Substituted imidazopyridines and imidazopyrimidines, and their use to treat, ameliorate and / or prevent retinal degeneration

Abstract

The present disclosure provides a method of treating, ameliorating and / or preventing retinal degeneration in a subject, such as, but not limited to, anterior segment of the eye disease and / or age-related macular degeneration (AMD). In certain embodiments, the methods comprise administering to the subject a therapeutically effective amount of a compound of the disclosure. In certain embodiments, the compounds of the present disclosure prevent and / or minimize cellular attacks, such as oxidative stress-related cellular attacks, and / or promote cell survival.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] Pursuant to 35 U.S.C. §119(e), this application claims priority to U.S. Provisional Patent Application Nos. 63 / 338,264, filed on May 4, 2022, and 63 / 411,405, filed on September 29, 2022, all of which are incorporated herein by reference in their entirety. Background Art

[0003] Retinal degeneration is the leading cause of incurable blindness worldwide. The disease occurs in many forms, including retinitis pigmentosa (RP), which is known to be caused by approximately 200 different genetic defects; choroideremia; retinal ganglion cell atrophy in glaucoma; and age-related macular degeneration (AMD), which is the leading cause of blindness in older patients, affecting more than 8 million people in the United States alone. Given the large number of patients with retinal degeneration and the rapidly increasing aging population, the number of patients affected by these disorders is expected to increase in the future.

[0004] Aside from vitamins and antioxidants recommended by the Age-Related Eye Disease Study, there are currently no effective treatments for the 90% of AMD patients who have the “dry” or atrophic form of AMD. There are also no known treatments for the other retinal degenerations listed above. Treatments that slow or delay the development and progression of retinal disorders are needed. As a specific example, effective strategies need to be developed to limit the progression of geographic atrophy (GA) and prevent progression from dry to wet AMD. The AMD treatment market in the United States, United Kingdom, Germany, France, Spain, Italy, and Japan alone is expected to double in value, from $5.3 billion in 2015 to $10.1 billion by 2023.

[0005] 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 in maintaining vision, including phagocytosis of photoreceptor outer segments, processing of retinoids, and polarized secretion of factors such as vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF).

[0006] Age-related changes in RPE cells are a hallmark of early AMD and contribute to the pathology and visual morbidity associated with late AMD. Oxidative stress, a factor that drives these changes, has also been implicated in other diseases for which aging is a risk factor, including Alzheimer's disease and Parkinson's disease. In addition, Mendelian disorders, such as most forms of RP, are also accelerated by the presence of oxidative stress, leading to degeneration of the neurosensory retina, such as photoreceptors. In vitro and in vivo studies have shown that oxidative stress accelerates the death of cone photoreceptors in animal models of RP.

[0007] Anterior segment diseases, including the cornea, lens, and trabecular meshwork, are the leading causes of blindness worldwide. Oxidative stress and mitochondrial dysfunction have been implicated in these anterior segment diseases, including but not limited to Fuchs' endothelial corneal dystrophy (FECD), cataracts, glaucoma, and keratoconus.

[0008] Age-related changes in the corneal endothelial cells are the hallmark of FECD and contribute to pathology and visual morbidity. FECD is a progressive bilateral disease characterized by the progressive loss of corneal endothelial cells (CECs). Loss of CECs impairs the cornea's ability to maintain hydration and leads to a progressive decrease in corneal transparency, which in turn causes decreased vision. It is estimated that approximately 4% of the population is affected by FECD, with the majority of these people being between the ages of 40 and 50. CECs are a highly metabolic cell type, and exposure to sunlight and the lack of a significant ability for CECs to naturally regenerate make them susceptible to mitochondrial dysfunction and oxidative damage. Increased oxidative stress in FECD corneas leads to endothelial oxidative DNA damage, morphological changes, and CEC apoptosis.

[0009] 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 the lens epithelium are the hallmark of cataract formation and contribute to pathology and visual morbidity. Factors such as ultraviolet light and hydrogen peroxide increase oxidative stress, both of which are risk factors for cataract development. Currently, the only effective treatment is removal of the cataractous lens followed by implantation of an intraocular lens (IOL). However, this surgery itself carries an inherent risk of postoperative complications such as irritation, chronic inflammation, cystic macular edema, corneal edema, endophthalmitis, retinal detachment, vitreous hemorrhage, and other disorders. In addition, inadequate surgical facilities and the high cost of artificial IOLs are also major limitations to treatment in developing countries.

[0010] Keratoconus is the leading cause of corneal transplantation in young people, accounting for approximately 25% of all transplants. Chronic keratocyte apoptosis, especially apoptosis of anterior stromal keratocytes, can lead to stromal thinning in keratoconus. Oxidative stress is one of the key factors in the pathogenesis of keratoconus.

[0011] Oxidative stress, including oxidative damage to trabecular meshwork cells, has been implicated in the pathogenesis of glaucoma. Statistically significant correlations have been shown between oxidative DNA damage and daily mean, minimum, and maximum intraocular pressure (IOP) values.

[0012] Therefore, it is necessary to take early intervention measures to protect or save RPE, because this intervention measure will be beneficial to treatment, improvement and / or prevention of disease progression. In addition, it is also necessary to be used to treat, improve and / or prevent the composition and method of anterior segment obstacle (such as but not limited to FECD, cataract, glaucoma and / or keratoconus). The present disclosure solves this demand. Summary of the invention

[0013] In one aspect, the present disclosure provides compounds of formula (I), and compositions comprising the compounds:

[0014]

[0015] The variable R 2 -R 6 , R 9 -R 12 and X 1 -X 4 Defined elsewhere in this document.

[0016] In another aspect, the present disclosure provides a compound of formula (II), and a composition comprising the compound:

[0017]

[0018] The variable R 1 -R 13 Defined elsewhere in this document.

[0019] In yet another aspect, the present disclosure provides a method for treating, ameliorating and / or preventing retinal degeneration in a subject. In certain embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound and / or composition of the present disclosure.

[0020] In yet another aspect, the present disclosure provides a method for treating, ameliorating and / or preventing anterior segment disorders in a subject. In certain embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound and / or composition of the present disclosure.

[0021] In yet another aspect, the present disclosure provides a method for treating, ameliorating and / or preventing cell death and / or promoting cell survival. In certain embodiments, the method comprises administering to a subject a therapeutically effective amount of a compound and / or composition of the present disclosure.

[0022] In yet another aspect, the present disclosure provides a method for treating, improving and / or preventing blue light damage to lens epithelial cells in a subject. In certain embodiments, the method comprises administering a therapeutically effective amount of a compound and / or composition of the present disclosure to the subject. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] The following detailed description of illustrative embodiments of the present disclosure will be better understood when read in conjunction with the accompanying drawings. To illustrate the present disclosure, specific embodiments are shown in the accompanying drawings. However, it should be understood that the present disclosure is not limited to the precise arrangements and tools of the embodiments shown in the accompanying drawings.

[0024] 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) protect 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 the cell survival rate of human ARPE-19 cells after exposure to TBHP. ****p<0.0001.

[0025]

[0026] Figure 2 : DH421 protects human retinal pigment epithelial (RPE) cells from oxidative stress-induced cell death. Human ARPE-19 cells (CRL-2302; American Type Culture Collection) were pre-incubated with 0.9 μM DH421 for 24 hours and then exposed to 250 μM tert-butyl hydroperoxide (TBHP) for 24 hours to induce cell death. DH421 significantly increased the cell viability of human ARPE-19 cells after exposure to TBHP and had no effect on cell growth inhibition. ****p<0.0001.

[0027] Figure 3: DH421 and DH381-2 protect human retinal pigment epithelial (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 DH421 or DH381-2 compounds for 24 hours and then exposed to 300 μM tert-butyl hydroperoxide (TBHP) for 24 hours to induce cell death. There was a protective effect on human ARPE-19 cells treated with DH421 and DH381-2. ****p<0.0001.

[0028] Figure 4 : DH421 and DH381-2 protect human retinal pigment epithelial (RPE) cells from blue light damage. Human ARPE-19 cells (CRL-2302; American Type Culture Collection) were pre-incubated with 0.6 μM of DH421 or DH381-2 compounds for 24 hours and then exposed to blue light (156.7 LUX, 36 hours). Compounds DH421 or DH381-2 have a protective effect on human ARPE-19 cells exposed to blue light (156.7 LUX, 36 hours). Control = no compound used. *p<0.05, ***p<0.01.

[0029] Figure 5 : Treatment with compound DH421 or DH381-2 enhances the survival of human retinal pigment epithelial (RPE) cells 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. Compound DH421 or DH381-2 has a protective effect on human ARPE-19 cells seeded on nitrite-modified ECM. *p<0.05, **p<0.01.

[0030] Figure 6 : DH421 or DH381-2 protects human retinal pigment epithelial (RPE) cells from oxidative stress-induced cell death. Human RPE cells 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. There was a protective effect on human RPE cells treated with DH421 and DH381-2. ****p<0.0001.

[0031] Figure 7: DH421 and DH381-2 protect human retinal pigment epithelial (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). Compound DH421 or DH381-2 has a protective effect on human RPE cells exposed to blue light (156.7 LUX, 36 hours). Control = no compound. *p<0.05, ***p<0.01.

[0032] Figure 8 : Treatment with compound DH421 or DH381-2 enhances the survival rate of human retinal pigment epithelial (RPE) cells on nitrite-modified extracellular matrix (ECM). Human RPE cells were treated with 1 μM of compound DH421 or DH381-2 and then seeded on nitrite-modified ECM and untreated (normal) ECM for 24 hours. Compound DH421 or DH381-2 has a protective effect on RPE cells seeded on nitrite-modified ECM. *p<0.05.

[0033] Figures 9A-9B DH381-2 and DH421 improve 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 of tert-butyl hydroperoxide (TBHP) for 24 hours. Oxygen consumption rate (OCR) was determined by Seahorse XF analyzer to measure mitochondrial function. ATP production was significantly reduced in TBHP-treated cells compared to the control group, however, compound DH381-2 or DH421 treatment increased ATP production when compared to the TBHP-treated group. **p<0.001.

[0034] Fig.10 : The cytotoxicity level of human retinal pigment epithelial (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. After treatment with TBHP and compounds DH381-2 and DH421, cytotoxicity in human RPE cells was measured by CellTox Green cytotoxicity assay. DETAILED DESCRIPTION

[0035] definition

[0036] Reference will now be made in detail to certain embodiments of the disclosed subject matter, examples of which are partially illustrated in the accompanying drawings.While the disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that the illustrated subject matter is not intended to limit the claims to the disclosed subject matter.

[0037] In the methods described herein, the acts may be performed in any order except where explicitly stated in a time or order of operations. In addition, certain acts may be performed simultaneously unless explicit claim language specifies that they may be performed separately. For example, a claimed act X and a claimed act Y may be performed simultaneously in a single operation, and the resulting method would fall within the literal scope of the claimed process.

[0038] In this document, numerical values ​​expressed in range format should be interpreted in a flexible manner to include not only the numerical values ​​explicitly stated as the limits of the range, but also all individual numerical values ​​or sub-ranges contained in the range, as if each numerical value and sub-range were explicitly stated. For example, a range of "about 0.1% to about 5%" or "about 0.1% to 5%" should be interpreted not only to include about 0.1% to about 5%, but also to include individual numerical values ​​(e.g., 1%, 2%, 3% and 4%) and sub-ranges within the specified range (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%). Unless otherwise specified, the expression "about X to Y" has the same meaning as "about X to about Y". Likewise, unless otherwise specified, the expression "about X, Y, or about Z" has the same meaning as "about X, about Y, or about Z."

[0039] In this document, unless the context clearly dictates otherwise, the terms "a", "an" or "the" are used to include one or more. Unless otherwise indicated, "or" is used to refer to a non-exclusive "or". The expressions "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". In addition, it should be understood that the phrases or terms used herein, unless otherwise qualified, are used for description only and not for limitation. The use of any section headings is intended to assist in reading this document and should not be construed as limiting; information related to the section headings may appear within or outside that particular section. All publications, patents, and patent documents mentioned in this document are incorporated herein by reference in their entirety, as if individually incorporated by reference.

[0040] As used herein, "about" when referring to a measurable value (e.g., an amount, a duration, etc.) refers to variations of ±20% or ±10%, more preferably ±5%, even more preferably ±1%, and still more preferably ±0.1% from the specified value, as these variations are suitable for performing the disclosed methods.

[0041] A disease or disorder is "alleviated" if there is a decrease in the severity of the symptoms of the disease or disorder, the frequency with which a patient experiences such symptoms, or both.

[0042] As used herein, "Compound 414" or "YU162779-01" refers to ChemDiv library compound number C325-0414, or a salt and / or solvate thereof, which has the formula:

[0043]

[0044] As used herein, "Compound 434" or "YU162787-01" refers to ChemDiv library compound number C325-0434, or a salt and / or solvate thereof, which has the formula:

[0045]

[0046] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound used in the present disclosure and a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a patient or subject. There are a variety of techniques for administering compounds in the art, including but not limited to intravenous, oral, aerosol, parenteral, ocular (including but not limited to topical, subconjunctival, sub-Tenon, suprachoroidal, intravitreal or subretinal), pulmonary, and topical administration.

[0047] "Disease" means a health condition in an animal in which the animal is unable to maintain homeostasis and in which the animal's health condition will continue to deteriorate if the disease is not ameliorated.

[0048] In contrast, a "disorder" in an animal is a healthy state in which the animal is able to maintain homeostasis, but the animal is not as healthy as it would be without the disorder. If untreated, the disorder will not necessarily lead to a further decline in the animal's health.

[0049] A disease or disorder is "alleviated" if there is a decrease in the severity of the symptoms of the disease or disorder, the frequency with which a patient experiences such symptoms, or both.

[0050] 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:

[0051]

[0052] C 17 H 12 BrN5O, molecular weight 382.21, and monoisotopic mass 381.022. Mass spectrometry: m / z = 381.

[0053] 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:

[0054]

[0055] C 22 H 20 BrN3, molecular weight 422.318, and monoisotopic mass 421.079. Mass spectrometry: m / z [M+H] = 422.

[0056] As used herein, the terms "effective amount", "pharmaceutically 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 a reduction and / or alleviation of the signs, symptoms or causes of a disease, or any other desired change in a biological system. One of ordinary skill in the art can determine the appropriate therapeutic amount in any individual case using routine experimentation.

[0057] As used herein, the term "independently selected from" or "independently selected from the group consisting of" refers to the same, different, or a mixture thereof, unless the context clearly indicates otherwise. 1 , X 2 and X 3 independently selected from inert gases (X 1 ,X 2 ,and X 3 are independently selected from noblegases)" would include situations where, for example, X 1 , X 2 , X 3 are the same, where X 1 , X 2 , X 3 are different, among which X 1 and X 2 Same but X 3 different, and other similar arrangements.

[0058] The terms "patient", "subject", "individual" and the like are used interchangeably herein and refer to any animal or cell thereof, whether in vitro or in situ, suitable for the methods described herein. In certain non-limiting embodiments, the patient, subject or individual is a human.

[0059] As used herein, the term "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively nontoxic, i.e., the material can be administered to a subject without causing undesirable biological effects and does not interact in a deleterious manner with any component of the composition in which it is contained.

[0060] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, stabilizer, dispersant, substrate, suspending agent, diluent, excipient, thickener, solvent or encapsulating material, which is involved in carrying or transporting the useful compounds of the present disclosure into the body or to the patient so that it can perform its intended function. Typically, such constructs will be carried or transported from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable", that is, compatible with the other ingredients in the formulation (including the useful compounds of the present disclosure) and will not cause harm to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; polyols, such as glycerol, 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; ethanol; phosphate buffered saline; and other nontoxic, compatible substances used in pharmaceutical formulations. As used herein, "pharmaceutically acceptable carriers" also include any and all coatings, antibacterial and antifungal agents, and absorption delaying agents that are compatible with the activity of the compounds useful in the present disclosure and that are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the composition. "Pharmaceutically acceptable carriers" may further include pharmaceutically acceptable salts of compounds useful in the present disclosure. Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the present disclosure are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0061] As used herein, the expression "pharmaceutically acceptable salt" refers to salts of the administered compound prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids or bases, organic acids or bases, solvates, hydrates or clathrates thereof.

[0062] Suitable pharmaceutically acceptable acid addition salts can be prepared from inorganic acids or from organic acids. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid (including sulfates and hydrogen sulfates) and phosphoric acid (including hydrogen phosphates and dihydrogen phosphates). Suitable organic acids may be selected from aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic acid classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, malonic, saccharin, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, p-aminobenzenesulfonic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric, salicylic, galactaric and galacturonic acid.

[0063] Suitable pharmaceutically acceptable base addition salts of the compounds described herein include, for example, ammonium salts, metal salts (including alkali metal, alkaline earth metal and transition metal salts, such as calcium, magnesium, potassium, sodium and zinc salts). Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts can be prepared from the corresponding compounds by, for example, reacting the compounds with an appropriate acid or base.

[0064] The term "solvent" as used herein refers to a liquid that can dissolve solids, liquids or gases. Non-limiting examples of solvents are siloxanes, organic compounds, water, alcohols, ionic liquids and supercritical fluids.

[0065] As used herein, the term "substantially" refers to most or most of, 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%. As used herein, the term "substantially free of" may refer to not containing or containing a small amount of material such that the amount of material present does not affect the material properties of the composition including the material, such that the composition is about 0 wt % to about 5 wt %, or about 0 wt % to about 1 wt %, or about 5 wt % or less of the material, or less than, equal to or greater than about 4.5 wt %, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01 or about 0.001 wt % or less. The term "substantially free of" can mean having a small amount such that the composition comprises from about 0 wt % to about 5 wt %, 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, or about 0 wt % of the material.

[0066] "Therapeutic" treatment refers to treatment administered to a subject displaying signs of a pathology with the goal of reducing or eliminating those signs.

[0067] Range: In the present disclosure, various aspects of the present 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 present disclosure. Therefore, the description of a range should be considered to have specifically disclosed all possible subranges and individual numerical values ​​within the range. For example, a description of a range such as 1 to 6 should be considered to have specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., and individual numbers within the range, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0068] illustrate

[0069] In its various aspects and embodiments, the present disclosure provides compounds and methods for treating, preventing and / or ameliorating retinal degeneration, including but not limited to AMD.

[0070] In its various aspects and embodiments, the present disclosure provides compounds and methods for treating, preventing and / or ameliorating anterior segment disorders of the eye, such as, but not limited to, Fuchs' endothelial corneal dystrophy (FECD), cataracts, glaucoma and / or keratoconus.

[0071] Do not wish to be limited by theory, in certain embodiments, these compounds protect retinal cells (such as RPE cells) from cell death (cell death induced by oxidative stress in non-limiting examples). In other embodiments, these compounds protect retinal cells (such as RPE cells) from cell death on damaged extracellular matrix. In other embodiments, these compounds improve cell survival rate, wherein the cell is, for example, lens epithelial cell. In other embodiments, these compounds protect retinal cells (such as RPE cells) from blue light damage. Using 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 "dryness" AMD.

[0072] The disclosure herein should not be construed as being limited to cell death induced by AMD and / or oxidative stress. Oxidative stress is associated with a variety of retinal degenerations, and oxidative stress has been shown to reduce photoreceptor / neuron survival rates in human diseases, including age-related macular degeneration (AMD), atherosclerosis, Alzheimer's disease, etc. Oxidative stress is a general mechanism by which cells and tissues are damaged in a hyperoxic environment. The mechanism varies depending on the disease process, but includes mitochondrial damage and dysfunction, peroxide production, free radical formation, and other mechanisms. Without loss of generality, drugs that prevent or reverse tissue damage caused by oxidative stress can be used to slow down or reverse the progression of human diseases. Non-limiting examples of such diseases include heart failure and other cardiovascular diseases, such as atherosclerosis; retinal degeneration, such as age-related macular degeneration; pulmonary fibrosis; renal (kidney) disease; diabetic macular edema and retinopathy; neurodegenerative diseases, such as Alzheimer's disease; certain skeletal muscle diseases, such as mitochondrial myopathy and Barth syndrome; ocular disorders and diseases, such as cataracts and glaucoma; and liver disease.

[0073] As described herein, exemplary compounds of the present disclosure are found to mitigate the risk of oxidative damage in disease tissue culture models. For example, compounds of the present disclosure are shown to protect human retinal pigment epithelial (RPE) cells from oxidative stress-induced cell death, and are conducive to treating, improving and / or preventing the diseases considered herein. In non-limiting embodiments, compounds of the present disclosure enhance metabolic functions in RPE cells, such as adenosine triphosphate (ATP) production, basal respiration, maximum respiration and spare respiration.

[0074] Compound

[0075] In certain embodiments, the present invention provides a compound of formula (I), or a salt, solvate, tautomer and / or stereoisomer thereof (such as but not limited to its geometric isomers and / or enantiomers and / or diastereomers):

[0076]

[0077] in:

[0078] X 1 N or CR 1 ;

[0079] One of the following applies:

[0080] X 2 It is N, X 3 Yes CR 7 , and X 4 Yes CR 8 ,or

[0081] X 2 Yes CR 7 , X 3 is N, and X 4 Yes CR 8 ,or

[0082] X 2 Yes CR 7 , X 3 Yes CR 8 , and X 4 is N;

[0083] 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 Independently selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, F, Cl, Br and I.

[0084] In certain embodiments, X 1 It is N.

[0085] In certain embodiments, X 1 Yes CR 1 .

[0086] In certain embodiments, X 2It is N, X 3 Yes CR 7 , and X 4 Yes CR 8 .

[0087] In certain embodiments, X 2 Yes CR 7 , X 3 is N, and X 4 Yes CR 8 .

[0088] In certain embodiments, X 2 Yes CR 7 , X 3 Yes CR 8 , and X 4 It is N.

[0089] In certain embodiments, R 1 is H. In certain embodiments, R 1 is CH3. In certain embodiments, R 1 is CH2CH3. In certain embodiments, R 1 is CH2CH2CH3. In certain embodiments, R 1 is CH(CH3)2. In certain embodiments, R 1 is F. In certain embodiments, R 1 is Cl. In certain embodiments, R 1 is Br. In certain embodiments, R 1 It's I.

[0090] In certain embodiments, R 2 is H. In certain embodiments, R 2 is CH3. In certain embodiments, R 2 is CH2CH3. In certain embodiments, R 2 is CH2CH2CH3. In certain embodiments, R 2 is CH(CH3)2. In certain embodiments, R 2 is F. In certain embodiments, R 2 is Cl. In certain embodiments, R 2 is Br. In certain embodiments, R 2 It's I.

[0091] In certain embodiments, R 3 is H. In certain embodiments, R 3 is CH3. In certain embodiments, R 3 is CH2CH3. In certain embodiments, R 3is CH2CH2CH3. In certain embodiments, R 3 is CH(CH3)2. In certain embodiments, R 3 is F. In certain embodiments, R 3 is Cl. In certain embodiments, R 3 is Br. In certain embodiments, R 3 It's I.

[0092] In certain embodiments, R 4 is H. In certain embodiments, R 4 is CH3. In certain embodiments, R 4 is CH2CH3. In certain embodiments, R 4 is CH2CH2CH3. In certain embodiments, R 4 is CH(CH3)2. In certain embodiments, R 4 is F. In certain embodiments, R 4 is Cl. In certain embodiments, R 4 is Br. In certain embodiments, R 4 It's I.

[0093] In certain embodiments, R 5 is H. In certain embodiments, R 5 is CH3. In certain embodiments, R 5 is CH2CH3. In certain embodiments, R 5 is CH2CH2CH3. In certain embodiments, R 5 is CH(CH3)2. In certain embodiments, R 5 is F. In certain embodiments, R 5 is Cl. In certain embodiments, R 5 is Br. In certain embodiments, R 5 It's I.

[0094] In certain embodiments, R 6 is H. In certain embodiments, R 6 is CH3. In certain embodiments, R 6 is CH2CH3. In certain embodiments, R 6 is CH2CH2CH3. In certain embodiments, R 6 is CH(CH3)2. In certain embodiments, R 6 is F. In certain embodiments, R 6 is Cl. In certain embodiments, R 6 is Br. In certain embodiments, R 6It's I.

[0095] In certain embodiments, R 7 is H. In certain embodiments, R 7 is CH3. In certain embodiments, R 7 is CH2CH3. In certain embodiments, R 7 is CH2CH2CH3. In certain embodiments, R 7 is CH(CH3)2. In certain embodiments, R 7 is F. In certain embodiments, R 7 is Cl. In certain embodiments, R 7 is Br. In certain embodiments, R 7 It's I.

[0096] In certain embodiments, R 8 is H. In certain embodiments, R 8 is CH3. In certain embodiments, R 8 is CH2CH3. In certain embodiments, R 8 is CH2CH2CH3. In certain embodiments, R 8 is CH(CH3)2. In certain embodiments, R 8 is F. In certain embodiments, R 8 is Cl. In certain embodiments, R 8 is Br. In certain embodiments, R 8 It's I.

[0097] In certain embodiments, R 9 is H. In certain embodiments, R 9 is CH3. In certain embodiments, R 9 is CH2CH3. In certain embodiments, R 9 is CH2CH2CH3. In certain embodiments, R 9 is CH(CH3)2. In certain embodiments, R 9 is F. In certain embodiments, R 9 is Cl. In certain embodiments, R 9 is Br. In certain embodiments, R 9 It's I.

[0098] In certain embodiments, R 10 is H. In certain embodiments, R 10 is CH3. In certain embodiments, R 10 is CH2CH3. In certain embodiments, R 10is CH2CH2CH3. In certain embodiments, R 10 is CH(CH3)2. In certain embodiments, R 10 is F. In certain embodiments, R 10 is Cl. In certain embodiments, R 10 is Br. In certain embodiments, R 10 It's I.

[0099] In certain embodiments, R 11 is H. In certain embodiments, R 11 is CH3. In certain embodiments, R 11 is CH2CH3. In certain embodiments, R 11 is CH2CH2CH3. In certain embodiments, R 11 is CH(CH3)2. In certain embodiments, R 11 is F. In certain embodiments, R 11 is Cl. In certain embodiments, R 11 is Br. In certain embodiments, R 11 It's I.

[0100] In certain embodiments, R 12 is H. In certain embodiments, R 12 is CH3. In certain embodiments, R 12 is CH2CH3. In certain embodiments, R 12 is CH2CH2CH3. In certain embodiments, R 12 is CH(CH3)2. In certain embodiments, R 12 is F. In certain embodiments, R 12 is Cl. In certain embodiments, R 12 is Br. In certain embodiments, R 12 It's I.

[0101] In certain embodiments, the compound of formula (I) is a compound of formula (Ia):

[0102]

[0103] In certain embodiments, the compound of formula (I) is a compound of formula (Ib):

[0104]

[0105] In certain embodiments, the compound of formula (I) is selected from the group consisting of:

[0106]

[0107]

[0108] In certain embodiments, the compound of formula (I) is selected from the group consisting of:

[0109]

[0110] In certain embodiments, the compound is:

[0111]

[0112] In certain embodiments, the present invention provides a compound of formula (II), or a salt, solvate, tautomer and / or stereoisomer thereof (such as but not limited to its geometric isomer and / or enantiomer and / or diastereomer):

[0113]

[0114] in:

[0115] R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 10 , R 11 , R 12 and R 13 independently selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, F, Cl, Br and I,

[0116] R 5 and R 9 Independently selected from the group consisting of CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, F, Cl, Br and I.

[0117] In certain embodiments, R 1 is H. In certain embodiments, R 1 is CH3. In certain embodiments, R 1 is CH2CH3. In certain embodiments, R 1 is CH2CH2CH3. In certain embodiments, R 1 is CH(CH3)2. In certain embodiments, R 1 is F. In certain embodiments, R 1 is Cl. In certain embodiments, R 1 is Br. In certain embodiments, R1 It's I.

[0118] In certain embodiments, R 2 is H. In certain embodiments, R 2 is CH3. In certain embodiments, R 2 is CH2CH3. In certain embodiments, R 2 is CH2CH2CH3. In certain embodiments, R 2 is CH(CH3)2. In certain embodiments, R 2 is F. In certain embodiments, R 2 is Cl. In certain embodiments, R 2 is Br. In certain embodiments, R 2 It's I.

[0119] In certain embodiments, R 3 is H. In certain embodiments, R 3 is CH3. In certain embodiments, R 3 is CH2CH3. In certain embodiments, R 3 is CH2CH2CH3. In certain embodiments, R 3 is CH(CH3)2. In certain embodiments, R 3 is F. In certain embodiments, R 3 is Cl. In certain embodiments, R 3 is Br. In certain embodiments, R 3 It's I.

[0120] In certain embodiments, R 4 is H. In certain embodiments, R 4 is CH3. In certain embodiments, R 4 is CH2CH3. In certain embodiments, R 4 is CH2CH2CH3. In certain embodiments, R 4 is CH(CH3)2. In certain embodiments, R 4 is F. In certain embodiments, R 4 is Cl. In certain embodiments, R 4 is Br. In certain embodiments, R 4 It's I.

[0121] In certain embodiments, R 5 is CH3. In certain embodiments, R 5 is CH2CH3. In certain embodiments, R 5 is CH2CH2CH3. In certain embodiments, R5 is CH(CH3)2. In certain embodiments, R 5 is F. In certain embodiments, R 5 is Cl. In certain embodiments, R 5 is Br. In certain embodiments, R 5 It's I.

[0122] In certain embodiments, R 6 is H. In certain embodiments, R 6 is CH3. In certain embodiments, R 6 is CH2CH3. In certain embodiments, R 6 is CH2CH2CH3. In certain embodiments, R 6 is CH(CH3)2. In certain embodiments, R 6 is F. In certain embodiments, R 6 is Cl. In certain embodiments, R 6 is Br. In certain embodiments, R 6 It's I.

[0123] In certain embodiments, R 7 is H. In certain embodiments, R 7 is CH3. In certain embodiments, R 7 is CH2CH3. In certain embodiments, R 7 is CH2CH2CH3. In certain embodiments, R 7 is CH(CH3)2. In certain embodiments, R 7 is F. In certain embodiments, R 7 is Cl. In certain embodiments, R 7 is Br. In certain embodiments, R 7 It's I.

[0124] In certain embodiments, R 8 is H. In certain embodiments, R 8 is CH3. In certain embodiments, R 8 is CH2CH3. In certain embodiments, R 8 is CH2CH2CH3. In certain embodiments, R 8 is CH(CH3)2. In certain embodiments, R 8 is F. In certain embodiments, R 8 is Cl. In certain embodiments, R 8 is Br. In certain embodiments, R 8 It's I.

[0125] In certain embodiments, R 9 is CH3. In certain embodiments, R 9 is CH2CH3. In certain embodiments, R 9 is CH2CH2CH3. In certain embodiments, R 9 is CH(CH3)2. In certain embodiments, R 9 is F. In certain embodiments, R 9 is Cl. In certain embodiments, R 9 is Br. In certain embodiments, R 9 It's I.

[0126] In certain embodiments, R 10 is H. In certain embodiments, R 10 is CH3. In certain embodiments, R 10 is CH2CH3. In certain embodiments, R 10 is CH2CH2CH3. In certain embodiments, R 10 is CH(CH3)2. In certain embodiments, R 10 is F. In certain embodiments, R 10 is Cl. In certain embodiments, R 10 is Br. In certain embodiments, R 10 It's I.

[0127] In certain embodiments, R 11 is H. In certain embodiments, R 11 is CH3. In certain embodiments, R 11 is CH2CH3. In certain embodiments, R 11 is CH2CH2CH3. In certain embodiments, R 11 is CH(CH3)2. In certain embodiments, R 11 is F. In certain embodiments, R 11 is Cl. In certain embodiments, R 11 is Br. In certain embodiments, R 11 It's I.

[0128] In certain embodiments, R 12 is H. In certain embodiments, R 12 is CH3. In certain embodiments, R 12 is CH2CH3. In certain embodiments, R 12 is CH2CH2CH3. In certain embodiments, R 12 is CH(CH3)2. In certain embodiments, R12 is F. In certain embodiments, R 12 is Cl. In certain embodiments, R 12 is Br. In certain embodiments, R 12 It's I.

[0129] In certain embodiments, R 13 is H. In certain embodiments, R 13 is CH3. In certain embodiments, R 13 is CH2CH3. In certain embodiments, R 13 is CH2CH2CH3. In certain embodiments, R 13 is CH(CH3)2. In certain embodiments, R 13 is F. In certain embodiments, R 13 is Cl. In certain embodiments, R 13 is Br. In certain embodiments, R 13 It's I.

[0130] In certain embodiments, the compound of formula (II) is a compound of formula (IIa):

[0131]

[0132] In certain embodiments, the compound of formula (II) is a compound of formula (IIb):

[0133]

[0134] In certain embodiments, the compound of formula (II) is a compound of formula (IIc):

[0135]

[0136] In certain embodiments, the compound of formula (II) is a compound of formula (IId):

[0137]

[0138] In certain embodiments, the compound of formula (II) is a compound of formula (IIe):

[0139]

[0140] In certain embodiments, the compound of formula (II) is a compound of formula (IIf):

[0141]

[0142] In certain embodiments, the compound of formula (II) is a compound of formula (IIg):

[0143]

[0144] In certain embodiments, the compound of formula (II) is:

[0145]

[0146] The compounds described herein may have one or more stereocenters, and each stereocenter may exist independently 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 include racemic, optically active, regioisomers and stereoisomeric forms, or combinations thereof, having therapeutically useful properties as described herein. The preparation of optically active forms may be achieved in any suitable manner, non-limiting examples include, by resolving racemic forms with recrystallization techniques, synthesizing from optically active starting materials, chiral synthesis, or chromatographic separation using chiral solid phases. In certain embodiments, a mixture of one or more isomers is used as a therapeutic compound described herein. In other embodiments, the compounds described herein contain one or more chiral centers. These compounds may be prepared in any manner, including stereoselective synthesis, enantioselective synthesis and / or separation of enantiomers and / or diastereomeric mixtures. The resolution of compounds and their isomers may be achieved in any manner, including but not limited to chemical processes, enzymatic processes, fractional crystallization, distillation and chromatography.

[0147] The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also referred to as polymorphs), solvates, amorphous phases, and / or pharmaceutically acceptable salts of compounds having any compound structure described herein, as well as metabolites and active metabolites of these compounds having the same active type. Solvates include water, ether (e.g., tetrahydrofuran, methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetates, and the like. In certain embodiments, the compounds described herein exist in the form of solvates with pharmaceutically acceptable solvents such as water and ethanol. In other embodiments, the compounds described herein exist in an unsolvated form.

[0148] In certain embodiments, the compounds described herein may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.

[0149] In certain embodiments, the compounds described herein are prepared as prodrugs. "Prodrug" refers to an agent that is converted into a prodrug in vivo. In certain embodiments, after in vivo administration, the prodrug is chemically converted into a biological, pharmaceutical or therapeutically active form of the compound. In other embodiments, the prodrug is enzymatically metabolized into a biological, pharmaceutical or therapeutically active form of the compound by one or more steps or processes.

[0150] In certain embodiments, sites on the aromatic ring portion of the compounds described herein are susceptible to various metabolic reactions. The introduction of appropriate substituents on the aromatic ring structure can reduce, minimize or eliminate such metabolic pathways. In certain embodiments, by way of example only, appropriate substituents to reduce or eliminate the susceptibility of the aromatic ring to metabolic reactions are deuterium, halogens or alkyl groups.

[0151] 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 the atomic mass or mass number usually found in nature. Examples of suitable isotopes for inclusion in the compounds described herein include, but are not limited to 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 S. In certain embodiments, isotope-labeled compounds can be used for drug and / or substrate tissue distribution studies. In other embodiments, substitution with heavier isotopes such as deuterium can provide greater metabolic stability (e.g., increase in vivo half-life or reduce dosage requirements). In still other embodiments, substitution with positron emitting isotopes (e.g., 11 C. 18 F. 15 O and 13 N) substitution can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds are prepared by any suitable method or process by using an appropriate isotopically labeled reagent in place of the unlabeled reagent otherwise employed.

[0152] In certain embodiments, the compounds described herein are labeled by other means, including but not limited to the use of chromophores or fluorescent groups, bioluminescent labels, or chemiluminescent labels.

[0153] The compounds described herein and other related compounds with various substituents are synthesized using the techniques and materials described herein, and are described, for example, in Fieser & Fieser, Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd, Chemistry of Carbon Compounds, Volumes 1-5 and Supplements (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock, Comprehensive Organic Transformations (VCH Publishing Co., Ltd., 1989), March, Advanced Organic Chemistry 4th Edition, (Wiley 1992); Carey & Sundberg, Advanced Organic Chemistry 4th Edition, Volumes A and B (Plenum 2000, 2001), and Green & Wuts, Protective Groups in Organic Synthesis 3rd Edition, (Wiley 1999) (all of which are incorporated by reference for the present disclosure). The general methods for preparing the compounds described herein are modified by using appropriate reagents and conditions to introduce the various moieties found in the formulae provided herein.

[0154] The compounds described herein are synthesized using any suitable procedures starting from commercially available compounds or compounds prepared using the procedures described herein.

[0155] In a non-limiting example, the compounds of the present disclosure can be prepared using the illustrative procedures exemplified 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 purchased commercially or prepared according to methods known in the art) can be contacted with an optionally substituted 2-hydroxybenzaldehyde (which can be purchased commercially 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, dimethyl sulfoxide, chloroform, dichloromethane, etc.) to generate the corresponding imine. The imine can be purified from the reaction mixture or used as is in the next reaction step. The imine may then be contacted with optionally substituted benzene isocyanide, optionally substituted 2-pyridine isocyanide, optionally substituted 3-pyridine isocyanide or optionally substituted 4-pyridine isocyanide (each of which may be purchased commercially or prepared according to methods known in the art) in a suitable solvent such as, but not limited to, methanol, ethanol, (iso)propanol, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, chloroform, dichloromethane, etc., optionally 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 optionally in the presence of a base such as, but not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, Hunig's base, pyridine, etc. The desired product may be isolated from the reaction mixture by (partial) removal of the solvent from the reaction mixture, addition of water and / or any other suitable solvent to the reaction mixture, seeding or any chemical / chromatographic method known in the art.

[0156]

[0157] In certain embodiments, protection reactive functional groups (such as hydroxyl, amino, imino, sulfenyl or carboxyl) are provided to prevent them from unnecessarily participating in the reaction. Protective groups are used to block part or all of the reactive moieties and prevent these groups from participating in chemical reactions until the protective groups are removed. In other embodiments, each protective group can be removed in different ways. The protective groups cracked under completely different reaction conditions satisfy the requirements of different removals.

[0158] In certain embodiments, the protecting group is removed by acid, base, reducing conditions (such as, for example, hydrogenolysis) and / or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal and tert-butyldimethylsilyl are acid unstable and are used to protect carboxyl and hydroxyl reactive moieties in the presence of amino groups protected with Cbz groups (Cbz groups can be removed by hydrogenolysis) and Fmoc groups (which are base unstable). Carboxylic acid and hydroxyl reactive moieties are blocked by base unstable groups such as, but not limited to, methyl, ethyl and acetyl in the presence of amines blocked with acid unstable groups (such as tert-butyl carbamate) or with carbamates that are stable to acid and base but can be removed by hydrolysis.

[0159] In certain embodiments, carboxylic acid and hydroxyl reactive moieties are blocked by hydrolytically removable protecting groups such as benzyl, while amine groups capable of hydrogen bonding with acids are blocked by base labile groups such as Fmoc. As exemplified herein, carboxylic acid reactive moieties are protected by conversion to simple ester compounds, including conversion to alkyl esters, or blocked with oxidatively removable protecting groups such as 2,4-dimethoxybenzyl, while coexisting amino groups are blocked with fluoride-labile silylcarbamates.

[0160] 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 π-acid catalysts. For example, in the presence of acid-labile tert-butyl carbamate or base-labile acetamide protecting groups, allyl blocked carboxylic acids are deprotected using palladium catalysis. Yet another form of protecting group is a resin with a compound or intermediate attached. As long as the residue is attached to the resin, the functional group will be blocked and will not react. Once released from the resin, the functional group can react.

[0161] Typically, blocking / protecting groups can be selected from:

[0162]

[0163] Other protecting groups, and techniques suitable for their creation and 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 purposes of the present disclosure.

[0164] Those skilled in the art will recognize that in various embodiments, it may be advantageous to incorporate the compound as a salt into a pharmaceutical composition. Various counterions will be required when different formulations and methods of administration are employed, and all pharmaceutically acceptable salts are contemplated for use in the present disclosure. In various embodiments, the pharmaceutical composition is formulated for ocular administration.

[0165] method

[0166] In one aspect, the invention provides a method of treating, improving and / or preventing AMD (such as but not limited to "dry" AMD) in a subject. In certain embodiments, the method comprises administering a therapeutically effective amount of a compound described herein to a subject (such as a subject in need thereof).

[0167] In one aspect, the present invention provides a method for treating, improving and / or preventing anterior segment diseases (such as but not limited to Fuchs' corneal endothelial dystrophy (FECD), cataracts, glaucoma and keratoconus). In certain embodiments, the method comprises administering a therapeutically effective amount of a compound described herein to a subject (such as a subject in need thereof).

[0168] In one aspect, the present invention provides a method for treating, improving and / or preventing blue light damage to lens epithelial cells in a subject. In certain embodiments, the method comprises administering a therapeutically effective amount of a compound described herein to a subject (such as a subject in need thereof).

[0169] Despite progress in understanding the pathophysiology of atrophic AMD, approved therapies for this disease remain elusive. Atrophic or "dry" forms of AMD are characterized by loss of RPE cells, including loss of photoreceptors and the choroidal vascular layer. Although the cause 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 an important role in the development of the disease. RPE cells are susceptible to oxidative stress, and factors such as strong irradiation or toxins in cigarettes can cause cumulative damage to the eyes caused by this process. In addition, antioxidant capacity decreases, and the efficiency of the repair system is impaired. 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 lead to retinal dysfunction and cell loss in atrophic AMD. The presence of hydrogen peroxide in RPE cells catalyzes oxidation reactions and produces reactive oxygen species (ROS), which cause irreversible damage to cells. As people age, the ability of these cells to resist ROS is impaired. Given the observations that mitochondrial DNA damage and repair in the RPE are associated with aging and AMD, reducing oxidative stress is a viable therapeutic target. In certain embodiments, the compounds of the present disclosure prevent or minimize cell death caused by any cellular attack, including oxidative stress-related cellular attack or any other form of cellular attack.

[0170] Tert-butyl hydroperoxide (TBHP) exposure has been shown to disrupt the junctional integrity of the RPE and lead to lipid peroxidation in the membrane bilayer, as well as oxidation of glutathione, endoplasmic reticulum Ca 2+ Release of intracellular calcium ([Ca 2+ ]) increases and mitochondrial inner membrane permeability increases. UV-B light damage has been shown to target mitochondrial DNA damage and produce reactive oxygen species. Chronic nitric oxide production caused by smoking and subsequent nitrite exposure are risk factors closely associated with AMD. These changes lead to cumulative damage to the BM and cause age-related collagen cross-linking, decreased collagen solubility, and subsequent membrane damage. In the following examples, when oxidative stress-induced cell dysfunction and death are induced with tert-butyl hydroperoxide, treatment with one or more compounds of the present disclosure can promote cell survival, as measured by cell viability assays. In certain embodiments, the compounds of the present disclosure can exhibit a protective effect by enhancing mitochondrial respiration. In certain embodiments, enhancing metabolic activity is an effective target for degenerative diseases such as AMD.

[0171] Administration / dosage / formulation

[0172] The administration scheme can affect the composition of effective dose. The therapeutic preparation can be administered to the subject before or after the onset of AMD. In addition, several separate dosages and staggered dosages can be administered every day or in sequence, or the dosage can be continuously infused or can be a rapid injection. In addition, the dosage of the therapeutic preparation can be increased or reduced in proportion to the emergency situation of the treatment or prevention situation.

[0173] The compositions of the present invention can be administered to patients, preferably mammals, more preferably humans, at dosages and time periods that are effective for treating the patient's disease using known procedures. The effective amount of the therapeutic compound required to achieve the therapeutic effect can vary according to factors such as the patient's disease or disorder state; the patient's age, sex and weight; and the ability of the therapeutic compound to treat the patient's AMD. The dosage regimen can be adjusted to provide the best therapeutic response. For example, several separate doses can be administered daily, or the dosage can be reduced proportionally according to the urgency of the treatment situation. Non-limiting examples of the effective dosage range of the therapeutic compound disclosed herein are from about 1 to 5000 mg / kg body weight / day. One of ordinary skill in the art will be able to study the relevant factors and determine the effective amount of the therapeutic compound without excessive experimentation.

[0174] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present disclosure may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0175] In particular, the selected dosage level will depend upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0176] A physician with ordinary skills in the art, such as a physician or veterinarian, can easily determine and prescribe the effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian can start the dosage of the disclosed compound 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.

[0177] In a particular embodiment, it is particularly advantageous to formulate the compound in a dosage unit form for ease of administration and uniformity of dosage. As used herein, a dosage unit form refers to a physically discrete unit suitable as a unit dose for a patient to be treated; each unit contains a predetermined amount of a therapeutic compound, which is calculated to produce a desired therapeutic effect in combination with a desired pharmaceutical carrier. The dosage unit form of the present disclosure is determined by and is directly dependent on: (a) the unique characteristics of the therapeutic compound and the specific therapeutic effect to be achieved, and (b) the inherent limitations in the field of compatibility / formulation of such a therapeutic compound for treating AMD in a patient.

[0178] 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.

[0179] In certain embodiments, the compositions of the present disclosure are applied to patients with a dosage of 1 to 5 times or more per day. In other embodiments, the compositions of the present disclosure are applied to patients with a certain dosage range, including but not limited to once a day, once every two days, once every three days to once a week, once every two weeks, once every three weeks, once a month, once every two months, once every three months and / or once every 1-12 weeks. It is easy for those skilled in the art to see that the frequency of application of the various combined compositions of the present disclosure varies from individual to individual, depending on many factors, including but not limited to age, disease to be treated or disorder, sex, overall health and other factors. Therefore, the present disclosure should not be construed as being limited to any specific dosage regimen, and the precise dosage and composition applied to any patient are determined by the attending physician after considering all other factors of the patient.

[0180] The range of the compounds of the present disclosure for administration can be from about 1 μg to about 10000 mg, about 20 μg to about 9500 mg, about 40 μg to approximately 9000 mg, about 75 μg to about 8500 mg, about 150 μg to 7500 mg, about 200 μg to 7000 mg, about 350 μg to 6000 mg, about 500 μg to 5000 mg, about 750 μg to 4000 mg, about 1 mg to 3000 mg, about 10 mg to 2500 mg, about 20 mg to 2000 mg, about 25 mg to 1500 mg, about 30 mg to 1000 mg, about 40 mg to 900 mg, about 50 mg to 800 mg, about 60 mg to about 750 mg, about 70 mg to about 600 mg, about 80 mg to about 500 mg, and any and all whole or partial increments therebetween.

[0181] In some embodiments, the dosage of the compounds of the present disclosure is from about 1 mg to about 2500 mg. In some embodiments, the dosage of the compounds of the present disclosure used in the compositions described herein is less than about 10000 mg, or less than about 8000 mg, or less than about 6000 mg, or less than about 5000 mg, or less than about 3000 mg, or less than about 2000 mg, or less than about 1000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Likewise, in some embodiments, the dose of the second compound described herein is less than about 1000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof.

[0182] In certain embodiments, the compounds of the present disclosure can be administered ocularly, such as by intraocular or periocular injection. In other embodiments, the compounds are administered as gels or pegylated materials. In other embodiments, the compounds themselves are pegylated or combined with long-acting biomolecules. In still other embodiments, the compounds are formulated for slow delivery to the eye, such as using contact lenses comprising polymers that slowly release the drug, using punctal plugs, and / or using any delivery method known in the art and compatible with the compounds.

[0183] In certain embodiments, the invention relates to packaged pharmaceutical compositions comprising a container holding a therapeutically effective amount of a compound, 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.

[0184] The preparations can be mixed with conventional excipients, i.e. pharmaceutically acceptable organic or inorganic carrier materials suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral or any other suitable administration known in the art. The drug preparations can be sterilized and, if necessary, can be mixed with adjuvants, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that affect osmotic pressure, buffers, colorants, flavorings and / or aromatic substances, etc. When necessary, they can also be combined with other active agents, such as other analgesics.

[0185] The administration route of any composition of the present disclosure includes oral, nasal, rectal, vaginal, parenteral, oral, sublingual, intraocular or topical. The compound used in the present disclosure can be formulated to be administered by any suitable route, such as oral or parenteral administration, such as transdermal, transmucosal (e.g., sublingual, lingual, (through) oral, (through) urethra, vagina (e.g., vaginal and perivaginal), nasal (intra) and (through) rectum), intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, topical administration and ocular (including but not limited to topical, subconjunctival, sub-Tenon, suprachoroidal, intravitreal or subretinal).

[0186] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, lozenges, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, granules, sera, lozenges, creams, pastes, plasters, lotions, disks, 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 useful in the present disclosure are not limited to the specific formulations and compositions described herein.

[0187] Oral administration

[0188] For oral use, tablets, dragees, liquids, drops, suppositories or capsules, caplets and gel caps are particularly suitable. Compositions for oral administration may be prepared according to any method known in the art, and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic, pharmaceutically acceptable excipients suitable for the manufacture of tablets. Such excipients include, for example, inert diluents, such as lactose; granulating and disintegrants, such as corn starch; binders, such as starch; and lubricants, such as magnesium stearate. Tablets may be uncoated or coated by known techniques for aesthetic or delayed release of the active ingredient. Oral preparations may also be presented in the form of hard gelatin capsules in which the active ingredient is mixed with an inert diluent.

[0189] The present disclosure also includes multilayer tablets comprising a layer providing delayed release of one or more compounds of the present disclosure and a further layer providing immediate release of a drug for treating certain diseases or disorders. Using wax / pH sensitive polymer mixtures, gastro-insoluble compositions can be obtained in which the active ingredient is embedded, ensuring its delayed release.

[0190] Parenteral administration

[0191] For parenteral administration, the compounds of the present disclosure can be formulated for injection or infusion, such as intravenous, intramuscular or subcutaneous injection or infusion, or for single dose and / or continuous infusion administration. Suspensions, solutions or emulsions in oily or aqueous vehicles can be used, optionally containing other formulation agents, such as suspending agents, stabilizers and / or dispersants.

[0192] Ocular administration

[0193] The present disclosure contemplates administration of compounds useful in the present disclosure to the eye.Any ocular formulations are useful in the present disclosure and which allow for application of compounds useful in the present disclosure to the eye.

[0194] In non-limiting examples, the compositions of the present disclosure include gamma-cyclodextrin (or γ-cyclodextrin). γ-cyclodextrin solutions can be prepared in water, and their concentrations can reach a solubility limit of about 23.2 mg / mL. Then, the pH value of this cyclodextrin solution can be adjusted to the pH value at which the active compound is most soluble. Then the active compound is added so that the molar ratio of γ-cyclodextrin to the active compound is 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), and then the pH value 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, then used directly, diluted to the desired concentration with a buffer, and / or lyophilized to provide a powder for redissolution. The lyophilized powder can be suspended in a certain amount of water, which will not completely dissolve the powder, but will provide a fine suspension. Then, this suspension can be further formulated with a thickener to improve adhesion to the eye. Thickening agents include, but are not limited to, carboxymethylcellulose (eg, at a concentration of about 0.05-5%) or other approved agents.

[0195] Other forms of administration

[0196] Other dosage forms disclosed herein 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 disclosed herein also include those described in U.S. Patent Application Nos. 20030147952; 20030104062; 20030104053; 20030044466; 20030039688 and 20020051820. Additional dosage forms disclosed herein 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.

[0197] Controlled release formulations and drug delivery systems

[0198] In certain embodiments, the formulations of the present disclosure may be, but are not limited to, short-term, rapid replenishment, and controlled release formulations, such as sustained release, delayed release, and pulsed release formulations.

[0199] The term sustained release is used in its traditional conventional sense to refer to a pharmaceutical formulation that provides a gradual release of a drug over a prolonged period of time and that may (although not necessarily) result in substantially constant blood levels of the drug over a prolonged period of time. This period of time may be as long as a month or more and should be a longer release than the same amount of agent administered in bolus form.

[0200] For sustained release, the compound may be formulated with a suitable polymer or hydrophobic material which provides the compound with sustained release properties.Thus, the compounds used in the disclosed methods may be administered in the form of microparticles, for example by injection or by implantation in the form of wafers or discs.

[0201] In certain embodiments, a compound of the present disclosure, alone or in combination with another pharmaceutical agent, is administered to a patient using a sustained release formulation.

[0202] As used herein, the term delayed release is used in its conventional sense to refer to drug formulations that provide initial release of the drug after a delay after administration, and such formulations (although not necessarily) include a delay of about 10 minutes to about 12 hours.

[0203] As used herein, the term pulsatile release is used in its conventional sense to refer to a drug formulation that provides release of the drug in a manner that produces a pulsatile plasma profile of the drug following administration of the drug.

[0204] As used herein, the term immediate release is used in its conventional sense to refer to a drug formulation that releases the drug immediately after administration of the drug.

[0205] As used herein, short-term refers to any time period up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes after drug administration, and any or all full or partial increments thereof.

[0206] As used herein, rapid offset refers to any time period after drug administration up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any or all full or partial increments thereof.

[0207] dose

[0208] The therapeutically effective amount or dosage of the disclosed compounds depends on the age, sex and weight of the patient, the patient's current medical condition and the progression of AMD in the patient being treated. Those skilled in the art will be able to determine the appropriate dosage based on these and other factors.

[0209] The suitable dosage of the disclosed compound can be in the range of from about 0.01 mg to about 5000 mg per day, such as from about 0.1 mg to about 1000 mg per day, for example, from about 1 mg to about 500 mg per day, such as from about 5 mg to about 250 mg per day. The dosage can be administered in a single dose or in multiple doses, for example, from 1 to 4 times or more per day. When multiple doses are used, the amount of each dose can be the same or different. For example, a dose of 1 mg per day can be administered in two 0.5 mg portions, with an interval of about 12 hours between the two administrations.

[0210] It should be understood that, in non-limiting examples, daily compound dosages may be administered every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, in the case of administration every other day, a daily dosage of 5 mg may be started on Monday, 5 mg may be administered the first time a day on Wednesday, 5 mg may be administered the second time a day on Friday, and so on.

[0211] In the event that the patient's condition does improve, at the doctor's discretion, the inhibitor of the present disclosure may be administered continuously; alternatively, the drug dosage may be temporarily reduced or suspended for a period of time (i.e., a "drug holiday"). The length of the drug holiday may optionally vary between 2 days and 1 year, including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. Dose reductions during a drug holiday include from 10% to 100%, including by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%.

[0212] Once the patient's condition has improved, a maintenance dose is taken as necessary. Subsequently, depending on the viral load, the dose or frequency of administration, or both, is reduced to a level that retains the improved disease. In certain embodiments, patients require long-term intermittent treatment when there is any recurrence of symptoms and / or infection.

[0213] The compounds used in the disclosed methods can be formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unit dosages for patients being treated, each unit containing a predetermined amount of active substance, which can be calculated to produce the desired therapeutic effect, optionally in combination with a suitable pharmaceutical carrier. The unit dosage form can be a single daily dose or multiple daily doses (e.g., about 1 to 4 times or more per day). When multiple daily doses are used, the unit dosage form of each dose may be the same or different.

[0214] The toxicity and therapeutic efficacy of such treatment regimens are optionally determined in cell culture or experimental animals, including but not limited to LD 50 (a dose lethal to 50% of the population) and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index, which is expressed as LD 50 and ED 50 The data obtained from cell culture assays and animal studies can optionally be used to formulate a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED with minimal toxicity. 50 The dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized.

[0215] Those skilled in the art will recognize or be able to determine, using no more than routine experimentation, many equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents are considered to be within the scope of this disclosure and are covered by the appended claims. For example, it should be understood that changes in reaction conditions, including but not limited to reaction times, reaction sizes / volumes, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, such as nitrogen atmospheres and reducing / oxidizing agents, and art-recognized alternatives, and using only routine experimentation, are within the scope of this application.

[0216] It should be understood that no matter where in this article provides value and range, all values ​​and ranges included in these values ​​and ranges are meant to be included in the scope of the present disclosure. In addition, this application also considers all values ​​falling within these ranges, as well as the upper or lower limit of the value range.

[0217] Exemplary Embodiments

[0218] The present disclosure is further described in detail by reference to the following exemplary embodiments. Unless otherwise indicated, these embodiments are provided for illustrative purposes only and are not intended to be limiting. Therefore, the present disclosure should never be interpreted as being limited to the following embodiments, but should be interpreted as including any and all variations that become apparent due to the teachings provided herein.

[0219] Without further description, it is believed that one of ordinary skill in the art can use the foregoing description and the following illustrative examples to make and utilize the compounds of the present disclosure and to practice the claimed methods. Therefore, the following working examples specifically point out preferred embodiments of the present disclosure and should not be construed as limiting the remainder of the disclosure in any way.

[0220] The materials and methods employed to practice the following examples are described herein:

[0221] Human retinal pigment epithelial (RPE) cell culture

[0222] 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 Sciences, 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).

[0223] Induction of oxidative stress using tert-butyl hydroperoxide

[0224] Human ARPE-19 cells were plated in DMEM supplemented with FBS and antibiotics for 24 hours in 96-well plates. ARPE-19 cells were pre-incubated with ciclopirox olamine (Sigma), compound 414 (Chemical Diversity, San Diego, CA), compound 434 (Chemical Diversity), or no compound for 24 hours and then exposed to different concentrations of tert-butyl hydroperoxide (TBHP; Sigma-Aldrich, St. Louis, MO) for 24 hours the next day. The next day, the cells were stained with a BioTek FLx800 TM The fluorescence reader (BioTek, Winooski, VT) was used with RealTime Glo TM Cell viability was measured by MT cell viability assay (Promega, Madison, WI).

[0225] Nitrite modification of the extracellular matrix (ECM)

[0226] 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 incubated in a humidified atmosphere of 5% CO2 and 95% air at 37°C. ARPE-19 cells were plated in 24 wells of a 12-well plate or a flat-bottom 24-well plate. Permeable supports (Corning, Inc.) were grown for 6-8 weeks to form ECM. ARPE-19 cells were then removed by adding 20mM ammonium hydroxide buffer for 20min and the ECM was washed with phosphate-buffered saline (PBS). PBS was removed from the RPE-ECM plates and dried. Subsequently, 100mM sodium nitrite was 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 hours. Finally, the plates were washed with PBS to completely remove nitrite. Cells were pre-incubated with drugs for 24 hours and then seeded on nitrite-modified ECM for 24 hours. Cell viability was measured using the RealTime Glo-MT assay (Promega) and a BioTekFLx800 fluorescence reader (Bio-Tek, Winooski, VT).

[0227] Inducing oxidative stress using blue light damage

[0228] Human ARPE-19 cells were placed 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 (156.7LUX, 36 hours). After 36 hours of blue light irradiation, cell viability was measured using RealTime Glo-MT assay (Promega) and BioTek FLx800 fluorescence reader (Bio-Tek, Winooski, VT).

[0229] Statistical analysis

[0230] 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 standard of α = 0.05 was used.

[0231] Example 1: Chemical synthesis

[0232]

[0233] General approach:

[0234] Solvents were purified according to standard procedures. All other starting materials were purchased from commercial sources. TLC analysis was performed using PolychromSI F254 plates. Column chromatography was performed using Kieselgel Merck 60 (230-400 mesh) as a solid phase. 1H 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)].

[0235] General procedure:

[0236] A solution of amine (2.0mmol), aldehyde (2.0mmol) and acetic acid (4.0mmol) in 20mL methanol was stirred for 20min at 20°C. The reaction mixture was cooled and isonitrile (2.0mmol) was added at 0°C. Stirring was continued for 5-6 hours (TCL monitoring) at 20°C. The product crystallized from the reaction mixture or crystallized after adding a few drops of water. The product was collected by filtration, washed with water (3-10mL), dried, and washed again with hexane (50mL). The crude product was crystallized (methanol) or purified by column chromatography (CH2Cl2-CH3OH, 15:5) to obtain a crystalline compound.

[0237] 4-Bromo-2-(3-(2-ethyl-6-methyl-anilino)imidazo[1,2-a]pyridin-2-yl)phenol (DH421).

[0238] Brown powder. Yield 73%.1 H NMR (400MHz, DMSO-d6) δ13.21 (d, J=3.4Hz, 1H), 7.99 (d, J=6.6Hz, 1H), 7.87 (t, J=3.0Hz, 1H), 7.70 (dd, J=9.1, 3.3Hz, 1H), 7.39 (t, J=7.9Hz, 1H), 7.32 ( d, J=3.5Hz, 1H), 7.24 (dd, J=8.6, 2.8Hz, 1H), 7.09-6.97 (m, 2H), 6.90 (d, J= 7.4Hz, 1H), 6.86-6.75 (m, 2H), 1.71 (d, J=3.4Hz, 3H), 1.02 (t, J=7.4Hz, 3H).

[0239] ESIMS. m / z: 423 (M+1) +.

[0240] 4-Bromo-2-(3-(pyridin-2-ylamino)imidazo[1,2-a]pyrimidin-2-yl)phenol(DH381-2)

[0241] Brown powder. Yield 15%. 1 H NMR (500MHz, DMSO-d6) δ13.20 (s, 1H), 9.04 (s, 1H), 8.02 (t, J = 5.0Hz, 2H), 7.96 (d, J = 5.0Hz, 1H), 7.74 (dd, J = 9.1, 3.6Hz, 1H), 7.65-7.56 ( m, 1H), 7.44 (dd, J=9.1, 6.5Hz, 1H), 7.29 (dd, J=8.6, 2.6Hz, 1H), 7.04 (q, J=6.8, 5.2Hz, 1H), 6.87 (dd, J=8.7, 3.3Hz, 1H), 6.79-6.70 (m, 2H).

[0242] ESIMS. m / z: 383 (M+1) +.

[0243] Embodiment 2:

[0244] like Figure 1As shown, 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) both protected human retinal pigment epithelial (RPE) cells from oxidative stress-induced cell death. Human ARPE-19 cells (CRL-2302; American Type Culture Collection) were pre-incubated with 0.9 μM of DH381-2 and DH421 for 24 h and then exposed to 300 μM of tert-butyl hydroperoxide (TBHP) for 24 h to induce cell death. DH381-2 and DH421 significantly increased the cell survival rate of human ARPE-19 cells after exposure to TBHP. ****p<0.0001.

[0245] Embodiment 3:

[0246] like Figure 2 As shown, DH421 protects human retinal pigment epithelial (RPE) cells from oxidative stress-induced cell death. Human ARPE-19 cells (CRL-2302; American Type Culture Collection) were pre-incubated 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 the cell survival of human ARPE-19 cells after exposure to TBHP and had no effect on cell growth inhibition. ****p<0.0001.

[0247] Embodiment 4:

[0248] like Figure 3 As shown, both DH421 and DH381-2 protect human retinal pigment epithelial (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 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. There was a protective effect on human ARPE-19 cells treated with DH421 and DH381-2. ****p<0.0001.

[0249] Embodiment 5:

[0250] like Figure 4As shown, both DH421 and DH381-2 protect human retinal pigment epithelial (RPE) cells from blue light damage. Human ARPE-19 cells (CRL-2302; American Type Culture Collection) were pre-incubated with 0.6 μM compound DH421 or DH381-2 for 24 hours and then exposed to blue light (156.7 LUX, 36 hours). Compound DH421 or DH381-2 has a protective effect on human ARPE-19 cells exposed to blue light (156.7 LUX, 36 hours). *p<0.05, ***p<0.01.

[0251] Embodiment 6:

[0252] like Figure 5 As shown, treatment with compound DH421 or DH381-2 enhanced the viability of human retinal pigment epithelial (RPE) cells 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. Compound DH421 or DH381-2 had a protective effect on human ARPE-19 cells seeded on nitrite-modified ECM. *p<0.05, **p<0.01

[0253] Embodiment 7:

[0254] like Figure 6 As shown, both DH421 and DH381-2 protected human retinal pigment epithelial (RPE) cells from oxidative stress-induced cell death. Human RPE cells were pre-incubated with 0.6 μM 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. There was a protective effect on human RPE cells treated with DH421 and DH381-2. ****p<0.0001.

[0255] Embodiment 8:

[0256] like Figure 7 As shown, DH421 and DH381-2 both protect human retinal pigment epithelial (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). Compound DH421 or DH381-2 has a protective effect on human RPE cells exposed to blue light (156.7 LUX, 36 hours). *p<0.05, ***p<0.01.

[0257] Embodiment 9:

[0258] like Figure 8 As shown, treatment with compound DH421 or DH381-2 enhanced the viability of human retinal pigment epithelial (RPE) cells on nitrite-modified extracellular matrix (ECM). Human RPE cells were treated with 1 μM of compound DH421 or DH381-2 and then seeded on nitrite-modified ECM and untreated (normal) ECM for 24 hours. Compound DH421 or DH381-2 had a protective effect on RPE cells seeded on nitrite-modified ECM. *p<0.05.

[0259] Embodiment 10:

[0260] like Figures 9A-9B As shown, both DH381-2 and DH421 improved mitochondrial function after oxidative stress-induced death of human retinal pigment epithelial (RPE) cells. Human RPE cells were pre-incubated with 1 μM 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 measured by Seahorse XF analyzer to measure mitochondrial function. ATP production was significantly reduced in TBHP-treated cells compared to the control group, while treatment with compounds DH381-2 or DH421 increased ATP production compared to the TBHP-treated group. **p<0.001.

[0261] Embodiment 11:

[0262] like Fig.10 As shown, the cytotoxicity level of human retinal pigment epithelial (RPE) cells was not affected after treatment with compounds DH381-2 and DH421. Human RPE cells were pre-incubated with 1 μM compounds DH381-2 and DH421 for 24 hours. After treatment with TBHP and compounds DH381-2 and DH421, cytotoxicity in human RPE cells was measured by CellTox Green cytotoxicity assay.

[0263] Examples of implementation methods

[0264] The following exemplary embodiments are provided, the numbering of which should not be construed as designating a level of importance:

[0265] Embodiment 1: Compound of formula (I):

[0266]

[0267] in:

[0268] X 1 N or CR 1;

[0269] One of the following applies:

[0270] X 2 It is N, X 3 Yes CR 7 , and X 4 Yes CR 8 ,or

[0271] X 2 Yes CR 7 , X 3 is N, and X 4 Yes CR 8 ,or

[0272] X 2 Yes CR 7 , X 3 Yes CR 8 , and X 4 is N;

[0273] 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 independently selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, F, Cl, Br and I;

[0274] or a salt, solvate, tautomer and / or stereoisomer thereof.

[0275] Embodiment 2: A compound according to claim 1, wherein X 1 It is N.

[0276] Embodiment 3: A compound according to claim 1, wherein X 1 Yes CR 1 .

[0277] Embodiment 4: A compound according to any one of claims 1 to 3, wherein X 2 It is N, X 3 Yes CR 7 , and X 4 Yes CR 8 .

[0278] Embodiment 5: A compound according to any one of claims 1 to 3, wherein X2 Yes CR 7 , X 3 is N, and X 4 Yes CR 8 .

[0279] Embodiment 6: A compound according to any one of claims 1 to 3, wherein X 2 Yes CR 7 , X 3 Yes CR 8 , and X 4 It is N.

[0280] Embodiment 7: A compound according to any one of claims 1 to 6, wherein R 10 It's Br.

[0281] Embodiment 8: A compound according to any one of claims 1 to 7, wherein R 5 , R 6 , R 7 and R 8 It's H.

[0282] Embodiment 9: A compound according to any one of claims 1 to 8, which is a compound of formula (Ia):

[0283]

[0284] Embodiment 10: A compound according to any one of claims 1 to 8, which is a compound of formula (Ib):

[0285]

[0286] Embodiment 11: A compound according to any one of claims 1 to 9 selected from the group consisting of:

[0287]

[0288]

[0289] Embodiment 12: A compound according to any one of claims 1 to 8 and 10 selected from the group consisting of:

[0290] Embodiment 13: A compound according to any one of claims 1 to 12, which is:

[0291]

[0292] Embodiment 14: The compound of formula (II) is:

[0293]

[0294] in:

[0295] R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 10 , R 11 , R 12 and R 13 independently selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, F, Cl, Br and I,

[0296] R 5 and R 9 independently selected from the group consisting of CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, F, Cl, Br and I;

[0297] or a salt, solvate, tautomer and / or stereoisomer thereof.

[0298] Embodiment 15: A compound according to claim 14, wherein R 11 It's Br.

[0299] Embodiment 16: A compound according to any one of claims 14 to 15, wherein R 6 , R 7 and R 8 It's H.

[0300] Embodiment 17: A compound according to any one of claims 14 to 16 selected from the group consisting of:

[0301]

[0302]

[0303] Embodiment 18: A compound according to any one of claims 14 to 17 selected from the group consisting of:

[0304]

[0305] Embodiment 19: A compound according to any one of claims 14 to 18 which is:

[0306]

[0307] Embodiment 20: A compound according to any one of claims 14 to 19, which is:

[0308]

[0309] Embodiment 21: A method for treating, improving and / or preventing retinal degeneration in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1 to 20.

[0310] Embodiment 22: The method of claim 21, wherein the retinal degeneration comprises age-related macular degeneration (AMD).

[0311] Embodiment 23: The method of claim 21, wherein the retinal degeneration comprises "dry" AMD.

[0312] Embodiment 24: A method for treating, improving and / or preventing anterior eye disorders in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 20.

[0313] Embodiment 25: The method of claim 24, wherein the disorder comprises at least one selected from the group consisting of Fuchs' endothelial corneal dystrophy, cataract, glaucoma, and keratoconus.

[0314] Embodiment 26: A method for treating, improving and / or preventing cell death and / or promoting cell survival in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 20.

[0315] Embodiment 27: The method according to claim 26, wherein the cell death comprises oxidative stress-induced cell death.

[0316] Embodiment 28: The method of claim 26, wherein the cells comprise lens epithelial cells.

[0317] Embodiment 29: The method 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 diseases; pulmonary fibrosis, kidney disease, diabetic macular edema and retinopathy, neurodegenerative diseases, mitochondrial myopathy, Barth syndrome and liver disease.

[0318] Embodiment 30: A method for treating, improving and / or preventing blue light damage in lens epithelial cells of a subject, the method comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 20 to the subject.

[0319] Embodiment 31: The method according to any one of claims 21-30, wherein the compound is formulated in a pharmaceutically acceptable composition, the composition further comprising at least one pharmaceutically acceptable excipient.

[0320] Embodiment 32: The method according to any one of claims 21-28 and 30-31, wherein the compound is administered ocularly.

[0321] Embodiment 33: A method according to any one of claims 21-32, wherein the compound is one of the following

[0322]

[0323] Embodiment 34: A pharmaceutical composition comprising a compound according to any one of claims 1 to 20 and at least one pharmaceutically acceptable excipient.

[0324] Embodiment 35: The pharmaceutical composition according to claim 34, formulated for ocular administration.

[0325] Embodiment 36: A pharmaceutical composition according to any one of claims 34-35, comprising gamma-cyclodextrin (γ-cyclodextrin).

[0326] Embodiment 37: The pharmaceutical composition according to any one of claims 34-36, which has a pH of about 5-8.

[0327] Embodiment 38: The pharmaceutical composition according to any one of claims 34 to 37, which is lyophilized.

[0328] Embodiment 39: The pharmaceutical composition according to any one of claims 34 to 38, further comprising a thickener.

[0329] The disclosures of each patent, patent application, and publication cited herein are hereby incorporated by reference in their entirety.

[0330] Although the present disclosure is disclosed with reference to specific embodiments, it is obvious that other skilled in the art can design other embodiments and variations of the present disclosure without departing from the true spirit and scope of the present disclosure. The appended claims are intended to be interpreted as including all such embodiments and equivalent variations.

Claims

1. A compound of formula (I): in: X 1 N or CR 1 ; One of the following applies: X 2 It is N, X 3 Yes CR 7 , and X 4 Yes CR 8 ,or X 2 Yes CR 7 , X 3 is N, and X 4 Yes CR 8 ,or X 2 Yes CR 7 , X 3 Yes CR 8 , and X 4 is N; 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 independently selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, F, Cl, Br and I; or a salt, solvate, tautomer and / or stereoisomer thereof.

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

3. The compound according to claim 1, wherein X 1 Yes CR 1 .

4. A compound according to any one of claims 1 to 3, wherein X 2 It is N, X 3 Yes CR 7 , and X 4 Yes CR 8 .

5. A compound according to any one of claims 1 to 3, wherein X 2 Yes CR 7 , X 3 is N, and X 4 Yes CR 8 .

6. A compound according to any one of claims 1 to 3, wherein X 2 Yes CR 7 , X 3 Yes CR 8 , and X 4 It is N.

7. A compound according to any one of claims 1 to 6, wherein R 10 It's Br.

8. A compound according to any one of claims 1 to 7, wherein R 5 , R 6 , R 7 and R 8 It's H.

9. A compound according to any one of claims 1 to 8, which is a compound of formula (Ia):

10. A compound according to any one of claims 1 to 8, which is a compound of formula (Ib):

11. A compound according to any one of claims 1 to 9, selected from the group consisting of:

12. A compound according to any one of claims 1 to 8 and 10, selected from the group consisting of:

13. A compound according to any one of claims 1 to 12, which is:

14. A compound of formula (II): in: R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 10 , R 11 , R 12 and R 13 independently selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, F, Cl, Br and I, R 5 and R 9 independently selected from the group consisting of CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, F, Cl, Br and I; or a salt, solvate, tautomer and / or stereoisomer thereof.

15. The compound according to claim 14, wherein R 11 It's Br.

16. A compound according to any one of claims 14 to 15, wherein R 6 , R 7 and R 8 It's H.

17. A compound according to any one of claims 14 to 16, selected from the group consisting of:

18. A compound according to any one of claims 14 to 17, selected from the group consisting of:

19. A compound according to any one of claims 14 to 18, which is:

20. A compound according to any one of claims 14 to 19, which is:

21. A method for treating, improving and / or preventing retinal degeneration in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of 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.

24. A method for treating, improving and / or preventing anterior eye disorders in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1 to 20.

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

26. A method for treating, ameliorating and / or preventing cell death and / or promoting cell survival in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 20.

27. The method of claim 26, wherein the cell death comprises oxidative stress-induced cell death.

28. The method of claim 26, wherein the cells comprise lens epithelial cells.

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

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

31. The method of any one of claims 21-30, wherein the compound is formulated in a pharmaceutically acceptable composition further comprising at least one pharmaceutically acceptable excipient.

32. The method of any one of claims 21-28 and 30-31, wherein the compound is administered ocularly.

33. The method of any one of claims 21-32, wherein the compound is one of:

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

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

36. The pharmaceutical composition according to any one of claims 34-35, comprising gamma-cyclodextrin (γ-cyclodextrin).

37. The pharmaceutical composition according to any one of claims 34-36, which has a pH of about 5-8.

38. The pharmaceutical composition according to any one of claims 34-37, which is lyophilized.

39. The pharmaceutical composition according to any one of claims 34-38, further comprising a thickener.

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