 5 is Cl. In some embodiments, R 5 is Br. In some embodiments, R 5 is I.

[0080] In one embodiment, R 6 is H. In some embodiments, R 6 CH 3 In some embodiments, R 6 CH 2 CH 3 In some embodiments, R 6CH 2 CH 2 CH 3 In some embodiments, R 6 is CH(CH 3 ) 2 In some embodiments, R 6 is F. In some embodiments, R 6 is Cl. In some embodiments, R 6 is Br. In some embodiments, R 6 is I.

[0081] In one embodiment, R 7 is H. In some embodiments, R 7 CH 3 In some embodiments, R 7 CH 2 CH 3 In some embodiments, R 7 CH 2 CH 2 CH 3 In some embodiments, R 7 is CH(CH 3 ) 2 In some embodiments, R 7 is F. In some embodiments, R 7 is Cl. In some embodiments, R 7 is Br. In some embodiments, R 7 is I.

[0082] In one embodiment, R 8 is H. In some embodiments, R 8 CH 3 In some embodiments, R 8 CH 2 CH 3 In some embodiments, R 8 CH 2 CH 2 CH 3 In some embodiments, R 8 is CH(CH 3 ) 2 In some embodiments, R 8 is F. In some embodiments, R 8is Cl. In some embodiments, R 8 is Br. In some embodiments, R 8 is I.

[0083] In one embodiment, R 9 CH 3 In some embodiments, R 9 CH 2 CH 3 In some embodiments, R 9 CH 2 CH 2 CH 3 In some embodiments, R 9 is CH(CH 3 ) 2 In some embodiments, R 9 is F. In some embodiments, R 9 is Cl. In some embodiments, R 9 is Br. In some embodiments, R 9 is I.

[0084] In one embodiment, R 10 is H. In some embodiments, R 10 CH 3 In some embodiments, R 10 CH 2 CH 3 In some embodiments, R 10 CH 2 CH 2 CH 3 In some embodiments, R 10 is CH(CH 3 ) 2 In some embodiments, R 10 is F. In some embodiments, R 10 is Cl. In some embodiments, R 10 is Br. In some embodiments, R 10 is I.

[0085] In one embodiment, R 11 is H. In some embodiments, R 11 CH 3 In some embodiments, R11 CH 2 CH 3 In some embodiments, R 11 CH 2 CH 2 CH 3 In some embodiments, R 11 is CH(CH 3 ) 2 In some embodiments, R 11 is F. In some embodiments, R 11 is Cl. In some embodiments, R 11 is Br. In some embodiments, R 11 is I.

[0086] In one embodiment, R 12 is H. In some embodiments, R 12 CH 3 In some embodiments, R 12 CH 2 CH 3 In some embodiments, R 12 CH 2 CH 2 CH 3 In some embodiments, R 12 is CH(CH 3 ) 2 In some embodiments, R 12 is F. In some embodiments, R 12 is Cl. In some embodiments, R 12 is Br. In some embodiments, R 12 is I.

[0087] In one embodiment, R 13 is H. In some embodiments, R 13 CH 3 In some embodiments, R 13 CH 2 CH 3 In some embodiments, R 13 CH 2 CH 2 CH 3 In some embodiments, R 13 is CH(CH 3) 2 In some embodiments, R 13 is F. In some embodiments, R 13 is Cl. In some embodiments, R 13 is Br. In some embodiments, R 13 is I.

[0088] In some embodiments, the compound of formula (II) has the formula (IIa): The compound is TIFF2025516315000016.tif53128.

[0089] In some embodiments, the compound of formula (II) has the formula (IIb): The compound is TIFF2025516315000017.tif59128.

[0090] In some embodiments, the compound of formula (II) has the formula (IIc): The compound is TIFF2025516315000018.tif53128.

[0091] In some embodiments, the compound of formula (II) has the formula (IId): The compound is TIFF2025516315000019.tif53128.

[0092] In some embodiments, the compound of formula (II) has the formula (IIe): The compound is TIFF2025516315000020.tif46128.

[0093] In some embodiments, the compound of formula (II) has the formula (IIf): The compound is TIFF2025516315000021.tif52128.

[0094] In some embodiments, the compound of formula (II) has the formula (IIg): The compound is TIFF2025516315000022.tif45128.

[0095] In some embodiments, the compound of formula (II) is The file is TIFF2025516315000023.tif30128.

[0096] The compounds described herein may have one or more stereocenters, and each stereocenter may independently exist in the (R) or (S) configuration. In certain embodiments, the compounds described herein exist in optically active or racemic forms. It should be understood that the compounds described herein encompass racemates, optically active forms, regioisomers and stereoisomers, or combinations thereof, that have the therapeutically useful properties described herein. Preparation of optically active forms is accomplished in any suitable manner, including, by way of non-limiting examples, resolution of racemates by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using chiral stationary phases. In certain embodiments, a mixture of one or more isomers is utilized as the therapeutic compounds described herein. In other embodiments, the compounds described herein include one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis, and / or separation of mixtures of enantiomers and / or diastereomers. Resolution of the compounds and their isomers is accomplished by any means, including, by way of non-limiting examples, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.

[0097] The methods and formulations described herein include the use of N-oxides (where appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and / or pharmaceutically acceptable salts of compounds having the structure of any of the compounds of the present invention, 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 some embodiments, the compounds described herein exist in solvated form with pharmaceutically acceptable solvents such as water and ethanol. In other embodiments, the compounds described herein exist in unsolvated form.

[0098] In certain embodiments, the compounds described herein may exist as tautomers, and all tautomers are included within the scope of the compounds presented herein.

[0099] In some embodiments, the compounds described herein are prepared as prodrugs. "Prodrug" refers to an agent that is converted to the parent drug in vivo. In some embodiments, when administered in vivo, prodrugs are chemically converted into the biologically active, pharmacologic or therapeutically active form of the compound. In other embodiments, prodrugs are enzymatically metabolized by one or more steps or processes into the biologically active, pharmacologic or therapeutically active form of the compound.

[0100] In some embodiments, for example, the site on the aromatic ring portion of the compounds described herein is susceptible to various metabolic reactions.The incorporation of suitable substituents in the aromatic ring structure can reduce, minimize, or eliminate this metabolic pathway.In some embodiments, suitable substituents for reducing or eliminating the susceptibility of aromatic ring to metabolic reactions are, by way of example only, deuterium, halogen, or alkyl group.

[0101] The compounds described herein also include isotopically labeled compounds, in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from that usually found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include: 2 H, 3 H, 11 C. 13 C. 14 C. 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O. 17 O. 18 O. 32 P, and 35 In some embodiments, isotope-labeled compounds are useful in drug and / or substrate tissue distribution studies. In other embodiments, substitution with heavier isotopes such as deuterium results in greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In yet other embodiments, 11 C. 18 F, 15 O, and 13 Substitution with positron emitting isotopes, such as N, is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds are prepared by any suitable method or process that employs an appropriately isotopically labeled reagent in place of a non-labeled reagent that would otherwise be used.

[0102] 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.

[0103] The compounds described herein, and other related compounds having different substituents, are described herein and in, for example, 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 4 th Ed., (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 their disclosure. The general methods for the preparation of the compounds described herein are modified by the use of appropriate reagents and conditions for the introduction of the various moieties found in the formulae as provided herein.

[0104] The compounds described herein are synthesized using any suitable procedure starting from compounds available from commercial sources or prepared using the procedures described herein.

[0105] In a non-limiting example, the compounds of the present disclosure can be prepared using the illustrative procedures illustrated in Example 1 herein. For example, an amine (which can be an optionally substituted 2-aminopyridine or an optionally substituted 2-aminopyrimidine, each of which can be commercially available or prepared according to methods known in the art) can be contacted with an optionally substituted 2-hydroxybenzaldehyde (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, etc.) or a base (such as, but not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, Hunig's base, pyridine, etc.) in a suitable solvent (such as, but not limited to, methanol, ethanol, (iso)propanol, acetonitrile, tetrahydrofuran, dimethylsulfoxide, chloroform, dichloromethane, etc.) to generate the corresponding imine. The imine can be purified from the reaction mixture or used directly in the next reaction step. The imine can then be contacted with an optionally substituted benzene isocyanide, an optionally substituted 2-pyridine isocyanide, an optionally substituted 3-pyridine isocyanide, or an optionally substituted 4-pyridine isocyanide (each of which may be commercially available or prepared according to methods known in the art) in a suitable solvent (e.g., but not limited to, methanol, ethanol, (iso)propanol, acetonitrile, tetrahydrofuran, dimethylsulfoxide, chloroform, dichloromethane, etc.) optionally in the presence of an acid (e.g., but not limited to, formic acid, acetic acid, propionic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.) or optionally in the presence of a base (e.g., but not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, Hunig's base, pyridine, etc.).The desired product can be isolated from the reaction mixture by (partial) removal of the solvent from the reaction mixture, by addition of water and / or any other suitable solvent to the reaction mixture, by seeding, or by any chemical / chromatographic method known in the art.

[0106] TIFF2025516315000024.tif167129

[0107] In some embodiments, reactive functional groups such as hydroxyl, amino, imino, thio or carboxy groups are protected to avoid their undesired participation in the reaction. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protecting group is removed. In other embodiments, each protecting group is removable by a different means. Protecting groups that are cleaved under completely different reaction conditions meet the requirement of differential removal.

[0108] In some embodiments, the protecting groups are removed by acid, base, reducing conditions (such as 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 hydrogenolysis-removable Cbz and base-labile Fmoc protected amino groups. Carboxylic acid and hydroxy reactive moieties are blocked with base labile groups such as t-butyl carbamate or amines blocked with carbamates that are both acid and base stable but hydrolytically removable.

[0109] In certain embodiments, carboxylic acid and hydroxy reactive moieties are blocked with hydrolytically removable protecting groups such as benzyl groups, 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 exemplified herein, including conversion to alkyl esters, or are blocked with oxidatively removable protecting groups such as 2,4-dimethoxybenzyl, while coexisting amino groups are blocked with fluoride labile silyl carbamates.

[0110] Allyl blocking groups are useful in the presence of acid and base protecting groups because the former are stable and subsequently removed by metal or pi-acid catalysts. For example, allyl-blocked carboxylic acids are deprotected in 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, its functional group is blocked and will not react. Once released from the resin, the functional group becomes available for reaction.

[0111] Typically, the blocking / protecting groups may be selected from: TIFF2025516315000025.tif83142

[0112] Detailed descriptions of other protecting groups and applicable techniques for the 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 disclosures.

[0113] Those skilled in the art will recognize that in various embodiments, it may be advantageous to incorporate compounds into pharmaceutical compositions as salts.When employing different formulations and administration methods, different counterions may be desirable, and all pharma-ceutically acceptable salts are contemplated for use in the present disclosure.In various embodiments, pharmaceutical compositions are formulated for ocular administration.

[0114] method In one aspect, the present disclosure provides a method of treating, ameliorating, and / or preventing AMD (such as, but not limited to, "dry" AMD) in a subject. In some embodiments, the method comprises administering to a subject (e.g., a subject in need thereof) a therapeutically effective amount of a compound contemplated herein.

[0115] In one aspect, the disclosure provides a method of treating, ameliorating, and / or preventing anterior segment ocular disorders, such as, but not limited to, Fuchs endothelial corneal dystrophy (FECD), cataracts, glaucoma, and / or keratoconus. In certain embodiments, the method comprises administering to a subject (e.g., a subject in need thereof) a therapeutically effective amount of a compound contemplated herein.

[0116] In one aspect, the present disclosure provides a method for treating, ameliorating, and / or preventing blue light damage in lens epithelial cells of a subject. In some embodiments, the method comprises administering to a subject (e.g., a subject in need thereof) a therapeutically effective amount of a compound contemplated herein.

[0117] Despite progress in understanding the pathophysiology of atrophic AMD, approved treatments for this form of the disease remain elusive. The atrophic or "dry" form of AMD is characterized by loss of RPE cells accompanied by loss of photoreceptors and choriocapillaris. Although the etiology of AMD is not fully understood, it is clear that risk factors such as advanced age, 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 strong illumination of the eye and toxins found in cigarettes contribute to the cumulative damage caused by this process. In addition, antioxidant capacity is reduced and the efficiency of the repair system is compromised. Age-related damage to Bruch's membrane (BM) caused by risk factors such as smoking is also associated with abnormal RPE cell behavior. These changes are hallmarks of AMD and result in the retinal dysfunction and cell loss seen in atrophic AMD. The presence of hydrogen peroxide in RPE cells catalyzes oxidative reactions, generating reactive oxygen species (ROS), which cause irreversible damage to the cells. As people age, the ability of these cells to protect against ROS is impaired.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 some embodiments, the compounds of the present disclosure prevent or minimize the cell death caused by any cell attack, including oxidative stress-related cell attack or any other form of cell attack.

[0118] Tert-butyl hydroperoxide (TBHP) exposure disrupts junctional integrity of the RPE and induces lipid peroxidation in the membrane bilayer, as well as oxidation of glutathione and endoplasmic reticulum Ca. 2+ release, and an increase in intracellular calcium ([Ca 2+]), and increased mitochondrial inner membrane permeability. UV-B light damage has been shown to target mitochondrial DNA damage and generate reactive oxygen species. Chronic nitric oxide production from smoking and subsequent nitrite exposure are risk factors strongly associated with AMD. These changes contribute to cumulative damage to BM, resulting in age-related collagen cross-linking, reduced collagen solubility, and subsequent membrane damage. In the following examples, treatment with one or more of the compounds of the present disclosure promotes cell survival as measured by cell viability assays when challenged with tert-butyl hydroperoxide, which causes oxidative stress-induced cell dysfunction and death. In some embodiments, the compounds of the present disclosure can show protective effects by enhancing mitochondrial respiration. In some embodiments, enhancing metabolic activity is a valid target for degenerative diseases such as AMD.

[0119] Administration / Dosage / Formulation Dosage regimen may affect what constitutes an effective amount.Therapeutic formulation may be administered to subject either before or after the onset of AMD.Furthermore, several divided doses, as well as staggered dosages, may be administered daily or sequentially, or the dose may be continuously infused or bolus injection.Furthermore, the dosage of therapeutic formulation may be increased or decreased proportionately when indicated by the exigencies of treatment or prevention situation.

[0120] Administration of the compositions of the present disclosure to a patient, preferably a mammal, more preferably a human, can be performed using known procedures at dosages and for periods of time effective to treat the disease in the patient. The effective amount of the therapeutic compound required to achieve a therapeutic effect can vary depending on 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 AMD in the patient. Dosage regimens can be adjusted to provide an optimal 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 treatment situation. A non-limiting example of an effective dose range for the therapeutic compounds of the present disclosure is about 1-5,000 mg / kg body weight / day. One of ordinary skill in the art would be able to study the relevant factors and make a determination regarding the effective amount of the therapeutic compound without undue experimentation.

[0121] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present disclosure may be varied 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 causing toxicity to the patient.

[0122] In particular, the selected dosage level will depend on a variety of factors, including the activity of the particular compound used, the time of administration, the rate of excretion of the compound, the duration of treatment, other drugs, compounds or substances used in combination with the compound, the age, sex, weight, condition, general health and previous medical history of the patient being treated, and similar factors well known in the medical arts.

[0123] A medical practitioner, such as a physician or veterinarian, having ordinary skill in the art can easily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian can start the dose of the compound of the present disclosure used in the pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

[0124] In certain embodiments, it is particularly advantageous to formulate compound in dosage unit form for ease of administration and uniformity of dosage.Dosage unit form as used herein refers to a physically separate unit suitable as a unitary dosage for the patient to be treated; each unit contains a predetermined amount of therapeutic compound calculated to produce desired therapeutic effect in association with required pharmaceutical vehicle.The dosage unit form of the present disclosure is determined by and directly depends on (a) the specific characteristics of therapeutic compound and the specific therapeutic effect to be achieved, and (b) the inherent limitations of the technology of compounding / preparing such therapeutic compound for treating AMD in patients.

[0125] The carrier can 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.

[0126] In some embodiments, the compositions of the present disclosure are administered to patients in dosages ranging from 1 to 5 times per day or more. In other embodiments, the compositions of the present disclosure are administered to patients in dosages ranging from, but not limited to, once per day, every 2 days, every 3 days, to once per week, once per 2 weeks, once per 3 weeks, once per month, once per 2 months, once per 3 months, and / or once per 1 to 12 weeks. It will be readily apparent to those skilled in the art that the frequency of administration of the various combination compositions of the present disclosure will vary from individual to individual depending on many factors, including but not limited to age, disease or disorder being treated, sex, general health, and other factors. Thus, the present disclosure should not be construed as being limited to any particular dosing regimen, and the exact dosage and composition administered to any patient will be determined by the attending physical, taking into account all other factors related to the patient.

[0127] The compound of the present disclosure for administration may be from about 1 μg to about 10,000 mg, from about 20 μg to about 9,500 mg, from about 40 μg to about 9,000 mg, from about 75 μg to about 8,500 mg, from about 150 μg to about 7,500 mg, from about 200 μg to about 7,000 mg, from about 350 μg to about 6,000 mg, from about 500 μg to about 5,000 mg, from about 750 μg to about 4,000 mg, from about 1 mg to about 3,000 mg, from about 10 mg to about 2,500 mg, from about 20 mg to about 2,000 mg, from about 25 mg to about 1,500 mg, from about 30 mg to about 1,000 mg, from about 40 mg to about 900 mg, from about 50 mg to about 800 mg, from about 60 mg to about 750 mg, from about 70 mg to about 600 mg, mg, in the range of about 80 mg to about 500 mg, and any and all whole or partial increments therebetween.

[0128] In some embodiments, the dosage of the disclosed compound is about 1 mg to about 2,500 mg. In some embodiments, the dosage of the disclosed compound used in the 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, the dose of the 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 total or partial increments thereof.

[0129] In some embodiments, the compounds of the present disclosure can be administered ophthalmologically, for example, by intraocular or periocular injection.In other embodiments, the compounds are administered in gels or PEGylated materials.In other embodiments, the compounds themselves are PEGylated or conjugated to long-lasting biomolecules.In still other embodiments, the compounds are formulated for slow delivery to the eye, for example, by using contact lenses that contain polymers that slowly release drug, by using punctual plugs, and / or by using any delivery method known in the art and compatible with the compounds.

[0130] 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 present disclosure, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat, prevent, or alleviate one or more symptoms of AMD in a patient.

[0131] The formulations can be used in admixture with conventional excipients, i.e., pharma- ceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration known in the art. Pharmaceutical preparations can be sterilized and mixed with auxiliary substances, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic buffers, coloring, flavoring and / or aromatic substances, if necessary. They can also be combined with other active agents, such as other analgesics, if desired.

[0132] The administration route of any of the compositions of the present disclosure includes oral, nasal, rectal, vaginal, parenteral, buccal, sublingual, intraocular, or topical.The compound for use in the present disclosure can be formulated for administration by any suitable route, such as oral or parenteral, for example, transdermal, transmucosal (e.g. sublingual, lingual, (trans)buccal, (trans)urethral, ​​vaginal (e.g. vaginal and perivaginal), nasal (intra) and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, topical administration, and ophthalmic (including but not limited to topical, subconjunctival, subtenon, suprachoroidal, intravitreal, or subretinal).

[0133] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gelcaps, 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 aerosol formulations for inhalation, compositions and formulations for intravesical administration, etc. It should be understood that the formulations and compositions that would be useful in the present disclosure are not limited to the specific formulations and compositions described herein.

[0134] Oral route For oral application, tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gelcaps are particularly suitable. Compositions intended for oral use may be prepared according to any method known in the art, and may contain one or more agents selected from the group consisting of inert, non-toxic, pharma- ceutically acceptable excipients suitable for the manufacture of tablets. Such excipients include, for example, inert diluents such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricants such as magnesium stearate. Tablets may be uncoated or may be coated by known techniques for aesthetics or to delay the release of the active ingredient. Formulations for oral use may also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert diluent.

[0135] The present disclosure also includes multi-layer tablets that include a layer that provides delayed release of one or more compounds of the present disclosure and an additional layer that provides immediate release of a drug for the treatment of a particular disease or disorder. A wax / pH-sensitive polymer mixture can be used to obtain a gastric insoluble composition in which the active ingredient is trapped to ensure its delayed release.

[0136] Parenteral Administration For parenteral administration, the compounds of the present disclosure can 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 oily or aqueous vehicles, optionally containing other formulating agents such as suspending agents, stabilizing agents and / or dispersing agents, can be used.

[0137] Ophthalmological Administration The present disclosure contemplates administering the compounds useful within the present disclosure to the eye. Any ophthalmic formulation may be useful within the present disclosure, as well as those that allow for the application of the compounds useful within the present disclosure to the eye.

[0138] In a non-limiting example, the composition of the present disclosure includes gamma cyclodextrin (or γ-cyclodextrin). A solution of gamma cyclodextrin can be prepared in water at a concentration up to its solubility limit of about 23.2 mg / mL. The pH of the cyclodextrin solution can then be adjusted to the pH at which the active compound is most soluble. The active compound is then added such that the molar ratio of gamma cyclodextrin to active compound ranges from about 1:1 to about 10:1. The resulting suspension or solution can then be stirred for a period of time (e.g., 1 hour), after which the pH is adjusted to about 5-8, preferably about 6.5-7.5. The suspension or solution can be stirred for up to about 24 hours, after which it can be used directly, diluted to the desired concentration with a buffer, and / or lyophilized to provide a powder for reconstitution. The lyophilized powder can be suspended in an amount of water that does not completely dissolve the powder but provides a fine suspension. The suspension can then be formulated with a thickening agent to improve adhesion to the eye. Viscosity enhancing agents include, but are not limited to, carboxymethylcellulose (e.g., at a concentration of about 0.05-5%), or other approved agents.

[0139] Additional Dosage Forms Additional dosage forms of the present disclosure include those described in U.S. Patent Nos. 6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790. Additional dosage forms of the present disclosure also include those described in U.S. Patent Application Publication Nos. 20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820. Additional dosage forms of the present disclosure also include those described in PCT Application 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.

[0140] 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 release formulations, rapid-offset formulations, or controlled release formulations, including sustained release formulations, delayed release formulations, and pulsatile release formulations.

[0141] The term sustained release is used in its conventional sense to refer to a drug formulation that provides gradual release of drug over an extended period of time and that can, but does not necessarily, result in a substantially constant blood concentration of drug over an extended period of time, which can be as long as a month or longer and should result in a longer release than would be obtained if the same amount of agent were administered in bolus form.

[0142] For sustained release, the compounds can be formulated with suitable polymeric or hydrophobic materials that provide sustained release properties to the compounds. Thus, the compounds for use in the methods of the present disclosure can be administered in the form of microparticles, for example by injection, or in the form of wafers or disks by implantation.

[0143] In certain embodiments, the compounds of the present disclosure are administered to a patient, alone or in combination with other pharmaceutical agents, using sustained release formulations.

[0144] The term delayed release is used in its conventional sense and refers herein to those drug formulations that provide an initial release of the drug after some delay following drug administration, and which may, but do not necessarily, include a delay of from about 10 minutes up to about 12 hours.

[0145] The term pulsatile release is used in its conventional sense herein to refer to such drug formulations that provide release of the drug in a manner that produces a pulsatile plasma profile of the drug following drug administration.

[0146] 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 administration.

[0147] As used herein, short-term refers to any period of time of 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 or less after drug administration, as well as any or all total or partial increments thereof after drug administration.

[0148] As used herein, rapid off-action refers to any period of 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 or less after drug administration, as well as any and all total or partial increments thereof.

[0149] dosage The therapeutically effective amount or dosage of the 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.Those skilled in the art can determine the appropriate dosage according to these and other factors.

[0150] Suitable doses of the compounds of the present disclosure may range from about 0.01 mg to about 5,000 mg per day, for example from about 0.1 mg to about 1,000 mg per day, for example from about 1 mg to about 500 mg, for example from about 5 mg to about 250 mg. The dose may be administered in a single dose or in multiple doses, for example from 1 to 4 or more times per day. When multiple doses are used, each dose 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 an interval of about 12 hours between doses.

[0151] It is understood that the amount of compound administered per day can be, in non-limiting examples, administered every day, every other day, every 2nd day, every 3rd day, every 4th day, or every 5th day. For example, every other day administration can start with a 5 mg dose per day on Monday, the first subsequent dose of 5 mg per day on Wednesday, the second subsequent dose of 5 mg per day on Friday, and so on.

[0152] If the patient's condition improves, at the physician's discretion, administration of the inhibitors of the present disclosure may be continued or the dose of the administered drug may be temporarily reduced or temporarily stopped (i.e., a "drug holiday") for a period of time. The length of the drug holiday may vary from 2 days to 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 days, 320 days, 350 days, or 365 days. Dose reductions during drug holidays include 10% to 100%, 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%.

[0153] Once the patient's condition is improved, maintenance doses are administered as necessary.Subsequently, depending on the viral load, dosage or frequency of administration, or both, are reduced to a level at which improved disease is maintained.In some embodiments, patients require long-term intermittent treatment when symptoms and / or infection recur.

[0154] The compounds for use in the disclosed methods may be formulated in unit dosage form. The term "unit dosage form" refers to a physically separate unit suitable as a single dosage for a patient undergoing treatment, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect, optionally with a suitable pharmaceutical carrier. The unit dosage form may be for one daily dose, or one of multiple daily doses (e.g., about 1-4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose.

[0155] The toxicity and therapeutic efficacy of such treatment regimens are optionally determined in cell cultures or experimental animals, and LD 50 (a dose lethal to 50% of the population) and ED 50 These include, but are not limited to, the determination of the dose that is therapeutically effective in 50% of the population. The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 and ED 50 The data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosages for use in humans. The dosage of such compounds is chosen so that it is possible to obtain a therapeutically effective dose that is minimally toxic and does not exceed the ED. 50 It is preferred that the dosage be within a circulating concentration range that includes the dosage form employed and the route of administration utilized.

[0156] Those skilled in the art will recognize or be able to ascertain using only routine experimentation many equivalents to the specific procedures, aspects, appended claims, and examples described herein.Such equivalents are considered to be within the scope of this disclosure and encompassed by the claims appended hereto.For example, it should be understood that variations in reaction conditions, including but not limited to reaction time, reaction size / volume, and experimental reagents, such as solvents, catalysts, pressure, ambient conditions, such as nitrogen atmosphere, and reducing / oxidizing agents, with art-recognized substitutions, and simply using routine experimentation, are within the scope of this application.

[0157] When values ​​and ranges are provided herein, it is to be understood that all values ​​and ranges subsumed within those values ​​and ranges are meant to be encompassed within the scope of the 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 this application. EXAMPLES

[0158] Experimental Example The present disclosure will be described in more detail with reference to the following experimental examples.These examples are provided for illustrative purposes only, and are not intended to be limiting unless otherwise specified.Therefore, the present disclosure should not be interpreted as being limited to the following examples in any way, but rather as encompassing any and all variations that become apparent as a result of the teachings provided herein.

[0159] 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 disclosed compounds and practice the claimed methods. Thus, the following examples specifically point out preferred aspects of the disclosure, and are not to be construed as limiting in any way the remainder of the disclosure.

[0160] The materials and methods used in carrying out the following examples are now described.

[0161] Human retinal pigment epithelium (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).

[0162] Induction of oxidative stress using tert-butyl hydroperoxide Human ARPE-19 cells were plated in 96-well plates in DMEM supplemented with FBS and antibiotics for 24 hours. ARPE-19 cells were pre-incubated with either ciclopirox olamine (Sigma), compound 414 (Chemical Diversity, San Diego, CA), compound 434 (Chemical Diversity) or without compound for 24 hours, and then exposed to various concentrations of tert-butyl hydroperoxide (TBHP; Sigma-Aldrich, St. Louis, MO) for 24 hours the next day. Cell viability was measured the next day by RealTime-Glo™ MT cell viability assay (Promega, Madison, WI) using a BioTek FLx800™ fluorescence reader (BioTek, Winooski, VT).

[0163] Nitrite modification of extracellular matrix (ECM) Immortalized human RPE (ARPE-19) cells were obtained from ATCC and 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 cultured and maintained in 5% CO at 37°C. 2 and incubated in a humidified atmosphere of 95% air. ARPE-19 cells were grown on 24-well Transwell® permeable supports (Corning, Inc.) in flat-bottom 24-well plates or 12-well plates for 6-8 weeks to allow for the formation of ECM. ARPE-19 cells were then removed by adding 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 allowed to dry. 100 mM sodium nitrite was then added to the ECM and incubated at 37°C for 7 days. The plates were then washed with PBS and incubated with PBS for 4 h. Finally, the plates were washed with PBS to completely remove the nitrite. Cells were preincubated with drugs for 24 h and then seeded on the nitrite-modified ECM for 24 h. Cell viability was measured using the RealTime-Glo MT assay (Promega) with a BioTek FLx800 fluorescence reader (Bio Tek, Winooski, VT).

[0164] Induction of oxidative stress using blue light damage Human ARPE-19 cells were plated in 96-well plates in DMEM supplemented with FBS and antibiotics for 24 hours. Cells were pre-incubated with drugs for 24 hours and then exposed to blue light (156.7 LUX, 36 hours). Cell viability was measured after 36 hours of blue light exposure using the RealTime-Glo MT assay (Promega) with a BioTek FLx800 fluorescence reader (Bio Tek, Winooski, VT).

[0165] statistical analysis All experiments were performed at least three times in triplicate. Independent two-tailed t-tests were performed using Prism (GraphPad Software, Inc., La Jolla, CA). A criterion of α = 0.05 was used.

[0166] Example 1: Chemical synthesis TIFF2025516315000026.tif73139

[0167] General method: Solvents were purified according to 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. 1 H NMR spectra were recorded on a Varian Gemini 2000 spectrometer. Tetramethylsilane was used as an internal standard. Mass spectra were recorded on an Agilent 1100 LCMSD SL instrument [electrospray ionization (ESI)].

[0168] General procedure: A solution of amine (2.0 mmol), aldehyde (2.0 mmol), and acetic acid (4.0 mmol) in 20 mL of methanol was stirred at 20 °C for 20 min. The reaction mixture was cooled and at 0 °C, isocyanide (2.0 mmol) was added in one portion. Stirring was continued at 20 °C for another 5-6 h (TCL monitoring). The product was crystallized from the reaction mixture or by adding a few drops of water. The product was collected by filtration, washed with water (3-10 mL), dried, and washed again with hexane (50 mL). The crude product was either crystallized (methanol) or purified by column chromatography (CH 2 Cl 2 -CH 3 OH, 15:5) to give a crystalline compound.

[0169] 4-Bromo-2-[3-(2-ethyl-6-methyl-anilino)imidazo[1,2-a]pyridin-2-yl]phenol (DH421). Brown powder. Yield: 73%. TIFF2025516315000027.tif31146

[0170] 4-Bromo-2-(3-(pyridin-2-ylamino)imidazo[1,2-a]pyrimidin-2-yl)phenol (DH381-2). Brown powder. Yield: 15%. TIFF2025516315000028.tif31143

[0171] Example 2: As shown in Figure 1, both DH381-2 (4-bromo-2-(3-(pyridin-2-ylamino)imidazo[1,2-a]pyrimidin-2-yl)phenol) and DH421 (4-bromo-2-(3-((2-ethyl-6-methylphenyl)amino)imidazo[1,2-a]pyridin-2-yl)phenol) protected human retinal pigment epithelial (RPE) cells from oxidative stress-induced cell death. Human ARPE-19 cells (CRL-2302; American Type Culture Collection) were preincubated with 0.9 μM DH381-2 and DH421 for 24 h and then exposed to 300 μM tert-butyl hydroperoxide (TBHP) for 24 h to induce cell death. DH381-2 and DH421 significantly increased cell survival of human ARPE-19 cells after exposure to TBHP. ****p<0.0001.

[0172] Example 3: As shown in Figure 2, DH421 protected human retinal pigment epithelium (RPE) cells from oxidative stress-induced cell death. Human ARPE-19 cells (CRL-2302; American Type Culture Collection) were preincubated with 0.9 μM DH421 for 24 h and then exposed to 250 μM tert-butyl hydroperoxide (TBHP) for 24 h to induce cell death. DH421 significantly increased cell survival of human ARPE-19 cells after exposure to TBHP and had no effect on cell proliferation inhibition. ****p<0.0001.

[0173] Example 4: As shown in Figure 3, both DH421 and DH381-2 protected human retinal pigment epithelium (RPE) cells from oxidative stress-induced cell death. Human ARPE-19 cells (CRL-2302; American Type Culture Collection) were pre-incubated with 0.6 μM of compound DH421 or DH381-2 for 24 hours, and then exposed to 300 μM tert-butyl hydroperoxide (TBHP) for 24 hours to induce cell death. Protective effect on human ARPE-19 cells treated with DH421 and DH381-2. ****p<0.0001.

[0174] Example 5: As shown in Figure 4, both DH421 and DH381-2 protected human retinal pigment epithelium (RPE) cells from blue light damage. Human ARPE-19 cells (CRL-2302; American Type Culture Collection) were pre-incubated with 0.6 μM of compound DH421 or DH381-2 for 24 hours, and then exposed to blue light (156.7 LUX, 36 hours). Protective effect of compound DH421 or DH381-2 on human ARPE-19 cells exposed to blue light (156.7 LUX, 36 hours). *p<0.05, ***p<0.01.

[0175] Example 6: As shown in Figure 5, treatment with compound DH421 or DH381-2 enhanced human retinal pigment epithelium (RPE) cell survival on nitrite-modified extracellular matrix (ECM). Human ARPE-19 cells (CRL-2302; American Type Culture Collection) were treated with 1 μM, 3 μM, and 10 μM of compound DH421 or DH381-2, and then seeded on nitrite-modified ECM and untreated (normal) ECM for 24 hours. Protective effect of compound DH421 or DH381-2 on human ARPE-19 cells seeded on nitrite-modified ECM. *p<0.05, **p<0.01.

[0176] Example 7: As shown in Figure 6, both DH421 and DH381-2 protected human retinal pigment epithelium (RPE) cells from oxidative stress-induced cell death. Human RPE cells were preincubated with 0.6 μM of compound DH421 or DH381-2 for 24 hours, and then exposed to 300 μM tert-butyl hydroperoxide (TBHP) for 24 hours to induce cell death. Protective effect on human RPE cells treated with DH421 and DH381-2. ****p<0.0001.

[0177] Example 8: As shown in Figure 7, both DH421 and DH381-2 protected human retinal pigment epithelium (RPE) cells from blue light damage. Human RPE cells were pre-incubated with 0.6 μM of compound DH421 or DH381-2 for 24 hours, and then exposed to blue light (156.7 LUX, 36 hours). Protective effect of compound DH421 or DH381-2 on human RPE cells exposed to blue light (156.7 LUX, 36 hours). *p<0.05, ***p<0.01.

[0178] Example 9: As shown in Figure 8, treatment with compound DH421 or DH381-2 enhanced human retinal pigment epithelium (RPE) cell survival on nitrite-modified extracellular matrix (ECM). Human RPE cells were treated with 1 μM compound DH421 or DH381-2, and then seeded on nitrite-modified ECM and untreated (normal) ECM for 24 hours. Protective effect of compound DH421 or DH381-2 on RPE cells seeded on nitrite-modified ECM. *p<0.05.

[0179] Example 10: As shown in Figures 9A-9B, both DH381-2 and DH421 improved mitochondrial function after oxidative stress-induced cell death in human retinal pigment epithelial (RPE) cells. Human RPE cells were pre-incubated with 1 μM of compounds DH381-2 and DH421 for 18 hours and then treated with 300 μM tert-butyl hydroperoxide (TBHP) for 24 hours. Oxygen consumption rate (OCR) was determined by a Seahorse XF analyzer to measure mitochondrial function. ATP production was significantly decreased in TBHP-treated cells compared to the control, while treatment with compounds DH381-2 or DH421 increased ATP production when compared to the TBHP-treated group. **p<0.001.

[0180] Example 11: As shown in Figure 10, the cytotoxicity level in human retinal pigment epithelium (RPE) cells was not affected after treatment with compounds DH381-2 and DH421. Human RPE cells were pre-incubated with 1 μM of compounds DH381-2 and DH421 for 24 hours. Cytotoxicity was measured by CellTox Green cytotoxicity assay in human RPE cells after treatment with TBHP and compounds DH381-2 and DH421.

[0181] Enumerated Aspects The following illustrative aspects are provided, the numbering of which should not be construed as indicating any level of importance. Embodiment 1: A compound of formula (I) or a salt, solvate, tautomer, and / or stereoisomer thereof: TIFF2025516315000029.tif53128In formula, X 1 is N or CR 1 and; below: X 2 is N and X 3 is CR 7 and X 4 is CR 8 or X 2 is CR 7 and X 3 is N and X 4 is CR 8 or X 2 is CR 7 and X 3 is CR 8 and X 4 is N One of the following is true; R 1 (if present), R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 H, CH 3 , C.H. 2 CH 3 , C.H. 2 CH 2 CH 3 , CH(CH 3 ) 2 , F, Cl, Br, and I. Aspect 2: X 1 The compound of claim 1, wherein is N. Aspect 3: X 1 CR 1 2. The compound of claim 1, wherein Aspect 4: X2 is N and X 3 CR 7 and X 4 CR 8 The compound according to any one of claims 1 to 3, wherein Aspect 5: X 2 CR 7 and X 3 is N and X 4 CR 8 The compound according to any one of claims 1 to 3, wherein Aspect 6: X 2 CR 7 and X 3 CR 8 and X 4 The compound according to any one of claims 1 to 3, wherein is N. Aspect 7: R 10 The compound according to any one of claims 1 to 6, wherein is Br. Aspect 8: R 5 , R 6 , R 7 , and R 8 The compound according to any one of claims 1 to 7, wherein is H. Embodiment 9: The compound according to any one of claims 1 to 8, which is a compound of TIFF2025516315000030.tif53128. Embodiment 10: Formula (Ib): The compound according to any one of claims 1 to 8, which is a compound of TIFF2025516315000031.tif54128. Aspect 11: The compound according to any one of claims 1 to 9, selected from the group consisting of TIFF2025516315000032.tif122143. Aspect 12: 11. The compound according to any one of claims 1 to 8 and 10, selected from the group consisting of TIFF2025516315000033.tif126144. Aspect 13: The compound according to any one of claims 1 to 12, which is TIFF2025516315000034.tif30128. Embodiment 14: A compound of formula (II) or a salt, solvate, tautomer, and / or stereoisomer thereof: TIFF2025516315000035.tif60128 formula, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 10 , R 11 , R 12 , and R 13 , H, CH 3 , C.H. 2 CH 3 , C.H. 2 CH 2 CH 3 , CH(CH 3 ) 2 , F, Cl, Br, and I; R 5 and R 9 is CH 3 , C.H. 2 CH 3 , C.H. 2 CH 2 CH 3 , CH(CH 3 ) 2 , F, Cl, Br, and I. Aspect 15: R 11 15. The compound of claim 14, wherein is Br. Aspect 16: R 6 , R 7 , and R 8 The compound according to any one of claims 14 to 15, wherein is H. Aspect 17: The compound according to any one of claims 14 to 16, selected from the group consisting of TIFF2025516315000036.tif116148. Aspect 18: The compound according to any one of claims 14 to 17, selected from the group consisting of TIFF2025516315000037.tif109141. Aspect 19: The compound according to any one of claims 14 to 18, which is TIFF2025516315000038.tif45128. Aspect 20: The compound according to any one of claims 14 to 19, which is TIFF2025516315000039.tif30128. Embodiment 21: A method of treating, ameliorating, and / or preventing retinal degeneration in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 20. 22. The method of claim 21, wherein the retinal degeneration comprises age-related macular degeneration (AMD). 23. The method of claim 21, wherein the retinal degeneration comprises "dry" AMD. Embodiment 24: A method of treating, ameliorating, and / or preventing an anterior segment eye disorder in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-20. 25. The method of claim 24, wherein the disorder comprises at least one selected from the group consisting of Fuchs endothelial corneal dystrophy, cataracts, glaucoma, and keratoconus. Embodiment 26: A method of treating, ameliorating, and / or preventing cell death and / or promoting cell survival in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-20. 27. The method of claim 26, wherein said cell death comprises oxidative stress-induced cell death. 28. The method of claim 26, wherein the cells comprise lens epithelial cells. Embodiment 29: The method of claim 26, wherein said 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 retinopathy, neurodegeneration, mitochondrial myopathy, Barth syndrome, and liver disease. Embodiment 30: A method for treating, ameliorating, and / or preventing blue light damage in lens epithelial cells in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 20. Aspect 31: The method of any one of claims 21 to 30, wherein the compound is formulated in a pharma- ceutically acceptable composition further comprising at least one pharma- ceutically acceptable excipient. Embodiment 32: The method of any one of claims 21-28 and 30-31, wherein the compound is administered ocularly. Aspect 33: The compound is selected from the group consisting of: 33. The method of any one of claims 21 to 32, wherein the image is one of the following: TIFF2025516315000040.tif30128. Embodiment 34: A pharmaceutical composition comprising a compound according to any one of claims 1 to 20 and at least one pharma- ceutically acceptable excipient. Embodiment 35: The pharmaceutical composition of claim 34, formulated for ocular administration. Embodiment 36: A pharmaceutical composition according to any one of claims 34 to 35, comprising gamma cyclodextrin (γ-cyclodextrin). Embodiment 37: The pharmaceutical composition of any one of claims 34 to 36, having a pH of about 5 to 8. Embodiment 38: The pharmaceutical composition of any one of claims 34 to 37, which is lyophilized. Aspect 39: The pharmaceutical composition of any one of claims 34 to 38, further comprising a viscosity enhancing agent.

[0182] The disclosures of all patents, patent applications, and publications cited herein are hereby incorporated by reference in their entireties.

[0183] Although the present disclosure has been disclosed with reference to particular embodiments, it will be apparent that other embodiments and modifications of the present disclosure may be made by others skilled in the art without departing from the true spirit and scope of the present disclosure, and it is intended that the appended claims be construed to include all such embodiments and equivalent modifications.

Claims

1. Compounds of formula (I), or their salts, solvates, tautomers, and / or stereoisomers: During the ceremony, X 1 is N or CR 1 And; below: X 2 is N, and X 3 CR 7 and X 4 CR 8 is, or X 2 is CR 7 and X 3 is N, and X 4 is CR 8 or X 2 CR 7 X 3 CR 8 and X 4 is N One of the following applies; R 1 (If present), R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 H, CH 3 CH 2 CH 3 CH 2 CH 2 CH 3 CH(CH 3 ) 2 It is independently selected from the group consisting of F, Cl, Br, and I.

2. X 1 The compound according to claim 1, wherein is N.

3. X 1 CR 1 The compound according to claim 1.

4. X 2 N is X 3 CR 7 and X 4 CR 8 The compound according to claim 1.

5. X 2 CR 7 X 3 If N and X 4 CR 8 The compound according to claim 1.

6. X 2 CR 7 X 3 CR 8 and X 4 The compound according to claim 1, wherein is N.

7. R 10 The compound according to claim 1, wherein is Br.

8. R 5 , R 6 , R 7 , and R 8 The compound according to claim 1, wherein is H.

9. Equation (Ia): The compound according to claim 1, which is a compound of, or a salt thereof, solvate, tautomer, and / or stereoisomer thereof.

10. Formula (Ib): The compound according to claim 1, which is a compound of, or a salt thereof, solvate, tautomer, and / or stereoisomer thereof.

11. The following formula: The compound according to claim 1, which is a compound selected from the group consisting of, or a salt, solvate, tautomer, and / or stereoisomer thereof.

12. The following formula: The compound according to claim 1, which is a compound selected from the group consisting of, or a salt, solvate, tautomer, and / or stereoisomer thereof.

13. The following: The compound according to claim 1, which is a compound of, or a salt thereof, solvate, tautomer, and / or stereoisomer thereof.

14. Compounds of formula (II), or their salts, solvates, tautomers, and / or stereoisomers: During the ceremony, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 10 , R 11 , R 12 , and R 13 H, CH 3 CH 2 CH 3 CH 2 CH 2 CH 3 CH(CH 3 ) 2 Independently selected from the group consisting of F, Cl, Br, and I, R 5 and R 9 CH 3 CH 2 CH 3 CH 2 CH 2 CH 3 CH(CH 3 ) 2 It is independently selected from the group consisting of F, Cl, Br, and I.

15. R 11 The compound according to claim 14, wherein R is Br.

16. R 6 , R 7 , and R 8 The compound according to claim 14, wherein is H.

17. The following formula: The compound according to claim 14, which is a compound selected from the group consisting of, or a salt, solvate, tautomer, and / or stereoisomer thereof.

18. The following formula: The compound according to claim 14, which is a compound selected from the group consisting of, or a salt, solvate, tautomer, and / or stereoisomer thereof.

19. The following formula: The compound according to claim 14, which is a compound of, or a salt thereof, solvate, tautomer, and / or stereoisomer thereof.

20. The following: The compound according to claim 14, which is a compound of, or a salt thereof, solvate, tautomer, and / or stereoisomer thereof.

21. A pharmaceutical composition for treating, improving, and / or preventing retinal degeneration in a subject, comprising a therapeutically effective amount of the compound described in any one of claims 1 to 20.

22. The pharmaceutical composition according to claim 21, wherein the retinal degeneration includes age-related macular degeneration (AMD).

23. The pharmaceutical composition according to claim 21, wherein the retinal degeneration includes "dry" AMD.

24. A pharmaceutical composition for treating, improving, and / or preventing anterior segment ocular disorders in a subject, comprising a therapeutically effective amount of the compound described in any one of claims 1 to 20.

25. The pharmaceutical composition according to claim 24, wherein the disorder comprises at least one selected from the group consisting of Fuchs corneal endothelial dystrophy, cataract, glaucoma, and keratoconus.

26. A pharmaceutical composition comprising a therapeutically effective amount of the compound described in any one of claims 1 to 20 for treating, improving, and / or preventing cell death and / or promoting cell survival in a subject.

27. The pharmaceutical composition according to claim 26, wherein the cell death includes oxidative stress-induced cell death.

28. The pharmaceutical composition according to claim 26, wherein the cells include lens epithelial cells.

29. The pharmaceutical composition according to claim 26, wherein the cell death is associated with at least one disease selected from the group consisting of heart failure and other cardiovascular conditions; pulmonary fibrosis, kidney disease, diabetic macular edema and retinopathy, neurodegeneration, mitochondrial myopathy, Barth syndrome, and liver disease.

30. A pharmaceutical composition for treating, improving, and / or preventing blue light damage in target lens epithelial cells, comprising a therapeutically effective amount of the compound described in any one of claims 1 to 20.

31. The pharmaceutical composition according to claim 21, wherein the compound is formulated into a pharmaceutically acceptable composition comprising at least one pharmaceutically acceptable excipient.

32. The pharmaceutical composition according to claim 21, wherein the compound is administered orally.

33. The aforementioned compound is as follows: The pharmaceutical composition according to claim 21, which is one of the following, or a salt thereof, a solvate, a tautomer, and / or a stereoisomer thereof.

34. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20 and at least one pharmaceutically acceptable excipient.

35. The pharmaceutical composition according to claim 34, formulated for ocular administration.

36. The pharmaceutical composition according to claim 34, comprising gamma cyclodextrin (γ-cyclodextrin).

37. The pharmaceutical composition according to claim 34, having a pH of approximately 5 to 8.

38. The pharmaceutical composition according to claim 34, which is freeze-dried.

39. The pharmaceutical composition according to claim 34, further comprising a thickening agent.

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