Peroxisome proliferator-activated receptor alpha (PPAR alpha) agonists and methods of use thereof

Abstract

Benzyl derivative compounds having peroxisome proliferator-activated receptor alpha (PPAR alpha) agonistic activity, kits and compositions comprising such compounds, and methods of their use to enhance PPAR alpha activity for the treatment of diseases and / or disorders involving inflammation and / or angiogenesis, in particular ocular diseases and / or disorders, such as inflammatory diseases and / or angiogenesis. Such as, but not limited to, retinal inflammation, retinal neovascularization, retinal vascular leakage, preterm retinopathy, diabetic retinopathy, age-related macular degeneration, and diabetic macular edema.

Description

[0001] Cross - reference to related applications

[0002] This patent application claims priority to U.S. Patent Application Serial No. 17 / 876,243, filed on July 28, 2022, under 35 U.S.C. 119(e). The entire content of this application is hereby incorporated by reference in its entirety.

[0003] Government support

[0004] This invention was made with government support under Grant No. R21EY028279 awarded by the National Eye Institute of the National Institutes of Health (NIH). The government has certain rights in this invention. Background of the invention

[0005] Retinal inflammation and the resulting neovascularization (NV) are the main causes of vision loss in various eye diseases such as retinopathy of prematurity (ROP), diabetic retinopathy (DR), and age - related macular degeneration (AMD). Diabetic macular edema (DME) is caused by retinal vascular leakage and is the main cause of vision loss in diabetic eye diseases. Increasing evidence suggests that DR is a chronic inflammatory disorder because multiple inflammatory factors such as tumor necrosis factor - α (TNF - α), intercellular adhesion molecule - 1 (ICAM - 1), and vascular endothelial growth factor (VEGF) are overexpressed in the diabetic retina. Inflammation plays a pathogenic role in impaired retinal vascular endothelial function, vascular leakage, and subsequent retinal NV. Anti - VEGF has become the main treatment option, but there are problems such as the need for frequent intraocular injections, high cost, and the need for specialized facilities. In addition, although effective for most patients, approximately 40 - 50% of patients are unresponsive to intravitreal injections of anti - VEGF and corticosteroids. This indicates that additional pathways and factors not addressed by current interventions play a role in the development and progression of the disease.

[0006] Peroxisome proliferator-activated receptors (PPARs) are a class of nuclear hormone-activated receptors and transcription factors. The PPAR family includes three members: PPAR alpha (PPARα), PPAR gamma (PPARγ), and PPAR delta (PPARδ) (the latter is sometimes referred to as PPAR beta (PPARβ) in the literature). Although these three PPAR members have significant sequence homology, they have different tissue distributions, diverse functions, and can be selectively targeted. PPARγ is mainly expressed in adipose tissue, while PPARα is expressed in cells with high mitochondrial activity, including the liver, vascular endothelial cells (ECs), smooth muscle cells, kidneys, and heart. Preliminary studies have shown that PPARα is highly expressed in the retina. However, until recently, the role of PPARα in regulating inflammation, apoptosis, and neovascularization (NV) in diabetic retinopathy has been revealed, opening up new avenues for PPARα agonists as therapeutic agents for ocular vascular diseases. When activated by endogenous or exogenous synthetic agonists, PPARα forms a heterodimer with retinoid X receptor (RXR) and binds to the PPAR response element (PPRE) in the promoter of its target genes, activating target gene transcription. In addition, PPARα indirectly regulates other genes by interfering with their transcriptional regulation. PPARα has been shown to regulate a large number of genes involved in lipid metabolism and vascular inflammation, such as nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB), ICAM-1, and interleukin-6 (IL-6). In addition, PPARα has been shown to regulate oxidation and angiogenesis. However, the function of PPARα in the retina is not well understood. It was not until the results of the FIELD and ACCORD clinical trials showed that the PPARα agonist fenofibric acid (a metabolite of fenofibrate) had a significant and unexpected therapeutic effect on DR, reducing the need for laser treatment in type 2 diabetes patients by 32 - 40%, that the role of PPARα in DR was recognized. Previous studies have shown that the level of PPARα is reduced in the retinas of animal models of type 1 and type 2 diabetes. In addition, activation of PPARα by fenofibrate effectively reduces retinal leukostasis and vascular leakage in diabetic models and improves ischemia-induced retinal NV.

[0007] Fenofibrate was initially recognized for its ability to lower cholesterol and triglyceride levels and has thus been widely used clinically to treat hyperlipidemia for over 30 years. Fenofibrate is the first low-cost and safe oral drug for the treatment of DR, with clinically proven efficacy against NV and DME in DR patients, thus attracting great attention from clinicians, basic scientists, and pharmaceutical companies interested in developing new DR therapeutics. It has been reported that the protective effect of fenofibrate against retinal NV and DME is independent of its lipid-lowering activity but rather stems from the interaction of its metabolite fenofibric acid with PPARα. Therefore, fenofibrate has significant therapeutic potential in the treatment of DR and AMD, but its binding affinity for PPARα is relatively low, and it has off-target nephrotoxic effects and other potential side effects. There is an urgent need to develop new treatment options that are non-invasive and complementary to current methods. Developing higher-affinity PPARα agonists to further improve the treatment of DR and other inflammatory and angiogenic disorders in the eye and other parts of the body is desirable and the goal of this work. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] This patent or application document contains at least one color drawing. After request and payment of the necessary fees, the Patent Office will provide a copy of this patent or patent application publication document with the color drawing.

[0009] Figure 1 Preliminary evaluation results of the agonistic effects of compounds 9-14 and 21-24 on hPPARα in a cell-based luciferase assay are shown. Results of a single experiment are expressed as fold induction relative to DMSO control ± S.E. (n = 3). Compound GW590735 was evaluated at 5 μM and 10 μM concentrations.

[0010] Figure 2A Western blot analysis results of mouse 661W cells treated with 10 μM, 50 μM, and 100 μM of compound 10 for 24 hours are shown.

[0011] Figure 2B Shows Figure 2A The densitometric quantification results of PPARα production in the Western blot analysis results of

[0012] Figure 2C Real-time PCR analysis results of mouse 661W cells treated with compound 10 for 24 hours (n = 6) are shown.

[0013] Figure 2D HRCEC wound healing assay results are shown, with treatment using compound 10 at 10-hour and 24-hour incubation time points. Unless otherwise specified, Figures 2A - 2DThe experiments in [ ] were performed in triplicate. All values are expressed as mean ± S.D. Student's t-test was used to test the statistical significance of differences between groups. *P < 0.05, **P < 0.01, ***P < 0.001.

[0014] Figure 3 Shows the (A) co-crystal structure of GW590735·hPPARα, (B) predicted binding pose of 10hPPARα, and (C) predicted binding pose of compound 28 on hPPARα. The binding pocket cavity is depicted by surface representation, PDB: 2P54.

[0015] Figure 4 Shows the dose-dependent agonistic effect of A91 on PPARα, as confirmed by luciferase quantification (luminescence) in a cell-based luciferase reporter assay. GW59 = GW590735 was used as a positive control. (A91 = ASD91 = 10).

[0016] Figure 5 Shows the dose-dependent agonistic effect of A91 on PPARγ, as confirmed by luciferase quantification (luminescence) in a cell-based luciferase reporter assay. Rosiglitazone was used as a positive control. (A91 = ASD91 = 10).

[0017] Figure 6 Shows the dose-dependent agonistic effect of A91 on PPARδ, as confirmed by luciferase quantification (luminescence) in a cell-based luciferase reporter assay. GW07 = GW0742 was used as a positive control. (A91 = ASD91 = 10).

[0018] Figure 7 Shows the dose-dependent agonistic effect of A190 on PPARα, as confirmed by luciferase quantification (luminescence) in a cell-based luciferase reporter assay. GW59 = GW590735 was used as a positive control. (A190 = 190 = ASD190).

[0019] Figure 8 Shows the dose-dependent agonistic effect of A190 on PPARγ, as confirmed by luciferase quantification (luminescence) in a cell-based luciferase reporter assay. Rosiglitazone was used as a positive control. (A190 = 190 = ASD190).

[0020] Figure 9Shows the dose-dependent agonistic effect of A190 on PPARδ, as confirmed by luciferase quantification (luminescence) in a cell-based luciferase reporter assay. GW07 = GW0742 was used as a positive control. (A190 = 190 = ASD190).

[0021] Figure 10A Shows the in vivo efficacy results of compound ASD91 (10) in terms of retinal permeability compared to fenofibric acid (FenoFA). Male Brown Norway rats, 7 - 8 weeks old, were injected with streptozotocin (STZ, 55 mg / kg). Two weeks after STZ injection, treatment with ASD091 or FenoFA was started daily for 26 - 28 days. ≠P < 0.05 (compared to FenoFA), *P < 0.05 (compared to STZ - DMSO).

[0022] Figure 10B Shows the in vivo efficacy results of compound ASD91 (10) in terms of liver phenotype compared to fenofibric acid (FenoFA). Male Brown Norway rats, 7 - 8 weeks old, were injected with streptozotocin (STZ, 55 mg / kg). Two weeks after STZ injection, treatment with ASD091 or FenoFA was started daily for 26 - 28 days. ≠P < 0.05 (compared to FenoFA), *P < 0.05 (compared to STZ - DMSO). Detailed Description

[0023] As described above, retinal inflammation and neovascularization are the major causes of vision loss in a variety of ocular disorders such as retinopathy of prematurity, diabetic retinopathy (DR), and age-related macular degeneration (AMD). Two large prospective clinical studies reported that the PPARα agonist fenofibrate has a significant therapeutic effect on DR. A new class of compounds is disclosed herein that, due to their PPARα agonistic activity, have an impact on retinal endothelial dysfunction, angiogenesis, and inflammation, indicating their therapeutic role in, for example, DR and AMD (such as wet AMD). The disclosed compositions can be used to treat ocular disorders or conditions such as, but not limited to, DR, AMD (such as wet AMD), retinal inflammation, retinal neovascularization (NV), retinal vascular leakage, retinopathy of prematurity (ROP), and diabetic macular edema (DME). Other diseases and / or conditions related to inflammation and / or angiogenesis that can be treated using the disclosed compounds are described below.

[0024] Before further describing various embodiments of the compounds, compositions, and methods of the present disclosure in detail by way of exemplary descriptions, examples, and results, it should be understood that the compounds, compositions, and methods of the present disclosure are not limited to the specific embodiments and applications of the examples set forth in the following detailed description. The descriptions provided herein are for illustrative purposes only and are not intended to be construed in a limiting sense. Thus, the language used herein is intended to have the broadest possible scope and meaning; the embodiments and examples are intended to be exemplary and not exhaustive. Additionally, it should be understood that, unless otherwise specified, the wording and terminology used herein should be regarded as descriptive rather than restrictive. Further, in the following detailed description, numerous specific details are set forth in order to provide a more thorough understanding of the present disclosure. However, it will be apparent to one of ordinary skill in the art that the present disclosure may be practiced without these specific details. In other instances, features well known to one of ordinary skill in the art are not described in detail to avoid unnecessary complication of the description. All alternatives, substitutions, modifications, and equivalents that are obvious to one of ordinary skill in the art are intended to be included within the scope of the present disclosure. All compounds, compositions, and production methods and their applications and uses disclosed herein can be made and implemented in accordance with the present disclosure. Thus, although the compounds, compositions, and methods of the present disclosure have been described in terms of specific embodiments, it will be apparent to those skilled in the art that changes may be made to the compounds, compositions, and / or methods described herein and to the steps or the order of the steps of the methods without departing from the concepts, spirit, and scope of the inventive concepts described herein.

[0025] All patents, published patent applications, and non-patent publications mentioned in the specification or cited in any part of the present application are hereby expressly incorporated by reference in their entirety as if each individual patent or publication was specifically and individually indicated to be incorporated by reference herein.

[0026] Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure shall have the meanings commonly understood by one of ordinary skill in the art. Additionally, unless the context otherwise requires, singular terms shall include the plural and plural terms shall include the singular.

[0027] When used in accordance with the methods and compositions of the present invention, unless otherwise specified, the following terms shall be understood to have the following meanings:

[0028] As used in the claims and / or the specification, the articles “a” or “an” when used in conjunction with the term “comprising” can mean “one” but is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.” The term “or” as used in the claims is used to mean “and / or,” unless explicitly indicated to refer to only alternative or when the alternatives are mutually exclusive, although the present disclosure supports definitions that refer to only alternatives and “and / or.” The term “at least one” will be understood to include one as well as any quantity more than one, including but not limited to 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 100, or any integer therebetween. The term “at least one” may extend up to 100 or 1000 or more, depending on the term to which it is attached; furthermore, the quantities of 100 / 1000 shall not be considered limiting since higher limits may also yield satisfactory results. In addition, the term “at least one of X, Y, and Z” will be understood to include only X, only Y, and only Z, as well as any combination of X, Y, and Z.

[0029] Unless the context clearly indicates otherwise, all numerical values or ranges used herein include fractions and integers of the values within the range, as well as fractions of the integers within the range. Thus, by way of example, a reference to a numerical range, such as 1-10, includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 1.1, 1.2, 1.3, 1.4, 1.5, etc., and so on. A reference to the range 1-50 thus includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, and 50, and 1.1, 1.2, 1.3, 1.4, 1.5, etc., 2.1, 2.2, 2.3, 2.4, 2.5, etc., and so on, where the range is not limited to integers. A reference to a series of ranges includes ranges that combine the boundary values of different ranges within the series. Thus, by way of example, a reference to a series of ranges, such as 1-1000, includes, for example, 1-10, 10-20, 20-30, 30-40, 40-50, 50-60, 60-75, 75-100, 100-150, 150-200, 200-250, 250-300, 300-400, 400-500, 500-750, 750-1,000, and includes ranges of 1-20, 10-50, 50-100, 100-500, and 500-1,000. Thus, a range of 100 units to 2000 units refers to and includes all unit values or ranges of unit values, as well as fractions of unit values and integers within the range, including, for example but not limited to, 100 units to 1000 units, 100 units to 500 units, 200 units to 1000 units, 300 units to 1500 units, 400 units to 2000 units, 500 units to 2000 units, 500 units to 1000 units, 250 units to 1750 units, 250 units to 1200 units, 750 units to 2000 units, 150 units to 1500 units, 100 units to 1250 units, and 800 units to 1200 units. Thus, according to embodiments of the present disclosure, any two values within the range of about 100 units to about 2000 units can be used to set the lower and upper limits of the range.

[0030] As used in this specification and the claims, the words "comprising" (and any form of comprising, such as "comprise" and "comprises"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "includes" and "include"), or "containing" (and any form of containing, such as "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0031] As used herein, the term "or combinations thereof" refers to all permutations and combinations of the items listed before that term. For example, "A, B, C, or combinations thereof" is intended to include at least one of the following: A, B, C, AB, AC, BC, or ABC, and if order is important in a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing with this example, combinations that contain one or more repeated items or terms are expressly included, such as BB, AAA, AAB, BBC, AAABCCCC, CBBAAA, CABABB, etc. Those skilled in the art will understand that, unless otherwise specified in the context, there is typically no limit on the number of items or terms in any combination.

[0032] In the present application, the terms "about" and "approximately" are used to indicate that a value includes the inherent error variations of a composition, the method for administering the composition, or the variations present in a subject. The qualifier "about" or "approximately" as used herein is intended to include not only the exact value, amount, degree, direction, or other defined characteristic or value, but also to include some minor variations caused by measurement errors, manufacturing tolerances, stresses applied to individual parts or components, observer errors, wear and tear, and combinations thereof. For example, when the terms "about" or "approximately" as used herein are used to refer to a measurable value (such as a quantity, duration of time, etc.), they are intended to encompass variations of, for example, ±20%, ±15%, ±10%, ±5%, ±1%, or ±0.1% of the specific value, as such variations are suitable for performing the disclosed methods and are understood by those of ordinary skill in the art. The term "substantially" as used herein means that the subsequently described event or situation occurs completely or that the subsequently described event or situation occurs to a large extent. For example, the term "substantially" means that the subsequently described event or situation has at least a 75% probability of occurring, or at least 80%, or at least 90%, or at least 95%, or at least 98%.

[0033] Any reference herein to "an embodiment" or "embodiments" means that the particular element, feature, structure, or property described in connection with that embodiment is included in at least one embodiment and may be included in other embodiments. The phrase "in one embodiment" that appears throughout the specification does not necessarily refer to the same embodiment and is not necessarily limited to a single or particular embodiment.

[0034] The pronoun "we" as used herein is intended to refer to all persons involved in a particular aspect of the present disclosure and may thus include non-inventor laboratory assistants and collaborators working under the supervision of the inventors.

[0035] The term "pharmaceutically acceptable" means that a compound and composition are suitable for administration to humans and / or animals and do not produce excessive adverse side effects (such as toxicity, irritation, and / or allergic reactions) and have a reasonable benefit / risk ratio. The compounds of the present disclosure can be combined with one or more pharmaceutically acceptable excipients (including carriers, vehicles, diluents, and adjuvants), which can enhance the solubility, deliverability, dispersibility, stability, and / or conformational integrity of the compound or its conjugate.

[0036] The term "active agent" as used herein is intended to refer to a substance having biological activity relevant to the present disclosure, particularly a therapeutic and diagnostic substance that can be used in the methods described in the present disclosure. The active agent can be a compound useful for the purposes disclosed herein.

[0037] As used herein, the term "pure" or "substantially pure" means that the target species is the major species present (i.e., on a molar basis, it is more abundant than any other target species in the composition), and in particular, a substantially purified fraction means a composition in which the target species comprises at least about 50% (molar basis) of all macromolecular species present. Generally, a substantially pure composition will comprise more than about 80% of all macromolecular species present in the composition, more specifically more than about 85%, more than about 90%, more than about 95%, or more than about 99%. The term "pure" or "substantially pure" also means that the target species is at least 60% (w / w) pure, or at least 70% (w / w) pure, or at least 75% (w / w) pure, or at least 80% (w / w) pure, or at least 85% (w / w) pure, or at least 90% (w / w) pure, or at least 92% (w / w) pure, or at least 95% (w / w) pure, or at least 96% (w / w) pure, or at least 97% (w / w) pure, or at least 98% (w / w) pure, or at least 99% (w / w) pure, or 100% (w / w) pure preparation.

[0038] Examples of animals or mammals within the scope and meaning of the term "subject" or "patient" include, but are not limited to, dogs, cats, rats, mice, rabbits, guinea pigs, chinchillas, horses, goats, pigs, cows, sheep, llamas, alpacas, zoo animals, Old and New World monkeys, non-human primates, and humans.

[0039] In at least some embodiments, the diseases and / or disorders that can be treated using the compounds of the present disclosure are characterized by inflammation and / or angiogenesis. Diseases and / or disorders having an inflammatory basis that can be treated using the compounds of the present disclosure include, but are not limited to, inflammatory bowel disease, type 1 diabetes, type 2 diabetes, Graves' disease, multiple sclerosis, various types of arthritis, vasculitis, dermatitis, glomerulonephritis, hepatitis, periodontitis, atherosclerosis, heart failure, obesity, Alzheimer's disease, and metabolic syndrome, as well as other afflictions and disorders disclosed herein.

[0040] Examples of ocular diseases having an inflammatory basis that can be treated using the compounds of the present disclosure include, but are not limited to, keratitis, endophthalmitis, blepharitis, conjunctivitis, scleritis, herpetic inflammation, uveitis, vasculitis, arteritis, orbital inflammations, optic neuritis, sympathetic ophthalmia, retinitis, and other autoimmune diseases, age-related macular degeneration, macular edema, diabetic retinopathy, glaucoma, proliferative vitreoretinopathy, corneal edema, uveal edema, and retinal edema.

[0041] Diseases and / or disorders having an angiogenesis basis that can be treated using the compounds of the present disclosure include ocular diseases and / or disorders such as, but not limited to, diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, retinal artery or vein occlusion, corneal transplant rejection, corneal neovascularization, neovascular glaucoma, and sickle cell retinopathy, as well as non-ocular diseases and / or disorders including, but not limited to, cancer, skin diseases, diabetic ulcers, diabetic nephropathy, cardiovascular diseases, and stroke.

[0042] "Treatment" refers to therapeutic treatment. "Prevention" refers to prophylactic or preventive treatment measures or reducing the onset of a disorder or disease. The term "treatment" refers to the administration of a composition to a subject for therapeutic purposes and / or prophylactic purposes. Non-limiting examples of the mode of administration include oral, topical, retrobulbar, subconjunctival, transdermal, parenteral, subcutaneous, intranasal, intramuscular, intraperitoneal, intravitreal, and intravenous routes (including topical and systemic applications). In addition, the compositions of the present disclosure can be formulated with carrier compounds that provide delayed, controlled, extended, and / or sustained release, for example, using formulation techniques that incorporate the active agent into a degradable polymer.

[0043] The term "topical" as used herein is defined as a mode of administration through an epithelial surface, such as, but not limited to, a substance administered by external application to the eye. Non-limiting examples of topical administration are by using eye drops or administering particles containing the active agent.

[0044] The terms "therapeutic composition" and "pharmaceutical composition" refer to a composition comprising a compound of the present disclosure (also referred to herein as the active agent) that can be administered to a subject by any method known in the art or any method contemplated herein, wherein the administration of the composition results in the therapeutic effects described elsewhere herein. As previously mentioned, the compositions of the present disclosure can be designed to provide delayed, controlled, extended, and / or sustained release using appropriate formulation techniques.

[0045] The term "effective amount" refers to an amount of the active agent that, when used in the manner of the present disclosure, is sufficient to exhibit a detectable therapeutic or treatment effect in a subject without undue adverse side effects (such as significant toxicity, irritation, and allergic reactions) and has a reasonable benefit / risk ratio. The effective amount for a subject will depend on the type, size, and health status of the subject, the nature and severity of the disorder to be treated, the method of administration, the duration of treatment, the nature of concurrent treatments (if any), the specific formulation used, etc. Accordingly, an exact effective amount cannot be specified in advance. However, one of ordinary skill in the art can determine the effective amount for a given situation by routine experimentation based on the information provided herein. The term "activity enhancing amount" refers to an amount of the active agent that is sufficient to increase PPARα activity in a cell or subject.

[0046] The term "improvement" refers to a detectable or measurable improvement in the condition of a subject or its symptoms. A detectable or measurable improvement includes a subjective or objective reduction, decrease, inhibition, suppression, limitation, or control of the occurrence, frequency, severity, progression, or duration of a disorder, or an improvement in the underlying cause or consequence of a symptom or disorder, or a reversal of a disorder. A successful treatment outcome can result in a "therapeutic effect", or "be beneficial" in improving, reducing, decreasing, inhibiting, suppressing, limiting, controlling, or preventing the occurrence, frequency, severity, progression, or duration of a disorder in a subject, or the consequences of a disorder.

[0047] A reduction or decrease in the worsening condition (such as stabilizing a disorder) is also a successful treatment outcome. Thus, a therapeutic effect does not require complete elimination or reversal of a disorder, or any one, most, or all of the adverse symptoms, complications, consequences, or underlying causes associated with a disorder. Thus, a satisfactory endpoint can be achieved when there is an incremental improvement (such as a partial reduction, decrease, inhibition, suppression, limitation, control, or prevention) in the occurrence, frequency, severity, progression, or duration of a disorder, or inhibition or reversal (such as stabilization) over a short or long duration (e.g., seconds, minutes, hours).

[0048] The term "phosphate" as used herein refers to the following moiety:

[0049]

[0050] wherein each R x is independently selected from H, substituted alkyl, unsubstituted alkyl, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, unsubstituted alkynyl, substituted cycloalkyl, unsubstituted cycloalkyl, substituted heterocyclic group, unsubstituted heterocyclic group, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted amine, and unsubstituted amine. In certain embodiments, one R x = H or a salt thereof, and one R x ≠ H. In certain embodiments, two R x = H or a salt thereof.

[0051] The term "phosphonate" as used herein refers to the following moiety:

[0052]

[0053] wherein each R xIndependently selected from H, substituted alkyl, unsubstituted alkyl, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, unsubstituted alkynyl, substituted cycloalkyl, unsubstituted cycloalkyl, substituted heterocyclic group, unsubstituted heterocyclic group, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted amine, and unsubstituted amine. In certain embodiments, -OR x wherein R x = H or a salt thereof. In certain embodiments, -OR x wherein R x ≠ H.

[0054] As used herein, the term "compound" refers to a chemical substance that contains two or more different elements. The term compound also includes isomers and tautomers of the compound, solvates of the compound, and solvates of isomers and tautomers of the compound.

[0055] The term "isomers" includes conformational isomers, geometric isomers, stereoisomers, and / or optical isomers. For example, the compounds of the present disclosure may include one or more chiral centers and / or double bonds, and thus may exist as stereoisomers, such as double bond isomers (i.e., geometric isomers), enantiomers, diastereomers, and mixtures thereof (such as racemic mixtures). "Stereoisomers" refer to compounds that differ in chirality at one or more stereocenters. Stereoisomers include enantiomers and diastereomers.

[0056] "Tautomers" refer to different forms of a compound that differ in the position of a proton, such as enol forms, keto forms, and mixtures thereof. Tautomers can be imine-enamine tautomers, or tautomeric forms of heteroaryls containing a ring atom that is connected to a ring -NH- moiety and a ring =N- moiety, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

[0057] As used herein, the term "linking group" refers to a divalent saturated or unsaturated aliphatic or aromatic hydrocarbon group, which may include heteroatoms and is unsubstituted or substituted with 1 to 5, preferably 1 to 3, more preferably 1 to 2 substituents selected from the group consisting of alkyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxylester, (carboxylester)amino, (carboxylester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halogen, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic group, substituted heterocyclic group, heterocyclooxy, substituted heterocyclooxy, heterocyclicthio, substituted heterocyclicthio, nitro, SO 3 H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio.

[0058] As used herein, the terms alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, and alkynyl generally are intended to refer to branched or unbranched structures containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, unless otherwise indicated. Haloalkyl may refer to, for example, a haloalkyl of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms having 1 to 3 halogen atoms. Haloalkoxy may refer to, for example, a haloalkyl of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms having 1 to 3 halogen atoms. Halogen may refer to chlorine (Cl), fluorine (F), bromine (Br), and / or iodine (I). Halogen may be abbreviated as "halo" herein.

[0059] "Alkyl" refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms and more specifically 1 to 6 carbon atoms. The term includes, for example but not limited to, linear and branched hydrocarbon groups such as methyl (CH 3 -), ethyl (CH 3 CH 2 -), n-propyl (CH 3 CH 2 CH 2 -), isopropyl ((CH 3 ) 2 CH-), n-butyl (CH 3 CH 2 CH 2 CH2 -), isobutyl ((CH 3 ) 2 CHCH 2 -), sec-butyl ((CH 3 )(CH 3 CH 2 )CH-), tert-butyl ((CH 3 ) 3 C-), n-pentyl (CH 3 CH 2 CH 2 CH 2 CH 2 -), and neopentyl ((CH 3 ) 3 CCH 2 -).

[0060] "Alkenyl" means a monovalent straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms, more specifically 2 to 4 carbon atoms, and having at least 1, and preferably 1 to 2, vinyl (>C═C<) unsaturation sites. Examples of such groups include vinyl, allyl, and but-3-en-1-yl. The term includes cis isomers and trans isomers or mixtures of these isomers.

[0061] "Alkynyl" means a straight-chain or branched monovalent hydrocarbon group having 2 to 6 carbon atoms, more specifically 2 to 3 carbon atoms, and having at least 1, and more specifically 1 to 2, ethynyl (-C≡C-) unsaturation sites. Examples of such alkynyl groups include ethynyl (-C≡CH) and propargyl (-CH 2 C≡CH).

[0062] "Substituted alkyl" means an alkyl group having 1 to 5, preferably 1 to 3, more specifically 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halogen, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic group, substituted heterocyclic group, heterocycloxy, substituted heterocycloxy, heterocyclicthio, substituted heterocyclicthio, nitro, SO 3The group consisting of H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio and substituted alkylthio, wherein the substituents are as defined herein.

[0063] "Substituted alkenyl" means alkenyl having from 1 to 3 substituents and more specifically 1 to 2 substituents, the substituents being selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halogen, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic group, substituted heterocyclic group, heterocyclooxy, substituted heterocyclooxy, heterocyclicthio, substituted heterocyclicthio, nitro, SO 3 The group consisting of H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio and substituted alkylthio, wherein the substituents are as defined herein, provided that any hydroxy or thiol substitution is not attached to a vinyl (unsaturated) carbon atom.

[0064] "Substituted alkynyl" means alkynyl having from 1 to 3 substituents and more specifically 1 to 2 substituents, the substituents being selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halogen, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic group, substituted heterocyclic group, heterocyclooxy, substituted heterocyclooxy, heterocyclicthio, substituted heterocyclicthio, nitro, SO 3the group consisting of H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio and substituted alkylthio, wherein the substituents are as defined herein, provided that any hydroxy or thiol substitution is not attached to an acetylenic carbon atom.

[0065] "Alkylene" means a straight-chain or branched-chain divalent saturated aliphatic hydrocarbon group having 1 to 6 carbon atoms and more specifically 1 to 3 carbon atoms. Examples of this term are, for example, methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), n-propylene (-CH 2 CH 2 CH 2 -), isopropylidene (-CH 2 CH(CH 3 ) or -CH(CH 3 )CH 2 -), butylene (-CH 2 CH 2 CH 2 CH 2 -), isobutylene (-CH 2 CH(CH 3 )CH 2 -), sec-butylene (-CH 2 CH 2 (CH 3 )CH-), etc.

[0066] "Substituted alkylene" means an alkylene in which 1 to 3 hydrogens are replaced by substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxy, nitro, carboxyl, carboxyl ester, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle and oxo, wherein the substituents are as defined herein. In some embodiments, the alkylene has 1 to 2 of the above groups, or 1-3 carbon atoms are replaced by -O-, -S- or -NR- moieties, where R is H or C 1 -C 6 alkyl. When the alkylene is substituted by an oxo group, 2 hydrogens attached to the same carbon of the alkylene are replaced by "=O".

[0067] "Alkoxy" means the group: -O-alkyl, where alkyl is as defined herein. Alkoxy includes, for example but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy and n-pentyloxy.

[0068] "Substituted alkoxy" means the group: -O-(substituted alkyl), where the substituted alkyl is as defined herein.

[0069] "Acyl" means the groups: H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)- and substituted heterocyclic-C(O)-, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. Acyl also includes the "acetyl" group CH 3 C(O)-.

[0070] "Acylamino" means the groups: -NR a C(O)alkyl, -NR a C(O)substituted alkyl, -NR a C(O)cycloalkyl, -NR a C(O)substituted cycloalkyl, -NR a C(O)cycloalkenyl, -NR a C(O)substituted cycloalkenyl, -NR a C(O)alkenyl, -NR a C(O)substituted alkenyl, -NR a C(O)alkynyl, -NR a C(O)substituted alkynyl, -NR a C(O)aryl, -NR a C(O)substituted aryl, -NR a C(O)heteroaryl, -NR a C(O)substituted heteroaryl, -NR a C(O)heterocyclic and -NR a C(O)substituted heterocyclic, where R a is hydrogen or alkyl, and where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0071] "Acyloxy" means a group: alkyl-C(O)O-, substituted alkyl-C(O)O-, alkenyl-C(O)O-, substituted alkenyl-C(O)O-, alkynyl-C(O)O-, substituted alkynyl-C(O)O-, aryl-C(O)O-, substituted aryl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, cycloalkenyl-C(O)O-, substituted cycloalkenyl-C(O)O-, heteroaryl-C(O)O-, substituted heteroaryl-C(O)O-, heterocyclic-C(O)O- and substituted heterocyclic-C(O)O-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0072] "Amino" means a group: -NH 2 。

[0073] "Substituted amino" means a group: -NR b R c wherein R b and R c are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -alkenyl, -SO 2 -substituted alkenyl, -SO 2 -cycloalkyl, -SO 2 -substituted cycloalkyl, -SO 2 -cycloalkenyl, -SO 2 -substituted cycloalkenyl, -SO 2 -aryl, -SO 2 -substituted aryl, -SO 2 -heteroaryl, -SO 2 -substituted heteroaryl, -SO 2 -heterocyclic and -SO 2 -substituted heterocyclic, and wherein R b and R c optionally together with the nitrogen to which they are attached form a heterocyclic or substituted heterocyclic group, provided that R b and R cNone of them is hydrogen, and the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group and substituted heterocyclic group are as defined herein. When R b is hydrogen and R c is alkyl, the substituted amino group is sometimes referred to herein as alkylamino. When R b and R c are both alkyl, the substituted amino group is sometimes referred to herein as dialkylamino. When referring to a monosubstituted amino group, it means that only one of R b or R c is hydrogen. When referring to a disubstituted amino group, it means that neither R b nor R c is hydrogen.

[0074] "Aminocarbonyl" means the group: -C(O)NR b R c , where R b and R c are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic group and substituted heterocyclic group, and R b and R c optionally together with the nitrogen to which they are attached form a heterocyclic group or a substituted heterocyclic group, and where the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group and substituted heterocyclic group are as defined herein.

[0075] "Aminothiocarbonyl" means the group: -C(S)NR b R c , where R b and R c are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic group and substituted heterocyclic group, and R b and R c optionally together with the nitrogen to which they are attached form a heterocyclic group or a substituted heterocyclic group, and where the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group and substituted heterocyclic group are as defined herein.

[0076] "aminocarbonylamino" means the group: -NR a C(O)NR b R c , where R a is hydrogen or alkyl, and R b and R c are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic group, and substituted heterocyclic group, and R b and R c optionally together with the nitrogen to which they are attached form a heterocyclic group or a substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group, and substituted heterocyclic group are as defined herein.

[0077] "aminothiocarbonylamino" means the group: -NR a C(S)NR b R c , where R a is hydrogen or alkyl, and R b and R c are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic group, and substituted heterocyclic group, and R b and R c optionally together with the nitrogen to which they are attached form a heterocyclic group or a substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group, and substituted heterocyclic group are as defined herein.

[0078] "aminocarbonyloxy" means the group: -O-C(O)NR b R c , where R b and R c are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic group, and substituted heterocyclic group, and R b and R cOptionally, together with the nitrogen to which it is attached, forms a heterocyclic group or a substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group and substituted heterocyclic group are as defined herein.

[0079] "Sulfamoyl" means the group: -SO 2 NR b R c , wherein R b and R c are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic group and substituted heterocyclic group, and R b and R c optionally, together with the nitrogen to which it is attached, forms a heterocyclic group or a substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group and substituted heterocyclic group are as defined herein.

[0080] "Sulfamoyloxy" means the group: -O-SO 2 NR b R c , wherein R b and R c are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic group and substituted heterocyclic group, and R b and R c optionally, together with the nitrogen to which it is attached, forms a heterocyclic group or a substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group and substituted heterocyclic group are as defined herein.

[0081] "Sulfamoylamino" means the group: -NR a SO 2 NR b R c , wherein R a is hydrogen or alkyl, and R b and R cIndependently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic group and substituted heterocyclic group, and R b and R c optionally together with the nitrogen to which it is attached form a heterocyclic group or a substituted heterocyclic group, and wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group and substituted heterocyclic group are as defined herein.

[0082] "Amidino" means the group: -C(=NR d )NR b R c , wherein R b , R c and R d are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic group and substituted heterocyclic group, and R b and R c optionally together with the nitrogen to which it is attached form a heterocyclic group or a substituted heterocyclic group, and wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group and substituted heterocyclic group are as defined herein.

[0083] "Aryl" or "Ar" means a monovalent aromatic carbocyclic group having 6 to 14 carbon atoms, which has a single ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthracenyl), and these fused rings can be aromatic or non-aromatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7-yl, etc.), provided that the point of attachment is on an aromatic carbon atom. Aryl groups include, for example, phenyl and naphthyl.

[0084] "Substituted aryl" means an aryl group substituted with 1 to 5, such as 1 to 3, more specifically 1 to 2 substituents selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halogen, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic group, substituted heterocyclic group, heterocyclooxy, substituted heterocyclooxy, heterocyclicthio, substituted heterocyclicthio, nitro, SO 3 H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio and substituted alkylthio, wherein the substituents are as defined herein.

[0085] "Aryloxy" means the group: -O-aryl, wherein aryl is as defined herein, including, for example, phenoxy and naphthyloxy.

[0086] "Substituted aryloxy" means the group: -O-(substituted aryl), wherein substituted aryl is as defined herein.

[0087] "Arylthio" means the group: -S-aryl, wherein aryl is as defined herein.

[0088] "Substituted arylthio" means the group: -S-(substituted aryl), wherein substituted aryl is as defined herein.

[0089] "Carbonyl" means the divalent group: -C(O)-, equivalent to -C(=O)-.

[0090] "Carboxyl" or "carboxylic acid" means -COOH or its salts.

[0091] "Carboxylic acid ester" or "carboxylate ester" refers to the group: -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)O-alkenyl, -C(O)O-substituted alkenyl, -C(O)O-alkynyl, -C(O)O-substituted alkynyl, -C(O)O-aryl, -C(O)O-substituted aryl, -C(O)O-cycloalkyl, -C(O)O-substituted cycloalkyl, -C(O)O-cycloalkenyl, -C(O)O-substituted cycloalkenyl, -C(O)O-heteroaryl, -C(O)O-substituted heteroaryl, -C(O)O-heterocyclic group and -C(O)O-substituted heterocyclic group, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group and substituted heterocyclic group are as defined herein.

[0092] "(Carboxylic acid ester) amino" refers to the group: -NR a C(O)O-alkyl, -NR a C(O)O-substituted alkyl, -NR a C(O)O-alkenyl, -NR a C(O)O-substituted alkenyl, -NR a C(O)O-alkynyl, -NR a C(O)O-substituted alkynyl, -NR a C(O)O-aryl, -NR a C(O)O-substituted aryl, -NR a C(O)O-cycloalkyl, -NR a C(O)O-substituted cycloalkyl, -NR a C(O)O-cycloalkenyl, -NR a C(O)O-substituted cycloalkenyl, -NR a C(O)O-heteroaryl, -NR a C(O)O-substituted heteroaryl, -NR a C(O)O-heterocyclic group and -NR a C(O)O-substituted heterocyclic group, where R a is alkyl or hydrogen, and where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group and substituted heterocyclic group are as defined herein.

[0093] "(Carboxyester)oxy" means a group: -O-C(O)O-alkyl, -O-C(O)O-substituted alkyl, -O-C(O)O-alkenyl, -O-C(O)O-substituted alkenyl, -O-C(O)O-alkynyl, -O-C(O)O-substituted alkynyl, -O-C(O)O-aryl, -O-C(O)O-substituted aryl, -O-C(O)O-cycloalkyl, -O-C(O)O-substituted cycloalkyl, -O-C(O)O-cycloalkenyl, -O-C(O)O-substituted cycloalkenyl, -O-C(O)O-heteroaryl, -O-C(O)O-substituted heteroaryl, -O-C(O)O-heterocyclic group and -O-C(O)O-substituted heterocyclic group, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group and substituted heterocyclic group are as defined herein.

[0094] "Cyano" means a group: -CN.

[0095] "Cycloalkyl" means a cyclic alkyl group having 3 to 10 carbon atoms, having a single ring or multiple rings, including fused ring systems, bridged ring systems and spiro ring systems. The fused ring can be an aromatic ring, provided that the non-aromatic ring portion is attached to the rest of the molecule. Examples of suitable cycloalkyl groups include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclooctyl.

[0096] "Cycloalkenyl" means a non-aromatic cyclic alkyl group having 3 to 10 carbon atoms, having a single ring or multiple rings, and having at least one >C═C< ring unsaturation site, such as 1 to 2 >C═C< ring unsaturation sites.

[0097] "Substituted cycloalkyl" and "substituted cycloalkenyl" refer to cycloalkyl or cycloalkenyl groups having 1 to 5, 1 to 4, or 1 to 3 substituents, where the substituents are selected from the group consisting of oxo, thio, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halogen, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic group, substituted heterocyclic group, heterocyclooxy, substituted heterocyclooxy, heterocyclicthio, substituted heterocyclicthio, nitro, SO 3 H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, where the substituents are as defined herein.

[0098] "Cycloalkoxy" means: -O-cycloalkyl. "Substituted cycloalkoxy" means: -O-(substituted cycloalkyl). "Cycloalkylthio" means: -S-cycloalkyl. "Substituted cycloalkylthio" means: -S-(substituted cycloalkyl). "Cycloalkenyloxy" means: -O-cycloalkenyl. "Substituted cycloalkenyloxy" means: -O-(substituted cycloalkenyl). "Cycloalkenylthio" means: -S-cycloalkenyl. "Substituted cycloalkenylthio" means: -S-(substituted cycloalkenyl).

[0099] "Guanidino" means the group: -NHC(=NH)NH 2 . "Substituted guanidino" means: -NR e C(=NR e )N(R e ) 2 , where each R e is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclic group, and substituted heterocyclic group, and the two R e groups attached to the same guanidino nitrogen atom may optionally form a heterocyclic group or a substituted heterocyclic group together with the nitrogen to which they are attached, provided that at least one R e is not hydrogen, and where the substituents are as defined herein.

[0100] "Hydroxy" or "hydroxyl" refers to the group: -OH.

[0101] "Heteroaryl" refers to an aromatic group having 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple fused rings (e.g., indolyl or benzothienyl), where the fused rings can be aromatic or non-aromatic, and / or contain heteroatoms, provided that the point of attachment is through an atom of the aromatic heteroaryl group. In one embodiment, the nitrogen and / or sulfur ring atoms of the heteroaryl group can be optionally oxidized to provide N-oxide (N→O), sulfinyl, or sulfonyl moieties. Non-limiting examples of heteroaryl include pyridyl, pyrrolyl, indolyl, thienyl, and furyl.

[0102] "Substituted heteroaryl" refers to a heteroaryl group substituted with 1 to 5, 1 to 4, 1 to 3, or 1 to 2 substituents selected from the group consisting of the same substituents as defined for substituted aryl.

[0103] "Heteroaryloxy" refers to: -O-heteroaryl. "Substituted heteroaryloxy" refers to the group: -O-(substituted heteroaryl).

[0104] "Heteroarylthio" refers to the group: -S-heteroaryl. "Substituted heteroarylthio" refers to the group: -S-(substituted heteroaryl).

[0105] "Heterocycle" or "heterocyclic" or "heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially saturated but non-aromatic group having 1 to 10 ring carbon atoms and 1 to 4 ring heteroatoms selected from the group consisting of N, S, and O. Heterocycles include single rings or multiple fused rings, including fused ring systems, bridged ring systems, and spiro ring systems. In a fused ring system, one or more rings can be cycloalkyl, aryl, or heteroaryl, provided that the point of attachment is through a non-aromatic ring. In one embodiment, the nitrogen and / or sulfur atoms of the heterocyclic group can be optionally oxidized to provide N-oxide, sulfinyl, or sulfonyl moieties.

[0106] "Substituted heterocycle" or "substituted heterocycloalkyl" or "substituted heterocyclyl" refers to a heterocyclic group substituted with 1 to 5, 1 to 4, or 1 to 3 of the same substituents as defined for substituted cycloalkyl.

[0107] "Heterocyclyloxy" refers to the group: -O-heterocyclyl.

[0108] "Substituted heterocyclyloxy" refers to the group: -O-(substituted heterocyclyl).

[0109] "Heterocyclic thio group" means the group: -S-heterocyclic group. "Substituted heterocyclic thio group" means the group: -S-(substituted heterocyclic group).

[0110] Examples of heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also known as thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine, and tetrahydrofuranyl.

[0111] "Nitro" means the group: -NO 2 .

[0112] "Oxo" means a double-bonded atom (=O).

[0113] "Phenylene" means a divalent aromatic ring, wherein the ring contains 6 carbon atoms. Substituted phenylene means phenylene substituted with 1 to 4, 1 to 3, or 1 to 2 substituents selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxylester, (carboxylester)amino, (carboxylester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halogen, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic group, substituted heterocyclic group, heterocyclooxy, substituted heterocyclooxy, heterocyclic thio group, substituted heterocyclic thio group, nitro, SO3 The group consisting of H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio and substituted alkylthio, wherein the substituents are as defined herein.

[0114] "Spiroalkyl" and "spiro system" refer to a divalent cyclic group having 3 to 10 carbon atoms, having a cycloalkyl or heterocycloalkyl ring, and connected by a spiro linkage (a linkage formed by a single atom which is the only common member of the rings), as shown in the following structure:

[0115]

[0116] "Sulfonyl" refers to the divalent group: -S(O) 2 -.

[0117] "Substituted sulfonyl" refers to the group: -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -alkenyl, -SO 2 -substituted alkenyl, -SO 2 -cycloalkyl, -SO 2 -substituted cycloalkyl, -SO 2 -cycloalkenyl, -SO 2 -substituted cycloalkenyl, -SO 2 -aryl, -SO 2 -substituted aryl, -SO 2 -heteroaryl, -SO 2 -substituted heteroaryl, -SO 2 -heterocyclic group, -SO 2 -substituted heterocyclic group, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group and substituted heterocyclic group are as defined herein. Substituted sulfonyl includes groups such as methyl-SO 2 -, phenyl-SO 2 - and 4-methylphenyl-SO 2 -.

[0118] "Substituted sulfonyloxy" refers to the group: -OSO 2 -alkyl, -OSO 2 -substituted alkyl, -OSO 2 -alkenyl, -OSO 2 -substituted alkenyl, -OSO 2 -cycloalkyl, -OSO 2 -substituted cycloalkyl, -OSO 2 -cycloalkenyl, -OSO2 -substituted cycloalkenyl, -OSO 2 -aryl, -OSO 2 -substituted aryl, -OSO 2 -heteroaryl, -OSO 2 -substituted heteroaryl, -OSO 2 -heterocyclic group, -OSO 2 -substituted heterocyclic group, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group and substituted heterocyclic group are as defined herein.

[0119] "Thioacyl" means the group: H-C(S)-, alkyl-C(S)-, substituted alkyl-C(S)-, alkenyl-C(S)-, substituted alkenyl-C(S)-, alkynyl-C(S)-, substituted alkynyl-C(S)-, cycloalkyl-C(S)-, substituted cycloalkyl-C(S)-, cycloalkenyl-C(S)-, substituted cycloalkenyl-C(S)-, aryl-C(S)-, substituted aryl-C(S)-, heteroaryl-C(S)-, substituted heteroaryl-C(S)-, heterocyclic group-C(S)- and substituted heterocyclic group-C(S)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group and substituted heterocyclic group are as defined herein.

[0120] "Thiol" means the group: -SH.

[0121] "Thiocarbonyl" means the divalent group: -C(S)-, equivalent to -C(=S)-.

[0122] "Thio" means the atom (=S).

[0123] "Alkylthio" means the group: -S-alkyl, wherein alkyl is as defined herein. "Substituted alkylthio" means the group: -S-(substituted alkyl), wherein substituted alkyl is as defined herein.

[0124] As used herein, the term "salt" refers to a compound that comprises an ionic combination of a negatively charged moiety (phosphate / phosphonate compound) and a positively charged cationic atom or compound such that the compound has no net charge. The salts of the present disclosure are intended to be pharmaceutically acceptable, i.e., salts suitable for pharmaceutical use. Generally, pharmaceutically acceptable salts are those that retain one or more of the desired pharmacological activities of the parent compound and are suitable for administration to humans or other animals as defined elsewhere herein. Cations of the phosphate and phosphonate compounds of the present disclosure include, but are not limited to, metal ions such as alkali metal ions (e.g., sodium, potassium, lithium), alkaline earth metal ions (e.g., magnesium, calcium, barium), or aluminum ions. The cation can be an ammonium ion, a quaternary ammonium alkyl, a quaternary ammonium aryl, or an ammonium ion derived from an organic base, including but not limited to ethanolamine, diethanolamine, triethanolamine, N-methylglucosamine, morpholine, piperidine, pyridine, dimethylamine, diethylamine, trimethylamine, triethylamine, isopropylamine, 2-ethylaminoethanol, histidine, lysine, procaine, and tris(2-amino-2-(hydroxymethyl)propane-1,3-diol).

[0125] Unless otherwise indicated, the naming of substituents not explicitly defined herein is determined by naming the terminal portion of the functional group and then proceeding towards the adjacent functional group at the point of attachment. For example, the substituent "arylalkoxycarbonyl" refers to the group (aryl)-(alkyl)-O-C(O)-.

[0126] As used herein, the term "prodrug" refers to a recognized modification of one or more functional groups such that these functional groups are metabolized in vivo to provide the active agent or its active metabolite. Such functional groups are well known in the art and include acyl or thioacyl groups for hydroxy and / or amino substitution, conversion of one or more hydroxy groups to monophosphate, diphosphate, and triphosphate esters, wherein one or more side-chain hydroxy groups of the monophosphate, diphosphate, and triphosphate esters are optionally converted to alkoxy, substituted alkoxy, aryloxy, or substituted aryloxy groups, etc.

[0127] Prodrug derivatives may exhibit various pharmacologically desirable properties, such as but not limited to increased water solubility, increased bioavailability, and altered activity of the active agent. "Bioactivity" refers to the ability to alter the physiological system of a cell, tissue, or organism without reference to how the active agent exerts its physiological effect. Such prodrugs may (but need not) be pharmacologically inactive prior to conversion to their active drug form. The compounds disclosed herein may include prodrug derivatives that hydrolyze or otherwise cleave under the conditions of use.

[0128] Examples of suitable prodrug derivatives of the present disclosure include, but are not limited to, active agents in which a hydroxyl group, an amino group, a thiol group, or a carboxyl group is derivatized to form a prodrug. For example, a hydroxyl functional group (including a phenolic hydroxyl group and an aliphatic hydroxyl group) can be masked as a phosphate ester, a phosphonate ester, a sulfonate ester, an ester, or a carbonate-containing pro-group. As used herein, a pro-group refers to a group that binds to an active agent to provide a prodrug derivative. These prodrugs can be hydrolyzed in vivo to provide a hydroxyl group. An amino functional group can be masked as an amide, a carbamate, an imine, a urea, a phosphorophenyl, a phosphoryl, or a sulfenyl pro-group. These prodrugs can be hydrolyzed in vivo to provide an amino group. A carboxyl group can be masked as an ester (including a silyl ester and a thioester), an amide, or an oxadiazole pro-group. These prodrugs can be hydrolyzed in vivo to provide a carboxyl group.

[0129] Compared with the active agent, a prodrug can increase the water solubility of the prodrug. Thus, a pro-group (e.g., a phosphate ester or a phosphonate ester moiety, or a linker containing a phosphate ester or a phosphonate ester moiety) can include or can be one or more groups suitable for imparting enhanced water solubility to the drug molecule. These groups are well known and include, but are not limited to, hydrophilic groups such as phosphates or phosphonates, or alkyl, aryl, aralkyl, or cycloheteroalkyl groups substituted with one or more phosphates (i.e., phosphates or phosphonates), amines, alcohols, carboxylic acids, sulfoxides, sugars, amino acids, thiols, polyols, ethers, thioethers, and quaternary ammonium salts. Examples of methods for synthesizing prodrugs are described, for example, in Ettmayer et al., (2004), J. Med. Chem. 47(10):2393 - 2404, and Bundgaard et al., (1989) J. Med. Chem. 32(12):2503 - 2507, and those skilled in the art can apply them to synthesize the prodrug derivatives of the present disclosure after reading the present disclosure.

[0130] For example, various ester groups (including phosphate esters or phosphonate esters) generally undergo acid-catalyzed hydrolysis upon exposure to the acidic conditions of the stomach to produce the parent hydroxyl group, or base-catalyzed hydrolysis upon exposure to the basic conditions of the intestine or blood. Thus, when administered orally to a subject, a compound containing an ester moiety can be considered a prodrug of its corresponding hydroxyl group, whether or not the ester form has pharmacological activity. For example, a prodrug can be chemically cleaved in the stomach to form an active compound, and a pro-group including such an ester can be used. Alternatively, a pro-group can be designed to be metabolized in the presence of enzymes such as, but not limited to, phosphatases, esterases, amidases, lipases (including ATPases and kinases). Pro-groups including bonds capable of being metabolized in vivo are well known and include, but are not limited to, ethers, thioethers, silyl ethers, silyl thioethers, esters, thioesters, carbonates, thiocarbonates, carbamates, thiocarbamates, ureas, thioureas, and carboxamides.

[0131] Prodrugs can also be metabolized under the desired conditions of use, such as the acidic conditions found in the stomach and / or the enzymatic action found in the body, to produce a bioactive group, such as the compounds described herein. Those skilled in the art will understand that the pro-group can include almost any known or later discovered hydroxyl, amine, or thiol protecting group. Examples of protecting groups suitable for use in the compounds of the present disclosure include, but are not limited to, those found in “Greene’s Protective Groups in OrganicSynthesis,” P.G.M. Wuts, 5 th Ed, Wiley, New York, 2014.

[0132] The identity of the pro-group can also be selected to impart the desired properties to the prodrug. For example, hydrophilic groups can be used to increase water solubility. In this way, prodrugs specifically designed for the selected mode of administration can be obtained. Prodrugs can also help, for example, to improve passive intestinal absorption, improve transporter-mediated intestinal absorption, prevent rapid metabolism (sustained-release prodrugs), tissue-selective delivery, passive enrichment in target tissues, and targeting specific transporters. The various groups described in these references can be used in the prodrugs described herein.

[0133] This work demonstrates how the novel class of compounds of the present disclosure can be used, for example, as ophthalmic compositions for the treatment of ocular disorders and conditions such as, but not limited to, retinal inflammation, retinal neovascularization, retinal vascular leakage, retinopathy of prematurity (ROP), diabetic retinopathy (DR), age-related macular degeneration (e.g., wet AMD), and diabetic macular edema (DME), as well as other ocular and non-ocular diseases and / or conditions described herein.

[0134] In certain non-limiting embodiments, the present disclosure includes compounds having Chemical Structural Formula I:

[0135]

[0136] wherein Ring A is benzene or pyridine containing nitrogen (N) at the 2, 4, 5, or 6 position;

[0137] wherein Ring B is benzene or pyridine containing N at the 2, 3, 5, or 6 position;

[0138] wherein Ring C is benzene or pyridine containing N at the 2, 3, 4, 5, or 6 position;

[0139] wherein X is selected from the group consisting of oxygen (O), NH, sulfur (S), and CH 2 ;

[0140] wherein Y is selected from the group consisting of O, NH, S, and CH 2 ;

[0141] where k is from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms; and

[0142] wherein in at least some embodiments, the R on the "A" ring of Chemical Structure I 1 substituents are selected from the chemical structures i-x shown in Table 1 below:

[0143] Table 1. Examples of R1 substituents

[0144]

[0145]

[0146] In a non-limiting embodiment, the R of Structure ix in Table 1 8 and R 9 are each independently selected from the group consisting of: hydrogen (H), halogen (F, Cl, Br, I), alkyl (e.g., branched or unbranched C 1 to C 10 ), alkoxy (e.g., branched or unbranched C 1 to C 10 ), and a ring (R 8 connected to R 9 ). In Structure ix of Table 1, X can be O, NH, S, or CH 2 . In a non-limiting embodiment, the R of Structure x in Table 1 10 and R 11 can each independently be selected from the group consisting of: H, alkyl (e.g., branched or unbranched C 1 to C 10 ), and a ring (R 10 connected to R 11 ).

[0147] In other non-limiting embodiments, the R in Chemical Structure I 1 can be selected from the group consisting of carboxylic acids and carboxylic acid isosteres, including hydroxamic acids, hydroxamic esters, phosphonic acids, phosphinic acids, sulfonic acids, sulfinic acids, sulfonamides, acylsulfonamides, sulfonylureas, acylureas, tetrazoles, thiazolidinediones, oxazolidinediones, oxadiazol-5(4H)-ones, thiadiazol-5(4H)-ones, oxathiadiazol-2-oxides, oxadiazol-5(4H)-thiones, isoxazoles, tetramic acids, cyclopentane 1,3-diones, cyclopentane 1,2-diones, squaric acids, substituted phenols, heteroarenes, amidines, hydroxyamides, alkylhydroxyamidines, including the exemplary structures shown in Table 2, and also including salts of any of the above structures.

[0148] Table 2. R1 Other examples

[0149]

[0150]

[0151]

[0152] In at least some non-limiting embodiments, R of Chemical Structure I 2 substituents are selected from the group consisting of: H, F, Cl, Br, I, nitro (NO 2 ), alkyl (e.g., CH 3 , CH 2 CH 3 , or any alkyl chain having 3 - 10 carbon atoms, branched or unbranched), alkoxy (e.g., OCH 3 , OCH 2 CH 3 , or any alkoxy chain having 3 - 10 carbon atoms, branched or unbranched), haloalkyl (e.g., CH 2 Cl, CHBr 2 , CF 3 ), haloalkoxy (e.g., OCH 2 Cl, OCHBr 2 , OCF 3 ), haloalkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms with, for example, 1 to 3 halogen atoms, haloalkoxy having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms with, for example, 1 to 3 halogen atoms, cycloalkyl, halo-cycloalkyl, O - p - alkylbenzyl (e.g., where the alkyl is methyl, ethyl or propyl); O - p - alkoxybenzyl (e.g., where the alkyl is methyl, ethyl or propyl); and O - p - halobenzyl (where the halogen = Cl, F, Br or I).

[0153] In at least some non-limiting embodiments, R of ring "C" in Chemical Structure I 3 substituents are selected from the group consisting of: H, F, Cl, Br, I, NO 2 , alkyl (e.g., CH 3 , CH 2 CH 3 , or any alkyl chain having 3 - 10 carbon atoms, branched or unbranched), alkoxy (e.g., OCH 3 , OCH 2 CH 3 , or any alkoxy chain having 3 - 10 carbon atoms, branched or unbranched), haloalkyl (e.g., CH 2 Cl, CHBr 2, CF 3 ), haloalkoxy (e.g., OCH 2 Cl, OCHBr 2 , OCF 3 ), haloalkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbons with, for example, 1 to 3 halogen atoms, haloalkoxy having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbons with, for example, 1 to 3 halogen atoms, cycloalkyl and halocycloalkyl, wherein the "C" ring contains one, two, three, four or five of said R 3 substituents, and the R 3 substituents are substituted with any combination of the R 3 substituents and are arranged in the "C" ring in any pattern, including ortho, meta, para, mono-substituted, di-substituted, tri-substituted, tetra-substituted and penta-substituted.

[0154] In at least some non-limiting embodiments, each R 4 and R 5 substituent of Chemical Structure I can be selected from the group consisting of: H, F, Cl, Br, I, NO 2 , alkyl (e.g., branched or unbranched, C 1 to C 10 ), and haloalkyl (e.g., CH 2 Cl, CHBr 2 , CF 3 ). R 4 and R 5 can together form a double bond O.

[0155] In at least some non-limiting embodiments, R 4 and R 5 together form a cycloalkyl containing 2 to 10 carbon atoms, or a halocycloalkyl containing 2 to 10 carbon atoms and substituted with one or more halogen (Cl, F, Br, I) atoms.

[0156] In at least some embodiments, when one of R 4 and R 5 is alkyl or cycloalkyl (as defined herein), the other of R 4 and R 5 is H.

[0157] In at least some non-limiting embodiments, each R 6 and R 7 substituent of Chemical Structure I can be selected from the group consisting of: H, F, Cl, Br, I, alkyl (e.g., branched or unbranched, C 1 to C 10 ), and haloalkyl (e.g., CH 2 Cl, CHBr2 , CF 3 ). R 6 and R 7 can together form a double bond O.

[0158] In at least some non-limiting embodiments, R 6 and R 7 together form a cycloalkyl group having 2 to 10 carbon atoms, or a halogenated cycloalkyl group having 2 to 10 carbon atoms and substituted with one or more halogen (Cl, F, Br, I) atoms.

[0159] In at least some embodiments, when one of R 6 and R 7 is an alkyl or cycloalkyl group (as defined herein), the other of R 6 and R 7 is H.

[0160] As described above, in some embodiments, ring A and / or ring B and / or ring C of chemical structure I can be pyridine. The following Schemes 1-3 show exemplary, non-limiting synthetic routes that can be used to form the structures of the present disclosure that include ring A and / or ring B as pyridine:

[0161] Scheme 1:

[0162]

[0163] Schemes 2 and 3:

[0164]

[0165] In at least some alternative embodiments, the present disclosure includes an active agent composition and a method of using a compound having chemical structural formula II to treat ocular disorders and conditions, particularly retinal disorders and conditions, which in some non-limiting embodiments include retinal inflammation, retinal neovascularization, retinal vascular leakage, retinopathy of prematurity (ROP), diabetic retinopathy (DR), age-related macular degeneration (e.g., wet AMD), and diabetic macular edema (DME) (or other disorders or conditions described elsewhere herein):

[0166]

[0167] Wherein:

[0168] k is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms;

[0169] m is 0, 1, 2, 3, 4, or 5 carbon atoms;

[0170] n is 0, 1, 2, 3, 4 or 5 carbon atoms;

[0171] R 2 is selected from the following groups: hydrogen (H), chlorine (Cl), fluorine (F), bromine (Br), iodine (I), nitro (NO 2 ), CH 3 ), CH 2 CH 3 ), a branched or unbranched alkyl chain having 3 - 10 carbon atoms, OCH 3 ), OCH 2 CH 3 ), a branched or unbranched alkoxy chain having 3 - 10 carbon atoms, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, O - p - alkylbenzyl, O - p - alkoxybenzyl and O - p - halobenzyl, wherein the benzene ring containing R 2 contains one, two, three or four of said R 2 substituents, and the R 2 substituents are substituted with any combination of said R 2 substituents and arranged in the ring in any pattern, including ortho, meta, mono - substitution, di - substitution, tri - substitution and tetra - substitution;

[0172] R 3 is selected from the following groups: H, Cl, F, Br, I, NO 2 ), CH 3 ), CH 2 CH 3 ), a branched or unbranched alkyl chain having 3 - 10 carbon atoms, OCH 3 ), OCH 2 CH 3 ), a branched or unbranched alkoxy chain having 3 - 10 carbon atoms, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, O - p - alkylbenzyl, O - p - alkoxybenzyl and O - p - halobenzyl, wherein the benzene ring containing R 3 contains one, two, three, four or five of said R 3 substituents, and the R 3 substituents are substituted with any combination of said R 3 substituents and arranged in the ring in any pattern, including ortho, meta, para, mono - substitution, di - substitution, tri - substitution, tetra - substitution and penta - substitution;

[0173] R 4 is selected from the following groups: H, alkyl and acyl;

[0174] R 5 is selected from the following groups: H, Cl, F, Br, I, NO 2 ), CH 3 ), CH2 CH 3 , a branched or unbranched alkyl chain having 3 to 10 carbon atoms, OCH 3 , OCH 2 CH 3 , a branched or unbranched alkoxy chain having 3 to 10 carbon atoms, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, O - para - alkylbenzyl, O - para - alkoxybenzyl, and O - para - halobenzyl, wherein the benzene ring containing R 5 contains one, two, three, or four of said R 5 substituents, and the R 5 substituents are substituted with any combination of said R 5 substituents and are arranged in the ring in any pattern, including ortho, meta, para, mono - substitution, di - substitution, tri - substitution, and tetra - substitution;

[0175] R 1 is selected from the group consisting of carboxylic acid, carboxylic acid bioisostere, hydroxamic acid, hydroxamic ester, phosphonic acid, phosphinic acid, sulfonic acid, sulfinic acid, sulfonamide, acylsulfonamide, sulfonylurea, acylurea, tetrazole, thiazolidinedione, oxazolidinedione, oxadiazol - 5(4H)-one, thiadiazol - 5(4H)-one, oxathiadiazole - 2 - oxide, oxadiazol - 5(4H)-thione, isoxazole, tetramic acid, cyclopentane 1,3 - dione, cyclopentane 1,2 - dione, squaric acid, substituted phenol, heteroarene, amidine, hydroxyamide, alkylhydroxyamidine, and their salts.

[0176] R 8 and R 9 are independently selected from the group consisting of H, F, Cl, Br, I, alkyl, alkoxy, and cycloalkyl containing R 8 connected to R 9 ;

[0177] R 10 and R 11 are independently selected from the group consisting of H, alkyl, and cycloalkyl (wherein R 10 is connected to R 11 ); and

[0178] X is O, NH, S, or CH 2 .

[0179] More specifically, in certain non - limiting embodiments of the present disclosure, examples of the compounds having Chemical Structural Formula II (Compounds 9 - 14, 21 - 24, 26, and 28) are shown below:

[0180]

[0181]

[0182]

[0183]

[0184] Compounds 9-14, 21-24, 26, and 28 are also numbered 117, 91, 120, 122, 118, 119, 116, 114, 123, 121, 92, and 115 herein (e.g., in Tables 4 and 5), respectively. Compounds ASD152, ASD160, ASD178, ASD179, ASD181, ASD200, ASD203, and ASD207 are also referred to as Compounds 152, 160, 178, 179, 181, 200, 203, and 207 herein, respectively.

[0185] In certain embodiments, the compounds (but not necessarily the methods) of the present disclosure may exclude the following compounds having Chemical Structural Formula II, wherein (1) R 1 = COOH, and R 2 -R 5 = H, and (2) R 1 = COOH, R 3 = CH 3 ), and R 2 , R 4 and R 5 = H, for example, the structure:

[0186]

[0187]

[0188] In at least some alternative embodiments, the present disclosure includes methods of treating ocular disorders and conditions, particularly retinal disorders and conditions, with an active agent composition and a compound having Chemical Structural Formula III or a salt or isomer thereof. In certain non-limiting embodiments, the disorders and conditions include retinal inflammation, retinal neovascularization, retinal vascular leakage, retinopathy of prematurity (ROP), diabetic retinopathy (DR), age-related macular degeneration (e.g., wet AMD), and diabetic macular edema (DME) (or other disorders or conditions described elsewhere herein):

[0189]

[0190] wherein:

[0191] k is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms;

[0192] m is 0, 1, 2, 3, 4 or 5 carbon atoms;

[0193] n is 0, 1, 2, 3, 4 or 5 carbon atoms;

[0194] R 1 is selected from the group consisting of phosphate esters, phosphonate esters, and their salts;

[0195] R 2 is selected from the following groups: CH 3 , hydrogen (H), chlorine (Cl), fluorine (F), bromine (Br), iodine (I), nitro (NO 2 ), CH 2 CH 3 , a branched or unbranched alkyl chain having 3 - 10 carbon atoms, OCH 3 , OCH 2 CH 3 , a branched or unbranched alkoxy chain having 3 - 10 carbon atoms, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, O - para - alkylbenzyl, O - para - alkoxybenzyl, and O - para - halobenzyl, wherein the benzene ring containing R 2 contains one, two, three, or four of said R 2 substituents, and the R 2 substituents are substituted with any combination of said R 2 substituents and arranged in any pattern in the ring, including ortho, meta, mono - substitution, di - substitution, tri - substitution, and tetra - substitution;

[0196] R 3 is selected from the following groups: F, H, Cl, Br, I, NO 2 , CH 3 , CH 2 CH 3 , a branched or unbranched alkyl chain having 3 - 10 carbon atoms, OCH 3 , OCH 2 CH 3 , a branched or unbranched alkoxy chain having 3 - 10 carbon atoms, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, O - para - alkylbenzyl, O - para - alkoxybenzyl, and O - para - halobenzyl, wherein the benzene ring containing R 3 contains one, two, three, four, or five of said R 3 substituents, and the R 3 substituents are substituted with any combination of said R 3 substituents and arranged in any pattern in the ring, including ortho, meta, para, mono - substitution, di - substitution, tri - substitution, tetra - substitution, and penta - substitution;

[0197] R 4Selected from the group consisting of: H, alkyl, and acyl; and

[0198] R 5 Selected from the group consisting of: H, Cl, F, Br, I, NO 2 , CH 3 , CH 2 CH 3 , a branched or unbranched alkyl chain having 3 to 10 carbon atoms, OCH 3 , OCH 2 CH 3 , a branched or unbranched alkoxy chain having 3 to 10 carbon atoms, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, O - para - alkylbenzyl, O - para - alkoxybenzyl, and O - para - halobenzyl, wherein the benzene ring containing R 5 contains one, two, three, or four of said R 5 substituents, and the R 5 substituents are substituted with any combination of said R 5 substituents and are arranged in the ring in any pattern, including ortho, meta, para, mono - substitution, di - substitution, tri - substitution, and tetra - substitution.

[0199] In a specific embodiment, the compound has the chemical structural formula IIIA:

[0200]

[0201] wherein R is selected from the group consisting of phosphate esters, phosphonate esters, and their salts.

[0202] In one embodiment, the compound is the monosodium salt named by the identifier ZH - 2021 - 162 and has the following structure:

[0203]

[0204] In one embodiment, the compound is the monotris salt named by the identifier ZH - 2021 - 164 and has the following structure:

[0205]

[0206] Exemplary salts of phosphate and phosphonate compounds include, but are not limited to, sodium salts, potassium salts, calcium salts, magnesium salts, ammonium salts, iron salts, quaternary alkylammonium salts, and quaternary arylammonium salts. The cation can be a metal ion, such as an alkali metal ion (e.g., sodium, potassium, lithium), an alkaline earth metal ion (e.g., magnesium, calcium, barium), or an aluminum ion. The cation can be an ammonium ion, a quaternary alkylammonium, a quaternary arylammonium, or an ammonium ion derived from an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, N-methylglucosamine, morpholine, piperidine, pyridine, dimethylamine, diethylamine, trimethylamine, triethylamine, isopropylamine, 2-ethylaminoethanol, histidine, lysine, procaine, and tris(2-amino-2-(hydroxymethyl)propane-1,3-diol).

[0207] The relative solubilities of the various compounds are shown in Table 3.

[0208] Table 3. Solubilities of Various Compounds

[0209]

[0210] Certain non-limiting embodiments of the present disclosure include pharmaceutical compositions that comprise at least one pharmaceutically acceptable carrier in combination with one or more of the compounds described herein, which are PPARα agonists and have anti-inflammatory and anti-angiogenic activity in the eye (particularly the retina and macula). Specific non-limiting examples of pharmaceutical (therapeutic) compositions formulated according to the present disclosure include: (a) a pharmaceutical composition comprising a PPARα agonist in combination with at least one pharmaceutically acceptable carrier, such as a polymer; and (b) a combination of a PPARα agonist with at least one other therapeutic active agent and at least one pharmaceutically acceptable carrier, such as a polymer.

[0211] As described above, the active agents of the present disclosure can be used to treat diseases and conditions associated with retinal endothelial dysfunction, angiogenesis, and inflammation, such as DR and AMD (e.g., wet AMD), retinal inflammation, retinal neovascularization (NV), retinal vascular leakage, retinopathy of prematurity (ROP), and diabetic macular edema (DME).

[0212] Suitable carriers, vehicles, excipients, diluents, and other ingredients that can be included in the formulations are described, for example, in Remington: The

[0213] Science and Practice of Pharmacy, 21 st Ed and 22 nd Ed. The term "pharmaceutically acceptable" means that the carrier is a non-toxic material that does not interfere with the biological activity of the active agent. The properties of the carrier will depend on a variety of factors, including, but not limited to, the route of administration.

[0214] The active agents disclosed herein (i.e., phosphate ester compounds and / or phosphonate ester compounds) can be formulated into a composition for delivery to a subject. The composition can be administered alone or in admixture with a pharmaceutically acceptable vehicle or excipient. Suitable vehicles are, for example (but not limited to), water, saline, dextrose, glycerol, ethanol, etc. and combinations thereof. In addition, the vehicle can contain minor amounts of auxiliary substances such as, for example (but not limited to), wetting or emulsifying agents, pH buffering agents or adjuvants. The compositions of the present disclosure can also include auxiliary substances, including other medicaments.

[0215] The active agent can be delivered alone or as a pharmaceutical composition by any route known in the art, such routes being, for example (but not limited to), systemic, regional or local delivery; by intraarterial, intrathecal (IT), intravenous (IV), parenteral, intrapleural, topical, oral, transdermal delivery or local administration (such as ocular, subcutaneous, intratracheal (e.g., by aerosol) or mucosal (e.g., oral, bladder, vaginal, uterine, rectal, nasal mucosa)), subcutaneous, intracranial, intraocular, intracerebral, intracavitary, intraperitoneal, intranasal, intralymphatic or intramuscular administration. Intravenous administration can be, for example (but not limited to), by infusion over, for example (but not limited to), 30 - 90 minutes or by a single bolus injection. As described above, the composition can be formulated as a neutral or salt form composition.

[0216] The composition for treatment can be administered in a single - dose treatment or a multi - dose treatment according to a schedule suitable for the age, weight and condition of the subject, the particular composition used and the route of administration. In one non - limiting embodiment, a single dose of the composition according to the present disclosure is administered. In other non - limiting embodiments, multiple doses are administered. The frequency of administration can vary according to a variety of factors, such as the severity of the symptoms, or whether the composition is for prophylactic or therapeutic purposes. For example, in certain non - limiting embodiments, the composition is administered once a month, twice a month, three times a month, once every two weeks, once a week, twice a week, three times a week, four times a week, five times a week, six times a week, every other day, once a day, twice a day or three times a day. The duration of treatment (i.e., the period during which the composition is administered) can vary according to a variety of factors, such as the response of the subject. For example, the composition can be administered for about one day to about one week, about two weeks to about four weeks, about one month to about two months, about two months to about four months, about four months to about six months, about six months to about eight months, about eight months to about 1 year, about 1 year to about 2 years, or about 2 years to about 4 years or longer.

[0217] The composition can be combined with a pharmaceutically acceptable carrier (excipient) to form a pharmaceutical composition. The pharmaceutically acceptable carrier can contain a physiologically acceptable compound that serves, for example but not limited to, to stabilize or increase or decrease the absorption rate or clearance rate of the pharmaceutical composition. The physiologically acceptable compound can include (for example but not limited to): carbohydrates (such as glucose, sucrose or dextran); antioxidants (such as ascorbic acid or glutathione); chelating agents; low molecular weight proteins; detergents; liposome carriers; excipients; or other stabilizers and / or buffers. Other physiologically acceptable compounds include (but are not limited to) wetting agents, emulsifying agents, dispersing agents or preservatives.

[0218] When administered orally, the composition of the present invention can be protected from digestion. This can be achieved by combining the active agent with the composition such that it resists acid and enzymatic degradation, or by packaging the active agent in a suitably resistant carrier (such as but not limited to liposomes, as shown in U.S. Patent No. 5,391,377).

[0219] For transmucosal or transdermal administration, permeating agents suitable for the permeation barrier can be used in the formulation. These permeating agents are generally known in the art and include (for example) bile salts and fusidic acid derivatives for transmucosal administration. In addition, detergents can be used to facilitate permeation. Transmucosal administration can be carried out by nasal spray or using suppositories. For topical transdermal administration, the active agent is formulated into ointments, creams, pastes, powders and gels. Transdermal delivery systems can also include (such as but not limited to) patches. The composition of the present invention can also be administered by a sustained delivery or slow release mechanism. For example, biodegradable microspheres or capsules or other biodegradable polymer configurations capable of sustained delivery can be used.

[0220] In one aspect, the composition is prepared with a carrier that protects the active agent from being rapidly cleared from the body, and the carrier is, for example (but not limited to), a controlled release formulation, including implants and microencapsulation delivery systems. Biodegradable, biocompatible polymers can be used, such as (but not limited to) ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid. The methods for preparing these formulations are obvious to those skilled in the art.

[0221] Generally, the active agent can be formulated into a composition containing one or more pharmaceutically suitable excipients, surfactants, polyols, buffers, salts, amino acids or other components or some combinations of these components. This can be achieved by known methods for preparing pharmaceutically useful doses, in which the active compound is mixed with one or more pharmaceutically suitable excipients to form a mixture. Sterile phosphate buffered saline is a non-limiting example of a pharmaceutically suitable excipient.

[0222] In parenteral administration, the composition will be formulated with a pharmaceutically acceptable excipient in a unit dosage injectable form (such as, but not limited to, a solution, suspension or emulsion). These excipients are essentially non-toxic and have no therapeutic effect. Non-limiting examples of these excipients include saline, Ringer’s solution, glucose solution and Hanks’ solution. Non-aqueous excipients can also be used, such as (but not limited to) fixed oils and ethyl oleate. Another non-limiting excipient is 5% glucose saline. The excipient may contain small amounts of additives, such as (but not limited to) substances that enhance isotonicity and chemical stability, including buffers and preservatives.

[0223] The formulated composition containing the active agent can be used for (such as, but not limited to) subcutaneous, intramuscular or transdermal administration. The composition can be provided in unit dosage form, such as provided in an ampoule or a multi-dose container, and a preservative is added. The composition can also be in the form of a suspension, solution or emulsion in an oily or aqueous vehicle, and may contain formulating agents (such as suspending agents, stabilizers and / or dispersing agents). Alternatively, the composition can be in powder form for mixing with a suitable vehicle (such as sterile pyrogen-free water) before use.

[0224] In certain non-limiting embodiments, the pharmaceutical composition for parenteral administration is sterile, substantially isotonic, and produced under GMP conditions. The pharmaceutical composition can be provided in unit dosage form (i.e., the dose for a single administration). The pharmaceutical composition can be formulated using one or more physiologically acceptable carriers, diluents, excipients or adjuvants. The formulation depends on the selected route of administration. For injection, the active agent can be formulated in an aqueous solution, such as (but not limited to) formulated in a physiologically compatible buffer (such as Hanks’ solution, Ringer’s solution) or saline or acetate buffer (to reduce discomfort at the injection site). The solution may contain formulating agents, such as suspending agents, stabilizers and / or dispersing agents. Alternatively, the active agent can be in lyophilized form for mixing with a suitable vehicle (such as sterile pyrogen-free water) before use.

[0225] Some non-limiting embodiments provided herein include kits. In some non-limiting embodiments, a kit can include an amount of an active agent, such as an active agent described or contemplated herein. In some non-limiting embodiments, the active agent is lyophilized. In some non-limiting embodiments, the active agent is in an aqueous solution or in other carriers described herein. In some non-limiting embodiments, the kit includes a pharmaceutical carrier for administering the active agent. Certain non-limiting embodiments of the present disclosure include kits that contain components suitable for treatment or diagnosis. Exemplary kits can include at least one active agent. In some non-limiting embodiments, a device capable of delivering the kit components by injection, such as a syringe for subcutaneous injection, can be included. When transdermal administration is used, the kit in some non-limiting embodiments may include a delivery device, such as a hollow microneedle delivery device. Exemplary transdermal delivery devices are known in the art, such as (but not limited to) hollow microstructured transdermal systems (such as products of 3M Company), and any such known devices can be used. The components of the kit can be packaged together or divided into two or more containers. In some non-limiting embodiments, the container can be a vial that contains a sterile lyophilized formulation of a composition suitable for reconstitution. The kit can also include one or more buffers suitable for reconstituting and / or diluting other reagents. Alternatively, the active agent can be delivered and stored in a liquid formulation. Other containers that may be used include, but are not limited to, bags, trays, boxes, tubes, etc. The components of the kit can be aseptically packaged and stored within the container. Another component that can be included is instructions for using the kit for treatment.

[0226] The term "co-administer" refers to the administration of two or more active agents (such as a PPARα agonist and another active agent). The timing of co-administration depends in part on the combination and composition being administered and can include simultaneous administration, administration before or after one or more other therapies. Co-administration includes the simultaneous or sequential administration, alone or in combination, of compounds and / or compositions. Thus, when needed, these formulations can also be combined with other active substances (such as to reduce metabolic degradation).

[0227] For inhaled administration, the compositions of the present invention can be delivered using any system known in the art, including (but not limited to) dry powder aerosols, liquid delivery systems, air jet nebulizers, propellant systems, etc. For example (but not limited to), the pharmaceutical formulation can be administered in the form of an aerosol or mist. For aerosol administration, the formulation can be provided in a subdivided form together with a surfactant and a propellant. In another aspect, a device for delivering the formulation to the respiratory tissue is an inhaler in which the formulation evaporates. Other liquid delivery systems include (such as but not limited to) air jet nebulizers.

[0228] The active agent of the present disclosure can be present in the pharmaceutical composition at any concentration that allows the pharmaceutical composition to function according to the present disclosure; for example (but not limited to), the compound can be present in a range, the lower limit of which is selected from 0.0001%, 0.005%, 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9% and 2.0%; the upper limit is selected from 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% and 95%. Non-limiting examples of specific ranges include the range from about 0.0001% to about 95%, the range from about 0.001% to about 75%, the range from about 0.005% to about 50%, the range from about 0.01% to about 40%, the range from about 0.05% to about 35%, the range from about 0.1% to about 30%, the range from about 0.1% to about 25%, the range from about 0.1% to about 20%, the range from about 1% to about 15%, the range from about 2% to about 12%, the range from about 5% to about 10%, etc. Any other range, as long as its lower limit is selected from the above lower limit concentrations and its upper limit is selected from the above upper limit concentrations, also falls within the scope of the present disclosure.

[0229] Exemplary non-limiting ranges for the active agent in a therapeutically or prophylactically effective amount include ranges from about 0.001 mg / kg of subject body weight to about 500 mg / kg of subject body weight, such as but not limited to ranges from about 0.01 mg / kg to about 250 mg / kg, from about 0.1 mg / kg to about 100 mg / kg, from about 0.1 mg / kg to about 50 mg / kg, from about 1 mg / kg to about 30 mg / kg, from about 1 mg / kg to about 25 mg / kg, from about 2 mg / kg to about 30 mg / kg, from about 2 mg / kg to about 20 mg / kg, from about 2 mg / kg to about 15 mg / kg, from about 2 mg / kg to about 12 mg / kg, from about 2 mg / kg to about 10 mg / kg, from about 3 mg / kg to about 30 mg / kg, from about 3 mg / kg to about 20 mg / kg, from about 3 mg / kg to about 15 mg / kg, from about 3 mg / kg to about 12 mg / kg, or from about 3 mg / kg to about 10 mg / kg, or as a fixed dose from about 10 mg to about 1500 mg.

[0230] The composition is formulated to contain an effective amount of the active agent, where the dosage depends on the subject to be treated and the severity of the subject's condition. In certain non-limiting embodiments, the dosage range of the active agent can be from about 0.001 mg to about 10 g, from about 0.01 mg to about 10 g, from about 0.1 mg to about 10 g, from about 1 mg to about 10 g, from about 1 mg to about 9 g, from about 1 mg to about 8 g, from about 1 mg to about 7 g, from about 1 mg to about 6 g, from about 1 mg to about 5 g, from about 10 mg to about 10 g, from about 50 mg to about 5 g, from about 50 mg to about 5 g, from about 50 mg to about 2 g, from about 0.05 μg to about 1.5 mg, from about 10 μg to about 1 mg of protein, from about 30 μg to about 500 μg, from about 40 μg to about 300 μg, from about 0.1 μg to about 200 mg, from about 0.1 μg to about 5 μg, from about 5 μg to about 10 μg, from about 10 μg to about 25 μg, from about 25 μg to about 50 μg, from about 50 μg to about 100 μg, from about 100 μg to about 500 μg, from about 500 μg to about 1 mg, or from about 1 mg to about 2 mg. The specific dosage level for any particular subject depends on a variety of factors, including (but not limited to) the activity of the specific active agent, age, body weight, general health, gender, diet, time of administration, route of administration and rate of excretion, drug combination, and the severity of the disease of the subject being treated.

[0231] In some non-limiting embodiments, the concentration of the amount of the active agent is about 1 nM, about 5 nM, about 10 nM, about 25 nM, about 50 nM, about 75 nM, about 100 nM, about 150 nM, about 200 nM, about 250 nM, about 300 nM, about 350 nM, about 400 nM, about 500 nM, about 550 nM, about 600 nM, about 700 nM, about 800 nM, about 900 nM, about 1 μM, about 2 μM, about 3 μM, about 4 μM, about 5 μM, about 6 μM, about 7 μM, about 8 μM, about 9 μM, about 10 μM, about 15 μM, about 20 μM, about 25 μM, about 30 μM, about 35 μM, about 40 μM, about 45 μM, about 50 μM, about 60 μM, about 70 μM, about 75 μM, about 80 μM, about 90 μM, about 100 μM, about 125 μM, about 150 μM, about 175 μM, about 200 μM, about 250 μM, about 300 μM, about 350 μM, about 400 μM, about 500 μM, about 600 μM, about 700 μM, about 750 μM, about 800 μM, about 900 μM, about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 11 mM, about 12 mM, about 13 mM, about 14 mM, about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 45 mM, about 50 mM, about 55 mM, about 60 mM, about 65 mM, about 70 mM, about 75 mM, about 80 mM, about 85 mM, about 90 mM, about 95 mM, about 100 mM, about 100 mM, about 110 mM, about 120 mM, about 130 mM, about 140 mM, about 150 mM, about 160 mM, about 170 mM, about 180 mM, about 190 mM, about 200 mM, about 250 mM, about 300 mM, about 400 mM, about 500 mM, about 600 mM, about 700 mM, about 800 mM, about 900 mM, about 1000 mM, about 1 M, about 1.1 M, about 1.2 M, about 1.3 M, about 1.4 M, about 1.5 M, about 1.6 M, about 1.7 M, about 1.8 M, about 1.9 M, about 2 M, about 3 M, about 4 M, about 5 M, about 6 M, about 7 M, about 8 M, about 9 M, about 10 M, about 15 M, about 20 M, about 25 M, about 30 M, about 35 M, about 40 M, about 45 M, about 50 M, about 75 M, about 100 M, or any range between any two of the above concentrations, including the two concentrations as the endpoints of the range, or any value between any two of the above concentrations.

[0232] The dosage of the active agent administered to humans will vary depending on a variety of factors such as, but not limited to, the patient's age, weight, height, gender, general health status, and medical history. In certain non-limiting embodiments, a dosage of the active agent in the range of about 1 mg to about 1000 mg is provided to the recipient in the form of a single infusion or single or multiple injections, although lower or higher dosages may also be administered. In certain non-limiting embodiments, for a typical adult, the dosage range may be about 25 mg to about 100 mg per square meter of body surface area (m 2 ) although lower or higher dosages may also be administered. Other non-limiting examples of dosages that may be administered to human subjects also include 1 mg to 500 mg, 1 mg to 70 mg, or 1 mg to 20 mg, although higher or lower dosages may also be used. The dosage may be repeated as needed, for example, but not limited to, once a week for 4 - 10 weeks, once a week for 8 weeks, or once a week for 4 weeks. It may also be administered at a lower frequency, for example, but not limited to, once every other week for several months, or at a higher frequency, such as twice a week or by continuous infusion.

[0233] The composition may be administered in solution form. Its formulation may be a solution containing a suitable pharmaceutically acceptable buffer (such as, but not limited to, phosphate, tris(hydroxymethyl)aminomethane - HCl, or citrate, etc.). The buffer concentration may be in the range of 1 mM to 100 mM. The formulated solution may also contain salts, such as, but not limited to, sodium chloride or potassium chloride, at a concentration of 50 mM to 150 mM. It may also contain an effective amount of a stabilizer, such as, but not limited to, mannitol, trehalose, sorbitol, glycerol, albumin, globulin, detergent, gelatin, protamine, or protamine salts.

[0234] The number of doses administered depends on the severity of the condition and the response to treatment (e.g., whether presenting as acute or chronic symptoms). For the recurrence or acute exacerbation of an acute disorder, treatment may be repeated. For a chronic disorder, the active agent may be administered regularly, for example, but not limited to, once a week, once every two weeks, once a month, once a quarter, once every six months, for at least 1 year, 5 years, or 10 years, or, if the condition is chronic, it may be administered throughout the patient's life cycle.

[0235] Other embodiments of the pharmaceutical compositions of the present disclosure may include incorporating or encapsulating the active agent in various types of drug delivery systems that are designed to provide targeted delivery, controlled release, and / or an extended half-life of the active agent. For example (but not limited to), the active agent may be encapsulated in microcapsules prepared by coacervation techniques or interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively). The active agent may also be encapsulated in macroemulsions or colloidal drug delivery systems (e.g., but not limited to liposomes, albumin microspheres, microemulsions, nanoparticles, nanocapsules, etc.). These techniques are well known to those of ordinary skill in the art and thus do not require further description.

[0236] In a specific non-limiting example, the pharmaceutical composition may include liposomes with the active agent disposed therein. In addition to other pharmaceutically acceptable carriers, the liposomes may also contain amphiphilic agents such as lipids that exist in aggregated forms such as micelles, insoluble monolayers, liquid crystals, or lamellar layers in an aqueous solution. Lipids suitable for liposomal formulations include, but are not limited to, monoglycerides, diglycerides, thioesters, lysophospholipids, phospholipids, saponins, bile acids, and combinations thereof, etc. The preparation of such liposomal formulations is within the level of those of ordinary skill in the art, such as that disclosed in U.S. Patent No. 4,235,871, U.S. Patent No. 4,501,728, U.S. Patent No. 4,837,028, and U.S. Patent No. 4,737,323, the entire contents of which are incorporated herein by reference.

[0237] In other non-limiting examples, the active agents of the present disclosure may be incorporated into particles of one or more polymeric materials, as such incorporation can be used to control the duration of action of the active agent by allowing for controlled release from the formulation, thereby increasing its half-life. Non-limiting examples of polymeric materials that can be used in this manner include polyesters, polyamides, polyamino acids, hydrogels, poly(lactic-co-glycolic acid), poly(lactic acid), ethylene vinyl acetate copolymers, copolymer micelles such as PEG and poly(asparagine), and combinations thereof.

[0238] In certain non-limiting embodiments, the form of the pharmaceutical composition containing the active agent can be an ophthalmic composition for topical application to the eyes of a subject. As used herein, the term "ophthalmic composition" is understood to refer to any composition specifically formulated for direct and topical administration to the eyes of a patient. The composition can be formulated for topical ocular administration or injection into the eye (i.e., intravitreal or intraocular injection). The ophthalmic composition can be provided in any formulation that permits topical administration to the eye and allows the active agent to function in accordance with the present disclosure. For example (but not limited to), the ophthalmic composition can be provided in the form of a solution, drops, spray / sprays, patches and pressure-sensitive adhesives, ointments, lotions, creams, gels, lyophilized / spray-dried forms, etc. In a particular non-limiting embodiment, the ophthalmic composition is provided in the form of a topical application, such as but not limited to an eye drop formulation. The ophthalmic composition of the present disclosure can vary depending on the particular active agent used, the desired drug release profile, the condition being treated, and / or the patient's medical history. Additionally, using formulation techniques well known in the art, the ophthalmic composition of the present disclosure can be designed to provide delayed, controlled, extended, and / or sustained release, as explained elsewhere herein.

[0239] The pharmaceutical compositions described or contemplated herein can also contain at least one delivery agent to assist in delivering the active agent to the desired site of delivery; for example (but not limited to), at least one delivery agent can be included in the ophthalmic composition to assist in penetrating the eye surface; in certain embodiments, the delivery agent can assist in delivering to the retina of the eye. For example, for topical application to be effective, the composition may need to be able to penetrate the eye surface in order to reach the desired tissue. This may include penetrating the conjunctiva and / or the cornea.

[0240] When the ophthalmic composition containing the active agent is formulated for injection administration, the composition can be in the form of a pyrogen-free aqueous solution or suspension. When preparing such solutions, factors such as pH, isotonicity, stability, etc. need to be considered, which are within the skills of those of ordinary skill in the art. Suitable carriers include but are not limited to biocompatible and pharmaceutically acceptable phosphate buffered saline solutions, which are particularly isotonic. For example (but not limited to), a particular ophthalmic composition can contain, in addition to the therapeutic compound, an isotonic vehicle such as sodium chloride injection, Ringer's injection, glucose injection, glucose and sodium chloride injection, lactated Ringer's injection, or other vehicles known in the art. Generally, materials used for intravenous injection in humans should comply with the regulations established by the US Food and Drug Administration, which are available to those in the field.

[0241] In addition to the ophthalmic administration modes discussed in detail herein, the therapeutic compositions of the present disclosure can also be formulated for administration by any other method known or contemplated in the art, provided that the administration route allows for the delivery of the active agent such that the compound can function according to the present disclosure, i.e., as a PPARα agonist. Examples of other administration routes include, but are not limited to, oral, topical, retrobulbar, subconjunctival, transdermal, parenteral, subcutaneous, intranasal, intramuscular, intraperitoneal, intravitreal, and intravenous routes, including both local and systemic application routes.

[0242] Another non-limiting embodiment of the present disclosure relates to a kit that contains one or more of any of the pharmaceutical compositions described or contemplated herein. The kit can also contain a second agent as described above herein for use in combination with the pharmaceutical composition. If the composition present in the kit is not provided in the form in which it is to be delivered, the kit can further contain a pharmaceutically (e.g., ophthalmically) acceptable carrier, vehicle, diluent, excipient, or other agent for mixing with the active agent to prepare the pharmaceutical composition. A kit that includes the composition and / or other reagents can also be packaged with instructions that are packaged for the administration and / or dosing of the composition contained in the kit. The instructions can be fixed in any tangible medium, such as printed paper, computer-readable magnetic or optical medium, or instructions that reference a remote computer data source, such as a global web page accessible via the Internet.

[0243] The kit can contain a single-dose or multi-dose pharmaceutical composition. When multiple doses are present, the doses can be placed together in a single container, or the multiple doses can be placed separately in the kit; i.e., the pharmaceutical composition can be present in the kit in unit-dose form to facilitate accurate dosing. As used herein, the term "unit-dose form" refers to a physically discrete unit suitable as a single dose for human subjects and other mammals; each unit contains a predetermined amount of the active substance calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient. Typical unit dosage forms for liquid compositions include prefilled, pre-measured ampoules or syringes; for solid compositions, typical unit dosage forms include pills, tablets, capsules, etc. In such compositions, the active agent may sometimes be a minor component (from about 0.1% to about 50% by weight, such as but not limited to from about 1% to about 40% by weight), and the remainder is various vehicles or carriers and processing aids that contribute to the formation of the desired dosage form.

[0244] As can be seen from the above, the active agent of the present disclosure is used as a PPARα agonist for treating, inhibiting, alleviating, and / or preventing degenerative retinal disorders. Accordingly, certain non-limiting embodiments of the present disclosure include methods for treating, inhibiting, and / or reducing retinal degeneration caused by retinal inflammation and neovascularization. A specific but non-limiting embodiment includes a method for treating, inhibiting, and / or reducing one or more pathological eye conditions associated with reduced PPARα activity in a subject. In this method, one or more of any active agents or pharmaceutical compositions described or contemplated herein are administered to a subject (such as, but not limited to, a mammal) that is experiencing retinal or macular degeneration, or is susceptible to retinal or macular degeneration or other eye conditions or disorders. The active agent or pharmaceutical composition is administered to the subject in an effective amount to have PPARα agonist activity in the retina of at least one eye of the subject.

[0245] The pathological eye condition can be any condition described herein, and the pathological eye condition may be characterized by retinal and / or macular degeneration. In one embodiment, the pharmaceutical composition can be administered topically to the eye of the subject (such as, but not limited to, eye drops). In another embodiment, the pharmaceutical composition can be administered by ocular injection or systemic administration.

[0246] The amount of the active agent effective in the treatment described herein can be determined by the attending diagnostician, such as one of ordinary skill in the art, by using conventional techniques and by observing results obtained in comparable circumstances. For example, in a non-limiting embodiment of the treatment, in determining a therapeutically effective dose, the attending diagnostician can consider a number of factors, including but not limited to: the species of the subject; the size, age, and general health of the subject; the particular disease and / or condition involved; the degree, extent, and / or severity of the disease and / or condition; the response of the individual subject; the particular active agent or other therapeutic compound administered; the mode of administration; the bioavailability characteristics of the administered formulation; the dosing regimen selected; the use of concomitant medications; and other relevant circumstances. The therapeutically effective amount of the pharmaceutical composition of the present disclosure also refers to the amount of the active agent that is effective in controlling and / or reducing or ameliorating the disease and / or condition.

[0247] For example, but not limited to, the therapeutically effective amount of the active agent used in the present disclosure generally comprises an amount of the active ingredient sufficient to be delivered in the range of from about 0.01 μg / kg to about 10 mg / kg (active ingredient weight / patient weight). For example, but not limited to, the composition will deliver from about 0.1 μg / kg to about 5 mg / kg, more specifically from about 1 μg / kg to about 1 mg / kg.

[0248] The implementation of the disclosed method may include administering to a subject a therapeutically effective amount of a pharmaceutical composition (comprising an active agent) in any suitable systemic and / or topical formulation in an amount effective to deliver the doses listed above. The dose may be administered, for example but not limited to, as a single administration, or multiple administrations (e.g., but not limited to, 1 - 5 times per day, or 1 - 2 times per week). According to the inventive concepts disclosed herein, the pharmaceutical composition may be administered alone or in combination with other therapies.

[0249] Certain novel embodiments of the present disclosure have been generally described above. By reference to the following examples, certain novel embodiments of the present disclosure will be more readily understood. These examples are for illustrative purposes only of certain aspects and embodiments of the present disclosure and are not intended to be limiting. As described above, the following detailed examples are to be construed as illustrative only and not limiting the present disclosure in any way. Those skilled in the art will quickly recognize appropriate variations in various compositions, structures, components, procedures, and methods.

[0250] Experiments

[0251] The anti - inflammatory and anti - angiogenic activities of certain active agents disclosed herein were investigated. Prior to this study, except for 7 - chloro - 8 - methyl - 2 - phenylquinoline - 4 - carboxylic acid (named Y - 0452 herein), fenofibrate, GW409544, and GW590735 (shown below), none of the compounds described herein were reported to have PPARα agonist activity:

[0252]

[0253] The PPARα agonistic effects of a series of derivatives with certain structural similarities to Y - 0452 were evaluated. Compounds 9 - 14 and 21 - 24 were designed to more effectively fill the hydrophobic binding pocket in PPARα.

[0254] Derivatives 9 - 14 were synthesized as shown in Scheme 4. Commercially available 4 - hydroxybenzaldehyde was coupled with various benzyl bromides 3 - 8 to give benzaldehydes 3a - 8a. Treatment of 3a - 8a with 3 - aminobenzoic acid in situ generated the respective imines, which were then reduced by addition of sodium triacetoxyborohydride to afford 9 - 14 in unoptimized yields of 40 - 82%.

[0255]

[0256] Scheme 4. Synthesis of benzoic acid derivatives 9 - 14. Reagents and conditions: (a) benzyl bromide (i.e., 3 - 8), K 2 CO 3 , DMF, 80 °C, 12 h; (b) 3 - aminobenzoic acid, toluene, 155 °C, 2 h; sodium triacetoxyborohydride, AcOH, THF, 0 °C to 25 °C, 12 h.

[0257] In addition to the benzoic acid derivatives 9 - 14, we also wanted to introduce the classical "head-group" of fenofibrate with the aim of enhancing the potency and selectivity of PPARα relative to other isoforms. Scheme 5 describes the preparation of these analogues. Commercially available 3-nitrophenol was coupled with ethyl α-bromoisobutyrate to give 15, which was then reduced to the corresponding aniline (16) under catalytic hydrogenation (H 2 and Pd / C in ethanol solution). Treatment of 16 with 3a, 4a, 6a or 8a, followed by reduction with sodium triacetoxyborohydride, gave 17 - 20 respectively. Hydrolysis of the side-chain esters afforded the desired products 21 - 24 in unoptimized yields of 46 - 88%.

[0258]

[0259] Scheme 5. Synthesis of 21 - 24. Reagents and conditions: (a) ethyl α-bromoisobutyrate, K 2 CO 3 , DMF, 80 °C, 12 h; (b) H 2 , Pd / C, ethanol, 12 h; (c) aldehyde (i.e., 3a, 4a, 6a or 8a), toluene, 155 °C, 2 h; sodium triacetoxyborohydride, AcOH, THF, 0 °C to 25 °C, 12 h; (d) LiOH·H 2 O, THF / MeOH / H 2 O, 12 h.

[0260] After obtaining a focused subset of analogues, our efforts turned to evaluating the PPARα agonist activity of these derivatives. The initial evaluation used a commercially available PPARα luciferase cell reporter assay (Indigo Biosciences). The cell line employed was engineered to constitutively express high levels of hPPARα. When interacting with an agonist, hPPARα translocates to the nucleus, binds to the PPRE, and upregulates gene transcription, including the inserted luciferase gene. Luciferase activity was indirectly detected by quantifying the production of oxyluciferin. Initially, compounds 9 - 14 and 21 - 24 were evaluated at 5 μM and 50 μM to understand the agonist activity levels at two 10-fold increasing concentrations. As Figure 1As shown, many compounds exhibited hPPARα agonist activity equivalent to or higher than that of the positive control GW590735 (5 μM and 10 μM) at one or two evaluation concentrations. A direct comparison of 9 / 21, 10 / 22, 12 / 23, 14 / 24 revealed that the introduction of the fenofibrate "head group" enhanced the PPARα agonist activity at 50 μM concentration. However, this data also indicated that the introduction of the fenofibrate "head group" decreased the potency, as 21 - 24 failed to elicit significant activity at 5 μM concentration, while the benzoic acid analogs 9 - 14 all exhibited significant PPARα agonist activity at this lower concentration. Compounds 10 and 22 were selected for more detailed evaluation, and a more extensive 10 - point dose - response evaluation was performed to obtain the EC 50 values (Table 4): Compound 10 (5.6 μM) and Compound 22 (25.3 μM).

[0261] To further confirm that this 4 - benzyloxy - benzylamino chemical type acts as a PPARα agonist, we evaluated Compound 10 in a variety of biochemical assays. As expected for a PPARα agonist, Compound 10 induced the expression of PPARα in a dose - dependent manner ( Figure 2A and 2B ), which was confirmed by Western blot analysis using a cell line derived from C57BL / 6N mouse photoreceptors (661W). Similarly, RT - PCR studies on the same cell line also confirmed the PPARα agonist activity, as treatment with Compound 10 induced the expression of multiple PPARα target genes ( Figure 2C ), including acyl - CoA dehydrogenase medium chain (Acadm), carnitine palmitoyltransferase 1A (Cpt1a), fatty acid - binding protein 3 (Fabp3), and solute carrier family 25 member 20 (Slc25a20). Compound 10 was also evaluated in an in vitro wound - healing assay using human retinal capillary endothelial cells (HRCEC). PPARα agonist activity reduces cell migration 12 , and Compound 10 did inhibit wound closure in a dose - dependent manner ( Figure 2D ).

[0262] After evidence emerged that 4-benzyloxy-benzylamino derivatives exhibit typical PPARα agonist activity in a variety of biological settings, the selectivity of compound 10 for PPARα agonist activity (relative to PPARδ and PPARγ) was evaluated. Luciferase assays were performed on isogenic cell lines engineered to overexpress PPARδ or PPARγ, in which the expression of the desired luciferase reporter gene is dependent on exogenous activation by each isoform. As shown in Table 4, compound 10 is ≥20-fold more selective for hPPARα than for hPPARδ and hPPARγ, while compound 22 exhibits pan-agonism. This is interesting because the fibrate "head group" is thought to be a key feature for PPARα selectivity, but it appears to be disadvantageous for this 4-benzyloxy-benzylamino chemical type.

[0263] Table 4. Human PPAR agonist activities of selected analogues.

[0264] Compound number <![CDATA[hPPARαEC 50 (μM)]]> <![CDATA[hPPARδEC 50 (μM)]]> <![CDATA[hPPARγEC 50 (μM)]]> 10 5.6(1.5) >100 >100 22 25.3(1.7) 38.6 18.3 26 5.1(1.1) >100 >100 28 2.1(1.4) 8.9 5.6 GW590735 0.012 n.d. n.d. Rosiglitazone n.d. n.d. 0.083 GW0742 n.d 0.002 n.d. Y-0452 52.4(0.3) n.d. n.d.

[0265] Data are expressed as the EC 50 (μM) of agonist activity for the corresponding luciferase reporter gene cell line (Indigo Biosciences). As a single experiment, dosing was performed in triplicate. n.d = not determined. Values in parentheses represent the ratio of agonist activity compared to GW590735.

[0266] To better visualize the 4-benzyloxy-benzylamino derivative in the hPPARα binding pocket, we utilized PDB2P54 (the GW590735·hPPARα co-crystal structure) for docking evaluations. GW590735 is a selective PPARα agonist that is ≥500-fold more selective for PPARα than for PPARγ and PPARδ. Without wishing to be bound by theory, as Figure 3 shown in Figures 3A and 3B, compound 10 is predicted to bind in a similar orientation to GW590735. Interestingly, however, 10 lacks the gem-dimethyl "head group" and the amide linker domain, both of which were previously considered key determinants of GW590735 selectivity and major enhancers of potency. However, the acid of compound 10 is predicted to form four hydrogen bonds with Ser280, Tyr314, His440, and Tyr464, which is consistent with the view that the deconstruction of the Y-0452 quinoline core and the transposition of the carboxylic acid would significantly improve PPARα agonist activity. We are interested in whether this 4-benzyloxy-benzylamino chemical type can be extended to exploit the apparent amphiphilic pocket located beneath GW590735 ( Figure 3A), the pocket contains Met330, Tyr334, Glu282, Thr279, Met320, Val324, Leu321, Ile317, and Met220. We hypothesized that functionalization of the meta-position to the ether bond in the B-ring of compound 10 (Schemes 5 and 6) would provide the best trajectory for accessing this amphiphilic pocket. To our knowledge, few PPARα agonists utilize this pocket, and there is little SAR data regarding the effect of occupying this domain on the level of agonist activity and / or isotype selectivity.

[0267] To investigate the possible effects of occupying the amphiphilic pocket, we synthesized two additional derivatives 26 and 28 (Scheme 6). Briefly, commercially available 2,4-dihydroxybenzaldehyde was treated with 4-methoxybenzaldehyde in the presence of an acetone solution of potassium carbonate to yield the di-p-methoxybenzyl (PMB)-functionalized resorcinol 25. This intermediate was coupled with 3-aminobenzoic acid or 16, and the resulting imine was subsequently reduced to afford analog 26 and methyl ester 27, respectively. After saponification of 27, the desired derivative 28 was obtained in 75% yield. The introduction of the 4-methoxybenzyl motif as a "third arm" was rather arbitrary at this point and was chosen based on the belief that: 1) it would be compatible with the predicted binding environment, and 2) it could be readily synthesized by double alkylation of an aldehyde already present in our chemical library.

[0268]

[0269] Scheme 6. Synthesis of derivatives 26 and 27. Reagents and conditions: (a) 4-methoxybenzyl bromide, K 2 CO 3 , acetone; (b) 3-aminobenzoic acid or 16, toluene, 155 °C, 2 h; sodium triacetoxyborohydride, AcOH, THF, 0 °C to 25 °C, 12 h; (c) LiOH·H 2 O, THF / MeOH / H 2 O, 12 h.

[0270] The hPPARα agonist activity and selectivity of derivatives 26 and 28 were evaluated in a luciferase cell line. Data analysis showed that for the benzoic acid derivatives (comparing 10 and 26), the additional 4-methoxybenzyl substituent did not affect potency and maintained selectivity, at least within the dose range evaluated. However, for the derivatives containing the fibrate "head group" (comparing 22 and 28), the addition of a third substituent on the B-ring increased potency by 10-fold, but the pan-agonist property was maintained. Docking of 26 and 28 was performed using the model we generated previously, and as Figure 3 shown in C, the additional 4-methoxybenzyl group was indeed predicted to extend into the amphiphilic pocket.

[0271] Representative examples of the compounds of the present disclosure and their cellular luciferase activities are shown in Tables 5-8. Chemical structural formula IIa (Tables 5 and 6) is a version of chemical structural formula II where k = 0. Chemical structural formula IIb (Tables 7 and 8) is a version of chemical structural formula IIa where the R 1 group is in the para position of ring A.

[0272]

[0273] Table 5. Representative examples of compounds having chemical structural formula IIa

[0274]

[0275]

[0276] 1 OPMB represents -O-p-methoxybenzyl; 2 OPFB represents -O-p-fluorobenzyl.

[0277] Table 6. Cellular luciferase activities

[0278]

[0279]

[0280]

[0281] a Fold = fold increase in luciferase compared to the DMSO negative control. These values are not necessarily used to compare two compounds as they may not have been run under the same conditions. b EC50 = compound concentration (μM) that produces 50% maximum activity.

[0282]

[0283] Table 7. Representative examples of compounds having chemical structural formula IIb

[0284] <![CDATA[R 1 > <![CDATA[R 4 > m n <![CDATA[R 3 > <![CDATA[R 2 > <![CDATA[R 5 > Compound number COOH H 1 1 <![CDATA[4-CF 3 > H H 155 COOH H 1 1 <![CDATA[4 - OCH 3 > H H 162 <![CDATA[OC(CH 3 ) 2 COOH]]> H 1 1 4-F H H 182 COOH H 1 1 4-F H H 183

[0285] Table 8. Cellular luciferase activities

[0286]

[0287] a Fold = fold increase in luciferase compared to the DMSO negative control. These values are not necessarily used to compare two compounds as they may not have been run under the same conditions.

[0288] The data in Table 5-8 indicate that this chemical type is active in the whole cell environment and binds to the desired target PPARα. In addition, the results show a clear structure-activity relationship, an adjustable agonist activity level, and a selectivity curve of this chemical type for PPARα that is superior to other isotypes. Figures 4 - 6 The results in Figures 4 - 6 indicate that compound 91(10) exhibits dose-dependent activity in cell-based assays and shows >20-fold selectivity over other isotypes. Figures 7 - 9 The results in Figures 7 - 9 indicate that compound 190 exhibits dose-dependent activity in cell-based assays and shows >2000-fold selectivity over other isotypes. This indicates that the potency of this chemical type can be improved while enhancing or maintaining selectivity.

[0289] Figure 10A and 10B The data in 10B indicate that pharmacological activation of PPARα in humans has clinical benefits in reducing the prevalence of diabetic retinopathy, as reported by the FIELD and ACCORD studies. We demonstrated in Figure 10A Figure 10A and 10B that compound 91 exhibits in vivo efficacy in a well-established STZ-rat model of diabetic retinopathy (DR). As shown in Figure 10A Figure 10A and 10B , compound 91 reduced retinal vascular leakage in diabetic rats - a major culprit in diabetic macular edema and subsequent vision loss. Interestingly, compound 91 did not appear to show signs of hepatomegaly, a common side effect of fenofibrate that can lead to dose-limiting toxicity. These preliminary results provide proof of concept that: (1) compound 91(1) exhibits in vivo efficacy in a relevant DR model after systemic administration, (2) crosses the blood-eye barrier and reaches the retina, (3) has bioavailability, (4) survives well in first-pass metabolism and clearance mechanisms to maintain efficacy, and (5) exhibits relatively safe characteristics (no visible toxicity) after daily injection for one month.

[0290] In at least some embodiments of the present disclosure, the compound has highly selective agonist activity for PPARα compared to the PPARγ and PPARδ isotypes. For example, the PPARα agonist activity can be 1000-fold, or 2000-fold, or 2500-fold or higher than the agonist activity of the compound for PPARγ or PPARδ. For example, compound 190 (A190) was found to be particularly effective, with an EC 50 of 37 nM and a selectivity for PPARα that is >2700-fold higher than that for the PPARγ and PPARδ isotypes (calculated as EC 50 (PPARγ) / EC 50 (PPARα) or EC50 (PPARδ) / EC 50 (PPARα)).

[0291] Table 9 shows several compounds of the present disclosure (specific embodiments of Chemical Structural Formula II) and their activities, including PPARα activity.

[0292] Table 9. Compounds and Activities

[0293]

[0294]

[0295] Ratio (5 / 50): Ratio of relative light unit (RLU) signals at 5 μM and 50 μM compound concentrations.

[0296] Signal fold: Ratio of the maximum signal intensity observed from the target compound to the maximum signal intensity obtained with the compound GW590735.

[0297] EC 50 hPPARα (μM): Mean ± SEM of at least two independent experiments performed in triplicate. OPFB = O - p - fluorobenzyl. The numbers shown are based on the name of the final product. Blank cells indicate that the compound was not selected for the corresponding assay.

[0298] In summary, in at least some embodiments, the present disclosure relates to compounds of Chemical Structural Formula III and their salts and isomers:

[0299]

[0300] where (1) k is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, (2) m is 0, 1, 2, 3, 4, or 5 carbon atoms, (3) n is 0, 1, 2, 3, 4, or 5 carbon atoms, (4) R 1 is selected from phosphate esters and phosphonate esters, (5) R 2 is selected from CH 3 , hydrogen (H), chlorine (Cl), fluorine (F), bromine (Br), iodine (I), nitro (NO 2 ), CH 2 CH 3 , a branched or unbranched alkyl chain having 3 - 10 carbon atoms, OCH 3 , OCH 2 CH 3 , a branched or unbranched alkoxy chain having 3 - 10 carbon atoms, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, O - p - alkylbenzyl, O - p - alkoxybenzyl, and O - p - halobenzyl, where R contains2 The benzene ring contains one, two, three or four of said R 2 substituents, and said R 2 substituents are substituted with any combination of said R 2 substituents and arranged in the ring in any pattern, including ortho, meta, mono-substituted, di-substituted, tri-substituted and tetra-substituted, (6) R 3 is selected from F, H, Cl, Br, I, NO 2 , CH 3 , CH 2 CH 3 , a branched or unbranched alkyl chain having 3 to 10 carbon atoms, OCH 3 , OCH 2 CH 3 , a branched or unbranched alkoxy chain having 3 to 10 carbon atoms, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, O-p-alkylbenzyl, O-p-alkoxybenzyl and O-p-halobenzyl, wherein the benzene ring containing R 3 contains one, two, three, four or five of said R 3 substituents, and said R 3 substituents are substituted with any combination of said R 3 substituents and arranged in the ring in any pattern, including ortho, meta, para, mono-substituted, di-substituted, tri-substituted, tetra-substituted and penta-substituted, (7) R 4 is selected from H, alkyl and acyl; (8) R 5 is selected from H, Cl, F, Br, I, NO 2 , CH 3 , CH 2 CH 3 , a branched or unbranched alkyl chain having 3 to 10 carbon atoms, OCH 3 , OCH 2 CH 3 , a branched or unbranched alkoxy chain having 3 to 10 carbon atoms, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, O-p-alkylbenzyl, O-p-alkoxybenzyl and O-p-halobenzyl, wherein the benzene ring containing R 5 contains one, two, three or four of said R 5 substituents, and said R 5 substituents are substituted with any combination of said R 5 substituents and arranged in the ring in any pattern, including ortho, meta, para, mono-substituted, di-substituted, tri-substituted and tetra-substituted, wherein the compound has PPARα agonist activity. R 1 can be a phosphate ester, and its chemical structure is:

[0301]

[0302] Each R x is independently selected from H, substituted alkyl, unsubstituted alkyl, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, unsubstituted alkynyl, substituted cycloalkyl, unsubstituted cycloalkyl, substituted heterocyclic group, unsubstituted heterocyclic group, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted amine and unsubstituted amine. R1 can also be a phosphonate ester, and its chemical structure is:

[0303]

[0304] Each R x is independently selected from H, substituted alkyl, unsubstituted alkyl, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, unsubstituted alkynyl, substituted cycloalkyl, unsubstituted cycloalkyl, substituted heterocyclic group, unsubstituted heterocyclic group, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted amine and unsubstituted amine.

[0305] The PPARα agonist activity of the compound may be at least 1,000 times higher than the PPARγ agonist activity or PPARδ agonist activity of the compound. One or more compounds can be placed in a pharmaceutically acceptable carrier, vehicle or diluent to form a composition. The composition can be formulated to provide delayed release, controlled release, extended release and / or sustained release of one or more compounds. The compound or composition can be a component of a kit. The kit may include instructions for its use in treating a disorder or condition in a subject. The disorders or conditions that the kit can be used to treat can be ocular disorders or conditions, such as retinal inflammation, retinal neovascularization, retinal vascular leakage, retinopathy of prematurity (ROP), diabetic retinopathy (DR), age-related macular degeneration (AMD), macular edema, diabetic macular edema (DME), keratitis, endophthalmitis, blepharitis, conjunctivitis, scleritis, herpetic inflammation, uveitis, vasculitis, arteritis, orbital inflammation, optic neuritis, sympathetic ophthalmia, retinitis, glaucoma, proliferative vitreoretinopathy, corneal edema, uveal edema or retinal edema.

[0306] In at least some embodiments, the present disclosure relates to a method of increasing peroxisome proliferator-activated receptor alpha (PPARα) activity in retinal cells by administering to the retinal cells an amount of the above-described compound or composition that enhances PPARα activity. In at least some embodiments, the present disclosure relates to a method of treating a disorder or condition in a subject by administering a therapeutically effective amount of the above-described compound or composition to a subject in need of such treatment, thereby causing an increase in peroxisome proliferator-activated receptor alpha (PPARα) activity. The compound may be provided in a composition that is formulated to provide delayed release, controlled release, extended release, and / or sustained release of the compound. The disorder or condition may be retinal inflammation, retinal neovascularization, retinal vascular leakage, retinopathy of prematurity (ROP), diabetic retinopathy (DR), age-related macular degeneration (AMD), or diabetic macular edema (DME). The disorder or condition may be characterized by inflammation and / or angiogenesis. The disorder or condition may be inflammatory bowel disease, type 1 diabetes, type 2 diabetes, Graves' disease, multiple sclerosis, osteoarthritis, rheumatoid arthritis, vasculitis, dermatitis, glomerulonephritis, hepatitis, periodontitis, atherosclerosis, heart failure, obesity, Alzheimer's disease, or metabolic syndrome. The disorder or condition may be an ocular disorder or condition selected from keratitis, endophthalmitis, blepharitis, conjunctivitis, scleritis, herpetic inflammation, uveitis, vasculitis, arteritis, orbital inflammation, optic neuritis, sympathetic ophthalmia, retinitis, macular edema, glaucoma, proliferative vitreoretinopathy, corneal edema, uveal edema, and retinal edema. The disorder or condition may be retinal artery or vein occlusion, corneal transplant rejection, corneal neovascularization, neovascular glaucoma, sickle cell retinopathy, cancer, skin disease, diabetic ulcer, diabetic nephropathy, cardiovascular disease, or stroke.

[0307] Although the present disclosure has been described in connection with certain embodiments for the purpose of more fully understanding and appreciating the various aspects of the present disclosure, the present disclosure is not limited to these particular embodiments. On the contrary, it is intended that all alternatives, modifications, and equivalents be included within the scope of the present disclosure as defined herein. Accordingly, the above-described examples including the specific embodiments will be used to illustrate the practice of the inventive concepts of the present disclosure, and it should be understood that the details shown are by way of example and for purposes of illustrative discussion of the specific embodiments only, and are presented in order to provide what is considered to be the most useful and readily understood description of the processes as well as the principles and concepts of the present disclosure. Changes may be made to the formulations of the various compositions described herein, the methods described herein, or the steps or order of steps of the methods described herein without departing from the spirit and scope of the present disclosure. In addition, although the various embodiments of the present disclosure have been described in the claims below, this is not intended to limit the present disclosure to these particular claims.

Claims

1. A compound comprising Chemical Structural Formula III: and its salts and isomers, wherein: k is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms; m is 0, 1, 2, 3, 4 or 5 carbon atoms; n is 0, 1, 2, 3, 4 or 5 carbon atoms; R 1 selected from the following groups: phosphate esters and phosphonate esters; R 2 selected from the following groups: CH 3 , hydrogen (H), chlorine (Cl), fluorine (F), bromine (Br), iodine (I), nitro (NO 2 ), CH 2 CH 3 , a branched or unbranched alkyl chain having 3 to 10 carbon atoms, OCH 3 , OCH 2 CH 3 , a branched or unbranched alkoxy chain having 3 to 10 carbon atoms, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, O - p - alkylbenzyl, O - p - alkoxybenzyl and O - p - halobenzyl, wherein the benzene ring containing R 2 contains one, two, three or four of said R 2 substituents, and the R 2 substituents are substituted with any combination of said R 2 substituents and are arranged in the ring in any pattern, including ortho, meta, mono - substitution, di - substitution, tri - substitution and tetra - substitution; R 3 selected from the following groups: F, H, Cl, Br, I, NO 2 , CH 3 , CH 2 CH 3 , a branched or unbranched alkyl chain having 3 to 10 carbon atoms, OCH 3 , OCH 2 CH 3 , a branched or unbranched alkoxy chain having 3 to 10 carbon atoms, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, O - p - alkylbenzyl, O - p - alkoxybenzyl and O - p - halobenzyl, wherein the benzene ring containing R 3 contains one, two, three, four or five of said R 3 substituents, and the R 3 substituents are substituted with any combination of said R 3 substituents and arranged in the ring in any pattern, including ortho, meta, para, mono - substitution, di - substitution, tri - substitution, tetra - substitution and penta - substitution; R 4 selected from the group consisting of: H, alkyl, and acyl; and R 5 selected from the group consisting of: H, Cl, F, Br, I, NO 2 , CH 3 , CH 2 CH 3 , a branched or unbranched alkyl chain having 3 to 10 carbon atoms, OCH 3 , OCH 2 CH 3 , a branched or unbranched alkoxy chain having 3 to 10 carbon atoms, haloalkyl, haloalkoxy, cycloalkyl, halocycloalkyl, O - p - alkylbenzyl, O - p - alkoxybenzyl and O - p - halobenzyl, wherein the benzene ring containing R 5 contains one, two, three or four of said R 5 substituents, and the R 5 substituents are substituted with any combination of said R 5 substituents and arranged in the ring in any pattern, including ortho, meta, para, mono - substitution, di - substitution, tri - substitution and tetra - substitution; and wherein the compound has PPARα agonist activity.

2. The compound according to claim 1, wherein R 1 is a phosphate ester having the following chemical structure: Each R x is independently selected from H, substituted alkyl, unsubstituted alkyl, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, unsubstituted alkynyl, substituted cycloalkyl, unsubstituted cycloalkyl, substituted heterocyclic group, unsubstituted heterocyclic group, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted amine, and unsubstituted amine.

3. The compound according to claim 1, wherein R 1 is a phosphonate having the following chemical structure: Each R x is independently selected from H, substituted alkyl, unsubstituted alkyl, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, unsubstituted alkynyl, substituted cycloalkyl, unsubstituted cycloalkyl, substituted heterocyclic group, unsubstituted heterocyclic group, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted amine, and unsubstituted amine.

4. The compound according to claim 1, wherein the PPARα agonist activity of the compound is at least 1,000 times higher than the PPARγ agonist activity or the PPARδ agonist activity of the compound.

5. A composition comprising one or more compounds according to claim 1 in a pharmaceutically acceptable carrier, vehicle or diluent.

6. The composition according to claim 5, which is formulated to provide delayed release, controlled release, extended release and / or sustained release of one or more compounds.

7. A kit comprising the composition according to claim 5 and instructions for using it to treat a disorder or condition in a subject.

8. The kit according to claim 7, wherein the disorder or condition is an ocular disorder or condition selected from the group consisting of: retinal inflammation, retinal neovascularization, retinal vascular leakage, retinopathy of prematurity (ROP), diabetic retinopathy (DR), age-related macular degeneration (AMD), macular edema, diabetic macular edema (DME), keratitis, endophthalmitis, blepharitis, conjunctivitis, scleritis, herpetic inflammation, uveitis, vasculitis, arteritis, orbital inflammation, optic neuritis, sympathetic ophthalmia, retinitis, glaucoma, proliferative vitreoretinopathy, corneal edema, uveal edema and retinal edema.

9. A method of increasing peroxisome proliferator-activated receptor α (PPARα) activity in retinal cells, the method comprising: administering to the retinal cells a PPARα activity-enhancing amount of the compound according to claim 1.

10. A method of treating a disorder or condition in a subject by causing an increase in peroxisome proliferator-activated receptor α (PPARα) activity, the method comprising: administering to a subject in need of such treatment a therapeutically effective amount of the compound according to claim 1, wherein the compound is optionally provided in the form of a composition that is formulated to provide delayed release, controlled release, extended release and / or sustained release of the compound.

11. The method according to claim 10, wherein the disorder or condition is selected from the group consisting of: retinal inflammation, retinal neovascularization, retinal vascular leakage, retinopathy of prematurity (ROP), diabetic retinopathy (DR), age-related macular degeneration (AMD) and diabetic macular edema (DME).

12. The method according to claim 10, wherein the disorder or condition is characterized by inflammation and / or angiogenesis.

13. The method according to claim 10, wherein the disease is selected from inflammatory bowel disease, type 1 diabetes, type 2 diabetes, Graves' disease, multiple sclerosis, osteoarthritis, rheumatoid arthritis, vasculitis, dermatitis, glomerulonephritis, hepatitis, periodontitis, atherosclerosis, heart failure, obesity, Alzheimer's disease, and metabolic syndrome.

14. The method according to claim 10, wherein the disease or disorder is an ocular disease or disorder selected from keratitis, endophthalmitis, blepharitis, conjunctivitis, scleritis, herpetic inflammation, uveitis, vasculitis, arteritis, orbital inflammation, optic neuritis, sympathetic ophthalmia, retinitis, macular edema, glaucoma, proliferative vitreoretinopathy, corneal edema, uveal edema, and retinal edema.

15. The method according to claim 10, wherein the disease or disorder is selected from retinal artery or vein occlusion, corneal transplant rejection, corneal neovascularization, neovascular glaucoma, sickle cell retinopathy, cancer, skin disease, diabetic ulcer, diabetic nephropathy, cardiovascular disease, and stroke.

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