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

Abstract

Benzyl derivative compounds having peroxisome proliferator-activated receptor alpha (PPARα) agonist activity, kits and compositions containing such compounds, and methods of using them to enhance PPARα activity to treat diseases and / or conditions involving inflammation and / or angiogenesis, particularly diseases and / or conditions of the eye such as, but not limited to, retinal inflammation, retinal neovascularization, retinal vascular leakage, retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration, and diabetic macular edema.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This patent application claims the benefit under 35 U.S.C. 119(e) of U.S. Patent Application No. 17 / 876,243, filed July 28, 2022, the entire contents of which are hereby expressly incorporated herein by reference.

[0002] Government support This invention was made with government support under Grant No. R21EY028279 awarded by the National Institutes of Health (NIH). The government has certain rights in this invention. [Background technology]

[0003] Retinal inflammation and the resulting neovascularization (NV) are the primary cause of blindness in several ocular disorders, such as retinopathy of prematurity (ROP), diabetic retinopathy (DR), and age-related macular degeneration (AMD). Diabetic macular edema (DME), caused by retinal vascular leakage, is the leading cause of blindness in diabetic eye diseases. Accumulating evidence suggests that DR is a chronic inflammatory disorder in which multiple inflammatory factors, such as tumor necrosis factor alpha (TNF-α), intercellular adhesion molecule 1 (ICAM-1), and vascular endothelial growth factor (VEGF), are overexpressed in the diabetic retina. Inflammation plays a causative role in the impairment of retinal vascular endothelial function, vascular leakage, and subsequent retinal NV. Anti-VEGF drugs have emerged as a primary treatment option, but they are problematic due to the requirements of frequent intraocular injections, high costs, and the need for specialized facilities. Furthermore, although effective in most patients, approximately 40–50% of patients are refractory to intravitreal injections of anti-VEGF drugs and corticosteroids. This implies that auxiliary pathways and factors that remain unaddressed by current interventions are involved in the etiology and progression of the disease.

[0004] Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone-activated receptors and transcription factors. The PPAR family includes three members: PPARα (PPARα), PPARγ (PPARγ), and PPARδ (PPARδ), sometimes referred to in the art as PPARβ (PPARβ). These three PPAR members share significant sequence homology but have distinct tissue distributions, diverse functions, and can be selectively targeted. PPARγ is primarily expressed in adipose tissue, while PPARα is expressed in cells with high mitochondrial activity, including the liver, vascular endothelial cells (ECs), smooth muscle cells, kidney, and heart. Previous studies have shown that PPARα is abundantly expressed in the retina. However, the role of PPARα in regulating inflammation, apoptosis, and neovascularization (NV) in diabetic retina has only recently been elucidated, establishing novel strategies for the use of PPARα agonists as therapeutic agents for ocular vascular disease. Upon activation by endogenous or exogenous synthetic agonists, PPARα heterodimerizes with the retinoid x receptor (RXR) and binds to the PPAR response element (PPRE) in the promoter of its target genes, activating their transcription. Furthermore, PPARα indirectly regulates other genes by interfering with their transcriptional regulation. PPARα activates the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). KPPARα has been shown to regulate numerous genes involved in lipid metabolism and vascular inflammation, such as ICAM-1 and interleukin-6 (IL-6). Furthermore, PPARα has been shown to regulate oxidation and angiogenesis. However, the function of PPARα in the retina is poorly understood. The role of PPARα in DR was not recognized until findings from the FIELD and ACCORD clinical trials demonstrated that the PPARα agonist fenofibric acid (a metabolite of fenofibrate) has robust and unexpected therapeutic effects on DR, reducing the need for laser treatment by 32–40% in type 2 diabetic patients. Previous studies have demonstrated that PPARα levels are reduced in the retina of both type 1 and type 2 diabetic animal models. Furthermore, activation of PPARα by fenofibrate effectively reduces retinal leukocyte retention and vascular leakage in diabetic models, ameliorating ischemia-induced retinal NV. Summary of the Invention

[0005] Fenofibrate was initially recognized for its ability to lower cholesterol and triglyceride levels and has therefore been widely used clinically to treat dyslipidemia for over 30 years. Fenofibrate is the first low-cost, safe, oral DR medication with clinically proven efficacy against NV and DME in DR patients, making it of great interest to clinicians, basic scientists, and pharmaceutical companies interested in developing novel DR therapeutics. It has been reported that the preventive effect of fenofibrate on retinal NV and DME is not correlated with its lipid-lowering activity but rather results from the interaction of its metabolite, fenofibric acid, with PPARα. Therefore, fenofibrate has significant therapeutic potential for the treatment of DR and AMD, but its binding affinity to PPARα is relatively low, and it also has off-target nephrotoxic effects and other potential side effects. There is a significant need to develop novel treatment options that are noninvasive and complementary to current approaches. It is desirable, and this is the aim of the present research, to develop high affinity agonists of PPARα to further improve the treatment of DR and other inflammatory and angiogenic disorders of the eye and elsewhere in the body.

[0006] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the U.S. Patent and Trademark Office upon request and payment of the necessary fee. [Brief explanation of the drawings]

[0007] [Figure 1] Figure 1 shows the initial evaluation results of compounds 9-14 and 21-24 for hPPARα agonism in a cell-based luciferase assay. Results are presented from one experiment as fold induction versus DMSO control ± SE (n=3). Compound GW590735 was evaluated at 5 μM and 10 μM. [Figure 2A] FIG. 1 shows Western blot analysis of 661W mouse cells after treatment with 10 μM, 50 μM and 100 μM of Compound 10 for 24 hours. [Figure 2B] FIG. 2B shows the results of densitometric quantification of PPARα production from the Western blot analysis of FIG. 2A. [Figure 2C] Figure 1 shows real-time PCR analysis of 661W mouse cells after treatment with compound 10 for 24 hours (n=6). [Figure 2D] Figure 2 shows the results of an HRCEC wound healing assay for compound 10 at both 10 and 24 hour incubation times. Unless otherwise stated, experiments in Figures 2A-D were performed three times in triplicate. All values ​​shown are expressed as mean ± SD. Differences between groups were tested for statistical significance using Student's t-test. *P<0.05, **P<0.01, ***P<0.001. [Figure 3] (A) Co-crystal structure of GW590735·hPPARα, (B) predicted binding mode of 10 hPPARα, and (C) predicted binding mode of compound 28 to hPPARα. The binding pocket cavity is shown by a surface representation. PDB: 2P54. [Figure 4] Figure 1 shows dose-dependent agonism of PPARα by A91 as demonstrated by luciferase quantification (luminescence) in a cell-based luciferase reporter assay. GW59=GW590735 is used as a positive control. (A91=ASD91=10). [Figure 5] FIG. 1 shows dose-dependent agonism of PPARγ by A91 as demonstrated by luciferase quantification (luminescence) in a cell-based luciferase reporter assay. Rosiglitazone is used as a positive control. (A91=ASD91=10). [Figure 6] FIG. 1 shows dose-dependent agonism of PPARδ by A91 as demonstrated by luciferase quantification (luminescence) in a cell-based luciferase reporter assay. GW07=GW0742 is used as a positive control. (A91=ASD91=10). [Figure 7]Figure 1 shows dose-dependent agonism of PPARα by A190 as demonstrated by luciferase quantification (luminescence) in a cell-based luciferase reporter assay. GW59=GW590735 is used as a positive control. (A190=190=ASD190). [Figure 8] FIG. 1 shows dose-dependent agonism of PPARγ by A190 as demonstrated by luciferase quantification (luminescence) in a cell-based luciferase reporter assay. Rosiglitazone is used as a positive control. (A190=190=ASD190). [Figure 9] Figure 1 shows dose-dependent agonism of PPARδ by A190 as demonstrated by luciferase quantification (luminescence) in a cell-based luciferase reporter assay. GW07=GW0742 is used as a positive control. (A190=190=ASD190). [Figure 10A] Figure 1 shows the in vivo efficacy of compound ASD91 (10) compared with fenofibric acid (FenoFA) on retinal permeability. Male Brown Norway rats aged 7–8 weeks were injected with streptozotocin (STZ, 55 mg / kg). Two weeks after STZ injection, daily treatment (ip injection) with ASD91 or FenoFA was initiated and continued for 26–28 days. ≠P<0.05 (vs. FenoFA), *P<0.05 (vs. STZ-DMSO). [Figure 10B] Figure 1 shows the in vivo efficacy of compound ASD91 (10) compared with fenofibric acid (FenoFA) on hepatic phenotype. Male Brown Norway rats aged 7–8 weeks were injected with streptozotocin (STZ, 55 mg / kg). Two weeks after STZ injection, daily treatment (ip injection) with ASD91 or FenoFA was initiated and continued for 26–28 days. ≠P<0.05 (vs. FenoFA), *P<0.05 (vs. STZ-DMSO). DETAILED DESCRIPTION OF THE INVENTION

[0008] As mentioned above, retinal inflammation and angiogenesis are the main causes of blindness in several ocular disorders, such as retinopathy of prematurity, diabetic retinopathy (DR), and age-related macular degeneration (AMD). Two large-scale prospective clinical trials have reported that fenofibrate, a PPARα agonist, has robust therapeutic effects on DR. Disclosed herein is a novel class of compounds that, due to their PPARα agonist activity, have effects on retinal endothelial dysfunction, angiogenesis, and inflammation, suggesting therapeutic effects on, for example, DR and AMD (e.g., wet AMD). The compositions of the present disclosure may be used to treat ocular disorders or conditions, such as, but not limited to, DR, AMD (e.g., wet AMD), retinal inflammation, retinal neovascularization (NV), retinal vascular leakage, retinopathy of prematurity (ROP), and diabetic macular edema (DME). Other diseases and / or conditions associated with inflammation and / or angiogenesis that can be treated using the compounds of the present disclosure are described below.

[0009] Before further describing in more detail various embodiments of the compounds, compositions, and methods of the present disclosure using illustrative descriptions, examples, and results, it should be understood that the application of the compounds, compositions, and methods of the present disclosure is not limited to the details of the specific embodiments and examples set forth in the following description. The descriptions set forth herein are for illustrative purposes only and are not to be construed in a limiting sense. Accordingly, the language used herein is intended to be given the broadest possible scope and meaning, and the embodiments and examples are intended to be illustrative rather than comprehensive. It is also understood that the phraseology and terminology used herein are for descriptive purposes and should not be considered limiting unless otherwise indicated. Furthermore, in the following detailed description, numerous specific details are set forth to facilitate a more complete understanding of the present disclosure. However, it will be apparent to those skilled in the art that the present disclosure may be practiced without these specific details. In other instances, features well known to those skilled in the art are not described in detail to avoid unnecessarily complicating the description. All alternatives, substitutions, modifications, and equivalents apparent to those skilled in the art are intended to be included within the scope of the present disclosure. All of the compounds, compositions, and manufacturing methods disclosed herein, and their applications and uses, can be made and carried out in light of this disclosure.Thus, although the compounds, compositions, and methods of this disclosure have been described with reference to specific embodiments, it will be apparent to those skilled in the art that variations may be applied to the compounds, compositions, and / or methods described herein, and to the steps or order of steps of the methods, without departing from the concept, spirit, and scope of the inventive concept described herein.

[0010] All patents, published patent applications and non-patent publications mentioned in this specification or referenced anywhere in this application are expressly incorporated herein by reference in their entirety to the same extent as if each individual patent or publication was specifically and individually indicated to be incorporated by reference.

[0011] Unless otherwise defined herein, scientific and technical terms used in connection with this disclosure shall have the meanings commonly understood by those of ordinary skill in the art. Further, unless the context otherwise requires, singular terms shall include the plural and plural terms shall include the singular.

[0012] As utilized in accordance with the methods and compositions of the present disclosure, unless otherwise indicated, the following terms shall be understood to have the following meanings:

[0013] When used in conjunction with the term "comprising" in the claims and / or this specification, the use of the words "a" or "an" may mean "one," but is also consistent with the meanings of "one or more," "at least one," and "one or more than one." The use of the term "or" in the claims is used to mean "and / or" unless expressly indicated to refer to alternatives only, or where the alternatives are mutually exclusive, but the present disclosure supports the definition to refer to alternatives only and "and / or." The use of the term "at least one" is understood to include not just one, but any quantity greater 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 in between. The term "at least one" may extend to 100 or 1000 or more, depending on the term with which it is accompanied. Furthermore, the amount of 100 / 1000 should not be considered limiting, as greater limitations may produce better results. Additionally, use of the term "at least one of X, Y, and Z" is understood to include any combination of X, Y, and Z, not just X alone, Y alone, and Z alone.

[0014] As used herein, all numerical values ​​or ranges include fractions of values ​​and integers within such ranges and fractions of integers within such ranges unless the context clearly dictates otherwise. Thus, by way of example, reference to a numerical range such as 1 to 10 includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 as well as 1.1, 1.2, 1.3, 1.4, 1.5, etc. Thus, a reference to a range of 1 to 50 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, 50 as well as 1.1, 1.2, 1.3, 1.4, 1.5 etc., 2.1, 2.2, 2.3, 2.4, 2.5 etc. and is not limited to integers only. Reference to a series of ranges includes ranges combining the limits of the different ranges within that series. Thus, to illustrate reference to a series of ranges, for example, a range of 1 to 1,000 includes, for example, 1 to 10, 10 to 20, 20 to 30, 30 to 40, 40 to 50, 50 to 60, 60 to 75, 75 to 100, 100 to 150, 150 to 200, 200 to 250, 250 to 300, 300 to 400, 400 to 500, 500 to 750, 750 to 1,000, including ranges of 1 to 20, 10 to 50, 50 to 100, 100 to 500, and 500 to 1,000. Thus, the range of 100 units to 2000 units refers to and includes all values ​​or ranges of values ​​of units within said range, including, but not limited to, for example, 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, any two values ​​within the range of about 100 units to about 2000 units can be used to establish the lower and upper boundaries of a range according to embodiments of the present disclosure.

[0015] As used in this specification and 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.

[0016] As used herein, the term "or combinations thereof" refers to all permutations and combinations of the items listed before the term. For example, "A, B, C, or combinations thereof" is intended to include at least one of A, B, C, AB, AC, BC, or ABC, and, if order is important in the particular context, BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing this example, combinations containing repeats of one or more items or terms are expressly included, such as BB, AAA, AAB, BBC, AAABCCCC, CBBAAA, CABABB, etc. Those skilled in the art will understand that there is typically no limit to the number of items or terms in any combination unless otherwise apparent from the context.

[0017] Throughout this application, the terms "about" and "approximately" are used to indicate that a value includes variations in error inherent in the composition, the method used to administer the composition, or the variation that exists between test subjects. As used herein, the modifier "about" or "approximately" is intended to include not only the exact value, amount, degree, direction, or other modified characteristic or value, but also some degree of slight variation due to, for example, measurement error, manufacturing tolerances, stresses on various parts or components, observer error, wear and tear, and combinations thereof. When used herein to refer to a measurable value, such as an amount or length of time, the term "about" or "approximately" is intended to encompass variations of, for example, ±20%, ±15%, ±10%, ±5%, ±1%, or ±0.1% from the particular value, as understood by those skilled in the art, as such variations are appropriate for performing the disclosed methods. As used herein, the term "substantially" means that the subsequently described event or circumstance occurs absolutely, or that the subsequently described event or circumstance occurs to a significant extent or degree. For example, the term "substantially" means that the subsequently described event or circumstance occurs at least 75% of the time, or at least 80% of the time, or at least 90% of the time, or at least 95% of the time, or at least 98% of the time.

[0018] As used herein, any reference to "one embodiment" or "an embodiment" means that a particular element, feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment and may be included in other embodiments. The appearances of the phrase "in one embodiment" in various places in this specification are not necessarily all referring to the same embodiment, and are not necessarily limited to a single or specific embodiment.

[0019] As used herein, the pronoun "the investigators" is intended to refer to all persons involved in a particular aspect of the research disclosed herein, and thus may include laboratory assistants and collaborators other than the inventors working under the supervision of the inventors.

[0020] The term "pharmaceutically acceptable" refers to compounds and compositions that are suitable for administration to humans and / or animals without undue adverse side effects, such as toxicity, irritation, and / or allergic response, commensurate with a reasonable benefit / risk ratio. The compounds of the present disclosure may be combined with one or more pharmaceutically acceptable excipients, including carriers, vehicles, diluents, and adjuvants, which may enhance the solubility, delivery, dispersion, stability, and / or conformational integrity of the compound or its complex.

[0021] The term "active agent," as used herein, is intended to refer to an agent having biological activity relevant to the present disclosure, and particularly refers to therapeutic and diagnostic agents that may be used in the methods described herein. An active agent may be a chemical compound useful for the purposes disclosed herein.

[0022] As used herein, "pure" or "substantially pure" means that the target species is the predominant species present (i.e., more abundant, on a molar basis, than any other target species in the composition), and particularly, a substantially purified fraction is a composition in which the target species constitutes at least about 50 percent (on a molar basis) of all macromolecular species present. Generally, a substantially pure composition will contain greater than about 80%, more particularly greater than about 85%, greater than about 90%, greater than about 95%, or greater than about 99% of all macromolecular species present in the composition. The terms "pure" or "substantially pure" also refer to a preparation in which the species of interest 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.

[0023] 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.

[0024] In at least certain embodiments, diseases and / or conditions that can be treated with the compounds of the present disclosure are characterized by inflammation and / or angiogenesis. Such diseases and / or conditions with an inflammatory basis that can be treated with 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 disorders and conditions disclosed herein.

[0025] Examples of eye diseases with an inflammatory basis that can be treated with the compounds of the present disclosure include, but are not limited to, keratitis, endophthalmitis, blepharitis, conjunctivitis, scleritis, herpetic inflammation, uveitis, vasculitis, arteritis, orbital inflammation, 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.

[0026] Diseases and / or conditions with an inflammatory underpinning that may be treated with the compounds of the present disclosure include, but are not limited to, ophthalmic diseases and / or conditions such as 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 conditions, including, but not limited to, cancer, skin diseases, diabetic ulcers, diabetic nephropathy, cardiovascular disease, and stroke.

[0027] "Treatment" refers to therapeutic treatment. "Prevention" refers to prophylactic or preventative treatment measures or reducing the onset of a condition or disease. The term "treating" refers to administering a composition to a subject for therapeutic and / or preventative purposes. Non-limiting examples of modes of administration include oral, topical, retrobulbar, subconjunctival, transdermal, parenteral, subcutaneous, intranasal, intramuscular, intraperitoneal, intravitreal, and intravenous routes, including both local and systemic application. Furthermore, the compositions of the present disclosure may be formulated with carrier compounds that provide delayed, controlled, sustained, and / or extended release, for example, using formulation techniques that incorporate the active agent into degradable polymers.

[0028] The term "topical" is used herein to define 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 administration by the use of eye drops or by application of particles containing the active agent.

[0029] The terms "therapeutic composition" and "pharmaceutical composition" refer to a composition comprising a compound of the present disclosure (also referred to herein as an active agent), which may be administered to a subject by any method known in the art or otherwise contemplated herein, wherein administration of the composition results in a therapeutic effect as described elsewhere herein. As noted, compositions of the present disclosure may be designed to provide delayed, controlled, sustained, and / or extended release using appropriate formulation techniques.

[0030] The term "effective amount" refers to an amount of an active substance sufficient to produce a detectable therapeutic or treatment effect in a subject without excessive adverse side effects (e.g., substantial toxicity, irritation, and allergic response), and that is commensurate with a reasonable benefit / risk ratio when used in the methods disclosed herein. The effective amount for a subject will depend on the type, size, and health of the subject, the nature and severity of the condition being treated, the method of administration, the duration of treatment, the nature of concomitant therapy (if any), the particular formulation used, and the like. Therefore, it is not possible to specify an exact effective amount in advance. However, an effective amount for a given situation can be determined by one of ordinary skill in the art using routine experimentation based on the information provided herein. The term "activity-enhancing amount" refers to an amount of an active substance sufficient to increase PPARα activity in a cell or subject.

[0031] The term "ameliorate" refers to a detectable or measurable improvement in a subject's condition or a symptom thereof. A detectable or measurable improvement includes a subjective or objective decrease, reduction, inhibition, suppression, limitation, or control of the occurrence, frequency, severity, progression, or duration of a condition, or an improvement in the symptoms or underlying causes or consequences of a condition, or a reversal of a condition. The result of successful treatment can result in a "therapeutic effect" or "benefit" of improving, reducing, reducing, inhibiting, suppressing, limiting, controlling, or preventing the occurrence, frequency, severity, progression, or duration of a condition in a subject, or the consequences of a condition.

[0032] Successful treatment also results in a reduction or reduction in deterioration, such as stabilization of a condition.Therefore, therapeutic benefit does not necessarily require the complete elimination or reversal of a condition, or any one, most, or all of the adverse symptoms, complications, consequences, or underlying causes associated with the condition.Therefore, a successful endpoint can be achieved when there is a partial reduction, reduction, inhibition, suppression, restriction, control, or prevention of the occurrence, frequency, severity, progression, or duration of a condition over a short or long period (e.g., seconds, minutes, hours), or incremental improvement, such as inhibition or reversal (e.g., stabilization).

[0033] As used herein, the term "phosphate" refers to the moiety:

[0034] [ka] (In the formula, 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 heterocyclyl, unsubstituted heterocyclyl, 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 of R x ≠H. In certain embodiments, both R x =H or a salt thereof.

[0035] As used herein, the term "phosphonate" refers to the moiety:

[0036] [ka] (In the formula, each R x refers to H, substituted alkyl, unsubstituted alkyl, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, unsubstituted alkynyl, substituted cycloalkyl, unsubstituted cycloalkyl, substituted heterocyclyl, unsubstituted heterocyclyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted amine, and unsubstituted amine. In certain embodiments, -OR x R x ═H or a salt thereof. In certain embodiments, —OR x R x ≠H.

[0037] 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 a compound, solvates of a compound, and solvates of isomers and tautomers of a compound.

[0038] The term "isomer" includes conformational isomers, geometric isomers, stereoisomers, and / or optical isomers. For example, compounds of the present disclosure may contain one or more chiral centers and / or double bonds and, as a result, may exist as stereoisomers such as double bond isomers (i.e., geometric isomers), enantiomers, diastereomers, and mixtures thereof, such as racemic mixtures. "Stereoisomers" are compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.

[0039] "Tautomer" refers to alternative forms of a compound that differ in the location of a proton, such as the enol form, the keto form, and mixtures thereof. Tautomers may be imine-enamine tautomers or tautomeric forms of heteroaryl groups that contain ring atoms attached to both the -NH- and =N- ring moieties, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

[0040] The term "linker" as used herein may contain heteroatoms and may be unsubstituted or may be 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, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, "cycloalkenyl" refers to a divalent saturated or unsaturated aliphatic or aromatic hydrocarbyl group substituted by 1 to 5, preferably 1 to 3, and more preferably 1 to 2 substituents selected from the group consisting of cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio.

[0041] As used herein, the terms alkyl, haloalkyl, alkoxyl, haloalkoxyl, alkenyl, and alkynyl, unless otherwise specified, are generally intended to refer to branched or unbranched structures containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbons. Haloalkyl may refer to, for example, a haloalkyl of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbons having 1 to 3 halogen atoms. Haloalkoxyl may refer to, for example, a haloalkyl of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbons having 1 to 3 halogen atoms. Halogen may refer to chlorine (Cl), fluorine (F), bromine (Br), and / or iodine (I). Halogen may be abbreviated herein as "halo."

[0042] "Alkyl" refers to a monovalent saturated aliphatic hydrocarbyl group having 1 to 10 carbon atoms, more particularly 1 to 6 carbon atoms. This term includes, by way of example and not limitation, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2-), and neopentyl ((CH3)3CCH2-).

[0043] "Alkenyl" refers to monovalent linear or branched hydrocarbyl groups having 2 to 6 carbon atoms, more specifically 2 to 4 carbon atoms, and having at least 1, and preferably 1 to 2, sites of vinyl (>C=C<) unsaturation. Such groups are exemplified, for example, by vinyl, allyl, and but-3-en-1-yl. Included within this term are cis and trans isomers or mixtures of these isomers.

[0044] "Alkynyl" refers to a linear or branched monovalent hydrocarbyl group having from 2 to 6 carbon atoms, more specifically 2 to 3 carbon atoms, and having at least 1, and more specifically 1 or 2, sites of acetylenic (-C≡C-) unsaturation. Examples of such alkynyl groups include acetylenyl (-C≡CH) and propargyl (-CHC≡CH).

[0045] "Substituted alkyl" includes 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, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cyano, cycloalkyl-, cycloalkyl-, cycloalkyl-, cycloalkylthio-, cycloalkyl-, cycloalkyl-, cycloalkyl-, cycloalkyl-, cycloalkyl-, cycloalkyl-, cycloalkyl-, cycloalkyl-, cycloalkyl-, cycloalkyl-, cycloalkyl-, cycloalkenyl-, substituted cyano, cycloalkyl- ...alkyl-, cycloalkyl-, cycloalkyl-, cycloalkyl-, cycloalkyl-, cycloalkyl-, cycloalkyl-, cycloalkyl-, cycloalkyl-, cycloalkyl- " refers to an alkyl group having 1 to 5, preferably 1 to 3, and more particularly 1 to 2 substituents selected from the group consisting of cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein.

[0046] "Substituted alkenyl" includes 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, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cyclo "Alkenyl" refers to an alkenyl group having 1 to 3 substituents, more particularly 1 to 2 substituents, selected from the group consisting of alkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein, with the proviso that the hydroxyl or thiol substitutions are not attached to a vinyl (unsaturated) carbon atom.

[0047] "Substituted alkynyl" includes 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, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted " refers to an alkynyl group bearing one to three substituents, more particularly one to two substituents, selected from the group consisting of cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein, with the proviso that the hydroxyl or thiol substitutions are not attached to an acetylenic carbon atom.

[0048] "Alkylene" refers to a divalent saturated aliphatic hydrocarbyl group having 1 to 6, more specifically 1 to 3, carbon atoms, which is either straight-chained or branched. This term is exemplified by groups such as methylene (-CH-), ethylene (-CHCH-), n-propylene (-CHCHCH-), isopropylene (-CHCH(CH)- or -CH(CH)CH-), butylene (-CHCHCHCHCH-), isobutylene (-CHCH(CH)CH-), sec-butylene (-CHCH(CH)CH-), and the like.

[0049] "Substituted alkylene" refers to an alkylene group having 1 to 3 hydrogen atoms replaced with a substituent 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, hydroxyl, nitro, carboxyl, carboxyl ester, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and oxo, wherein said substituents are defined herein. In some embodiments, the alkylene has 1 to 2 of the aforementioned groups or 1 to 3 carbon atoms replaced with an -O-, -S-, or -NR- moiety, where R is H or a C1-C6 alkyl. When an alkylene is substituted with an oxo group, two hydrogen atoms bonded to the same carbon atom of the alkylene group are replaced with "=O."

[0050] "Alkoxy" refers to the group -O-alkyl, where alkyl is as defined herein. Alkoxy includes, by way of example and not limitation, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy.

[0051] "Substituted alkoxy" refers to the group --O-(substituted alkyl), where substituted alkyl is defined herein.

[0052] "Acyl" refers to the groups HC(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 CHC(O)-.

[0053] "Acylamino" refers to the group -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 rings, R ais hydrogen or alkyl, and 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.

[0054] "Acyloxy" refers to the groups 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-, cycloalkyl-C(O)O-, cycloalkenyl-C(O)O-, substituted cycloalkenyl-C(O)O-, heteroaryl-C(O)O-, cycloalkyl-C(O)O-, cycloalkenyl-C(O)O-, heteroaryl-C(O)O-, cycloalkyl-C(O)O-, cycloalkenyl-C(O)O-, heteroaryl-C(O)O-, cycloalkyl-C(O)O-, heteroaryl-C(O)O-, cycloalkenyl-C(O)O-, heteroaryl ... (O)O—, substituted heteroaryl-C(O)O—, heterocyclic-C(O)O—, and substituted heterocyclic-C(O)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.

[0055] "Amino" refers to the group -NH2.

[0056] "Substituted amino" is the group -NR b R c refers to R b and R cis 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, -SC-alkyl, -SO2-substituted alkyl, -SO2-alkenyl, -SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl, -SO2-cycloalkenyl, -SO2-substituted cycloalkenyl, -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted heteroaryl, -SO2-heterocyclic, and -SO2-substituted heterocyclic; R b and R c optionally joined together with the nitrogen attached thereto to form a heterocyclic or substituted heterocyclic group, with the proviso that R b and R c are not both hydrogen, and 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. b is hydrogen and R c When R is alkyl, the substituted amino group is sometimes referred to herein as alkylamino. b and R c When R is alkyl, the substituted amino group is sometimes referred to herein as dialkylamino. When referring to a monosubstituted amino, R b or R c When referring to a disubstituted amino, it means that only one of R b MoR c This means that it is not hydrogen.

[0057] "Aminocarbonyl" refers to the group -C(O)NR b R c refers to R b and R cis 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, and substituted heterocyclic; R b and R c is optionally joined together with the nitrogen bound thereto to form a heterocyclic or 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 are as defined herein.

[0058] "Aminothiocarbonyl" is the group -C(S)NR b R c refers to R b and R c is 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, and substituted heterocyclic; R b and R c is optionally joined together with the nitrogen bound thereto to form a heterocyclic or 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 and substituted heterocyclic are as defined herein.

[0059] "Aminocarbonylamino" is the group -NR a C(O)NR b R c refers to R a is hydrogen or alkyl, and R b and R cis 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, and substituted heterocyclic; R b and R c is optionally joined together with the nitrogen bound thereto to form a heterocyclic or 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 and substituted heterocyclic are as defined herein.

[0060] "Aminothiocarbonylamino" refers to the group -NR a C(S)NR b R c refers to R a is hydrogen or alkyl, and R b and R c is 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, and substituted heterocyclic; R b and R c is optionally joined together with the nitrogen bound thereto to form a heterocyclic or 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, and substituted heterocyclic are as defined herein.

[0061] "Aminocarbonyloxy" is the group -OC(O)NR b R c refers to R b and Rc is 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, and substituted heterocyclic; R b and R c is optionally joined together with the nitrogen bound thereto to form a heterocyclic or 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 and substituted heterocyclic are as defined herein.

[0062] "Aminosulfonyl" refers to the group -SO2NR b R c refers to R b and R c is 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, and substituted heterocyclic; R b and R c is optionally joined together with the nitrogen bound thereto to form a heterocyclic or 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 and substituted heterocyclic are as defined herein.

[0063] "Aminosulfonyloxy" refers to the group -O-SONR b R c refers to R b and R cis 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, and substituted heterocyclic; R b and R c is optionally joined together with the nitrogen bound thereto to form a heterocyclic or 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 and substituted heterocyclic are as defined herein.

[0064] "Aminosulfonylamino" refers to the group -NR a SO2NR b R c refers to R a is hydrogen or alkyl, and R b and R c is 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, and substituted heterocyclic; R b and R c is optionally joined together with the nitrogen bound thereto to form a heterocyclic or 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 and substituted heterocyclic are as defined herein.

[0065] "Amidino" is the group -C(=NR d )NR b R c refers to R b , Rc and R d is 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, and substituted heterocyclic; R b and R c is optionally joined together with the nitrogen bound thereto to form a heterocyclic or 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 and substituted heterocyclic are as defined herein.

[0066] "Aryl" or "Ar" refers to a monovalent aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring {e.g., phenyl) or multiple fused rings {e.g., naphthyl or anthryl) which may or may not be aromatic {e.g., 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7-yl, etc.), provided that the point of attachment is at an aromatic carbon atom. Aryl groups include, for example, phenyl and naphthyl.

[0067] "Substituted aryl" includes 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, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio. " refers to an aryl group substituted by 1 to 5, for example 1 to 3, more particularly 1 to 2 substituents selected from the group consisting of cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein.

[0068] "Aryloxy" refers to the group --O-aryl, where aryl is as defined herein, that includes, by way of example, phenoxy and naphthoxy.

[0069] "Substituted aryloxy" refers to the group --O-(substituted aryl), where substituted aryl is as defined herein.

[0070] "Arylthio" refers to the group -S-aryl, where aryl is as defined herein.

[0071] "Substituted arylthio" refers to the group -S-(substituted aryl), where substituted aryl is as defined herein.

[0072] "Carbonyl" refers to the divalent group -C(O)- which is equivalent to -C(=O)-.

[0073] "Carboxyl" or "carboxy" refers to -COOH or salts thereof.

[0074] "Carboxyl ester" or "carboxy ester" refers to the groups -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, refers to -C(O)O-heteroaryl, -C(O)O-substituted heteroaryl, -C(O)O-heterocyclic, and -C(O)O-substituted heterocyclic, 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.

[0075] "(Carboxyl 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 aC(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, and -NR a C(O)O-substituted heterocyclic rings, R a is alkyl or hydrogen, and 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.

[0076] "(Carboxyl ester)oxy" refers to the groups -OC(O)O-alkyl, -OC(O)O-substituted alkyl, -OC(O)O-alkenyl, -OC(O)O-substituted alkenyl, -OC(O)O-alkynyl, -OC(O)O-substituted alkynyl, -OC(O)O-aryl, -OC(O)O-substituted aryl, -OC(O)O-cycloalkyl, -OC(O)O-substituted cycloalkyl, -OC(O)O-cycloalkenyl, -OC(O)O-substituted cycloalkenyl, refers to -OC(O)O-heteroaryl, -OC(O)O-substituted heteroaryl, -OC(O)O-heterocyclic, and -OC(O)O-substituted heterocyclic, 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.

[0077] "Cyano" refers to the group --CN.

[0078] "Cycloalkyl" refers to cyclic alkyl groups of 3 to 10 carbon atoms having single or multiple cyclic rings, including fused, bridged, and spiro ring systems. Fused rings may also be aryl rings, provided that the non-aryl portion remains connected to the remainder of the molecule. Examples of suitable cycloalkyl groups include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl.

[0079] "Cycloalkenyl" refers to a non-aromatic cyclic alkyl group of 3 to 10 carbon atoms having a single or multiple cyclic rings and having at least one >C=C< ring unsaturation, e.g., 1 to 2 sites of >C=C< ring unsaturation.

[0080] "Substituted cycloalkyl" and "substituted cycloalkenyl" include oxo, thioxo, 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, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, " refers to a cycloalkyl or cycloalkenyl group having 1 to 5, 1 to 4, or 1 to 3 substituents selected from the group consisting of substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein.

[0081] "Cycloalkyloxy" refers to -O-cycloalkyl. "Substituted cycloalkyloxy" refers to -O-(substituted cycloalkyl). "Cycloalkylthio" refers to -S-cycloalkyl. "Substituted cycloalkylthio" refers to -S-(substituted cycloalkyl). "Cycloalkenyloxy" refers to -O-cycloalkenyl. "Substituted cycloalkenyloxy" refers to -O-(substituted cycloalkenyl). "Cycloalkenylthio" refers to -S-cycloalkenyl. "Substituted cycloalkenylthio" refers to -S-(substituted cycloalkenyl).

[0082] "Guanidino" refers to the group -NHC(=NH)NH2. "Substituted guanidino" refers to the group -NR e C(=NR e )N(R e )2, each R e are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclic, and substituted heterocyclic, and are connected to a common guanidino nitrogen atom by two R e groups, optionally together with the nitrogen attached thereto, to form a heterocyclic or substituted heterocyclic group, provided that at least one R e is not hydrogen, and said substituents are as defined herein.

[0083] "Hydroxy" or "hydroxyl" refers to the group --OH.

[0084] "Heteroaryl" refers to an aromatic group of 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., pyridinyl or furyl) or multiple fused rings (e.g., indolizinyl or benzothienyl), which may or may not be aromatic and / or may 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 are optionally oxidized to provide N-oxide (N→O), sulfinyl, or sulfonyl moieties. Non-limiting examples of heteroaryls include pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl.

[0085] "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 defined for substituted aryl.

[0086] "Heteroaryloxy" refers to the group -O-heteroaryl. "Substituted heteroaryloxy" refers to the group -O-(substituted heteroaryl).

[0087] "Heteroarylthio" refers to the group -S-heteroaryl. "Substituted heteroarylthio" refers to the group -S-(substituted heteroaryl).

[0088] "Heterocycle" or "heterocyclic" or "heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially saturated, but not 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 encompass single rings or multiple condensed rings, including fused, bridged, and spiro ring systems. In condensed ring systems, one or more rings may 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 are optionally oxidized to provide N-oxide, sulfinyl, or sulfonyl moieties.

[0089] "Substituted heterocyclic" or "substituted heterocycloalkyl" or "substituted heterocyclyl" refers to a heterocyclyl group substituted with 1 to 5, 1 to 4, or 1 to 3 of the same substituents as defined for substituted cycloalkyl.

[0090] "Heterocyclyloxy" refers to the group -O-heterocyclyl.

[0091] "Substituted heterocyclyloxy" refers to the group --O-(substituted heterocyclyl).

[0092] "Heterocyclylthio" refers to the group -S-heterocyclyl. "Substituted heterocyclylthio" refers to the group -S-(substituted heterocyclyl).

[0093] Examples of heterocycles and heteroaryls include 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, These include, but are not limited to, 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 called thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine, and tetrahydrofuranyl.

[0094] "Nitro" refers to the group -NO2.

[0095] "Oxo" refers to a double-bonded atom (=O).

[0096] "Phenylene" refers to a divalent aryl ring containing 6 carbon atoms. Substituted phenylene includes 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, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkenyl ... "phenylene substituted by 1-4, 1-3, or 1-2 substituents selected from the group consisting of alkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein.

[0097] "Spirocycloalkyl" and "spiro ring system" refer to a divalent cyclic group of 3 to 10 carbon atoms having a cycloalkyl or heterocycloalkyl ring with a spiro linkage (a linkage formed by a single atom that is the only common member of the rings), as exemplified by the following structure:

[0098] [ka]

[0099] "Sulfonyl" refers to the divalent group -S(O)2-.

[0100] "Substituted sulfonyl" refers to the group -SO2-alkyl, -SO2-substituted alkyl,

[0101] "S02-alkenyl," "S02-substituted alkenyl," "S02-cycloalkyl," "S02-substituted cycloalkyl," "S02-cycloalkenyl," "S02-substituted cycloalkenyl," "S02-aryl," "S02-substituted aryl," "S02-heteroaryl," "S02-substituted heteroaryl," "S02-heterocyclic," and "S02-substituted heterocyclic," 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. Substituted sulfonyl includes groups such as methyl-S02-, phenyl-S02-, and 4-methylphenyl-S02-.

[0102] "Substituted sulfonyloxy" refers to the groups -OSO2-alkyl, -OSO2-substituted alkyl, -OSO2-alkenyl, -OSO2-substituted alkenyl, -OSO2-cycloalkyl, -OSO2-substituted cycloalkyl, -OSO2-cycloalkenyl, -OSO2-substituted cycloalkenyl, -OSO2-aryl, -OSO2-substituted aryl, -OSO2-heteroaryl, -OSO2-substituted heteroaryl, -OSO2-heterocyclic, -OSO2-substituted heterocyclic, 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.

[0103] "Thioacyl" refers to the groups HC(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)-,

[0033] This refers to 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.

[0104] "Thiol" refers to the group --SH.

[0105] "Thiocarbonyl" refers to the divalent group -C(S)- which is equivalent to -C(=S)-.

[0106] "Thioxo" refers to the atom (=S).

[0107] "Alkylthio" refers to the group -S-alkyl, where alkyl is as defined herein. "Substituted alkylthio" refers to the group -S-(substituted alkyl), where substituted alkyl is as defined herein.

[0108] As used herein, the term "salt" refers to a chemical compound containing a negatively charged moiety (phosphate / phosphonate compound) and a positively charged cation atom or ionic aggregate of the compound, resulting in a compound with no net charge. The salts of the present disclosure are intended to be pharmaceutically acceptable, i.e., suitable for pharmaceutical use. Generally, pharmaceutically acceptable salts substantially 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 may be an ammonium ion, a quaternary alkylammonium, a quaternary arylammonium, or an ammonium ion derived from an organic base, including, but not limited to, ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, piperidine, pyridine, dimethylamine, diethylamine, trimethylamine, triethylamine, isopropylamine, 2-ethylaminoethanol, histidine, lysine, procaine, and tris(2-amino-2-(hydroxymethyl)propane-1,3-diol).

[0109] Unless otherwise indicated, the nomenclature of substituents not explicitly defined herein is derived by naming the terminal portion of the functional group followed by the adjacent functional group toward the point of attachment. For example, the substituent "arylalkyloxycarbonyl" refers to the group (aryl)-(alkyl)-OC(O)-.

[0110] As used herein, the term "prodrug" refers to art-recognized modifications to one or more functional groups such that the functional group is metabolized in vivo to yield an active agent or its active metabolites. Such functional groups are well known in the art, including hydroxyl and / or amino substitutions, acyl or thioacyl groups for conversion of one or more hydroxyl groups to monophosphates, diphosphates, and triphosphates, optionally in which one or more of the pendent hydroxyl groups of the monophosphates, diphosphates, and triphosphates have been converted to alkoxy, substituted alkoxy, aryloxy, or substituted aryloxy groups, etc.

[0111] Prodrug derivatives may exhibit various pharmacologically desirable properties, including, but not limited to, increased water solubility, increased bioavailability, and altered activity of the active agent. "Biologically active" refers to the ability to modify the physiological system of a cell, tissue, or organism, without reference to how the active agent has its physiological effect. Such prodrugs may, but need not, be pharmacologically inactive until converted to their active drug form. The compounds disclosed herein may include prodrug derivatives that are hydrolyzed or otherwise cleaved under conditions of use.

[0112] Examples of suitable prodrug derivatives of the present disclosure include, but are not limited to, active agents in which hydroxyl, amino, thiol, or carboxyl groups have been derivatized to form prodrugs. For example, hydroxyl functional groups, including phenolic and aliphatic hydroxyl groups, may be masked as phosphates, phosphonates, sulfonates, esters, or with carbonate-containing progroups. As used herein, a progroup refers to a group attached to an active agent to provide a prodrug derivative. These prodrugs can be hydrolyzed in vivo to provide the hydroxyl group. Amino functional groups can be masked as amide, carbamate, imine, urea, phosphenyl, phosphoryl, or sulfenyl progroups. These prodrugs can be hydrolyzed in vivo to provide the amino group. Carboxyl groups can be masked as esters (including silyl esters and thioesters), amide, or oxadiazole progroups. These prodrugs can be hydrolyzed in vivo to provide the carboxyl group.

[0113] Prodrugs can increase the water solubility of the prodrug compared to the active substance.Therefore, progroups, such as phosphate or phosphonate moieties, or linkers containing phosphate or phosphonate moieties, can include or be one or more groups suitable for imparting improved water solubility to drug molecules.Such groups are well known, and examples include, but are not limited to, alkyl, aryl and arylalkyl, or cycloheteroalkyl groups substituted with one or more of hydrophilic groups, such as phosphate or phosphonate, or phosphorous acid (i.e., phosphate or phosphonate), amine, alcohol, carboxylic acid, sulfoxide, sugar, amino acid, thiol, polyol, ether, thioether, and quaternary amine salt. Exemplary 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 may be adapted by those skilled in the art, upon reading this disclosure, to synthesize the prodrug derivatives of the present disclosure.

[0114] For example, various ester groups, including phosphate or phosphonate, generally undergo acid-catalyzed hydrolysis when exposed to the acidic conditions of the stomach, and undergo base-catalyzed hydrolysis to generate the parent hydroxyl group when exposed to the basic conditions of the intestine or blood. Therefore, when orally administered to a subject, a compound containing an ester moiety can be considered a prodrug of the corresponding hydroxyl, regardless of whether the ester is pharmacologically active. For example, a prodrug can utilize a progroup containing such an ester that can be chemically cleaved in the stomach to form an active compound. Alternatively, the progroup can be designed to be metabolized in the presence of enzymes such as, but not limited to, phosphatases, esterases, amidases, and lipases, including ATPases and kinases. Progroups containing in vivo metabolizable linkages are well known, and examples include, but are not limited to, ethers, thioethers, silyl ethers, silyl thioethers, esters, thioesters, carbonates, thiocarbonates, carbamates, thiocarbamates, ureas, thioureas, and carboxamides.

[0115] Prodrugs may also be metabolized under the desired conditions of use, for example, under acidic conditions found in the stomach, and / or by enzymes found in vivo, to yield biologically active groups, such as the compounds described herein. Those skilled in the art will understand that progroups may include virtually any known or later discovered hydroxyl, amine, or thiol protecting group. Examples of suitable protecting groups that can be used in the compounds of the present disclosure include, but are not limited to, those found in "Greene's Protective Groups in Organic Synthesis," PGM Wuts, 5th Ed., Wiley, New York, 2014.

[0116] The identity of the progroup can also be selected to impart desired properties to the prodrug. For example, hydrophilic groups can be used to increase water solubility. In this way, a prodrug specifically tailored to the selected mode of administration can be obtained. Prodrugs can also aid in, for example, improving passive intestinal absorption, improving transport-mediated intestinal absorption, protecting against rapid metabolism (sustained-release prodrugs), tissue-selective delivery, passive concentration in target tissues, and targeting specific transporters. The various groups described in these references can be utilized in the prodrugs described herein.

[0117] This work demonstrates how the novel class of compounds of the present disclosure can be used as ophthalmic compositions to treat 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.

[0118] In certain non-limiting embodiments, the present disclosure provides a compound represented by chemical structure I:

[0119] [ka] wherein ring A is benzene or pyridine containing nitrogen (N) at the 2-, 4-, 5-, or 6-position; wherein ring B is benzene or pyridine containing N at the 2-, 3-, 5- or 6-position; wherein ring C is benzene or pyridine containing N at the 2-, 3-, 4-, 5-, or 6-position; wherein X is selected from the group consisting of oxygen (O), NH, sulfur (S), and CH; wherein Y is selected from the group consisting of O, NH, S, and CH; wherein k is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms; wherein, in at least certain embodiments, R on the “A” ring of chemical structure I 1 The substituents are selected from the chemical structures i to x shown in Table 1 below. The compound includes compounds having the formula:

[0120] [Table 1]

[0121] In a non-limiting embodiment, R of structure ix in Table 1 8 and R 9 is hydrogen (H), halogen (F, Cl, Br, I), alkyl (e.g., branched or unbranched, C1-C 10 ), alkoxy (e.g., branched or unbranched, C1-C 10 ), and cyclo(R 8 R 9 In structure ix of Table 1, X can be O, NH, S, or CH. In a non-limiting embodiment, R in structure x of Table 1 can be selected from the group 10 and R 11 is H, alkyl (e.g., branched or unbranched, C1-C 10 ) and cyclo(R 10 R 11 (linked to)

[0122] In another non-limiting example, R in chemical structure I 1may be selected from the group of carboxylic acid and carboxylic acid isosteres including hydroxamic acids, hydroxamic acid esters, phosphonic acids, phosphinic acids, sulfonic acids, sulfinic acids, sulfonamides, acylsulfonamides, sulfonylureas, acylureas, tetrazole, thiazolidinedione, oxazolidinedione, oxadiazol-5(4H)-one, thiadiazol-5(4H)-one, oxathiadiazole-2-oxide, oxadiazole-5(4H)-thione, isoxazole, tetramic acid, cyclopentane 1,3-dione, cyclopentane 1,2-dione, squaric acid, substituted phenols, heteroarenes, amidines, hydroxyamides, alkylhydroxyamidines, the group including exemplary structures shown in Table 2, and further including salts of any of the above.

[0123] [Table 2-1]

[0124] [Table 2-2]

[0125] [Table 2-3]

[0126] In at least certain non-limiting embodiments, R of chemical structure I 2Substituents include H, F, Cl, Br, I, nitro (NO2), alkyl (e.g., CH3, CH2CH3, or any branched or unbranched alkyl chain having 3 to 10 carbon atoms), alkoxy (e.g., OCH3, OCH2CH3, or any branched or unbranched alkoxy chain having 3 to 10 carbon atoms), haloalkyl (e.g., CH2Cl, CHBr2, CF3), haloalkoxyl (e.g., OCH2Cl, OCHBr2, O ... selected from the group of haloalkyl of 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbons, e.g., haloalkoxyl of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbons having 1 to 3 halogen atoms, cycloalkyl, halocycloalkyl, O-para-alkylbenzyl (e.g., alkyl is methyl, ethyl or propyl), O-para-alkyloxybenzyl (e.g., alkyl is methyl, ethyl or propyl), and O-para-halobenzyl (halo = Cl, F, Br or I).

[0127] In at least certain non-limiting embodiments, R of ring "C" of chemical structure I 3 The substituents are selected from the group of H, F, Cl, Br, I, NO, alkyl (e.g., CH, CHCH, or any branched or unbranched alkyl chain having 3 to 10 carbon atoms), alkoxy (e.g., OCH, OCHCH, or any branched or unbranched alkoxy chain having 3 to 10 carbon atoms), haloalkyl (e.g., CHCl, CHBr, CF), haloalkoxyl (e.g., OCHCl, OCHBr, OCF), haloalkyl of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbons having 1 to 3 halogen atoms, e.g., haloalkoxyl of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbons having 1 to 3 halogen atoms, cycloalkyl, and halocycloalkyl, and the "C" ring is ... 3 The R's are substituted with any combination of substituents and arranged on the "C" ring in any pattern, including ortho, meta, para, mono, di, tri, tetra, and penta substitutions. 3Contains 1, 2, 3, 4 or 5 of the substituents.

[0128] In at least certain non-limiting embodiments, each R of chemical structure I 4 and R 5 Substituents include H, F, Cl, Br, I, NO, alkyl (e.g., branched or unbranched, C1-C 10 ) and haloalkyl (e.g., CH2Cl, CHBr2, CF3). R 4 and R 5 may together consist of a double bonded O.

[0129] In at least certain non-limiting embodiments, R 4 and R 5 taken 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.

[0130] In at least certain embodiments, R 4 and R 5 When one of R is alkyl or cycloalkyl (as defined herein), R 4 and R 5 The other is H.

[0131] In at least certain non-limiting embodiments, each R of chemical structure I 6 and R 7 Substituents include H, F, Cl, Br, I, alkyl (e.g., branched or unbranched, C1-C 10 ) and haloalkyl (e.g., CH2Cl, CHBr2, CF3). R 6 and R 7 may together consist of a double bonded O.

[0132] In at least certain non-limiting embodiments, R 6 and R 7taken 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.

[0133] In at least certain embodiments, R 6 and R 7 When one of R is alkyl or cycloalkyl (as defined herein), R 6 and R 7 The other is H.

[0134] As noted, in certain embodiments, rings A and / or B and / or C of chemical structure I can be pyridines. Schemes 1-3 below show exemplary, non-limiting synthetic routes that can be used to form structures of the present disclosure that include rings A and / or B as pyridines:

[0135] Scheme 1:

[0136] [ka]

[0137] Schemes 2 and 3:

[0138] [ka]

[0139] In at least certain alternative embodiments, the present disclosure provides for the treatment of ocular disorders and conditions, particularly retinal conditions and disorders, which in certain 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), by administering to the ophthalmic patient a compound having the chemical structure II:

[0140] [ka] (In the formula, 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 2 is selected from the group consisting of hydrogen (H), chlorine (Cl), fluorine (F), bromine (Br), iodine (I), nitro (NO), CH, CHCH, a branched or unbranched alkyl chain containing 3 to 10 carbon atoms, OCH, OCHCH, a branched or unbranched alkoxy chain containing 3 to 10 carbon atoms, haloalkyl, haloalkoxyl, cycloalkyl, halocycloalkyl, O-para-alkylbenzyl, O-para-alkyloxybenzyl, and O-para-halobenzyl; R 2 The benzene ring containing 2 The R may be substituted with any combination of substituents and arranged on the ring in any pattern, including ortho, meta, mono, di, tri, and tetra substitution. 2 containing 1, 2, 3 or 4 of the substituents; R 3 is selected from the group consisting of H, Cl, F, Br, I, NO2, CH3, CH2CH3, a branched or unbranched alkyl chain containing 3 to 10 carbon atoms, OCH3, OCH2CH3, a branched or unbranched alkoxy chain containing 3 to 10 carbon atoms, haloalkyl, haloalkoxyl, cycloalkyl, halocycloalkyl, O-para-alkylbenzyl, O-para-alkyloxybenzyl and O-para-halobenzyl; R 3 The benzene ring containing 3 The R may be substituted with any combination of substituents and arranged on the ring in any pattern, including ortho, meta, para, mono, di, tri, tetra, and penta substitution. 3 containing 1, 2, 3, 4 or 5 of the substituents; R 4 is selected from H, alkyl and acyl; R 5is selected from the group consisting of H, Cl, F, Br, I, NO2, CH3, CH2CH3, a branched or unbranched alkyl chain containing 3 to 10 carbon atoms, OCH3, OCH2CH3, a branched or unbranched alkoxy chain containing 3 to 10 carbon atoms, haloalkyl, haloalkoxyl, cycloalkyl, halocycloalkyl, O-para-alkylbenzyl, O-para-alkyloxybenzyl and O-para-halobenzyl; R 5 The benzene ring containing 5 The R may be substituted with any combination of substituents and arranged on the ring in any pattern, including ortho, meta, para, mono, di, tri, and tetra substitution. 5 containing 1, 2, 3 or 4 of the substituents; R 1 are carboxylic acids, carboxylic acid isosteres, hydroxamic acids, hydroxamic acid esters, phosphonic acids, phosphinic acids, sulfonic acids, sulfinic acids, sulfonamides, acylsulfonamides, sulfonylureas, acylureas, tetrazoles, thiazolidinediones, oxazolidinedione, oxadiazol-5(4H)-one, thiadiazol-5(4H)-one, oxathiadiazole-2-oxide, oxadiazole-5(4H)-thione, isoxazoles, tetramic acids, cyclopentane 1,3-dione, cyclopentane 1,2-dione, squaric acid, substituted phenols, heteroarenes, amidines, hydroxyamides, alkylhydroxyamidines, and

[0141] [ka] and salts thereof; R 8 and R 9 is H, F, Cl, Br, I, alkyl, alkoxy and R 8 R 9 cycloalkyl linked to R 10 and R 11 is H, alkyl and R 10 R 11 cycloalkyl linked to X is O, NH, S or CH2 The present invention includes active agent compositions and methods for treatment using compounds having the formula:

[0142] More specifically, in certain non-limiting embodiments of the present disclosure, examples of compounds having chemical structure II (compounds 9-14, 21-24, 26, and 28) are shown below:

[0143] [ka]

[0144] [ka]

[0145] [ka]

[0146] [ka]

[0147] [ka]

[0148] [ka]

[0149] Compounds 9-14, 21-24, 26, and 28 are also numbered herein (e.g., in Tables 4 and 5) as 117, 91, 120, 122, 118, 119, 116, 114, 123, 121, 92, and 115, respectively. Compounds ASD152, ASD160, ASD178, ASD179, ASD181, ASD200, ASD203, and ASD207 are also referred to herein as 152, 160, 178, 179, 181, 200, 203, and 207, respectively.

[0150] In certain embodiments, the compounds (but not necessarily methods) of the present disclosure have the structure:

[0151] [ka] Chemical Structure II (wherein (1) R 1 =COOH, R 2 ~R 5 =H, (2)R 1 =COOH, R 3 =CH3, R 2 , R 4 and R 5 ═H).

[0152] In at least certain alternative embodiments, the present disclosure provides for the treatment of ocular disorders and conditions, particularly retinal conditions and disorders, which in certain 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), using compounds having the chemical structure III:

[0153] [ka] or a salt or isomer thereof, 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 is selected from the group of phosphates and phosphonates, and salts thereof, R 2 is selected from the group consisting of CH3, hydrogen (H), chlorine (Cl), fluorine (F), bromine (Br), iodine (I), nitro (NO2), CH2CH3, a branched or unbranched alkyl chain containing 3 to 10 carbon atoms, OCH3, OCH2CH3, a branched or unbranched alkoxy chain containing 3 to 10 carbon atoms, haloalkyl, haloalkoxyl, cycloalkyl, halocycloalkyl, O-para-alkylbenzyl, O-para-alkyloxybenzyl and O-para-halobenzyl; R 2 The benzene ring containing 2 The R may be substituted with any combination of substituents and arranged on the ring in any pattern, including ortho, meta, mono, di, tri, and tetra substitution. 2 containing 1, 2, 3 or 4 of the substituents; R 3 is selected from the group consisting of F, H, Cl, Br, I, NO2, CH3, CH2CH3, a branched or unbranched alkyl chain containing 3 to 10 carbon atoms, OCH3, OCH2CH3, a branched or unbranched alkoxy chain containing 3 to 10 carbon atoms, haloalkyl, haloalkoxyl, cycloalkyl, halocycloalkyl, O-para-alkylbenzyl, O-para-alkyloxybenzyl and O-para-halobenzyl; R 3 The benzene ring containing 3 The R may be substituted with any combination of substituents and arranged on the ring in any pattern, including ortho, meta, para, mono, di, tri, tetra, and penta substitution. 3 containing 1, 2, 3, 4 or 5 of the substituents; R 4 is selected from the group of H, alkyl and acyl; R 5is selected from the group consisting of H, Cl, F, Br, I, NO2, CH3, CH2CH3, a branched or unbranched alkyl chain containing 3 to 10 carbon atoms, OCH3, OCH2CH3, a branched or unbranched alkoxy chain containing 3 to 10 carbon atoms, haloalkyl, haloalkoxyl, cycloalkyl, halocycloalkyl, O-para-alkylbenzyl, O-para-alkyloxybenzyl and O-para-halobenzyl; R 5 The benzene ring containing 5 The R may be substituted with any combination of substituents and arranged on the ring in any pattern, including ortho, meta, para, mono, di, tri, and tetra substitution. 5 containing 1, 2, 3 or 4 of the substituents) The present invention includes active agent compositions and methods for treatment using compounds having the formula:

[0154] In certain embodiments, the compound has the chemical structure IIIA:

[0155] [ka] wherein R is selected from the group of phosphates and phosphonates, and salts thereof. It has.

[0156] In one embodiment, the compound is the monosodium salt designated by identifier ZH-2021-162 and has the following structure:

[0157] [ka] It has.

[0158] In one embodiment, the compound is a monotris salt designated by identifier ZH-2021-164 and has the following structure:

[0159] [ka] It has.

[0160] Exemplary salts of phosphate and phosphonate compounds include, but are not limited to, sodium, potassium, calcium, magnesium, ammonium, iron, quaternary alkylammonium, and quaternary arylammonium. The cation may be a metal ion, such as an alkali metal ion (e.g., sodium, potassium, or lithium), an alkaline earth metal ion (e.g., magnesium, calcium, or barium), or an aluminum ion. The cation may 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-methylglucamine, morpholine, piperidine, pyridine, dimethylamine, diethylamine, trimethylamine, triethylamine, isopropylamine, 2-ethylaminoethanol, histidine, lysine, procaine, and tris(2-amino-2-(hydroxymethyl)propane-1,3-diol).

[0161] The comparative solubilities of various compounds are shown in Table 3.

[0162] [Table 3]

[0163] Certain non-limiting embodiments of the present disclosure include pharmaceutical compositions comprising at least one pharmaceutically acceptable carrier in combination with one or more compounds described herein that are agonists of PPARα 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): pharmaceutical compositions comprising a PPARα agonist in combination with at least one pharmaceutically acceptable carrier, such as a polymer, and (b) a PPARα agonist in combination with at least one other therapeutically active agent and at least one pharmaceutically acceptable carrier, such as a polymer.

[0164] As noted 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, for example, DR and AMD (e.g., wet AMD), retinal inflammation, retinal neovascularization (NV), retinal vascular leakage, retinopathy of prematurity (ROP), and diabetic macular edema (DME).

[0165] Suitable carriers, vehicles, excipients, diluents and other ingredients that may be included in the formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 21 st Ed. and 22 nd The term "pharmaceutically acceptable" means that the carrier is a non-toxic material that does not interfere with the effectiveness of the biological activity of the active agent. The characteristics of the carrier depend on various factors, including, but not limited to, the route of administration.

[0166] The active substances (i.e., phosphate and / or phosphonate compounds) disclosed herein may be formulated into compositions for delivery to a subject. The compositions may be administered alone and / or mixed with a pharmaceutically acceptable vehicle or excipient. Suitable vehicles include, but are not limited to, water, saline, dextrose, glycerol, ethanol, and the like, and combinations thereof. In addition, the vehicle may contain minor amounts of auxiliary substances, such as, but not limited to, wetting or emulsifying agents, pH buffering agents, or adjuvants. The compositions of the present disclosure may also contain auxiliary substances, including other pharmacological agents.

[0167] The active agent, alone or as a pharmaceutical composition, may be delivered by any means known in the art, including, but not limited to, systemically, locally, or topically; intra-arterially, intrathecally (IT), intravenously (IV), parenterally, intrapleurally, topically, orally, transdermally, or by local administration, such as ophthalmic, subcutaneous, intratracheal (e.g., by aerosol), or transmucosally (e.g., buccal, bladder, vaginal, uterine, rectal, nasal), subcutaneous, intracranial, intraocular, intracerebral, intracavitary, intraperitoneal, intranasal, intralymphatic, or intramuscular. Intravenous administration may be, for example (but not limited to), by infusion over a period of time, such as, but not limited to, 30 to 90 minutes, or by a single bolus injection. As noted above, the composition may be formulated into either a neutral or salt form of the composition.

[0168] The therapeutic composition may be administered as a single dose or multiple doses, with a schedule and duration appropriate for the subject's age, weight, and condition, 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 another non-limiting embodiment, multiple doses are administered. The frequency of administration may vary depending on any of a variety of factors, such as the severity of symptoms or whether the composition is used 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, every other week, 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, daily, twice a day, or three times a day. The duration of treatment (i.e., the period over which the composition is administered) may vary depending on any of a variety of factors, such as the subject's response. For example, the composition may be administered for a period of about 1 day to about 1 week, about 2 weeks to about 4 weeks, about 1 month to about 2 months, about 2 months to about 4 months, about 4 months to about 6 months, about 6 months to about 8 months, about 8 months to about 1 year, about 1 year to about 2 years, or about 2 years to about 4 years, or longer.

[0169] The composition can be combined with a pharmaceutically acceptable carrier (excipient) to form a pharmacological composition. Pharmaceutically acceptable carriers can include, for example, but are not limited to, physiologically acceptable compounds that stabilize the pharmaceutical composition or increase or decrease the absorption or clearance rate. Physiologically acceptable compounds can include, but are 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.

[0170] When administered orally, the compositions of the present invention can be protected from digestion by combining the active agent with a composition that makes it resistant to acidic and enzymatic hydrolysis, or by packaging the active agent in a suitably resistant carrier, such as, but not limited to, liposomes as shown in U.S. Pat. No. 5,391,377.

[0171] For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated can be used in the formulation. Such penetrants 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 enhance penetration. Transmucosal administration can be through the use of nasal sprays or suppositories. For topical transdermal administration, the active substance can be formulated into ointments, creams, salves, powders, and gels. Transdermal delivery systems can also include (for example, but are not limited to) patches. The compositions of the present invention can also be administered via sustained delivery or sustained release mechanisms. For example, biodegradable microspheres or capsules, or other biodegradable polymer compositions capable of sustained delivery, can be used.

[0172] In one aspect, the composition is prepared with a carrier that protects the active substance from rapid excretion from the body, such as (but not limited to) controlled release formulations, including implants and microencapsulated delivery systems.Biodegradable and biocompatible polymers can be used, such as (but not limited to) ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for preparing such formulations are clear to those skilled in the art.

[0173] Active substance can generally be formulated to obtain a composition containing one or more pharmaceutically suitable excipients, surfactants, polyols, buffers, salts, amino acids, or additional components, or some combination thereof.This can be achieved by known methods for preparing pharmaceutically useful dosages, whereby active compound is combined with one or more pharmaceutically suitable excipients in a mixture.Sterile phosphate buffered saline is one non-limiting example of pharmaceutically suitable excipients.

[0174] For parenteral administration, the composition is formulated in a unit dosage injectable form, such as, but not limited to, a solution, suspension, or emulsion, in association with a pharmaceutically acceptable excipient. Such excipients are essentially non-toxic and non-therapeutic. Non-limiting examples of such excipients include saline, Ringer's solution, dextrose solution, and Hank's solution. Non-aqueous excipients, such as, but not limited to, fixed oils and ethyl oleate, may also be used. An alternative, non-limiting excipient is 5% dextrose in saline. The excipient may contain minor amounts of additives, such as, but not limited to, substances that enhance isotonicity and chemical stability, including buffers and preservatives.

[0175] The formulated composition containing the active substance may be used for (for example, but not limited to) subcutaneous, intramuscular, or transdermal administration. The composition may be presented in a unit dosage form, for example, in an ampule or in a multi-dose container, with a preservative added. The composition may also take 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 may be in powder form for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use.

[0176] In certain non-limiting embodiments, pharmaceutical compositions for parenteral administration are sterile, substantially isotonic, and manufactured under GMP conditions. Pharmaceutical compositions may be provided in unit dosage form (i.e., dosages for single administration). Pharmaceutical compositions may be formulated using one or more physiologically acceptable carriers, diluents, excipients, or adjuvants. The formulation will depend on the selected route of administration. For injection, the active agent may be formulated in an aqueous solution such as, but not limited to, Hank's solution, Ringer's solution, or a physiologically compatible buffer such as saline or acetate buffer (to reduce discomfort at the injection site). The solution may contain formulating agents such as suspending, stabilizing, and / or dispersing agents. Alternatively, the active agent may be in lyophilized form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0177] Some non-limiting embodiments provided herein include kits. In some non-limiting embodiments, the kit may include a quantity of an active agent described herein or otherwise contemplated. In some non-limiting embodiments, the active agent is lyophilized. In some non-limiting embodiments, the active agent is in an aqueous solution or other carrier described herein. In some non-limiting embodiments, the kit includes a pharmaceutical carrier for administration of the active agent. Certain non-limiting embodiments of the present disclosure include kits containing components suitable for treatment or diagnosis. Exemplary kits may 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 hypodermic injection, may be included. When transdermal administration is used, in some non-limiting embodiments, a delivery device such as a hollow microneedle delivery device may be included in the kit. Exemplary transdermal delivery devices, such as (but not limited to) the hollow Microstructured Transdermal System (e.g., 3M Corp.), are known in the art, and any such known device may be used. The components of the kit may be packaged together or separated into two or more containers. In some non-limiting embodiments, the container may be a vial containing a sterile lyophilized formulation of the composition suitable for reconstitution. The kit may also include one or more buffers suitable for reconstitution and / or dilution of other reagents. Alternatively, the active agent may be delivered and stored as a liquid formulation. Other containers that may be used include, but are not limited to, pouches, trays, boxes, tubes, etc. The components of the kit may be packaged within the container and maintained sterile. Another component that may be included is instructions for using the kit for treatment.

[0178] The term "co-administration" refers to the administration of two or more active substances, for example, a PPARα agonist and another active substance. The timing of co-administration depends in part on the combination and composition administered, and can include administration simultaneously with, immediately before, or immediately after the administration of one or more additional therapies. Co-administration is intended to include simultaneous or sequential administration of individual or combinations of compounds and / or compositions. Thus, the preparation can also be combined with other active substances if desired (e.g., to reduce metabolic degradation).

[0179] For inhalation, the composition may 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 may be administered in the form of an aerosol or mist. For aerosol administration, the formulation may be provided in finely divided form along with a surfactant and a propellant. In another embodiment, the device for delivering the formulation to respiratory tissues is an inhaler, in which the formulation is vaporized. Other liquid delivery systems include (for example, but not limited to) air-jet nebulizers.

[0180] The active agents of the present disclosure may be present in the pharmaceutical composition at any concentration that enables the pharmaceutical composition to function in accordance with the present disclosure. For example, but not limited to, the compounds may be present in the pharmaceutical composition at a concentration with a lower limit 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%; and 3%, 3% and 4%. It may be present in a range having an upper level selected from 0.5%, 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 about 0.0001% to about 95%, about 0.001% to about 75%, about 0.005% to about 50%, about 0.01% to about 40%, about 0.05% to about 35%, about 0.1% to about 30%, about 0.1% to about 25%, about 0.1% to about 20%, about 1% to about 15%, about 2% to about 12%, about 5% to about 10%, etc. Any other range with a lower limit selected from the concentrations of the lower level listed above and an upper limit selected from the concentrations of the upper level listed above is also within the scope of the present disclosure.

[0181] Exemplary non-limiting ranges of a therapeutically or prophylactically effective amount of an active agent are in the range of about 0.001 mg / kg to about 500 mg / kg of subject's body weight, including, but not limited to, about 0.01 mg / kg to about 250 mg / kg, about 0.1 mg / kg to about 100 mg / kg, about 0.1 mg / kg to about 50 mg / kg, about 1 mg / kg to about 30 mg / kg, about 1 mg / kg to about 25 mg / kg, about 2 mg / kg to about 30 mg / kg, Including a range of about 2 mg / kg to about 20 mg / kg, a range of about 2 mg / kg to about 15 mg / kg, a range of about 2 mg / kg to about 12 mg / kg, a range of about 2 mg / kg to about 10 mg / kg, a range of about 3 mg / kg to about 30 mg / kg, a range of about 3 mg / kg to about 20 mg / kg, a range of about 3 mg / kg to about 15 mg / kg, a range of about 3 mg / kg to about 12 mg / kg, or a range of about 3 mg / kg to about 10 mg / kg, or a range of about 10 mg to about 1500 mg as a fixed dosage.

[0182] The compositions are formulated to contain an effective amount of the active agent, the amount depending on the subject being treated and the severity of the subject's condition. In certain non-limiting embodiments, the active agent is present in an amount of about 0.001 mg to about 10 g, about 0.01 mg to about 10 g, about 0.1 mg to about 10 g, about 1 mg to about 10 g, about 1 mg to about 9 g, about 1 mg to about 8 g, about 1 mg to about 7 g, about 1 mg to about 6 g, about 1 mg to about 5 g, about 10 mg to about 10 g, about 50 mg to about 5 g, about 50 mg to about 5 g, about 50 mg to about 2 g, about 0.05 μg to about 1.5 mg The compound may be administered at a dose ranging from about 10 μg to about 1 mg of protein, about 30 μg to about 500 μg, about 40 μg to about 300 μg, about 0.1 μg to about 200 mg, about 0.1 μg to about 5 μg, about 5 μg to about 10 μg, about 10 μg to about 25 μg, about 25 μg to about 50 μg, about 50 μg to about 100 μg, about 100 μg to about 500 μg, about 500 μg to about 1 mg, or about 1 mg to about 2 mg. The specific dose level for any particular subject will depend on a variety of factors, including (but not limited to) the activity of the particular active agent, age, body weight, general health, sex, diet, time, route of administration, and excretion rate of the drug combination, and the severity of the disease in the subject being treated.

[0183] In some non-limiting embodiments, the amount of 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, Approximately 40μM, approximately 45μM, approximately 50μM, approximately 60μM, approximately 70μM, approximately 75μM, approximately 80μM, approximately 90μM, approximately 100μM, approximately 125μM, approximately 150μM, approximately 175μM, approximately 200μM, approximately 250μM, approximately 300μM, approximately 350μM, approximately 400μM, approximately 500 μM, approx. 600 μM, approx. 700 μM, approx. 750 μM, approx. 800 μM, approx. 900 μM, approx. 1mM, approx. 2mM, approx. 3mM, approx. 4mM, approx. 20mM, 25mM, 30mM, 35mM, 40mM, 45mM, 50mM, 55mM, 60mM, 65mM, 70mM, 75mM, 80mM, 85mM, 90mM, 95mM, 100mM, 100mM, 1 10mM, about 120mM, about 130mM, about 140mM, about 150mM, about 160mM, about 170mM, about 180mM, about 190 mM, approx. 200mM, approx. 250mM, approx. 300mM, approx. 400mM, approx. 500mM, approx. 600mM, approx. 700mM, approx. 800mM , 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 foregoing concentrations, or any number between any two of the foregoing concentrations, including two concentrations as the endpoints of the range.

[0184] The dosage of an active agent administered to a human will vary depending on factors such as, but not limited to, the patient's age, weight, height, sex, general medical condition, and medical history. In certain non-limiting embodiments, the recipient is provided with a dosage of the active agent ranging from about 1 mg to about 1000 mg as a single infusion or single or multiple injections, although lower or higher dosages may also be administered. In certain non-limiting embodiments, the dosage is based on the body surface area of ​​a typical adult human being per square meter (m 2 The dosage may range from about 25 mg to about 100 mg per dose, although lower or higher dosages may be administered. Non-limiting examples of dosages that may be administered to a human subject further include 1-500 mg, 1-70 mg, or 1-20 mg, although higher or lower doses may be used. Dosages may be repeated as needed, for example (but not limited to) once per week for 4-10 weeks, once per week for 8 weeks, or once per week for 4 weeks. Dosages may also be administered less frequently, such as (but not limited to) every other week for several months, or more frequently, such as twice per week or by continuous infusion.

[0185] The composition may be administered in a solution. The formulation may be in a solution with a suitable pharmaceutically acceptable buffer, such as, but not limited to, phosphoric acid, tris(hydroxymethyl)aminomethane-HCl, or citric acid. The concentration of the buffer may range from 1 to 100 mM. The formulated solution may also contain a salt, such as, but not limited to, sodium chloride or potassium chloride, at a concentration of 50 to 150 mM. An effective amount of a stabilizer, such as, but not limited to, mannitol, trehalose, sorbitol, glycerol, albumin, globulin, detergent, gelatin, protamine, or a salt of protamine, may also be included.

[0186] The number of dosages administered depends on the severity of the condition and the response to treatment (e.g., whether the condition is acute or chronic). Treatment may be repeated for recurrence or acute exacerbation of acute disorders. In the case of chronic disorders, the active substance may be administered at regular intervals, such as (but not limited to) weekly, biweekly, monthly, quarterly, or semi-annually, for at least 1, 5, or 10 years, or for the patient's lifetime if the condition is chronic.

[0187] Other embodiments of the pharmaceutical compositions of the present disclosure may include incorporating or encapsulating the active substance in various types of drug delivery systems that function to provide targeted delivery, controlled release, and / or increased half-life of the active substance. For example, but not limited to, the active substance can be encapsulated in microcapsules prepared by coacervation techniques or by interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively). The active substance can also be encapsulated in macroemulsion or colloid drug delivery systems (e.g., but not limited to, liposomes, albumin microspheres, microemulsions, nanoparticles, nanocapsules, etc.). Such techniques are well known to those skilled in the art and therefore further description thereof is not considered necessary.

[0188] In one specific, non-limiting example, the pharmaceutical composition may contain liposomes containing an active substance. In addition to other pharmaceutically acceptable carriers, the liposomes may contain amphiphilic substances, such as lipids that exist in aqueous solution in the form of micelles, insoluble monolayers, liquid crystals, or lamellar aggregates. Lipids suitable for liposomal formulations include, but are not limited to, monoglycerides, diglycerides, sulfatides, lysolecithin, phospholipids, saponins, bile acids, combinations thereof, and the like. The preparation of such liposomal formulations is well within the level of ordinary skill in the art, as disclosed, for example, in U.S. Pat. Nos. 4,235,871, 4,501,728, 4,837,028, and 4,737,323, the entire contents of each of which are incorporated herein by reference.

[0189] In another non-limiting example, the active agent of the present disclosure may be incorporated into particles of one or more polymeric materials, as this type of incorporation can be useful for controlling the duration of action of the active agent by allowing for controlled release from the preparation, thereby increasing its half-life. Non-limiting examples of polymeric materials that may be utilized in this manner include polyesters, polyamides, polyamino acids, hydrogels, poly(lactic-co-glycolic acid), poly(lactic acid), ethylene vinyl acetate copolymers, micelles of copolymers such as PEG and poly(l-aspartamide), and combinations thereof.

[0190] In certain non-limiting embodiments, the pharmaceutical composition containing the active agent may be in the form of an ophthalmic composition for topical application to the subject's eye. As used herein, the term "ophthalmic composition" is understood to refer to any composition specifically formulated for direct topical administration to a patient's eye. The composition may be formulated for topical administration to the eye or for injection into the eye (i.e., intravitreal or intraocular injection). The ophthalmic composition may be provided in any formulation that can be administered topically to the eye and that enables the active agent to function in accordance with the present disclosure. For example, but not limited to, the ophthalmic composition may be provided in the form of a solution, drops, mists / sprays, plasters and pressure-sensitive adhesives, ointments, lotions, creams, gels, lyophilized / spray-dried forms, etc. In one specific non-limiting embodiment, the ophthalmic composition is provided in a form for topical application, such as, but not limited to, an eye drop formulation. The ophthalmic compositions of the present disclosure may 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, the ophthalmic compositions of the present disclosure may be designed to provide delayed, controlled, sustained and / or extended release, as described elsewhere herein, using formulation techniques well known in the art.

[0191] The pharmaceutical compositions described herein or otherwise contemplated may further comprise at least one delivery agent that aids in delivering the active substance to the desired delivery site; for example, but not limited to, at least one delivery agent may be included in an ophthalmic composition to aid in penetration into the surface of the eye. In certain embodiments, the delivery agent may aid in delivery to the retina of the eye. For example, to be effective in topical application, the composition may need to be able to penetrate the surface of the eye so that it can be transferred to the desired tissue. This may include penetration into the conjunctiva and / or cornea.

[0192] When an ophthalmic composition containing an active substance is formulated for administration by injection, the composition may be in the form of a pyrogen-free aqueous solution or suspension. Preparation of such a solution, taking into due consideration pH, isotonicity, stability, and the like, is well within the skill of those skilled in the art. Suitable carriers include, but are not limited to, biocompatible, pharmaceutically acceptable phosphate-buffered saline solutions, particularly isotonic solutions. For example, but not limited to, certain ophthalmic compositions may contain, in addition to the therapeutic compound, an isotonic vehicle such as sodium chloride injection, Ringer's injection, dextrose injection, dextrose and sodium chloride injection, lactated Ringer's injection, or other vehicles known in the art. Generally, materials for intravenous injection into humans should comply with regulations established by the U.S. Food and Drug Administration, which are available to those skilled in the art.

[0193] In addition to the ophthalmic compositions discussed in detail herein above, the therapeutic compositions of the present disclosure may be formulated for administration in any other manner known or otherwise contemplated in the art, so long as the route of administration allows for delivery of the active agent so that the compound can function in accordance with the present disclosure, i.e., as a PPARα agonist. Examples of other routes of administration include, but are not limited to, oral, topical, retrobulbar, subconjunctival, transdermal, parenteral, subcutaneous, nasal, intramuscular, intraperitoneal, intravitreal, and intravenous routes, including both local and systemic routes of application.

[0194] Another non-limiting embodiment of the present disclosure relates to a kit containing one or more of any of the pharmaceutical compositions described herein or otherwise contemplated. The kit may further contain a second active substance as described herein above to be used in combination with the pharmaceutical composition. If the composition present in the kit is not provided in a form to be delivered, the kit may further contain a pharmaceutically (ophthalmically) acceptable carrier, vehicle, diluent, excipient, or other active substance to be mixed with the active substance to prepare the pharmaceutical composition. Kits containing compositions and / or other reagents may also be packaged with instructions for administration and / or dosing of the compositions contained in the kit. The instructions may be prepared as any tangible medium of expression, such as printed paper, or computer-readable magnetic or optical media, or instructions referencing a remote computer data source, such as an internet-accessible World Wide Web page.

[0195] The kit may contain single or multiple doses of the pharmaceutical composition. When multiple doses are present, the doses may be combined in bulk in a single container, or the multiple doses may be combined individually in the kit. That is, the pharmaceutical composition may be present in the kit in unit dosage form to facilitate accurate dosing. As used herein, the term "unit dosage form" refers to a physically discrete unit suitable as a unit dosage for human subjects and other mammals, each unit containing a predetermined amount of active ingredient calculated to produce a desired therapeutic effect in association with a suitable pharmaceutical excipient. Typical unit dosage forms for liquid compositions include prefilled, premeasured ampoules or syringes, while for solid compositions, typical unit dosage forms include pills, tablets, capsules, etc. In such compositions, the active agent may be a minor component (about 0.1 to about 50% by weight, for example, but not limited to, about 1 to about 40% by weight), with the remainder consisting of various vehicles or carriers and processing aids useful in forming the desired dosage form.

[0196] As is apparent from the above, the active substances of the present disclosure function as PPARα agonists to treat, inhibit, alleviate, and / or prevent degenerative retinal disorders. Accordingly, certain non-limiting embodiments of the present disclosure include methods for treating, inhibiting, and / or reducing the occurrence of retinal degeneration caused by retinal inflammation and neovascularization. One specific, but non-limiting, embodiment includes a method for treating, inhibiting, and / or reducing the occurrence of one or more ocular conditions associated with reduced PPARα activity in a subject. In the method, one or more of any of the active substances or pharmaceutical compositions described herein or otherwise contemplated is administered to a subject (e.g., but not limited to, a mammal) experiencing retinal or macular degeneration or susceptible to developing retinal or macular degeneration or other ocular conditions or disorders. The active substance or pharmaceutical composition is administered to the subject in an amount effective to have PPARα agonist activity in the retina of at least one eye of the subject.

[0197] The ocular condition may be any of the conditions described herein, and the ocular condition may be characterized by retinal and / or macular degeneration. In one embodiment, the pharmaceutical composition may be administered locally to the subject's eye (for example, but not limited to, as eye drops). In alternative embodiments, the pharmaceutical composition may be administered by injection into the eye or systemically.

[0198] The amount of the active substance effective for the treatment described herein can be determined by a diagnostician skilled in the art by using conventional techniques and observing the results obtained under similar circumstances.For example, in one non-limiting embodiment of treatment, in determining the therapeutically effective dose, the diagnostician may take into account a number of factors, including but not limited to, the species, size, age and general health of the subject, the specific disease and / or condition involved, the extent, lesion and / or severity of the disease and / or condition, the response of the individual subject, the specific active substance or other therapeutic compound administered, the mode of administration, the bioavailability characteristics of the administered preparation, the selected dosage regimen, 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 substance that is effective for controlling and / or reducing or improving a disease and / or condition.

[0199] For example, but not by way of limitation, a therapeutically effective amount of an active agent used in the present disclosure generally contains sufficient active ingredient to deliver in the range of about 0.01 μg / kg to about 10 mg / kg (weight of active ingredient / body weight of patient). For example, but not by way of limitation, compositions deliver about 0.1 μg / kg to about 5 mg / kg, more particularly about 1 μg / kg to about 1 mg / kg.

[0200] Practice of the disclosed methods may include administering to a subject a therapeutically effective amount of a pharmaceutical composition (containing an active agent) in any suitable systemic and / or local formulation in an amount effective to deliver the dosages listed above. The dosage may be administered once or multiple times (e.g., but not limited to, 1-5 times daily or once or twice weekly). The pharmaceutical composition may be administered alone or in combination with other therapeutic agents in accordance with the inventive concepts disclosed herein.

[0201] Certain novel embodiments of the present disclosure, generally described above, will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present disclosure and are not intended to be limiting. The following detailed examples, as noted above, should be construed as merely illustrative and not as limiting the present disclosure in any way. Those skilled in the art will readily recognize appropriate variations from the various compositions, structures, components, procedures, and methods.

[0202] experiment

[0203] The anti-inflammatory and anti-angiogenic activity of certain active agents disclosed herein was investigated. With the exception of 7-chloro-8-methyl-2-phenylquinoline-4-carboxylic acid (referred to herein as Y-0452), fenofibrate, GW409544, and GW590735, shown immediately below, none of the compounds described herein have been reported to have PPARα agonist activity prior to this study.

[0204] [ka]

[0205] A series of derivatives with some structural similarity to Y-0452 were evaluated for PPARα agonism. Compounds 9–14 and 21–24 were designed with the aim of filling the hydrophobic binding pocket of PPARα more efficiently.

[0206] 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 produced the respective imines in situ, which were then reduced by the addition of sodium triacetoxyborohydride to give 9–14 in unoptimized yields of 40–82%.

[0207] [ka]

[0208] To improve potency and establish selectivity for PPARα over other isoforms, it was necessary to incorporate the classic "head" of fenofibrate in addition to the benzoic acid derivatives 9–14. The preparation of these analogs is shown in Scheme 5. Commercially available 3-nitrophenol was coupled with ethyl α-bromoisobutyrate to give 15, which was reduced to the corresponding aniline (16) under catalytic hydrogenation conditions (H and Pd / C in ethanol). Treatment of 16 with 3a, 4a, 6a, or 8a, followed by reduction with sodium triacetoxyborohydride, afforded 17–20, respectively. Hydrolysis of the pendant ester afforded the desired products 21–24 in unoptimized yields of 46–88%.

[0209] [ka]

[0210] With a focused subset of analogs in hand, we moved on to assessing these derivatives for PPARα agonism. For preliminary evaluation, we utilized a commercially available PPARα luciferase cell reporter assay (Indigo Biosciences). The cell line used was engineered to constitutively express high levels of hPPARα. Upon interaction with an agonist, hPPARα translocates to the nucleus, binds to the PPRE, and upregulates gene transcription, including that of an inserted luciferase gene. Luciferase activity was indirectly detected by quantifying the production of oxyluciferin. Compounds 9-14 and 21-24 were first evaluated at 5 μM and 50 μM to capture agonism levels at two 10-fold increments. As shown in Figure 1, at one or both of the concentrations evaluated, many compounds demonstrated levels of hPPARα agonism comparable to or exceeding that of the positive control, GW590735 (5 μM and 10 μM). A direct comparison of 9 / 21, 10 / 22, 12 / 23, and 14 / 24 demonstrates that incorporating the fenofibrate "head" enhances the level of PPARα agonism at 50 μM. However, the data also demonstrate that incorporating the fenofibrate "head" reduces potency, as 21-24 elicit no appreciable activity at 5 μM, while benzoic acid analogs 9-14 all exhibit significant PPARα agonism at this low concentration. Compounds 10 and 22 were selected for further evaluation, and a more extensive 10-point dose-response assessment was performed to determine the EC 50 Values ​​were obtained (Table 4): 10 (5.6 μM) and 22 (25.3 μM).

[0211] To further confirm that this 4-benzyloxy-benzylamino species acts as a PPARα agonist, compound 10 was evaluated in various biochemical assays. As expected for a PPARα agonist, 10 induced PPARα expression in a dose-dependent manner, as demonstrated by Western blot analysis using a cell line derived from C57BL / 6N mouse photoreceptors (661W) (Figures 2A and 2B). Similarly, RT-PCR studies on the same cell line confirmed PPARα agonism by showing that treatment with 10 induced the expression of various PPARα target genes, including medium-chain acyl-CoA dehydrogenase (Acadm), carnitine palmitoyltransferase 1A (Cpt1a), fatty acid-binding protein 3 (Fabp3), and solute transporter family 25 member 20 (Slc25a20) (Figure 2C). Compound 10 was also evaluated in an in vitro wound-healing assay using human retinal capillary endothelial cells (HRCECs). PPARα agonism reduces cell migration, but 12 , 10 indeed inhibits wound closure in a dose-dependent manner (Figure 2D).

[0212] Given evidence that 4-benzyloxy-benzylamino derivatives exhibited distinctive PPARα agonist activity in multiple biochemical settings, we evaluated the selectivity of 10 for PPARα agonism relative to PPARδ and PPARγ. Luciferase assays, in which expression of an essential luciferase reporter gene depends on exogenous activation of each isoform, were performed on syngeneic cell lines engineered to overexpress either PPARδ or PPARγ. As shown in Table 4, compound 10 exhibits ≥20-fold selectivity for hPPARα relative to hPPARδ and hPPARγ, while 22 exhibits pan-agonism. This is intriguing because the fibrate "head" has been described as a key feature for PPARα selectivity, but appears to be detrimental in this 4-benzyloxy-benzylamino species.

[0213] [Table 4]

[0214] To better visualize the 4-benzyloxy-benzylamino derivative in the hPPARα binding pocket, we evaluated docking using the GW590735·hPPARα cocrystal structure, PDB2P54. GW590735 is a selective PPARα agonist that exhibits ≥500-fold selectivity for PPARα over PPARγ and PPARδ. Without wishing to be bound by theory, compound 10 is predicted to bind in a similar orientation to GW590735, as shown in Figures 3A and 3B. Interestingly, however, 10 lacks both the gem-dimethyl "head" and amide linker domains, both of which were previously hypothesized to be key determinants of the primary enhancer of GW590735's selectivity and potency. However, the acid in 10 is predicted to form four hydrogen bonds with Ser280, Tyr314, His440, and Tyr464, consistent with the notion that deconstruction of the quinoline core and rearrangement of the carboxylic acid in Y-0452 would result in significantly improved PPARα agonism. We were interested in whether this 4-benzyloxy-benzylamino species could be extended to exploit the apparent amphiphilic pocket located beneath GW590735 (Figure 3A) and consisting of Met330, Tyr334, Glu282, Thr279, Met320, Val324, Leu321, Ile317, and Met220. We hypothesized that functionalization of the meta position relative to the ether bond in the B ring of 10 (Schemes 5 and 6) would provide an optimal route to access this amphiphilic pocket. To our knowledge, only a few PPARα agonists utilize this pocket, and few SARs exist for the effects of occupying this domain at the level of agonism and / or isoform selectivity.

[0215] To explore the potential impact of occupying the amphiphilic pocket, two additional derivatives, 26 and 28, were synthesized (Scheme 6). Briefly, commercially available 2,4-dihydroxybenzaldehyde was treated with 4-methoxybenzaldehyde in acetone in the presence of potassium carbonate to produce di-p-methoxybenzyl (PMB)-functionalized resorcinol 25. This intermediate was coupled to either 3-aminobenzoic acid or 16, and the resulting imine was reduced to afford analogs 26 and 27, respectively. Saponification of 27 afforded the desired derivative 28 in 75% yield. The incorporation of the 4-methoxybenzyl motif as the "third arm" was somewhat arbitrary at this point, chosen based on the belief that the 4-methoxybenzyl motif was 1) compatible with the predicted binding environment and 2) readily accessible via dialkylation of aldehydes already in our chemical inventory.

[0216] [ka]

[0217] Derivatives 26 and 28 were evaluated for hPPARα agonist activity and selectivity in a luciferase cell line. Analysis of the data suggests that for the benzoic acid derivatives (compare 10 and 26), the additional 4-methoxybenzyl substituent does not affect potency and maintains selectivity, at least in the dose range evaluated. However, for derivatives containing the fibrate "head" (compare 22 and 28), adding a third substituent to the B ring improved potency by 10-fold while maintaining the pan-agonist profile. Both 26 and 28 were docked using our previously generated model, and as seen in Figure 3C, the additional 4-methoxybenzyl group is indeed predicted to fit into the amphipathic pocket.

[0218] Various non-limiting embodiments of compounds of the present disclosure and their cellular luciferase activity are shown in Tables 5-8. Chemical structure IIa (Tables 5 and 6) is a version of chemical structure II, where k=0. Chemical structure IIb (Tables 7 and 8) is a version of chemical structure IIa, where R 1 The group is in the para position of ring A.

[0219] [ka]

[0220] [Table 5-1]

[0221] [Table 5-2]

[0222] [Table 6-1]

[0223] [Table 6-2]

[0224] [ka]

[0225] [Table 7]

[0226] [Table 8]

[0227] The data in Tables 5-8 demonstrate that this species is active in a whole-cell setting and associates with the desired target, PPARα. Furthermore, the results demonstrate a clear structure-activity relationship, tunable levels of agonism, and a selectivity profile for PPARα relative to other isoforms of this species. The results shown in Figures 4-6 demonstrate that compound 91 (10) exhibits dose-dependent cell-based activity and >20-fold selectivity relative to other isoforms. The results shown in Figures 7-9 demonstrate that compound 190 exhibits dose-dependent cell-based activity and >2000-fold selectivity relative to other isoforms. This demonstrates that selectivity can be enhanced or maintained while improving the potency of this species.

[0228] The data in Figures 10A and 10B indicate that pharmacological activation of PPARα in humans has clinical benefit in reducing the prevalence of diabetic retinopathy, as reported in the FIELD and ACCORD studies. In Figures 10A and 10B, we demonstrate that compound 91 exhibits in vivo efficacy in the well-established STZ-rat model of diabetic retinopathy (DR). As shown in Figures 10A and 10B, compound 91 reduces retinal vascular leakage, a major cause of diabetic macular edema and resulting blindness, in diabetic rats. Interestingly, compound 91 appears to lack signs of hepatomegaly, a common side effect of fenofibrate that can confer dose-limiting toxicity. These initial results provide proof of concept that compound 91 (1) demonstrates in vivo efficacy in relevant DR models after systemic administration, (2) crosses the blood-ocular barrier to reach the retina, (3) is bioavailable, (4) survives metabolic first-pass and clearance mechanisms sufficiently to maintain efficacy, and (5) demonstrates a relatively safe profile (no observable toxicity) after one month of daily injections.

[0229] In at least certain embodiments of the present disclosure, the compounds have highly selective agonistic activity for PPARα compared to the isoforms PPARγ and PPARδ. For example, the PPARα agonistic activity may be 1000-fold, 2000-fold, or 2500-fold or more than the agonistic activity of the compound for either PPARγ or PPARδ. For example, compound 190 (A190) has been found to be particularly potent, with an EC of 37 nm. 50 and has a >2700-fold selectivity for PPARα compared to the isoforms PPARγ and PPARδ (EC 50 (PPARγ) / EC 50 (PPARα) or EC 50 (PPARδ) / EC 50 (calculated as PPARα).

[0230] Table 9 shows several compounds of the present disclosure (particular embodiments of chemical structure II) and their activity, including PPARα activity.

[0231] [Table 9]

[0232] In conclusion, in at least certain embodiments, the present disclosure provides a compound having chemical structure III:

[0233] [ka] and salts and isomers thereof, wherein (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; and (4) R 1 is selected from phosphates and phosphonates; (5) R 2is selected from CH3, hydrogen (H), chlorine (Cl), fluorine (F), bromine (Br), iodine (I), nitro (NO2), CH2CH3, a branched or unbranched alkyl chain containing 3 to 10 carbon atoms, OCH3, OCH2CH3, a branched or unbranched alkoxy chain containing 3 to 10 carbon atoms, haloalkyl, haloalkoxyl, cycloalkyl, halocycloalkyl, O-para-alkylbenzyl, O-para-alkyloxybenzyl, and O-para-halobenzyl; R 2 The benzene ring containing 2 The R may be substituted with any combination of substituents and arranged on the ring in any pattern, including ortho, meta, mono, di, tri, and tetra substitution. 2 (6) R 3 is selected from F, H, Cl, Br, I, NO2, CH3, CH2CH3, a branched or unbranched alkyl chain containing 3 to 10 carbon atoms, OCH3, OCH2CH3, a branched or unbranched alkoxy chain containing 3 to 10 carbon atoms, haloalkyl, haloalkoxyl, cycloalkyl, halocycloalkyl, O-para-alkylbenzyl, O-para-alkyloxybenzyl, and O-para-halobenzyl; R 3 The benzene ring containing 3 The R may be substituted with any combination of substituents and arranged on the ring in any pattern, including ortho, meta, para, mono, di, tri, tetra, and penta substitution. 3 (7) R 4 is selected from H, alkyl, and acyl; (8) R 5 is selected from H, Cl, F, Br, I, NO2, CH3, CH2CH3, a branched or unbranched alkyl chain containing 3 to 10 carbon atoms, OCH3, OCH2CH3, a branched or unbranched alkoxy chain containing 3 to 10 carbon atoms, haloalkyl, haloalkoxyl, cycloalkyl, halocycloalkyl, O-para-alkylbenzyl, O-para-alkyloxybenzyl, and O-para-halobenzyl; R 5 The benzene ring containing 5The R may be substituted with any combination of substituents and arranged on the ring in any pattern, including ortho, meta, para, mono, di, tri, and tetra substitution. 5 R relates to compounds containing 1, 2, 3 or 4 of the substituents, which have PPARα agonist activity. 1 The chemical structure:

[0234] [ka] (In the formula, 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 heterocyclyl, unsubstituted heterocyclyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted amine, and unsubstituted amine. 1 The chemical structure:

[0235] [ka] (In the formula, 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 heterocyclyl, unsubstituted heterocyclyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted amine, and unsubstituted amine.

[0236] The PPARα agonist activity of the compound may be at least 1,000 times greater than the PPARγ agonist activity or PPARδ agonist activity of the compound. One or more of the compounds may be formulated in a pharmaceutically acceptable carrier, vehicle, or diluent to form a composition. The composition may be formulated to provide delayed, controlled, sustained, and / or sustained release of one or more compounds. The compound or composition may be a component of a kit. The kit may include instructions for its use in treating a disorder or condition in a subject. The disorder or condition that the kit can be used to treat may be an ophthalmic disorder or condition 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.

[0237] In at least certain embodiments, the present disclosure relates to a method for increasing PPARα activity in retinal cells by administering to the retinal cells a PPARα activity-enhancing amount of the above-described compound or composition. In at least certain embodiments, the present disclosure relates to a method for treating a disorder or condition in a subject by causing increased peroxisome proliferator-activated receptor α (PPARα) activity by administering a therapeutic amount of the above-described compound or composition to a subject in need of treatment for the disorder or condition. The compound may be provided in a composition formulated to provide delayed, controlled, sustained, and / or extended 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 ophthalmic 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.

[0238] Although the present disclosure has been described herein with reference to certain specific embodiments so that its aspects may be more fully understood and appreciated, the present disclosure is not limited to these specific embodiments. Instead, all alternatives, modifications, and equivalents are intended to be included within the scope of the present disclosure as defined herein. Accordingly, it is understood that the above examples, including specific embodiments, serve to illustrate the implementation of the inventive concepts of the present disclosure, and that the details shown are by way of example and are presented solely for illustrative purposes of specific embodiments, and further to provide what is believed to be the most useful and readily understood description of the procedures and principles and conceptual aspects of the present disclosure. Changes may be made in the formulation 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. Furthermore, while various embodiments of the present disclosure are set forth in the following claims, the present disclosure is not limited to these specific claims.

Claims

1. Chemical structure III: 【Chemistry 1】 and salts and isomers thereof, 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 is selected from the group of phosphates and phosphonates, R ２ is CH ３ , hydrogen (H), chlorine (Cl), fluorine (F), bromine (Br), iodine (I), nitro (NO ２ ), C.H. ２ CH ３ , a branched or unbranched alkyl chain containing 3 to 10 carbon atoms, OCH ３ , OCH ２ CH ３ , a branched or unbranched alkoxy chain containing 3 to 10 carbon atoms, haloalkyl, haloalkoxyl, cycloalkyl, halocycloalkyl, O-para-alkylbenzyl, O-para-alkyloxybenzyl and O-para-halobenzyl; R ２ The benzene ring containing ２ The R groups may be substituted with any combination of substituents and arranged on the ring in any pattern, including ortho, meta, mono, di, tri, and tetra substitution. ２ containing 1, 2, 3 or 4 of the substituents; R ３ are F, H, Cl, Br, I, NO ２ , C.H. ３ , C.H. ２ CH ３ , a branched or unbranched alkyl chain containing 3 to 10 carbon atoms, OCH ３ , OCH ２ CH ３ , a branched or unbranched alkoxy chain containing 3 to 10 carbon atoms, haloalkyl, haloalkoxyl, cycloalkyl, halocycloalkyl, O-para-alkylbenzyl, O-para-alkyloxybenzyl and O-para-halobenzyl; R ３ The benzene ring containing ３ The R groups may be substituted with any combination of substituents and arranged on the ring in any pattern, including ortho, meta, para, mono, di, tri, tetra, and penta substitution. ３ containing 1, 2, 3, 4 or 5 of the substituents; R ４ is selected from the group of H, alkyl and acyl; R ５ are H, Cl, F, Br, I, NO ２ , C.H. ３ , C.H. ２ CH ３ , a branched or unbranched alkyl chain containing 3 to 10 carbon atoms, OCH ３ , OCH ２ CH ３ , a branched or unbranched alkoxy chain containing 3 to 10 carbon atoms, haloalkyl, haloalkoxyl, cycloalkyl, halocycloalkyl, O-para-alkylbenzyl, O-para-alkyloxybenzyl and O-para-halobenzyl; R ５ The benzene ring containing ５ The R groups may be substituted with any combination of substituents and arranged on the ring in any pattern, including ortho, meta, para, mono, di, tri, and tetra substitutions. ５ containing 1, 2, 3 or 4 of the substituents A compound comprising:

2. R １ But the chemical structure: 【Chemistry 2】 (In the formula, 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 heterocyclyl, unsubstituted heterocyclyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted amine, and unsubstituted amine.

3. R １ But the chemical structure: 【Transformation 3】 (In the formula, 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 heterocyclyl, unsubstituted heterocyclyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted amine, and unsubstituted amine.

4. 2. The compound of claim 1, having a PPARα agonist activity that is at least 1,000 times greater than the PPARγ or PPARδ agonist activity of said compound.

5. 10. A composition comprising one or more compounds of claim 1 formulated in a pharmaceutically acceptable carrier, vehicle or diluent.

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

7. 10. A kit comprising the composition of claim 5 and instructions for its use in treating a disorder or condition in a subject.

8. 8. The kit of 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. 10. A method for increasing peroxisome proliferator-activated receptor alpha (PPARα) activity in retinal cells, comprising administering to the retinal cells a PPARα activity-enhancing amount of a compound of claim 1.

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

11. 11. The method of 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. 11. The method of claim 10, wherein the disorder or condition is characterized by inflammation and / or angiogenesis.

13. 11. The method of claim 10, wherein the disorder 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. 11. The method of claim 10, wherein the disorder or condition is 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.

15. 11. The method of claim 10, wherein the disorder or condition 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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