EP4771004A1 - Macrolide-nox4 conjugates and uses thereof - Google Patents

Abstract

The present disclosure relates to compounds, compositions, and methods for inhibiting Nox4 signaling. Also described are methods of treating fibrotic disorders (e.g., pulmonary fibrosis, heart fibrosis, kidney fibrosis, liver fibrosis, skin fibrosis, mediastinal fibrosis, retroperitoneal cavity fibrosis, bone marrow fibrosis, scleroderma or systemic sclerosis), acute respiratory distress syndrome (ARDS) or for treating cancer (e.g., a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, plasma cell neoplasm (myeloma)) using the disclosed compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present disclosure.

Description

MACROLIDE-NOX4 CONJUGATES AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This Application claims the benefit of U.S. Application No.63/535,218, filed on August 29, 2023, the contents of which are incorporated herein by reference in their entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH [0002] This invention was made with government support under grant number W81XWH-17-1- 0443 awarded by the Department of Defense. The government has certain rights in the invention. BACKGROUND [0003] The regulation of redox homeostasis is crucial for the maintenance of normal cellular growth, metabolism, and survival. Oxidative stress is defined as the imbalance between the production of reactive oxygen species (ROS) and the capability of the cell to elicit an effective antioxidant response. Several sources of ROS in cells and tissue have been identified, including mitochondrial electron transfer chain (Liu et al. (2002) J. Neurochem.80(5): 780-787) and NADPH oxidase (NOX) enzymes (Bedhard and Krause (2007) Physiol. Rev.87(1): 245-313). NOX-derived ROS have been identified as the main source of oxidative stress, which promotes key events in the development of fibrotic diseases (such as skin fibrosis (Babalola et al. (2014) Arch. Dermatol. Res.306(4): 313-330), idiopathic pulmonary fibrosis (IPF) (Hecker et al. (2012) Cell Mol. Life Sci.69(14): 2365-2371), liver fibrosis (Minicis and Brenner (2007) Arch. Biochem. Biophys.462(2): 266-272), and kidney fibrosis (Holterman et al. (2015) Clin. Sci. (Lond.) 128(8): 465-481), and acute respiratory distress syndrome (ARDS) (Kellner et al. (2017) Pulmonary Vasculature Redox Signaling in Health and Disease 967: 105-137), as well as the initiation and progression of cancer (Roy et al. (2015) Clinical Sci. (Lond.) 128(12): 863-875). [0004] Fibrosis is a complex disease characterized by excessive synthesis and accumulation of extracellular matrices that occur as a result of activation and proliferation of fibroblasts and myofibroblasts. Notably, nearly 45% of all naturally-occurring deaths in the western world are attributed to some form of fibrotic disease (Bitterman and Henke (1991) Chest 99(3 Suppl): 81s- 84s). Briefly, the presence of ROS is believed to activate transforming growth factor beta (TGF- β) signaling pathways, then induces elevated production of NOX4-generated ROS (Chen et al. (2013) Biochem. Biophys. Res. Commun.430(3): 918-925). The presence of NOX4-generated ROS, in turn, activates various pathways that ultimately lead to fibrosis. Indeed, NOX4 mRNA expression has been found to be upregulated in both pulmonary fibroblasts isolated from IPF patients (Amara et al. (2010) Thorax 65(8): 733-738) and skin fibroblasts from scleroderma patients (Spadoni et al. (2015) Arthritis Rheumatol.67(6): 1611-1622), as well as in a number of in vivo fibrosis models, including liver fibrosis (Aoyama et al. (2012) Hepatology (Baltimore Md.) 56(6): 2316-2327), pulmonary fibrosis (Jarman et al. (2014) Am. J. Respir. Cell Mol. Biol. 50(1): 158-169; Hecker et al. (2009) Nat. Med.15 (9): 1077-1081), and diabetic neuropathy (kidney fibrosis associated with diabetes mellitus) (Sedeek et al. (2010) Am. J. Physiol. – Renal Physiol.299(6): F1348-F1358). In view of such research, suppression of NOX4 activity (by, for example, a NOX4 inhibitor) has been investigated as a possible route for treating fibrotic disorders. See, e.g., U.S. Patent No.10,654,802. [0005] High expression of NOX4 has also been detected in several cancer types including gliomas (Shono et al. (2008) Int. J. Cancer 123(4): 787-792), melanoma (Yamaura et al. (2009) Cancer Res.69(6): 2647-2654), breast cancer (Graham et al. (2010) Cancer Biol. Ther.10(3): 223-231), ovarian cancer (Graham et al. (2010) Cancer Biol. Ther.10(3): 223-231), and pancreatic cancer (Hiraga et al. (2013) Anticancer Res.33(10): 4431-4438). In cancer cell lines, elevated levels of NOX4 are associated with PI3K/Akt-regulated cell proliferation and invasion (Zhang et al. (2014) Oncotarget 5(12): 4392-4405), TGF-β/SMAD3-driven EMT and cell migration (Boudreau et al. (2012) Free Radic. Biol. Med.53(7): 1489-1499), as well as Tks5- dependent invadopodia formation (Diaz et al. (2009) Sci. Signal.2(88): ra53). Depletion of NOX4 with siRNA treatment significantly reduced tumor growth in the in vivo models of bladder cancer (Shimada et al. (2011) BMC Urol.11(1): 1-12), renal cancer (Gregg et al. (2014) Cancer Res.74(13): 3501-3511), and glioblastoma (Hsieh et al. (2011) PLoS One 6(9): e23945). Without wishing to be bound by theory, these results suggest that NOX4 is a potential target for pharmacological intervention for cancer treatment. [0006] ARDS is a critical syndrome caused by heterogeneous pathologic factors and characterized by acute development of respiratory failure, bilateral diffuse lung infiltrations, and severe hypoxemia. See, e.g., Kellner et al. (2017) Pulmonary Vasculature Redox Signaling in Health and Disease 967: 105-137. The severity of ARDS is associated with poor prognosis and higher mortality. Id. Moreover, the recent global COVID-19 pandemic has attenuated the urgent need to address ARDS, as this syndrome is the leading cause of death among COVI-19 patients (Wu C, et al. (2020) JAMA Intern Med.180(7):934-943). Critical pathological features of ARDS (e.g., loss of lung endothelial barrier integrity and inflammatory injury) are strongly associated with increased oxidative stress; however, clinical trials using antioxidant treatments have failed to reduce mortality in ARDS patients. [0007] Importantly, no cure for most of these diseases has yet been identified. Current approaches to treating fibrotic diseases, for example, have thus far remained limited to attempts at slowing down disease progression (e.g., via administration of pirfenidone for pulmonary fibrosis). For cancer, there are several treatment options, including chemotherapy, surgery, radiation, immunotherapy, and others. Although cures can be achieved in some cases (e.g., by early diagnosis), resistance and recurrence are common. Moreover, current treatment options remain plagued by the risk of off-target toxicities resulting from systemic exposure. Thus, new treatments are desired, and, ideally, those that are enriched or that preferentially accumulate at disease sites to elicit targeted inhibition of NOX4. Accordingly, there exists a need for targeted NOX4 inhibitors for use in the treatment of fibrotic disorders, ARDS, and cancer. SUMMARY [0008] In accordance with the purpose(s) of the invention, as embodied and broadly described herein, the invention, in one aspect, relates to compounds, compositions, and methods for inhibiting Nox4 signaling. The disclosed compounds and compositions can be useful in, for example, the treatment of fibrotic disorders (e.g., pulmonary fibrosis, heart fibrosis, kidney fibrosis, liver fibrosis, skin fibrosis, mediastinal fibrosis, retroperitoneal cavity fibrosis, bone marrow fibrosis, scleroderma or systemic sclerosis), acute respiratory distress syndrome (ARDS) or for treating cancer (e.g., a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, plasma cell neoplasm (myeloma)). [0009] Thus, disclosed are compounds having a structure represented by a formula: , wherein n is selected from 0, 1, 2, 3, 4, and 5, and wherein m is selected from 0 and 1, provided that when n is 0 then m is 0; wherein o is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8; wherein A¹ is selected from ‒O‒ and ‒CH₂‒, provided that when A¹ is O, then o is not 0 or 1; wherein L¹ is selected from C2 alkenyl, C2 alkynyl, ‒NHSO₂‒, ‒SO₂NH‒, ‒NHC(O)‒, ‒C(O)NH‒, and Ar⁵; wherein Ar⁵, when present, is a C2-C9 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R^1a, R^1b, R^1c, and R^1d is independently selected from hydrogen, halogen, ‒CN, ‒NH₂, ‒OH, and ‒NO₂; wherein R² is selected from hydrogen and C1-C4 alkyl; wherein one of R^3a and R^3b is C1-C4 alkyl and one of R^3a and R^3b is a structure selected from: ^; wherein R¹³ is selected from hydrogen and ‒OH; and wherein Ar¹ is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof. [0010] Also disclosed are compounds having a structure represented by a formula: , wherein r is selected from 1, 2, 3, 4, 5, 6, 7, and 8; wherein one of R^3a and R^3b is C1-C4 alkyl and one of R^3a and R^3b is a structure selected from: ^; wherein R¹³ is selected from hydrogen and ‒OH; wherein each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and wherein R¹⁰ is selected from hydrogen and a structure: ; wherein s is selected from 0 and 1; wherein A² is selected from ‒C(O)‒ and ‒SO₂‒; wherein L² is ‒(CR^11aR^11b)2‒; wherein each occurrence of R^11a and R^11b is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl, or wherein each of R^11a and R^11b together comprise =O; wherein R⁵, when present, is selected from hydrogen and C1-C4 alkyl; wherein R⁶ is selected from ‒NR^12aR^12b and Ar²; wherein R^12a is selected from hydrogen, C1-C4 alkyl, and Ar³; wherein Ar³ is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and wherein R^12b is selected from C1-C4 alkyl, ‒CH₂Ar⁴, and Ar⁴; wherein Ar⁴ is selected from C6- C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or wherein each of R^12a and R^12b together comprise a C2-C5 heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein Ar² is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒C(O)NH₂, ‒NHC(O)(C1-C4 alkyl), Cy¹, ‒OCy¹, and ‒NH(CH₂)_tCy¹; wherein t is selected from 0, 1, and 2; and wherein Cy¹ is selected from C3- C6 cycloalkyl, C3-C6 heterocycloalkyl, C6-C14 aryl, and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof. [0011] Also disclosed are pharmaceutical compositions comprising an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [0012] Also disclosed are methods of inhibiting NADPH Oxidase 4 (NOX4) signaling in a cell, the method comprising contacting the cell with an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof. [0013] Also disclosed are methods of inhibiting NADPH Oxidase 4 (NOX4) signaling in a subject in need thereof, the method comprising administering to the subject an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof. [0014] Also disclosed are methods of treating a fibrotic disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof. [0015] Also disclosed are methods of treating acute respiratory distress syndrome (ARDS) in a subject in need thereof, the method comprising administering to the subject an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof. [0016] Also disclosed are methods of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof. [0017] Also disclosed are kits comprising a disclosed compound or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an anti-fibrotic agent; (b) instructions for treating a fibrotic disorder; (c) an agent known to treat ARDS; (d) instructions for treating ARDS; (e) an agent known to treat cancer; and (f) instructions for treating cancer. [0018] While aspects of the present invention can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present invention can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification. BRIEF DESCRIPTION OF THE FIGURES [0019] The accompanying figures, which are incorporated in and constitute a part of this specification, illustrate several aspects and together with the description serve to explain the principles of the invention. [0020] FIG.1A and FIG.1B show a representative diagram illustrating a 2-hit preclinical aging muring model of severe ARDS and representative data comparing lung injury scores for young and aged mice, respectively. [0021] FIG.2A and FIG.2B show representative data illustrating that senescent ECs exhibit impaired barrier-regulatory responses. [0022] FIG.3A and FIG.3B show representative data illustrating that redox imbalance in senescent ECs corresponds with elevated Nox4 levels. [0023] FIG.4 shows representative data illustrating that age-dependent severe pre-clinical ARDS is associated with sustained Nox4 levels and excessive ROS production. [0024] FIG.5A and FIG.5B show representative data illustrating APX-115, Setanaxib, and GLX failed false-positive screening. [0025] FIG.6A-F show representative data illustrating that aged Nox4-eKO mice demonstrate striking protection from ALI. [0026] FIG.7A-D show representative data pertaining to the identification of novel Nox4 inhibitors. [0027] FIG.8A and FIG.8B show representative data illustrating that Nox4 inhibitors reverse established pro-fibrotic phenotypes in human IPF lung myofibroblasts. [0028] FIG.9A-G show representative data illustrating that Nox4 inhibitors protect from pre- clinical ARDS. [0029] FIG.10 shows representative structures of Nox4 inhibitors for IV delivery. [0030] FIG.11A and FIG.11B show a representative lung-targeted linker attached to a Nox4 inhibitor and predicted docking in Nox4 active site, respectively. [0031] FIG.12A and FIG.12B show representative data illustrating IC50 and ROS generation evaluation of compound 13 versus parent Nox4 inhibitors or macrolide alone. [0032] FIG.13A-C show representative data demonstrating elevated concentrations of lung targeting Nox4 inhibitor within the lung in vivo versus the parent Nox4 inhibitor. [0033] FIG.14A and FIG.14B show representative diagrams of the efficacy testing protocols. [0034] FIG.15 shows representative data illustrating BAL cell evaluation of lung targeting Nox4 inhibitor versus parent Nox4 inhibitor. [0035] FIG.16A and FIG.16B show representative data demonstrating reduced concentrations of lung targeting Nox4 inhibitor administered by IV versus the parent Nox4 inhibitor in systemic plasma when administered by IV delivery. [0036] FIG.17A-D show representative data demonstrating that lung targeting Nox4 inhibitor (LT-Nox4i-1) passed false-positive screening assays.. [0037] Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or can be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. DETAILED DESCRIPTION [0038] The present invention can be understood more readily by reference to the following detailed description of the invention and the Examples included therein. [0039] Before the present compounds, compositions, articles, systems, devices, and/or methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described. [0040] While aspects of this disclosure can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of this disclosure can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or description that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification. [0041] Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon. Nothing herein is to be construed as an admission that the present application is not entitled to antedate such publication by virtue of prior invention. Further, stated publication dates may be different from actual publication dates, which can require independent confirmation. A. DEFINITIONS [0042] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a functional group,” “an alkyl,” or “a residue” includes mixtures of two or more such functional groups, alkyls, or residues, and the like. [0043] As used in the specification and in the claims, the term “comprising” can include the aspects “consisting of” and “consisting essentially of.” [0044] Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed. [0045] As used herein, the terms “about” and “at or about” mean that the amount or value in question can be the value designated some other value approximately or about the same. It is generally understood, as used herein, that it is the nominal value indicated ±10% variation unless otherwise indicated or inferred. The term is intended to convey that similar values promote equivalent results or effects recited in the claims. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but can be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about” or “approximate” whether or not expressly stated to be such. It is understood that where “about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise. [0046] References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound. [0047] A weight percent (wt. %) of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included. [0048] As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. [0049] As used herein, the term “subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non- human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one aspect, the subject is a mammal. A patient refers to a subject afflicted with a disease or disorder. The term “patient” includes human and veterinary subjects. [0050] As used herein, the term “treatment” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. In various aspects, the term covers any treatment of a subject, including a mammal (e.g., a human), and includes: (i) preventing the disease from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i.e., arresting its development; or (iii) relieving the disease, i.e., causing regression of the disease. In one aspect, the subject is a mammal such as a primate, and, in a further aspect, the subject is a human. The term “subject” also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.). [0051] As used herein, the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed. [0052] As used herein, the term “diagnosed” means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein. [0053] As used herein, the terms “administering” and “administration” refer to any method of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition. [0054] As used herein, the terms “effective amount” and “amount effective” refer to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition. For example, a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a “prophylactically effective amount”; that is, an amount effective for prevention of a disease or condition. [0055] As used herein, “dosage form” means a pharmacologically active material in a medium, carrier, vehicle, or device suitable for administration to a subject. A dosage form can comprise a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, in combination with a pharmaceutically acceptable excipient, such as a preservative, buffer, saline, or phosphate buffered saline. Dosage forms can be made using conventional pharmaceutical manufacturing and compounding techniques. Dosage forms can comprise inorganic or organic buffers (e.g., sodium or potassium salts of phosphate, carbonate, acetate, or citrate) and pH adjustment agents (e.g., hydrochloric acid, sodium or potassium hydroxide, salts of citrate or acetate, amino acids and their salts) antioxidants (e.g., ascorbic acid, alpha- tocopherol), surfactants (e.g., polysorbate 20, polysorbate 80, polyoxyethylene9-10 nonyl phenol, sodium desoxycholate), solution and/or cryo/lyo stabilizers (e.g., sucrose, lactose, mannitol, trehalose), osmotic adjustment agents (e.g., salts or sugars), antibacterial agents (e.g., benzoic acid, phenol, gentamicin), antifoaming agents (e.g., polydimethylsilozone), preservatives (e.g., thimerosal, 2-phenoxyethanol, EDTA), polymeric stabilizers and viscosity-adjustment agents (e.g., polyvinylpyrrolidone, poloxamer 488, carboxymethylcellulose) and co-solvents (e.g., glycerol, polyethylene glycol, ethanol). A dosage form formulated for injectable use can have a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, suspended in sterile saline solution for injection together with a preservative. [0056] As used herein, “kit” means a collection of at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose. Individual member components may be physically packaged together or separately. For example, a kit comprising an instruction for using the kit may or may not physically include the instruction with other individual member components. Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation. [0057] As used herein, “instruction(s)” means documents describing relevant materials or methodologies pertaining to a kit. These materials may include any combination of the following: background information, list of components and their availability information (purchase information, etc.), brief or detailed protocols for using the kit, trouble-shooting, references, technical support, and any other related documents. Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation. Instructions can comprise one or multiple documents, and are meant to include future updates. [0058] As used herein, the terms “therapeutic agent” include any synthetic or naturally occurring biologically active compound or composition of matter which, when administered to an organism (human or nonhuman animal), induces a desired pharmacologic, immunogenic, and/or physiologic effect by local and/or systemic action. The term therefore encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like. Examples of therapeutic agents are described in well-known literature references such as the Merck Index (14^th edition), the Physicians' Desk Reference (64^th edition), and The Pharmacological Basis of Therapeutics (12^th edition) , and they include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment. For example, the term “therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants; anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations, anorexics, anti-inflammatory agents, anti-epileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antinauseants, antineoplastics, antipruritics, antipyretics; antispasmodics, cardiovascular preparations (including calcium channel blockers, beta-blockers, beta-agonists and antiarrythmics), antihypertensives, diuretics, vasodilators; central nervous system stimulants; cough and cold preparations; decongestants; diagnostics; hormones; bone growth stimulants and bone resorption inhibitors; immunosuppressives; muscle relaxants; psychostimulants; sedatives; tranquilizers; proteins, peptides, and fragments thereof (whether naturally occurring, chemically synthesized or recombinantly produced); and nucleic acid molecules (polymeric forms of two or more nucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA) including both double- and single-stranded molecules, gene constructs, expression vectors, antisense molecules and the like), small molecules (e.g., doxorubicin) and other biologically active macromolecules such as, for example, proteins and enzymes. The agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas. The term "therapeutic agent" also includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or pro- drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment. [0059] The term “pharmaceutically acceptable” describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner. [0060] As used herein, the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound. [0061] As used herein, the term “pharmaceutically acceptable carrier” refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use. Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers. [0062] A residue of a chemical species, as used in the specification and concluding claims, refers to the moiety that is the resulting product of the chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the moiety is actually obtained from the chemical species. Thus, an ethylene glycol residue in a polyester refers to one or more -OCH₂CH₂O- units in the polyester, regardless of whether ethylene glycol was used to prepare the polyester. Similarly, a sebacic acid residue in a polyester refers to one or more - CO(CH₂)8CO- moieties in the polyester, regardless of whether the residue is obtained by reacting sebacic acid or an ester thereof to obtain the polyester. [0063] As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms, such as nitrogen, can have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. Also, the terms “substitution” or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. It is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted). [0064] In defining various terms, “A¹,” “A²,” “A³,” and “A⁴” are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents. [0065] The term “aliphatic” or “aliphatic group,” as used herein, denotes a hydrocarbon moiety that may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridging, and spirofused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1- 20 carbon atoms. Aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. [0066] The term “alkyl” as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t- butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkyl group can be cyclic or acyclic. The alkyl group can be branched or unbranched. The alkyl group can also be substituted or unsubstituted. For example, the alkyl group can be substituted with one or more groups including, but not limited to, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo- oxo, or thiol, as described herein. A “lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms. The term alkyl group can also be a C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the like up to and including a C1-C24 alkyl. [0067] Throughout the specification “alkyl” is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group. For example, the term “halogenated alkyl” or “haloalkyl” specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine. Alternatively, the term “monohaloalkyl” specifically refers to an alkyl group that is substituted with a single halide, e.g. fluorine, chlorine, bromine, or iodine. The term “polyhaloalkyl” specifically refers to an alkyl group that is independently substituted with two or more halides, i.e. each halide substituent need not be the same halide as another halide substituent, nor do the multiple instances of a halide substituent need to be on the same carbon. The term “alkoxyalkyl” specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below. The term “aminoalkyl” specifically refers to an alkyl group that is substituted with one or more amino groups. The term “hydroxyalkyl” specifically refers to an alkyl group that is substituted with one or more hydroxy groups. When “alkyl” is used in one instance and a specific term such as “hydroxyalkyl” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “hydroxyalkyl” and the like. [0068] This practice is also used for other groups described herein. That is, while a term such as “cycloalkyl” refers to both unsubstituted and substituted cycloalkyl moieties, the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an “alkylcycloalkyl.” Similarly, a substituted alkoxy can be specifically referred to as, e.g., a “halogenated alkoxy,” a particular substituted alkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, the practice of using a general term, such as “cycloalkyl,” and a specific term, such as “alkylcycloalkyl,” is not meant to imply that the general term does not also include the specific term. [0069] The term “cycloalkyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. The term “heterocycloalkyl” is a type of cycloalkyl group as defined above, and is included within the meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted. For example, the cycloalkyl group and heterocycloalkyl group can be substituted with 0, 1, 2, 3, or 4 groups independently selected from C1-C4 alkyl, C3-C7 cycloalkyl, C1-C4 alkoxy, −NH₂, (C1-C4) alkylamino, (C1-C4)(C1-C4) dialkylamino, ether, halogen, −OH, C1-C4 hydroxyalkyl, −NO₂, silyl, sulfo-oxo, −SH, and C1-C4 thioalkyl, as described herein. [0070] The term “polyalkylene group” as used herein is a group having two or more CH₂ groups linked to one another. The polyalkylene group can be represented by the formula —(CH₂)_a—, where “a” is an integer of from 2 to 500. [0071] The terms “alkoxy” and “alkoxyl” as used herein to refer to an alkyl or cycloalkyl group bonded through an ether linkage; that is, an “alkoxy” group can be defined as —OA¹ where A¹ is alkyl or cycloalkyl as defined above. “Alkoxy” also includes polymers of alkoxy groups as just described; that is, an alkoxy can be a polyether such as —OA¹—OA² or —OA¹—(OA²)a—OA³, where “a” is an integer of from 1 to 200 and A¹, A², and A³ are alkyl and/or cycloalkyl groups. [0072] The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond. Asymmetric structures such as (A¹A²)C=C(A³A⁴) are intended to include both the E and Z isomers. This can be presumed in structural formulae herein wherein an asymmetric alkene is present, or it can be explicitly indicated by the bond symbol C=C. The alkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein. [0073] The term “cycloalkenyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one carbon-carbon double bound, i.e., C=C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like. The term “heterocycloalkenyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted. For example, the cycloalkenyl group and heterocycloalkenyl group can be substituted with 0, 1, 2, 3, or 4 groups independently selected from C1-C4 alkyl, C3-C7 cycloalkyl, C1-C4 alkoxy, C2-C4 alkenyl, C3-C6 cycloalkenyl, C2-C4 alkynyl, aryl, heteroaryl, aldehyde, −NH₂, (C1-C4) alkylamino, (C1-C4)(C1-C4) dialkylamino, carboxylic acid, ester, ether, halogen, −OH, C1-C4 hydroxyalkyl, ketone, azide, −NO₂, silyl, sulfo-oxo, −SH, and C1-C4 thioalkyl, as described herein. [0074] The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond. The alkynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein. [0075] The term “cycloalkynyl” as used herein is a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon triple bound. Examples of cycloalkynyl groups include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and the like. The term “heterocycloalkynyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkynyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkynyl group and heterocycloalkynyl group can be substituted or unsubstituted. The cycloalkynyl group and heterocycloalkynyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. [0076] The term “aromatic group” as used herein refers to a ring structure having cyclic clouds of delocalized π electrons above and below the plane of the molecule, where the π clouds contain (4n+2) π electrons. A further discussion of aromaticity is found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled “Aromaticity,” pages 477-497, incorporated herein by reference. The term “aromatic group” is inclusive of both aryl and heteroaryl groups. [0077] The term “aryl” as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like. The aryl group can be substituted or unsubstituted. The aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, ─NH₂, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term “biaryl” is a specific type of aryl group and is included in the definition of “aryl.” In addition, the aryl group can be a single ring structure or comprise multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carbon-carbon bond. For example, biaryl can be two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl. [0078] The term “aldehyde” as used herein is represented by the formula —C(O)H. Throughout this specification “C(O)” or “CO” is a short hand notation for a carbonyl group, i.e., C=O. [0079] The terms “amine” or “amino” as used herein are represented by the formula —NA¹A², where A¹ and A² can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. A specific example of amino is ─NH₂. [0080] The term “alkylamino” as used herein is represented by the formula —NH(-alkyl) where alkyl is a described herein. Representative examples include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, (tert-butyl)amino group, pentylamino group, isopentylamino group, (tert-pentyl)amino group, hexylamino group, and the like. [0081] The term “dialkylamino” as used herein is represented by the formula —N(-alkyl)2 where alkyl is a described herein. Representative examples include, but are not limited to, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group, di(tert-pentyl)amino group, dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, N-ethyl-N-propylamino group and the like. [0082] The term “carboxylic acid” as used herein is represented by the formula —C(O)OH. [0083] The term “ester” as used herein is represented by the formula —OC(O)A¹ or —C(O)OA¹, where A¹ can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “polyester” as used herein is represented by the formula —(A¹O(O)C-A²-C(O)O)_a— or —(A¹O(O)C-A²-OC(O))_a—, where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer from 1 to 500. “Polyester” is as the term used to describe a group that is produced by the reaction between a compound having at least two carboxylic acid groups with a compound having at least two hydroxyl groups. [0084] The term “ether” as used herein is represented by the formula A¹OA², where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein. The term “polyether” as used herein is represented by the formula —(A¹O-A²O)_a—, where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer of from 1 to 500. Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide. [0085] The terms “halo,” “halogen,” or “halide,” as used herein can be used interchangeably and refer to F, Cl, Br, or I. [0086] The terms “pseudohalide,” “pseudohalogen,” or “pseudohalo,” as used herein can be used interchangeably and refer to functional groups that behave substantially similar to halides. Such functional groups include, by way of example, cyano, thiocyanato, azido, trifluoromethyl, trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups. [0087] The term “heteroalkyl,” as used herein refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyls can be substituted as defined above for alkyl groups. [0088] The term “heteroaryl,” as used herein refers to an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions. The heteroaryl group can be substituted or unsubstituted. The heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein. Heteroaryl groups can be monocyclic, or alternatively fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. Further not limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl. [0089] The terms “heterocycle” or “heterocyclyl,” as used herein can be used interchangeably and refer to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon. Thus, the term is inclusive of, but not limited to, “heterocycloalkyl”, “heteroaryl”, “bicyclic heterocycle” and “polycyclic heterocycle.” Heterocycle includes pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1,2,3-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including, 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4- thiadiazole, triazole, including, 1,2,3-triazole, 1,3,4-triazole, tetrazole, including 1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine, including 1,2,4-triazine and 1,3,5-triazine, tetrazine, including 1,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like. The term heterocyclyl group can also be a C2 heterocyclyl, C2-C3 heterocyclyl, C2-C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like up to and including a C2-C18 heterocyclyl. For example, a C2 heterocyclyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl, oxiranyl, thiiranyl, and the like. Alternatively, for example, a C5 heterocyclyl comprises a group, which has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and the like. It is understood that a heterocyclyl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heterocyclyl ring. [0090] The term “bicyclic heterocycle” or “bicyclic heterocyclyl,” as used herein refers to a ring system in which at least one of the ring members is other than carbon. Bicyclic heterocyclyl encompasses ring systems wherein an aromatic ring is fused with another aromatic ring, or wherein an aromatic ring is fused with a non-aromatic ring. Bicyclic heterocyclyl encompasses ring systems wherein a benzene ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms or wherein a pyridine ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms. Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[1,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, 3,4-dihydro-2H-chromenyl, 1H-pyrazolo[4,3-c]pyridin-3-yl; 1H- pyrrolo[3,2-b]pyridin-3-yl; and 1H-pyrazolo[3,2-b]pyridin-3-yl. [0091] The term “heterocycloalkyl” as used herein refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems. The heterocycloalkyl ring-systems include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom optionally can be substituted. Representative heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl. [0092] The term “hydroxy” or “hydroxyl” as used herein is represented by the formula —OH. [0093] The term “ketone” as used herein is represented by the formula A¹C(O)A², where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. [0094] The term “azide” or “azido” as used herein is represented by the formula —N₃. [0095] The term “nitro” as used herein is represented by the formula —NO₂. [0096] The term “nitrile” or “cyano” as used herein is represented by the formula —CN or — C≡N. [0097] The term “silyl” as used herein is represented by the formula —SiA¹A²A³, where A¹, A², and A³ can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. [0098] The term “sulfo-oxo” as used herein is represented by the formulas —S(O)A¹, — S(O)2A¹, —OS(O)2A¹, or —OS(O)2OA¹, where A¹ can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. Throughout this specification “S(O)” is a short hand notation for S=O. The term “sulfonyl” is used herein to refer to the sulfo-oxo group represented by the formula —S(O)2A¹, where A¹ can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfone” as used herein is represented by the formula A¹S(O)2A², where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfoxide” as used herein is represented by the formula A¹S(O)A², where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. [0099] The term “thiol” as used herein is represented by the formula —SH. [00100] “R¹,” “R²,” “R³,” “Rⁿ,” where n is an integer, as used herein can, independently, possess one or more of the groups listed above. For example, if R¹ is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like. Depending upon the groups that are selected, a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group. For example, with the phrase “an alkyl group comprising an amino group,” the amino group can be incorporated within the backbone of the alkyl group. Alternatively, the amino group can be attached to the backbone of the alkyl group. The nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group. [00101] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogen of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are those that result in the formation of stable or chemically feasible compounds. In is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted). [00102] The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain aspects, their recovery, purification, and use for one or more of the purposes disclosed herein. [00103] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH₂)0–4R ^; –(CH₂)0–4OR ^; -O(CH₂)0-4R^o, –O– (CH₂)0–4C(O)OR°; –(CH₂)0–4CH(OR ^)2; –(CH₂)0–4SR ^; –(CH₂)0–4Ph, which may be substituted with R°; –(CH₂)0–4O(CH₂)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH₂)0–4O(CH₂)0–1-pyridyl which may be substituted with R°; –NO₂; –CN; –N₃; -(CH₂)_0–4N(R ^)₂; –(CH₂)_0–4N(R ^)C(O)R ^; –N(R ^)C(S)R ^; –(CH₂)_0– 4N(R ^)C(O)NR ^2; -N(R ^)C(S)NR ^2; –(CH₂)0–4N(R ^)C(O)OR ^; – N(R ^)N(R ^)C(O)R ^; -N(R ^)N(R ^)C(O)NR ^2; -N(R ^)N(R ^)C(O)OR ^; –(CH₂)0–4C(O)R ^; – C(S)R ^; –(CH₂)0–4C(O)OR ^; –(CH₂)0–4C(O)SR ^; -(CH₂)0–4C(O)OSiR ^3; –(CH₂)0–4OC(O)R ^; – OC(O)(CH₂)0–4SR–, SC(S)SR°; –(CH₂)0–4SC(O)R ^; –(CH₂)0–4C(O)NR ^2; –C(S)NR ^2; – C(S)SR°; -(CH₂)0–4OC(O)NR ^2; -C(O)N(OR ^)R ^; –C(O)C(O)R ^; –C(O)CH₂C(O)R ^; – C(NOR ^)R ^; -(CH₂)0–4SSR ^; –(CH₂)0–4S(O)2R ^; –(CH₂)0–4S(O)2OR ^; –(CH₂)0–4OS(O)2R ^; – S(O)2NR ^2; -(CH₂)0–4S(O)R ^; -N(R ^)S(O)2NR ^2; –N(R ^)S(O)2R ^; –N(OR ^)R ^; –C(NH)NR ^2; – P(O)2R ^; -P(O)R ^2; -OP(O)R ^2; –OP(O)(OR ^)2; SiR ^3; –(C1–4 straight or branched alkylene)O– N(R ^)₂; or –(C_1–4 straight or branched alkylene)C(O)O–N(R ^)₂, wherein each R ^ may be substituted as defined below and is independently hydrogen, C_1–6 aliphatic, –CH₂Ph, –O(CH₂)_0– 1Ph, -CH₂-(5-6 membered heteroaryl ring), or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ^, taken together with their intervening atom(s), form a 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below. [00104] Suitable monovalent substituents on R ^ (or the ring formed by taking two independent occurrences of R ^ together with their intervening atoms), are independently halogen, –(CH₂)0–2R ^●, –(haloR ^●), –(CH₂)0–2OH, –(CH₂)0–2OR ^●, –(CH₂)0– ₂CH(OR ^●)₂; -O(haloR ^●), –CN, –N₃, –(CH₂)_0–2C(O)R ^●, –(CH₂)_0–2C(O)OH, –(CH₂)_0–2C(O)OR ^●, – (CH₂)0–2SR ^●, –(CH₂)0–2SH, –(CH₂)0–2NH₂, –(CH₂)0–2NHR ^●, –(CH₂)0–2NR ^●2, –NO₂, –SiR ^●3, – OSiR ^●3, -C(O)SR ^●, –(C1–4 straight or branched alkylene)C(O)OR ^●, or –SSR ^● wherein each R ^● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C_1–4 aliphatic, –CH₂Ph, –O(CH₂)_0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R ^ include =O and =S. [00105] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O, =S, =NNR^*2, =NNHC(O)R^*, =NNHC(O)OR^*, * ^{* * * *} wherein each independent occurrence of R^* is selected from hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0– 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR^*2)2–3O–, wherein each independent occurrence of R^* is selected from hydrogen, C_1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00106] Suitable substituents on the aliphatic group of R^* include halogen, – R ^●, -(haloR ^●), -OH, –OR ^●, –O(haloR ^●), –CN, –C(O)OH, –C(O)OR ^●, –NH₂, –NHR ^●, –NR ^● ₂, or –NO₂, wherein each R ^● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C_1–4 aliphatic, –CH₂Ph, –O(CH₂)_0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00107] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R^†, –NR^† ₂, –C(O)R^†, –C(O)OR^†, –C(O)C(O)R^†, –C(O)CH₂C(O)R^†, – S(O)2R^†, -S(O)2NR^†2, –C(S)NR^†2, –C(NH)NR^†2, or –N(R^†)S(O)2R^†; wherein each R^† is independently hydrogen, C1–6 aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0– 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R^†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00108] Suitable substituents on the aliphatic group of R^† are independently halogen, – R ^●, -(haloR ^●), –OH, –OR ^●, –O(haloR ^●), –CN, –C(O)OH, –C(O)OR ^●, –NH₂, –NHR ^●, –NR ^● ₂, or –NO₂, wherein each R ^● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH₂Ph, –O(CH₂)0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00109] The term “leaving group” refers to an atom (or a group of atoms) with electron withdrawing ability that can be displaced as a stable species, taking with it the bonding electrons. Examples of suitable leaving groups include halides and sulfonate esters, including, but not limited to, triflate, mesylate, tosylate, and brosylate. [00110] The terms “hydrolysable group” and “hydrolysable moiety” refer to a functional group capable of undergoing hydrolysis, e.g., under basic or acidic conditions. Examples of hydrolysable residues include, without limitation, acid halides, activated carboxylic acids, and various protecting groups known in the art (see, for example, “Protective Groups in Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-Interscience, 1999). [00111] The term “organic residue” defines a carbon containing residue, i.e., a residue comprising at least one carbon atom, and includes but is not limited to the carbon-containing groups, residues, or radicals defined hereinabove. Organic residues can contain various heteroatoms, or be bonded to another molecule through a heteroatom, including oxygen, nitrogen, sulfur, phosphorus, or the like. Examples of organic residues include but are not limited alkyl or substituted alkyls, alkoxy or substituted alkoxy, mono or di-substituted amino, amide groups, etc. Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15, carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In a further aspect, an organic residue can comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms. [00112] A very close synonym of the term “residue” is the term “radical,” which as used in the specification and concluding claims, refers to a fragment, group, or substructure of a molecule described herein, regardless of how the molecule is prepared. For example, a 2,4- thiazolidinedione radical in a particular compound has the structure: , regardless of whether thiazolidinedione is used to prepare the compound. In some embodiments the radical (for example an alkyl) can be further modified (i.e., substituted alkyl) by having bonded thereto one or more “substituent radicals.” The number of atoms in a given radical is not critical to the present invention unless it is indicated to the contrary elsewhere herein. [00113] “Organic radicals,” as the term is defined and used herein, contain one or more carbon atoms. An organic radical can have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organic radical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbon atoms, 2- 8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organic radicals often have hydrogen bound to at least some of the carbon atoms of the organic radical. One example, of an organic radical that comprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2-naphthyl radical. In some embodiments, an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like. Examples of organic radicals include but are not limited to an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino, di-substituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein. A few non-limiting examples of organic radicals that include heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals and the like. [00114] “Inorganic radicals,” as the term is defined and used herein, contain no carbon atoms and therefore comprise only atoms other than carbon. Inorganic radicals comprise bonded combinations of atoms selected from hydrogen, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium, and halogens such as fluorine, chlorine, bromine, and iodine, which can be present individually or bonded together in their chemically stable combinations. Inorganic radicals have 10 or fewer, or preferably one to six or one to four inorganic atoms as listed above bonded together. Examples of inorganic radicals include, but not limited to, amino, hydroxy, halogens, nitro, thiol, sulfate, phosphate, and like commonly known inorganic radicals. The inorganic radicals do not have bonded therein the metallic elements of the periodic table (such as the alkali metals, alkaline earth metals, transition metals, lanthanide metals, or actinide metals), although such metal ions can sometimes serve as a pharmaceutically acceptable cation for anionic inorganic radicals such as a sulfate, phosphate, or like anionic inorganic radical. Inorganic radicals do not comprise metalloids elements such as boron, aluminum, gallium, germanium, arsenic, tin, lead, or tellurium, or the noble gas elements, unless otherwise specifically indicated elsewhere herein. [00115] Compounds described herein can contain one or more double bonds and, thus, potentially give rise to cis/trans (E/Z) isomers, as well as other conformational isomers. Unless stated to the contrary, the invention includes all such possible isomers, as well as mixtures of such isomers. [00116] Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture. Compounds described herein can contain one or more asymmetric centers and, thus, potentially give rise to diastereomers and optical isomers. Unless stated to the contrary, the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers, as well as isolated specific stereoisomers, are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers. [00117] Many organic compounds exist in optically active forms having the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non- superimposable mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula. As is used in the art, when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane). The Cahn-Ingold-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon. [00118] Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance. The disclosed compounds can be isotopically-labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³⁵ S, ¹⁸ F and ³⁶ Cl, respectively. Compounds further comprise prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as ³ H and ¹⁴ C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³ H, and carbon-14, i.e., ¹⁴ C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., ² H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent. [00119] The compounds described in the invention can be present as a solvate. In some cases, the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate. The compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution. In this connection, one, two, three or any arbitrary number of solvent or water molecules can combine with the compounds according to the invention to form solvates and hydrates. Unless stated to the contrary, the invention includes all such possible solvates. [00120] The term “co-crystal” means a physical association of two or more molecules which owe their stability through non-covalent interaction. One or more components of this molecular complex provide a stable framework in the crystalline lattice. In certain instances, the guest molecules are incorporated in the crystalline lattice as anhydrates or solvates, see e.g. “Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co- crystals Represent a New Path to Improved Medicines?” Almarasson, O., et. al., The Royal Society of Chemistry, 1889-1896, 2004. Examples of co-crystals include p-toluenesulfonic acid and benzenesulfonic acid. [00121] It is also appreciated that certain compounds described herein can be present as an equilibrium of tautomers. For example, ketones with an α-hydrogen can exist in an equilibrium of the keto form and the enol form. [00122] Likewise, amides with an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form. As another example, pyrazoles can exist in two tautomeric forms, N¹-unsubstituted, 3-A³ and N¹-unsubstituted, 5-A³ as shown below. [00123] Unless stated to the contrary, the invention includes all such possible tautomers. [00124] It is known that chemical substances form solids which are present in different states of order which are termed polymorphic forms or modifications. The different modifications of a polymorphic substance can differ greatly in their physical properties. The compounds according to the invention can be present in different polymorphic forms, with it being possible for particular modifications to be metastable. Unless stated to the contrary, the invention includes all such possible polymorphic forms. [00125] In some aspects, a structure of a compound can be represented by a formula: , which is understood to be equivalent to a formula: , wherein n is typically an integer. That is, Rⁿ is understood to represent five independent substituents, R^n(a), R^n(b), R^n(c), R^n(d), R^n(e). By “independent substituents,” it is meant that each R substituent can be independently defined. For example, if in one instance R^n(a) is halogen, then R^n(b) is not necessarily halogen in that instance. [00126] Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and supplemental volumes (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition); and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). [00127] Unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including: matters of logic with respect to arrangement of steps or operational flow; plain meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification. [00128] Disclosed are the components to be used to prepare the compositions of the invention as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the methods of the invention. [00129] It is understood that the compositions disclosed herein have certain functions. Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures that can perform the same function that are related to the disclosed structures, and that these structures will typically achieve the same result. B. COMPOUNDS [00130] In one aspect, the invention relates to compounds that inhibiting Nox4 signaling. The disclosed compounds can be useful in, for example, the treatment of fibrotic disorders (e.g., pulmonary fibrosis, heart fibrosis, kidney fibrosis, liver fibrosis, skin fibrosis, mediastinal fibrosis, retroperitoneal cavity fibrosis, bone marrow fibrosis, scleroderma or systemic sclerosis), acute respiratory distress syndrome (ARDS) or for treating cancer (e.g., a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, plasma cell neoplasm (myeloma)). [00131] It is contemplated that each disclosed derivative can be optionally further substituted. It is also contemplated that any one or more derivative can be optionally omitted from the invention. It is understood that a disclosed compound can be provided by the disclosed methods. It is also understood that the disclosed compounds can be employed in the disclosed methods of using. 1. STRUCTURE [00132] In one aspect, disclosed are compounds having a structure represented by a formula: , wherein n is selected from 0, 1, 2, 3, 4, and 5, and wherein m is selected from 0 and 1, provided that when n is 0 then m is 0; wherein o is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8; wherein A¹ is selected from ‒O‒ and ‒CH₂‒, provided that when A¹ is O, then o is not 0 or 1; wherein L¹ is selected from C2 alkenyl, C2 alkynyl, ‒NHSO₂‒, ‒SO₂NH‒, ‒NHC(O)‒, ‒C(O)NH‒, and Ar⁵; wherein Ar⁵, when present, is a C2-C9 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R^1a, R^1b, R^1c, and R^1d is independently selected from hydrogen, halogen, ‒CN, ‒NH₂, ‒OH, and ‒NO₂; wherein R² is selected from hydrogen and C1-C4 alkyl; wherein one of R^3a and R^3b is C1-C4 alkyl and one of R^3a and R^3b is a structure selected from:

^; wherein R¹³ is selected from hydrogen and ‒OH; and wherein Ar¹ is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof. [00133] In one aspect, disclosed are compounds having a structure represented by a formula: , wherein r is selected from 1, 2, 3, 4, 5, 6, 7, and 8; wherein one of R^3a and R^3b is C1-C4 alkyl and one of R^3a and R^3b is a structure selected from:

^; wherein R¹³ is selected from hydrogen and ‒OH; wherein each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and wherein R¹⁰ is selected from hydrogen and a structure: ; wherein s is selected from 0 and 1; wherein A² is selected from ‒C(O)‒ and ‒SO2‒; wherein L² is ‒(CR^11aR^11b)₂‒; wherein each occurrence of R^11a and R^11b is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl, or wherein each of R^11a and R^11b together comprise =O; wherein R⁵, when present, is selected from hydrogen and C1-C4 alkyl; wherein R⁶ is selected from ‒NR^12aR^12b and Ar²; wherein R^12a is selected from hydrogen, C1-C4 alkyl, and Ar³; wherein Ar³ is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and wherein R^12b is selected from C1-C4 alkyl, ‒CH₂Ar⁴, and Ar⁴; wherein Ar⁴ is selected from C6- C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or wherein each of R^12a and R^12b together comprise a C2-C5 heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein Ar² is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒C(O)NH₂, ‒NHC(O)(C1-C4 alkyl), Cy¹, ‒OCy¹, and ‒NH(CH₂)_tCy¹; wherein t is selected from 0, 1, and 2; and wherein Cy¹ is selected from C3- C6 cycloalkyl, C3-C6 heterocycloalkyl, C6-C14 aryl, and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof. [00134] In various aspects, the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof. [00135] In various aspects, the compound has a structure represented by a formula selected from: ^, or a pharmaceutically acceptable salt thereof. [00136] In various aspects, the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof. [00137] In various aspects, the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof. [00138] In various aspects, the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof. [00139] In various aspects, the compound has a structure represented by a formula:

, or a pharmaceutically acceptable salt thereof. [00140] In various aspects, the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof. [00141] In various aspects, the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof. [00142] In various aspects, the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof. [00143] In various aspects, the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof. [00144] In various aspects, the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof. [00145] In various aspects, the compound has a structure represented by a formula:

, or a pharmaceutically acceptable salt thereof. [00146] In various aspects, the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof. [00147] In various aspects, the compound is selected from:

, ,

, ,

,

, ,

, ,

,

, , ,

,

,

, ,

, ,

,

, or a pharmaceutically acceptable salt thereof. [00148] In various aspects, the compound is selected from:

,

, ,

,

or a pharmaceutically acceptable salt thereof [00149] In various aspects, the compound a has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof. [00150] In various aspects, the compound a has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof. [00151] In various aspects, the compound a has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof. [00152] In various aspects, the compound a has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof. [00153] In various aspects, the compound a has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof. [00154] In various aspects, the compound is selected from: ,

,

,

,

,

,

, or a pharmaceutically acceptable salt thereof. [00155] In various aspects, the compound is selected from: , or a pharmaceutically acceptable salt thereof. [00156] In various aspects, m is selected from 0 and 1. In a further aspect, m is 0. In a still further aspect, m is 1. [00157] In various aspects, n is selected from 0, 1, 2, 3, 4, and 5. In a further aspect, n is selected from 0, 1, 2, 3, and 4. In a yet further aspect, n is selected from 0, 1, 2, and 3. In a still further aspect, n is selected from 0, 1, and 2. In an even further aspect, n is selected from 0 and In a yet further aspect, n is 0. In a still further aspect, n is 1. [00158] In various aspects, o is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8. In a further aspect, o is selected from 0, 1, 2, 3, 4, 5, 6, and 7. In a still further aspect, o is selected from 0, 1, 2, 3, 4, 5, and 6. In an even further aspect, o is selected from 0, 1, 2, 3, 4, and 5. In yet a further aspect, o is selected from 0, 1, 2, 3, and 4. In a still further aspect, o is selected from 0, 1, 2, and 3. In a yet further aspect o is selected from 0, 1, and 2. In a still further aspect, o is selected from 0 and 1. In an even further aspect, o is 3. In a yet further aspect, o is 2. In a still further aspect, o is 1. [00159] In various aspects, r is selected from 1, 2, 3, 4, 5, 6, 7, and 8. In a further aspect, r is selected from 0, 1, 2, 3, 4, 5, 6, and 7. In a still further aspect, r is selected from 0, 1, 2, 3, 4, 5, and 6. In an even further aspect, r is selected from 0, 1, 2, 3, 4, and 5. In yet a further aspect, r is selected from 0, 1, 2, 3, and 4. In a still further aspect, r is selected from 0, 1, 2, and 3. In a yet further aspect, r is selected from 0, 1, and 2. In a still further aspect, r is selected from 0 and 1. In a yet further aspect, r is selected from 1, 2, and 4. In a further aspect, r is 4. In an even further aspect, r is 3. In a yet further aspect, r is 2. In a still further aspect, r is 1. [00160] In various aspects, s is selected from 0 and 1. In a further aspect, s is 0. In a further aspect, s is 1. [00161] In various aspects, t is selected from 0, 1, and 2. In a further aspect, t is selected from 0 and 1. In a still further aspect, t is selected from 0 and 2. In a yet further aspect, t is selected from 1 and 2. In an even further aspect, t is 2. In a yet further aspect, t is 1. In a yet further aspect, t is 0. a. A¹ GROUP [00162] In one aspect, A¹ is selected from ‒O‒ and ‒CH₂‒, provided that when A¹ is O, then o is not 0 or 1. In a further aspect, A¹ is –O‒. In a yet further aspect, A¹ is –CH₂‒. b. A² GROUP [00163] In one aspect, A² is selected from ‒C(O)‒ and ‒SO₂‒. In a further aspect, A² is ‒ C(O)‒. In a yet further aspect, A² is ‒SO₂‒. c. L¹ GROUP [00164] In one aspect, L¹ is selected from C2 alkenyl, C2 alkynyl, ‒NHSO₂‒, ‒SO₂NH‒, ‒ NHC(O)‒, ‒C(O)NH‒, and Ar⁵. In a further aspect, L¹ is selected from C2 alkenyl, C2 alkynyl, and Ar⁵. In a yet further aspect, L¹ is selected from C2 alkenyl and C2 alkynyl. In a still further aspect, L¹ is C2 alkenyl. In yet a further aspect, L¹ is C2 alkynyl. [00165] In various aspects, L¹ is selected from ‒NHSO2‒, ‒SO2NH‒, ‒NHC(O)‒, and ‒ C(O)NH‒. In a further aspect, L¹ is selected from ‒NHSO₂‒ and ‒SO₂NH‒. In a still further aspect, L¹ is selected from ‒NHC(O)‒ and ‒C(O)NH‒. In yet a further aspect, L¹ is ‒NHSO₂‒. In an even further aspect, L¹ is ‒SO2NH‒. In a still further aspect, L¹ is ‒NHC(O)‒. In yet a further aspect, L¹ is ‒C(O)NH‒. [00166] In various aspects, L¹ is Ar⁵. In a further aspect, Ar⁵ is selected from triazolyl, oxadiazolyl, thiazolyl, tetrazolyl, oxazolyl, and thiadiazolyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar⁵ is selected from triazolyl, oxadiazolyl, thiazolyl, tetrazolyl, oxazolyl, and thiadiazolyl, and is unsubstituted. In yet a further aspect, Ar⁵ is a structure selected from: ^, wherein * denotes a connection to ‒(CH₂)n‒ and ** denotes a connection to Ar¹. d. L² GROUP [00167] In one aspect, L² is ‒(CR^11aR^11b)₂ ‒. In a further aspect, L² is ‒(CH₂)₂ ‒. e. R^1A, R^1B, R^1C, AND R^1D GROUPS [00168] In one aspect, each of R^1a, R^1b, R^1c, and R^1d is independently selected from hydrogen, halogen, ‒CN, ‒NH₂, ‒OH, and ‒NO₂. In a further aspect, each of R^1a, R^1b, R^1c, and R^1d is independently selected from hydrogen, ‒F, ‒Cl, ‒CN, ‒NH₂, ‒OH, and ‒NO₂. In a further aspect, each of R^1a, R^1b, R^1c, and R^1d is independently selected from hydrogen, ‒F, and ‒OH. [00169] In various aspects, each of R^1a, R^1b, R^1c, and R^1d is independently selected from hydrogen and halogen. In a further aspect, each of R^1a, R^1b, R^1c, and R^1d is independently selected from hydrogen, ‒F, ‒Br, and ‒Cl. In a still further aspect, each of R^1a, R^1b, R^1c, and R^1d is independently selected from hydrogen, ‒F, and ‒Cl. In a still further aspect, each of R^1a, R^1b, R^1c, and R^1d is independently selected from hydrogen and ‒Cl. In yet a further aspect, each of R^1a, R^1b, R^1c, and R^1d is independently selected from hydrogen and ‒F. [00170] In various aspects, each of R^1a, R^1b, R^1c, and R^1d is hydrogen. f. R² GROUPS [00171] In one aspect, R² is selected from hydrogen and C1-C4 alkyl. In a further aspect, R² is selected from hydrogen, methyl, ethyl, propyl, and isopropyl. In a further aspect, R² is selected from hydrogen, methyl, and ethyl. In a still further aspect, R² is selected from hydrogen and ethyl. In yet a further aspect, R² is selected from hydrogen and methyl. [00172] In various aspects, R² is C1-C4 alkyl. In a further aspect, R² is selected from methyl, ethyl, propyl, and isopropyl. In a further aspect, R² is selected from methyl and ethyl. In a still further aspect, R² is ethyl. In yet a further aspect, R² is methyl. [00173] In various aspects, R² is hydrogen. g. R^3A AND R^3B GROUPS In one aspect, one of R^3a and R^3b is C1-C4 alkyl and one of R^3a and R^3b is a structure selected from: ^. [00174] In various aspects, one of R^3a and R^3b is C1-C4 alkyl. In a further aspect, one of R^3a and R^3b is selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, one of R^3a and R^3b is selected from methyl and ethyl. In yet a further aspect, one of R^3a and R^3b is methyl. [00175] In various aspects, one of R^3a and R^3b is a structure selected from:

^. [00176] In various aspects, one of R^3a and R^3b is a structure: . [00177] In various aspects, one of R^3a and R^3b is a structure: . [00178] In various aspects, one of R^3a and R^3b is a structure selected from:

^. [00179] In various aspects, one of R^3a and R^3b is a structure: . [00180] In various aspects, one of R^3a and R^3b is a structure: . [00181] In various aspects, one of R^3a and R^3b is a structure selected from:

^. [00182] In various aspects, one of R^3a and R^3b is a structure selected from: ^. [00183] In various aspects, one of R^3a and R^3b is a structure: . [00184] In various aspects, one of R^3a and R^3b is a structure:

. h. R^4A, R^4B, R^4C, AND R^4D GROUPS [00185] In one aspect, each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1- C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, –F, –Cl, –NH₂, –CN, –OH, ‒NO₂, methyl, ethyl, n- propyl, i-propyl, ethenyl, propenyl, isopropenyl, –CH₂F, –CH₂Cl, –CH₂CH₂F, –CH₂CH₂Cl, – CH₂CH₂CH₂F, –CH₂CH₂CH₂Cl, –CH(CH₃)CH₂F, –CH(CH₃)CH₂Cl, –CH₂CN, –CH₂CH₂CN, – CH₂CH₂CH₂CN, –CH(CH₃)CH₂CN, –CH₂OH, –CH₂CH₂OH, –CH₂CH₂CH₂OH, – CH(CH₃)CH₂OH, –OCF₃, –OCH₂CF₃, –OCH₂CH₂CF₃, –OCH(CH₃)CF₃, –OCH₃, –OCH₂CH₃, – OCH₂CH₂CH₃, –OCH(CH₃)CH₃, –NHCH₃, –NHCH₂CH₃, –NHCH₂CH₂CH₃, –NHCH(CH₃)CH₃, –N(CH₃)2, –N(CH₂CH₃)2, –N(CH₂CH₂CH₃)2, –N(CH(CH₃)CH₃)2, –N(CH₃)(CH₂CH₃), – CH₂NH₂, –CH₂CH₂NH₂, –CH₂CH₂CH₂NH₂, and –CH(CH₃)CH₂NH₂. In a further aspect, each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, –F, –Cl, –NH₂, –CN, –OH, ‒ NO₂, methyl, ethyl, ethenyl, –CH₂F, –CH₂Cl, –CH₂CH₂F, –CH₂CH₂Cl, –CH₂CN,–CH₂CH₂CN, –CH₂OH, –CH₂CH₂OH, –OCF₃, –OCH₂CF₃, –OCH₃, –OCH₂CH₃, –NHCH₃, –NHCH₂CH₃, – N(CH₃)₂, –N(CH₂CH₃)₂, –N(CH₃)(CH₂CH₃), –CH₂NH₂, and –CH₂CH₂NH₂. In a still further aspect, each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, –F, –Cl, –NH₂, – CN, –OH, ‒NO₂, methyl, –CH₂F, –CH₂Cl, –CH₂CN, –CH₂OH, –OCF₃, –OCH₂CF₃, –OCH₃, – NHCH₃, –N(CH₃)2, and –CH₂NH₂. [00186] In various aspects, each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, and C2-C4 alkenyl. In a further aspect, each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, –F, –Cl, –NH₂, – CN, –OH, ‒NO₂, methyl, ethyl, n-propyl, i-propyl, ethenyl, propenyl, and isopropenyl. In a further aspect, each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, –F, –Cl, – NH₂, –CN, –OH, ‒NO₂, methyl, ethyl, and ethenyl. In a still further aspect, each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, –F, –Cl, –NH₂, –CN, –OH, ‒NO₂, and methyl. [00187] In various aspects, each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, halogen, ‒CN, C1-C4 alkyl, and C1-C4 alkoxy. In a further aspect, each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, –F, –Cl, ‒CN, methyl, ethyl, n-propyl, i- propyl, –OCH₃, –OCH₂CH₃, –OCH₂CH₂CH₃, and –OCH(CH₃)CH₃. In a still further aspect, each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, –F, –Cl, ‒CN, methyl, ethyl, –OCH₃, and –OCH₂CH₃. In yet a further aspect, each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, –F, –Cl, ‒CN, methyl, and –OCH₃. [00188] In various aspects, each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen and C1-C4 alkyl. In a further aspect, each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, methyl, ethyl, n-propyl, and i-propyl. In a further aspect, each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, methyl, and ethyl. In a still further aspect, each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen and methyl. [00189] In various aspects, each of R^4a, R^4b, R^4c, and R^4d is independently C1-C4 alkyl. In a further aspect, each of R^4a, R^4b, R^4c, and R^4d is independently selected from methyl, ethyl, n- propyl, and i-propyl. In a further aspect, each of R^4a, R^4b, R^4c, and R^4d is independently selected from methyl and ethyl. In a still further aspect, each of R^4a, R^4b, R^4c, and R^4d is methyl. [00190] In various aspects, each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 haloalkyl, and C1-C4 cyanoalkyl. In a further aspect, each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, –F, –Cl, – NH₂, –CN, –OH, ‒NO₂, –CH₂F, –CH₂Cl, –CH₂CH₂F, –CH₂CH₂Cl, –CH₂CH₂CH₂F, – CH₂CH₂CH₂Cl, –CH(CH₃)CH₂F, –CH(CH₃)CH₂Cl, –CH₂CN, –CH₂CH₂CN, –CH₂CH₂CH₂CN, and –CH(CH₃)CH₂CN. In a further aspect, each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, –F, –Cl, –NH₂, –CN, –OH, ‒NO₂, –CH₂F, –CH₂Cl, –CH₂CH₂F, – CH₂CH₂Cl, –CH₂CN, and –CH₂CH₂CN. In a still further aspect, each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, –F, –Cl, –NH₂, –CN, –OH, ‒NO₂, –CH₂F, –CH₂Cl, and – CH₂CN. [00191] In various aspects, each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, and C1- C4 alkoxy. In a further aspect, each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, –F, –Cl, –NH₂, –CN, –OH, ‒NO₂, –CH₂OH, –CH₂CH₂OH, –CH₂CH₂CH₂OH, – CH(CH₃)CH₂OH, –OCF₃, –OCH₂CF₃, –OCH₂CH₂CF₃, –OCH(CH₃)CF₃, –OCH₃, –OCH₂CH₃, – OCH₂CH₂CH₃, and –OCH(CH₃)CH₃. In a further aspect, each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, –F, –Cl, –NH₂, –CN, –OH, ‒NO₂, –CH₂OH, – CH₂CH₂OH, –OCF₃, –OCH₂CF₃, –OCH₃, and –OCH₂CH₃. In a still further aspect, each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, –F, –Cl, –NH₂, –CN, –OH, ‒NO₂, – CH₂OH, –OCF₃, –OCH₂CF₃, and –OCH₃. [00192] In various aspects, each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, –F, –Cl, –NH₂, –CN, –OH, ‒NO₂, –NHCH₃, –NHCH₂CH₃, – NHCH₂CH₂CH₃, –NHCH(CH₃)CH₃, –N(CH₃)2, –N(CH₂CH₃)2, –N(CH₂CH₂CH₃)2, – N(CH(CH₃)CH₃)₂, –N(CH₃)(CH₂CH₃), –CH₂NH₂, –CH₂CH₂NH₂, –CH₂CH₂CH₂NH₂, and – CH(CH₃)CH₂NH₂. In a further aspect, each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, –F, –Cl, –NH₂, –CN, –OH, ‒NO₂, –NHCH₃, –NHCH₂CH₃, –N(CH₃)2, – N(CH₂CH₃)₂, –N(CH₃)(CH₂CH₃), –CH₂NH₂, and –CH₂CH₂NH₂. In a still further aspect, each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, –F, –Cl, –NH₂, –CN, –OH, ‒ NO₂, –NHCH₃, –N(CH₃)2, and –CH₂NH₂. [00193] In various aspects, each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen and halogen. In a further aspect, each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, –F, and –Cl. In a further aspect, each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen and –Cl. In a still further aspect, each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen and –F. [00194] In various aspects, each of R^4a, R^4b, R^4c, and R^4d is independently halogen. In a further aspect, each of R^4a, R^4b, R^4c, and R^4d is independently selected from –F and –Cl. In a further aspect, each of R^4a, R^4b, R^4c, and R^4d is –Cl. In a still further aspect, each of R^4a, R^4b, R^4c, and R^4d is –F. [00195] In various aspects, each of R^4a, R^4b, R^4c, and R^4d is hydrogen. i. R⁵ GROUPS [00196] In one aspect, R⁵, when present, is selected from hydrogen and C1-C4 alkyl. In a further aspect, R⁵, when present, is selected from hydrogen, methyl, ethyl, propyl, and isopropyl. In a further aspect, R⁵, when present, is selected from hydrogen, methyl, and ethyl. In a still further aspect, R⁵, when present, is selected from hydrogen and methyl. [00197] In various aspects, R⁵, when present, is C1-C4 alkyl. In a further aspect, R⁵, when present, is selected from methyl, ethyl, propyl, and isopropyl. In a further aspect, R⁵, when present, is selected from methyl and ethyl. In a still further aspect, R⁵, when present, is methyl. [00198] In various aspects, R⁵, when present, is hydrogen. j. R⁶ GROUPS [00199] In one aspect, R⁶ is selected from ‒NR^12aR^12b and Ar². In a further aspect, R⁶ is from ‒NR^12aR^12b. In a yet further aspect, R⁶ is Ar² _. k. R¹⁰ [00200] In one aspect, R¹⁰ is selected from hydrogen and a structure: . [00201] In various aspects, R¹⁰ is hydrogen. [00202] In various aspects, R¹⁰ is a structure: . l. R^11A AND R^11B GROUPS [00203] In one aspect, each occurrence of R^11a and R^11b is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl or each of R^11a and R^11b together comprise =O. [00204] In various aspects, each occurrence of R^11a and R^11b is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl. In a further aspect, each occurrence of R^11a and R^11b is independently selected from hydrogen, methyl, ethyl, n-propyl, i-propyl, ‒CH₂F, ‒ CH₂CH₂F, ‒CH₂CH₂CH₂F, ‒CH(CH₃)CH₂F, ‒CH₂Cl, ‒CH₂CH₂Cl, ‒CH₂CH₂CH₂Cl, and ‒ CH(CH₃)CH₂Cl. In a yet further aspect, each occurrence of R^11a and R^11b is independently selected from hydrogen, methyl, ethyl, ‒CH₂F, ‒CH₂CH₂F, ‒CH₂Cl, and ‒CH₂CH₂Cl. In a still further aspect, each occurrence of R^11a and R^11b is independently selected from hydrogen, methyl, ‒CH₂F, and ‒CH₂Cl. [00205] In various aspects, each occurrence of R^11a and R^11b is independently selected from hydrogen and C1-C4 alkyl. In a further aspect, each occurrence of R^11a and R^11b is independently selected from hydrogen, methyl, ethyl, n-propyl, and i-propyl. In a yet further aspect, each occurrence of R^11a and R^11b is independently selected from hydrogen, methyl, and ethyl. In a still further aspect, each occurrence of R^11a and R^11b is independently selected from hydrogen and methyl. [00206] In various aspects, each occurrence of R^11a and R^11b is independently C1-C4 alkyl. In a further aspect, each occurrence of R^11a and R^11b is independently selected from methyl, ethyl, n-propyl, and i-propyl. In a yet further aspect, each occurrence of R^11a and R^11b is independently selected from methyl and ethyl. In a still further aspect, each occurrence of R^11a and R^11b is methyl. [00207] In various aspects, each occurrence of R^11a and R^11b is independently selected from hydrogen and C1-C4 haloalkyl. In a further aspect, each occurrence of R^11a and R^11b is independently selected from hydrogen, ‒CH₂F, ‒CH₂CH₂F, ‒CH₂CH₂CH₂F, ‒CH(CH₃)CH₂F, ‒ CH₂Cl, ‒CH₂CH₂Cl, ‒CH₂CH₂CH₂Cl, and ‒CH(CH₃)CH₂Cl. In a yet further aspect, each occurrence of R^11a and R^11b is independently selected from hydrogen, ‒CH₂F, ‒CH₂CH₂F, ‒ CH₂Cl, and ‒CH₂CH₂Cl. In a still further aspect, each occurrence of R^11a and R^11b is independently selected from hydrogen, ‒CH₂F, and ‒CH₂Cl. [00208] In various aspects, each occurrence of R^11a and R^11b is hydrogen. [00209] In various aspects, each of R^11a and R^11b together comprise =O. m. R^12A AND R^12B GROUPS [00210] In one aspect, R^12a is selected from hydrogen, C1-C4 alkyl, and Ar³, and R^12b is selected from C1-C4 alkyl, ‒CH₂Ar⁴, and Ar⁴, or each of R^12a and R^12b together comprise a C2- C5 heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒ CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1- C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. [00211] In various aspects, R^12a is selected from hydrogen, C1-C4 alkyl, and Ar³, and R^12b is selected from C1-C4 alkyl, ‒CH₂Ar⁴, and Ar⁴. [00212] In various aspects, R^12a is selected from hydrogen, C1-C4 alkyl, and Ar³. In a further aspect, R^12a is selected from hydrogen, methyl, ethyl, propyl, isopropyl, and Ar³. In a further aspect, R^12a is selected from hydrogen, methyl, ethyl, and Ar³. In a still further aspect, R^12a is selected from hydrogen, methyl, and Ar³. [00213] In various aspects, R^12a is C1-C4 alkyl. In a further aspect, R^12a is selected from methyl, ethyl, propyl, and isopropyl. In a further aspect, R^12a is selected from methyl and ethyl. In a still further aspect, R^12a is methyl. [00214] In various aspects, R^12a is Ar³. [00215] In various aspects, R^12a is hydrogen. [00216] In various aspects, R^12b is selected from C1-C4 alkyl, ‒CH₂Ar⁴, and Ar⁴. In a further aspect, R^12b is selected from methyl, ethyl, propyl, isopropyl, ‒CH₂Ar⁴, and Ar⁴. In a further aspect, R^12b is selected from methyl, ethyl, ‒CH₂Ar⁴, and Ar⁴. In a still further aspect, R^12b is selected from methyl, ‒CH₂Ar⁴, and Ar⁴. [00217] In various aspects, R^12b is C1-C4 alkyl. In a further aspect, R^12b is selected from methyl, ethyl, propyl, and isopropyl. In a further aspect, R^12b is selected from methyl and ethyl. In a still further aspect, R^12b is methyl. [00218] In various aspects, R^12b is selected from ‒CH₂Ar⁴ and Ar⁴. In a further aspect, R^12b is Ar⁴. In a still further aspect, R^12b is ‒CH₂Ar⁴. [00219] In various aspects, each of R^12a and R^12b together comprise a C2-C5 heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, each of R^12a and R^12b together comprise a C2-C5 heterocycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1- C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a yet further aspect, each of R^12a and R^12b together comprise a C2-C5 heterocycloalkyl substituted with 0 or 1 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, each of R^12a and R^12b together comprise a C2-C5 heterocycloalkyl monosubstituted with a group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even still further aspect, each of R^12a and R^12b together comprise a C2-C5 heterocycloalkyl and is unsubstituted. n. AR¹ GROUPS [00220] In one aspect, Ar¹ is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒ NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Ar¹ is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar¹ is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar¹ is selected from C6-C10 aryl and C2-C9 heteroaryl, and is monosubstituted with a group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar¹ is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0 groups selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. [00221] In various aspects, Ar¹ is C6-C10 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. Examples of C6-C10 aryls include, but are not limited to, phenyl and naphthyl. In a further aspect, Ar¹ is a C6-C10 aryl substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar¹ is a C6-C10 aryl substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar¹ is a C6-C10 aryl monosubstituted with a group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar¹ is C6-C10 aryl with 0 groups selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.. [00222] In various aspects, Ar¹ is selected from phenyl and naphthyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Ar¹ is selected from phenyl and naphthyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar¹ is selected from phenyl and naphthyl, and is substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar¹ is selected from phenyl and naphthyl, and is monosubstituted with a group selected from halogen, ‒CN, ‒ NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO₂H, and ‒CO₂(C1-C4 alkyl). In an even further aspect, Ar¹ is selected from phenyl and naphthyl, and is substituted with 0 groups selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1- C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. [00223] In various aspects, Ar¹ is a C2-C9 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. Examples of C2-C9 heteroaryls include, but are not limited to, oxazole, oxadiazole, indole, indazole, isoindole, pyrazole, triazole, benzothiazole, benzoxazole, quinolone, isoquinoline, pyridine, pyrimidine, and pyrazine. In a further aspect, Ar¹ is a C2-C9 heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar¹ is a C2-C9 heteroaryl substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒ NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar¹ is a C2-C9 heteroaryl monosubstituted with a group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar¹ is a C2-C9 heteroaryl substituted with 0 groups selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. [00224] In various aspects, Ar¹ is a pyridinyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Ar¹ is a pyridinyl substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒ OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar¹ is a pyridinyl substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar¹ is a pyridinyl monosubstituted with a group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1- C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar¹ is a pyridinyl substituted with 0 groups selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. [00225] In various aspects, Ar¹ is a quinolinyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Ar¹ is a quinolinyl substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒ OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar¹ is a quinolinyl substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar¹ is a quinolinyl monosubstituted with a group selected from halogen, ‒CN, ‒NH₂, ‒ OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar¹ is a quinolinyl substituted with 0 groups selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. [00226] In various aspects, Ar¹ is a isoquinolinyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Ar¹ is a isoquinolinyl substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒ NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar¹ is a isoquinolinyl substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar¹ is a isoquinolinyl monosubstituted with 0a group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar¹ is a isoquinolinyl substituted with 0 groups selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. o. AR² GROUPS [00227] In one aspect, Ar² is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒ NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒C(O)NH₂, ‒NHC(O)(C1-C4 alkyl), Cy¹, ‒OCy¹, and ‒NH(CH₂)tCy¹. In a further aspect, Ar² is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, C1-C4 aminoalkyl, ‒C(O)NH₂, ‒NHC(O)(C1-C4 alkyl), Cy¹, ‒OCy¹, and ‒NH(CH₂)_tCy¹. In a still further aspect, Ar² is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, C1-C4 aminoalkyl, ‒C(O)NH₂, ‒ NHC(O)(C1-C4 alkyl), Cy¹, ‒OCy¹, and ‒NH(CH₂)tCy¹. In yet a further aspect, Ar² is selected from C6-C14 aryl and C2-C10 heteroaryl, and is monosubstitued with a group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, C1-C4 aminoalkyl, ‒C(O)NH₂, ‒NHC(O)(C1-C4 alkyl), Cy¹, ‒OCy¹, and ‒NH(CH₂)_tCy¹. In an even further aspect, Ar² is selected from C6-C14 aryl and C2-C10 heteroaryl and is unsubstituted. [00228] In various aspects, Ar² is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒ NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Ar² is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and C1-C4 aminoalkyl. In a still further aspect, Ar² is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and C1-C4 aminoalkyl. In yet a further aspect, Ar² is selected from C6-C14 aryl and C2-C10 heteroaryl, and is monosubstitued with a group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and C1-C4 aminoalkyl. In an even further aspect, Ar² is selected from C6-C14 aryl and C2-C10 heteroaryl, and is unsubstituted. [00229] In various aspects, Ar² is C6-C14 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒C(O)NH₂, ‒NHC(O)(C1-C4 alkyl), Cy¹, ‒OCy¹, and ‒NH(CH₂)_tCy¹. In a further aspect, Ar² is C6-C14 aryl substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, C1-C4 aminoalkyl, ‒C(O)NH₂, ‒NHC(O)(C1-C4 alkyl), Cy¹, ‒OCy¹, and ‒NH(CH₂)_tCy¹. In a still further aspect, Ar² is C6-C14 aryl substituted with 0 or 1 group selected from halogen, ‒CN, ‒ NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, C1-C4 aminoalkyl, ‒C(O)NH₂, ‒NHC(O)(C1-C4 alkyl), Cy¹, ‒OCy¹, and ‒NH(CH₂)tCy¹. In yet a further aspect, Ar² is C6-C14 aryl monosubstitued with a group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, C1-C4 aminoalkyl, ‒C(O)NH₂, ‒ NHC(O)(C1-C4 alkyl), Cy¹, ‒OCy¹, and ‒NH(CH₂)_tCy¹. In an even further aspect, Ar² is an unsubstituted C6-C14 aryl. [00230] In various aspects, Ar² is a C6-C14 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Ar² is a C6-C14 aryl substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar² is a C6-C14 aryl substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar² is a C6-C14 aryl monosubstitued with a group selected from halogen, ‒CN, ‒NH₂, ‒ OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar² is an unsubstituted C6-C14 aryl. [00231] In various aspects, Ar² is C2-C10 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒C(O)NH₂, ‒NHC(O)(C1-C4 alkyl), Cy¹, ‒OCy¹, and ‒NH(CH₂)_tCy¹. In a further aspect, Ar² is C2-C10 heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, C1-C4 aminoalkyl, ‒C(O)NH₂, ‒NHC(O)(C1-C4 alkyl), Cy¹, ‒OCy¹, and ‒ NH(CH₂)tCy¹. In a still further aspect, Ar² is C2-C10 heteroaryl substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, C1-C4 aminoalkyl, ‒C(O)NH₂, ‒ NHC(O)(C1-C4 alkyl), Cy¹, ‒OCy¹, and ‒NH(CH₂)_tCy¹. In yet a further aspect, Ar² is C2-C10 heteroaryl monosubstitued with a group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, C1-C4 aminoalkyl, ‒C(O)NH₂, ‒NHC(O)(C1-C4 alkyl), Cy¹, ‒OCy¹, and ‒ NH(CH₂)tCy¹. In an even further aspect, Ar² is an unsubstituted C2-C10 heteroaryl. [00232] In various aspects, Ar² is a C2-C10 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Ar² is a C2-C10 heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar² is a C2-C10 heteroaryl substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar² is a C2-C10 heteroaryl monosubstitued with a group selected from halogen, ‒ CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1- C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar² is an unsubstituted C2-C10 heteroaryl. [00233] In various aspects, Ar² is selected from C6-C14 aryl and C2-C10 heteroaryl, and is monosubstitued with a group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. [00234] In various aspects, Ar² is phenyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Ar² is phenyl substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar² is phenyl substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar² is phenyl monosubstitued with a group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar² is unsubstituted phenyl. [00235] In various aspects, Ar² is phenyl monosubstitued with a group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. [00236] In various aspects, Ar² is phenyl monosubstituted with a C1-C4 haloalkyl group. In a further aspect, Ar² is phenyl monosubstituted with a group selected from ‒CH₂F, ‒ CH₂CH₂F, ‒CH₂CH₂CH₂F, ‒CH(CH₃)CH₂F, ‒CH₂Cl, ‒CH₂CH₂Cl, ‒CH₂CH₂CH₂Cl, and ‒ CH(CH₃)CH₂Cl. In a still further aspect, Ar² is phenyl monosubstituted with a group selected from ‒CH₂F, ‒CH₂CH₂F, ‒CH₂Cl, and ‒CH₂CH₂Cl. In a still further aspect, Ar² is phenyl monosubstitued with a group selected from ‒CH₂F and ‒CH₂Cl. p. AR³ GROUPS [00237] In one aspect, Ar³ is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒ NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Ar³ is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar³ is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar³ is selected from C6-C10 aryl and C2-C9 heteroaryl, and is monosubstituted with a group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar³ is selected from C6-C10 aryl and C2-C9 heteroaryl, and is unsubstituted. [00238] In various aspects, Ar³ is C6-C10 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. Examples of C6-C10 aryls include, but are not limited to, phenyl and naphthyl. In a further aspect, Ar³ is a C6-C10 aryl substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar³ is a C6-C10 aryl substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar³ is a C6-C10 aryl monosubstituted with a group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar³ is an unsubstituted C6-C10 aryl. [00239] In various aspects, Ar³ is selected from phenyl and naphthyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Ar³ is selected from phenyl and naphthyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar³ is selected from phenyl and naphthyl, and is substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar³ is selected from phenyl and naphthyl, and is monosubstituted with a group selected from halogen, ‒CN, ‒ NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO₂H, and ‒CO₂(C1-C4 alkyl). In an even further aspect, Ar³ is selected from unsubstituted phenyl and unsubstituted naphthyl. [00240] In various aspects, Ar³ is a C2-C9 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. Examples of C2-C9 heteroaryls include, but are not limited to, oxazole, oxadiazole, indole, indazole, isoindole, pyrazole, triazole, benzothiazole, benzoxazole, quinolone, isoquinoline, pyridine, pyrimidine, and pyrazine. In a further aspect, Ar³ is a C2-C9 heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar³ is a C2-C9 heteroaryl substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒ NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar³ is a C2-C9 heteroaryl monosubstituted with a group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar³ is an unsubstituted C2-C9 heteroaryl. [00241] In various aspects, Ar³ is a pyridinyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Ar³ is a pyridinyl substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒ OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar³ is a pyridinyl substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar³ is a pyridinyl monosubstituted with a group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1- C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar³ is an unsubstituted pyridinyl. [00242] In various aspects, Ar³ is a quinolinyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Ar³ is a quinolinyl substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒ OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar³ is a quinolinyl substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar³ is a quinolinyl monosubstituted with a group selected from halogen, ‒CN, ‒NH₂, ‒ OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar³ is an unsubstituted quinolinyl. [00243] In various aspects, Ar³ is a isoquinolinyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Ar³ is a isoquinolinyl substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒ NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar³ is a isoquinolinyl substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar³ is a isoquinolinyl monosubstituted with 0a group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar³ is an unsubstituted isoquinolinyl. q. AR⁴ GROUPS [00244] In one aspect, Ar⁴ is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒ NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Ar⁴ is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar⁴ is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar⁴ is selected from C6-C10 aryl and C2-C9 heteroaryl, and is monosubstituted with a group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar⁴ is selected from C6-C10 aryl and C2-C9 heteroaryl, and is unsubstituted. [00245] In various aspects, Ar⁴ is C6-C10 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. Examples of C6-C10 aryls include, but are not limited to, phenyl and naphthyl. In a further aspect, Ar⁴ is a C6-C10 aryl substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar⁴ is a C6-C10 aryl substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar⁴ is a C6-C10 aryl monosubstituted with a group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar⁴ is an unsubstituted C6-C10 aryl. [00246] In various aspects, Ar⁴ is selected from phenyl and naphthyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Ar⁴ is selected from phenyl and naphthyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar⁴ is selected from phenyl and naphthyl, and is substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar⁴ is selected from phenyl and naphthyl, and is monosubstituted with a group selected from halogen, ‒CN, ‒ NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO₂H, and ‒CO₂(C1-C4 alkyl). In an even further aspect, Ar⁴ is selected from unsubstituted phenyl and unsubstituted naphthyl. [00247] In various aspects, Ar⁴ is a C2-C9 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. Examples of 5- to 10- membered heteroaryls include, but are not limited to, oxazole, oxadiazole, indole, indazole, isoindole, pyrazole, triazole, benzothiazole, benzoxazole, quinolone, isoquinoline, pyridine, pyrimidine, and pyrazine. In a further aspect, Ar⁴ is a C2-C9 heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar⁴ is a C2-C9 heteroaryl substituted with 0 or 1 group selected from halogen, ‒ CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1- C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar⁴ is a C2-C9 heteroaryl monosubstituted with a group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar⁴ is an unsubstituted C2-C9 heteroaryl. [00248] In various aspects, Ar⁴ is a pyridinyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Ar⁴ is a pyridinyl substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒ OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar⁴ is a pyridinyl substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar⁴ is a pyridinyl monosubstituted with a group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1- C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar⁴ is an unsubstituted pyridinyl. [00249] In various aspects, Ar⁴ is a quinolinyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Ar⁴ is a quinolinyl substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒ OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar⁴ is a quinolinyl substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar⁴ is a quinolinyl monosubstituted with a group selected from halogen, ‒CN, ‒NH₂, ‒ OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar⁴ is an unsubstituted quinolinyl. [00250] In various aspects, Ar⁴ is a isoquinolinyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Ar⁴ is a isoquinolinyl substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒ NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar⁴ is a isoquinolinyl substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar⁴ is a isoquinolinyl monosubstituted with 0a group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar⁴ is an unsubstituted isoquinolinyl. r. AR⁵ GROUPS [00251] In various aspects, Ar⁵ is a C2-C9 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. Examples of C2-C9 heteroaryls include, but are not limited to, oxazole, oxadiazole, indole, indazole, isoindole, pyrazole, triazole, benzothiazole, benzoxazole, quinolone, isoquinoline, pyridine, pyrimidine, and pyrazine. In a further aspect, Ar⁵ is a C2-C9 heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar⁵ is a C2-C9 heteroaryl substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒ NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Ar⁵ is a C2-C9 heteroaryl monosubstituted with a group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar⁵ is an unsubstituted C2-C9 heteroaryl. [00252] In various aspects, Ar⁵ is selected from triazolyl, oxadiazolyl, thiazolyl, tetrazolyl, oxazolyl, and thiadiazolyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Ar⁵ is selected from triazolyl, oxadiazolyl, thiazolyl, tetrazolyl, oxazolyl, and thiadiazolyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a yet further aspect, Ar⁵ is selected from triazolyl, oxadiazolyl, thiazolyl, tetrazolyl, oxazolyl, and thiadiazolyl, and is substituted with 0 or 1 groups independently selected from halogen, ‒CN, ‒ NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Ar⁵ is selected from triazolyl, oxadiazolyl, thiazolyl, tetrazolyl, oxazolyl, and thiadiazolyl, and is monosubstituted with a group selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar⁵ is selected from triazolyl, oxadiazolyl, thiazolyl, tetrazolyl, oxazolyl, and thiadiazolyl, and is unsubstituted. [00253] In various aspects, Ar⁵ is selected from triazolyl, oxadiazolyl, thiazolyl, tetrazolyl, oxazolyl, and thiadiazolyl, and is unsubstituted. In a further aspect, Ar⁵ is selected from triazolyl, oxadiazolyl, tetrazolyl, and oxazolyl, and is unsubstituted. In a yet further aspect, Ar⁵ is selected from triazolyl and tetrazolyl, and is unsubstituted. In an even further aspect, Ar⁵ is an unsubstituted triazole. [00254] In various aspects, Ar⁵ is a structure selected from: ^, wherein * denotes a connection to ‒(CH₂)n‒ and ** denotes a connection to Ar¹. s. CY¹ GROUPS [00255] In one aspect, Cy¹ is selected from C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C6-C14 aryl, and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl. In a further aspect, Cy¹ is selected from C3- C6 cycloalkyl, C3-C6 heterocycloalkyl, C6-C14 aryl, and C2-C10 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl. In a yet further aspect, Cy¹ is selected from C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C6-C14 aryl, and C2-C10 heteroaryl, and is substituted with 0 or 1 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl. In a still further aspect, Cy¹ is selected from C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C6-C14 aryl, and C2-C10 heteroaryl, and is monosubstituted with a groups selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl. In an even further aspect, Cy¹ is selected from C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C6-C14 aryl, and C2-C10 heteroaryl, and is unsubstituted. [00256] In one aspect, Cy¹ is selected from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒ OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl. In a further aspect, Cy¹ is selected from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl. In a yet further aspect, Cy¹ is selected from C3- C6 cycloalkyl and C3-C6 heterocycloalkyl, and is substituted with 0 or 1 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl. In a still further aspect, Cy¹ is selected from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl, and is monosubstituted with a groups selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl. In an even further aspect, Cy¹ is selected from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl, and is unsubstituted. [00257] In one aspect, Cy¹ is selected from C6-C14 aryl, and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒ NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl. In a further aspect, Cy¹ is selected from C6-C14 aryl, and C2-C10 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl. In a yet further aspect, Cy¹ is selected from C6-C14 aryl, and C2-C10 heteroaryl, and is substituted with 0 or 1 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒ NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl. In a still further aspect, Cy¹ is selected from C6-C14 aryl, and C2-C10 heteroaryl, and is monosubstituted with a groups selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl. In an even further aspect, Cy¹ is selected from C6-C14 aryl, and C2-C10 heteroaryl, and is unsubstituted. [00258] In one aspect, Cy¹ is a C3-C6 cycloalkyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl. In a further aspect, Cy¹ is a C3-C6 cycloalkyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl. In a yet further aspect, Cy¹ is a C3-C6 cycloalkyl, and is substituted with 0 or 1 groups independently selected from halogen, ‒CN, ‒ NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl. In a still further aspect, Cy¹ is a C3-C6 cycloalkyl, and is monosubstituted with a groups selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl. In an even further aspect, Cy¹ is a C3-C6 cycloalkyl, and is unsubstituted. [00259] In one aspect, Cy¹ is a C3-C6 heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl. In a further aspect, Cy¹ is a C3-C6 heterocycloalkyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl. In a yet further aspect, Cy¹ is a C3-C6 heterocycloalkyl, and is substituted with 0 or 1 groups independently selected from halogen, ‒ CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1- C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl. In a still further aspect, Cy¹ is a C3-C6 heterocycloalkyl, and is monosubstituted with a groups selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl. In an even further aspect, Cy¹ is a C3-C6 heterocycloalkyl, and is unsubstituted. [00260] In one aspect, Cy¹ is a C6-C14 aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl. In a further aspect, Cy¹ is a C6- C14 aryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒ NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl. In a yet further aspect, Cy¹ is selected a C6-C14 aryl, and is substituted with 0 or 1 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl. In a still further aspect, Cy¹ is a C6-C14 aryl, and is monosubstituted with a groups selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl. In an even further aspect, Cy¹ is a C6-C14 aryl, and is unsubstituted. [00261] In one aspect, Cy¹ is a C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl. In a further aspect, Cy¹ is a C2-C10 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl. In a yet further aspect, Cy¹ is selected a C2- C10 heteroaryl, and is substituted with 0 or 1 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl. In a still further aspect, Cy¹ is a C2-C10 heteroaryl, and is monosubstituted with a groups selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl. In an even further aspect, Cy¹ is a C2-C10 heteroaryl, and is unsubstituted. 2. EXEMPLARY COMPOUNDS [00262] In one aspect, a compound can be present as one or more of the following structures: ,

,

, ,

or a pharmaceutically acceptable salt thereof. [00263] In one aspect, a compound can be present as the following structure:

, or a pharmaceutically acceptable salt thereof. 3. PROPHETIC EXEMPLARY COMPOUNDS [00264] The following compound examples are prophetic, and can be prepared using the synthesis methods described herein above and other general methods as needed as would be known to one skilled in the art. It is anticipated that the prophetic compounds would be active as inhibitors of NOX4 signaling, and such activity can be determined using the assay methods described herein below. [00265] Thus, in one aspect, a compound is: ,

, ,

,

, ,

, ,

, ,

,

, , ,

,

,

,

,

, or a pharmaceutically acceptable salt thereof. [00266] In one aspect, a compound is: ,

, ,

,

,

, or a pharmaceutically acceptable salt thereof. [00267] In another aspect, a compound is: ,

, , or a pharmaceutically acceptable salt thereof. [00268] In one aspect, a compound can be present as the following structure: , or a pharmaceutically acceptable salt thereof. [00269] It is contemplated that one or more compounds can optionally be omitted from the disclosed invention. [00270] It is understood that the disclosed compounds can be used in connection with the disclosed methods, compositions, kits, and uses. [00271] It is understood that pharmaceutical acceptable derivatives of the disclosed compounds can be used also in connection with the disclosed methods, compositions, kits, and uses. The pharmaceutical acceptable derivatives of the compounds can include any suitable derivative, such as pharmaceutically acceptable salts as discussed below, isomers, radiolabeled analogs, tautomers, and the like. C. PHARMACEUTICAL COMPOSITIONS [00272] In one aspect, disclosed are pharmaceutical compositions comprising an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [00273] Thus, in one aspect, disclosed are pharmaceutical compositions comprising an effective amount of a compound having a structure represented by a formula: , wherein n is selected from 0, 1, 2, 3, 4, and 5, and wherein m is selected from 0 and 1, provided that when n is 0 then m is 0; wherein o is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8; wherein A¹ is selected from ‒O‒ and ‒CH₂‒, provided that when A¹ is O, then o is not 0 or 1; wherein L¹ is selected from C2 alkenyl, C2 alkynyl, ‒NHSO₂‒, ‒SO₂NH‒, ‒NHC(O)‒, ‒C(O)NH‒, and Ar⁵; wherein Ar⁵, when present, is a C2-C9 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R^1a, R^1b, R^1c, and R^1d is independently selected from hydrogen, halogen, ‒CN, ‒NH₂, ‒OH, and ‒NO₂; wherein R² is selected from hydrogen and C1-C4 alkyl; wherein one of R^3a and R^3b is C1-C4 alkyl and one of R^3a and R^3b is a structure selected from:

^; wherein R¹³ is selected from hydrogen and ‒OH; and wherein Ar¹ is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [00274] In one aspect, disclosed are pharmaceutical compositions comprising an effective amount of a compound having a structure represented by a formula: , wherein r is selected from 1, 2, 3, 4, 5, 6, 7, and 8; wherein one of R^3a and R^3b is C1-C4 alkyl and one of R^3a and R^3b is a structure selected from:

^; wherein R¹³ is selected from hydrogen and ‒OH; wherein each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and wherein R¹⁰ is selected from hydrogen and a structure: ; wherein s is selected from 0 and 1; wherein A² is selected from ‒C(O)‒ and ‒SO2‒; wherein L² is ‒(CR^11aR^11b)₂‒; wherein each occurrence of R^11a and R^11b is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl, or wherein each of R^11a and R^11b together comprise =O; wherein R⁵, when present, is selected from hydrogen and C1-C4 alkyl; wherein R⁶ is selected from ‒NR^12aR^12b and Ar²; wherein R^12a is selected from hydrogen, C1-C4 alkyl, and Ar³; wherein Ar³ is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and wherein R^12b is selected from C1-C4 alkyl, ‒CH₂Ar⁴, and Ar⁴; wherein Ar⁴ is selected from C6- C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or wherein each of R^12a and R^12b together comprise a C2-C5 heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein Ar² is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒C(O)NH₂, ‒NHC(O)(C1-C4 alkyl), Cy¹, ‒OCy¹, and ‒NH(CH₂)_tCy¹; wherein t is selected from 0, 1, and 2; and wherein Cy¹ is selected from C3- C6 cycloalkyl, C3-C6 heterocycloalkyl, C6-C14 aryl, and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [00275] In various aspects, the compounds and compositions of the invention can be administered in pharmaceutical compositions, which are formulated according to the intended method of administration. The compounds and compositions described herein can be formulated in a conventional manner using one or more physiologically acceptable carriers or excipients. For example, a pharmaceutical composition can be formulated for local or systemic administration, e.g., administration by drops or injection into the ear, insufflation (such as into the ear), intravenous, topical, or oral administration. [00276] The nature of the pharmaceutical compositions for administration is dependent on the mode of administration and can readily be determined by one of ordinary skill in the art. In various aspects, the pharmaceutical composition is sterile or sterilizable. The therapeutic compositions featured in the invention can contain carriers or excipients, many of which are known to skilled artisans. Excipients that can be used include buffers (for example, citrate buffer, phosphate buffer, acetate buffer, and bicarbonate buffer), amino acids, urea, alcohols, ascorbic acid, phospholipids, polypeptides (for example, serum albumin), EDTA, sodium chloride, liposomes, mannitol, sorbitol, water, and glycerol. The nucleic acids, polypeptides, small molecules, and other modulatory compounds featured in the invention can be administered by any standard route of administration. For example, administration can be parenteral, intravenous, subcutaneous, or oral. A modulatory compound can be formulated in various ways, according to the corresponding route of administration. For example, liquid solutions can be made for administration by drops into the ear, for injection, or for ingestion; gels or powders can be made for ingestion or topical application. Methods for making such formulations are well known and can be found in, for example, Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA 1990. [00277] In various aspects, the disclosed pharmaceutical compositions comprise the disclosed compounds (including pharmaceutically acceptable salt(s) thereof) as an active ingredient, a pharmaceutically acceptable carrier, and, optionally, other therapeutic ingredients or adjuvants. The instant compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy. [00278] In various aspects, the pharmaceutical compositions of this invention can include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of the compounds of the invention. The compounds of the invention, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds. [00279] The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. [00280] In preparing the compositions for oral dosage form, any convenient pharmaceutical media can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets can be coated by standard aqueous or nonaqueous techniques [00281] A tablet containing the composition of this invention can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. [00282] The pharmaceutical compositions of the present invention comprise a compound of the invention (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents or adjuvants. The instant compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy. [00283] Pharmaceutical compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms. [00284] Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof. [00285] Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, mouth washes, gargles, and the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations can be prepared, utilizing a compound of the invention, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency. [00286] In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above can include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound of the invention, and/or pharmaceutically acceptable salts thereof, can also be prepared in powder or liquid concentrate form. [00287] In a further aspect, an effective amount is a therapeutically effective amount. In a still further aspect, an effective amount is a prophylactically effective amount. [00288] In a further aspect, the pharmaceutical composition is administered to a mammal. In a still further aspect, the mammal is a human. In an even further aspect, the human is a patient. [00289] In a further aspect, the pharmaceutical composition is used to treat a disorder associated with over-activation of NOX4 signaling. In a still further aspect, the pharmaceutical composition is used to treat a disorder that is a fibrotic disorder or acute respiratory distress syndrome (ARDS). In a yet further aspect, the fibrotic disorder is pulmonary fibrosis, heart fibrosis, kidney fibrosis, liver fibrosis, skin fibrosis, mediastinal fibrosis, retroperitoneal cavity fibrosis, bone marrow fibrosis, or scleroderma or systemic sclerosis. [00290] It is understood that the disclosed compositions can be prepared from the disclosed compounds. It is also understood that the disclosed compositions can be employed in the disclosed methods of using. D. METHODS OF INHIBITING NADPH OXIDASE 4 (NOX4) SIGNALING IN A CELL [00291] In various aspects, the compounds and compositions disclosed herein are useful for inhibiting NADPH Oxidase 4 (NOX4) signaling in a cell. Thus, in one aspect, disclosed are methods of inhibiting NADPH Oxidase 4 (NOX4) signaling in a cell, the method comprising contacting the cell with an effective amount of a compound having a structure represented by a formula: , wherein n is selected from 0, 1, 2, 3, 4, and 5, and wherein m is selected from 0 and 1, provided that when n is 0 then m is 0; wherein o is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8; wherein A¹ is selected from ‒O‒ and ‒CH₂‒, provided that when A¹ is O, then o is not 0 or 1; wherein L¹ is selected from C2 alkenyl, C2 alkynyl, ‒NHSO₂‒, ‒SO₂NH‒, ‒NHC(O)‒, ‒C(O)NH‒, and Ar⁵; wherein Ar⁵, when present, is a C2-C9 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R^1a, R^1b, R^1c, and R^1d is independently selected from hydrogen, halogen, ‒CN, ‒NH₂, ‒OH, and ‒NO₂; wherein R² is selected from hydrogen and C1-C4 alkyl; wherein one of R^3a and R^3b is C1-C4 alkyl and one of R^3a and R^3b is a structure selected from:

^; wherein R¹³ is selected from hydrogen and ‒OH; and wherein Ar¹ is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof. [00292] In one aspect, disclosed are methods of inhibiting NADPH Oxidase 4 (NOX4) signaling in a cell, the method comprising contacting the cell with an effective amount of a compound having a structure represented by a formula: , wherein r is selected from 1, 2, 3, 4, 5, 6, 7, and 8; wherein one of R^3a and R^3b is C1-C4 alkyl and one of R^3a and R^3b is a structure selected from:

^; wherein R¹³ is selected from hydrogen and ‒OH; wherein each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and wherein R¹⁰ is selected from hydrogen and a structure: ; wherein s is selected from 0 and 1; wherein A² is selected from ‒C(O)‒ and ‒SO2‒; wherein L² is ‒(CR^11aR^11b)₂‒; wherein each occurrence of R^11a and R^11b is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl, or wherein each of R^11a and R^11b together comprise =O; wherein R⁵, when present, is selected from hydrogen and C1-C4 alkyl; wherein R⁶ is selected from ‒NR^12aR^12b and Ar²; wherein R^12a is selected from hydrogen, C1-C4 alkyl, and Ar³; wherein Ar³ is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and wherein R^12b is selected from C1-C4 alkyl, ‒CH₂Ar⁴, and Ar⁴; wherein Ar⁴ is selected from C6- C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or wherein each of R^12a and R^12b together comprise a C2-C5 heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein Ar² is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒C(O)NH₂, ‒NHC(O)(C1-C4 alkyl), Cy¹, ‒OCy¹, and ‒NH(CH₂)_tCy¹; wherein t is selected from 0, 1, and 2; and wherein Cy¹ is selected from C3- C6 cycloalkyl, C3-C6 heterocycloalkyl, C6-C14 aryl, and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof. [00293] In various aspects, the cell is mammalian. [00294] In various aspects, the cell is a human. [00295] In various aspects, the cell has been isolated from a mammal prior to the contacting step. [00296] In various aspects, the contacting is ex vivo. [00297] In various aspects, the contacting is in vitro. [00298] In various aspects, contacting is via administration to a mammal. In a further aspect, the mammal has been diagnosed with a need for inhibiting NOX4 signaling prior to the administering step. In a further aspect, the mammal has been diagnosed with a need for treatment of a disorder associated with over-activation of NOX4 signaling prior to the administering step. In a yet further aspect, the disorder is a fibrotic disorder or acute respiratory distress syndrome (ARDS). In a still further aspect, the mammal has been diagnosed with a need for inhibition of NOX4 signaling prior to the administering step. E. METHODS OF INHIBITING NADPH OXIDASE 4 (NOX4) SIGNALING IN A SUBJECT [00299] In one aspect, disclosed are methods of inhibiting NADPH Oxidase 4 (NOX4) signaling in a subject in need thereof, the method comprising administering to the subject an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof. Thus, in one aspect, disclosed are methods of inhibiting NADPH Oxidase 4 (NOX4) signaling in a subject, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula: , wherein n is selected from 0, 1, 2, 3, 4, and 5, and wherein m is selected from 0 and 1, provided that when n is 0 then m is 0; wherein o is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8; wherein A¹ is selected from ‒O‒ and ‒CH₂‒, provided that when A¹ is O, then o is not 0 or 1; wherein L¹ is selected from C2 alkenyl, C2 alkynyl, ‒NHSO₂‒, ‒SO₂NH‒, ‒NHC(O)‒, ‒C(O)NH‒, and Ar⁵; wherein Ar⁵, when present, is a C2-C9 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R^1a, R^1b, R^1c, and R^1d is independently selected from hydrogen, halogen, ‒CN, ‒NH₂, ‒OH, and ‒NO₂; wherein R² is selected from hydrogen and C1-C4 alkyl; wherein one of R^3a and R^3b is C1-C4 alkyl and one of R^3a and R^3b is a structure selected from:

^; wherein R¹³ is selected from hydrogen and ‒OH; and wherein Ar¹ is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof. [00300] In one aspect, disclosed are methods of inhibiting NADPH Oxidase 4 (NOX4) signaling in a subject, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula: , wherein r is selected from 1, 2, 3, 4, 5, 6, 7, and 8; wherein one of R^3a and R^3b is C1-C4 alkyl and one of R^3a and R^3b is a structure selected from:

^; wherein R¹³ is selected from hydrogen and ‒OH; wherein each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and wherein R¹⁰ is selected from hydrogen and a structure: ; wherein s is selected from 0 and 1; wherein A² is selected from ‒C(O)‒ and ‒SO2‒; wherein L² is ‒(CR^11aR^11b)₂‒; wherein each occurrence of R^11a and R^11b is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl, or wherein each of R^11a and R^11b together comprise =O; wherein R⁵, when present, is selected from hydrogen and C1-C4 alkyl; wherein R⁶ is selected from ‒NR^12aR^12b and Ar²; wherein R^12a is selected from hydrogen, C1-C4 alkyl, and Ar³; wherein Ar³ is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and wherein R^12b is selected from C1-C4 alkyl, ‒CH₂Ar⁴, and Ar⁴; wherein Ar⁴ is selected from C6- C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or wherein each of R^12a and R^12b together comprise a C2-C5 heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein Ar² is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒C(O)NH₂, ‒NHC(O)(C1-C4 alkyl), Cy¹, ‒OCy¹, and ‒NH(CH₂)_tCy¹; wherein t is selected from 0, 1, and 2; and wherein Cy¹ is selected from C3- C6 cycloalkyl, C3-C6 heterocycloalkyl, C6-C14 aryl, and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof. [00301] In various aspects, the subject is a mammal. [00302] In various aspects, the subject is a human. [00303] In various aspects, the subject has been diagnosed with a need for inhibiting NOX4 signaling to the administering step. [00304] In various aspects, the method further comprising identifying a subject in need of inhibition of NOX4 signaling as further described herein. F. METHODS OF TREATING A FIBROTIC DISORDER IN A SUBJECT [00305] In one aspect, disclosed are methods of treating a fibrotic disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof. The reactive oxygen species (ROS)-generating enzyme, NADPH oxidase (Nox4), is a critical mediator of myofibroblast functions and Nox4 expression is elevated in the lungs of patients with IPF and in IPF lung fibroblasts. [00306] Thus, in one aspect, disclosed are methods of treating a fibrotic disorder in a subject, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula: , wherein n is selected from 0, 1, 2, 3, 4, and 5, and wherein m is selected from 0 and 1, provided that when n is 0 then m is 0; wherein o is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8; wherein A¹ is selected from ‒O‒ and ‒CH₂‒, provided that when A¹ is O, then o is not 0 or 1; wherein L¹ is selected from C2 alkenyl, C2 alkynyl, ‒NHSO₂‒, ‒SO₂NH‒, ‒NHC(O)‒, ‒C(O)NH‒, and Ar⁵; wherein Ar⁵, when present, is a C2-C9 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R^1a, R^1b, R^1c, and R^1d is independently selected from hydrogen, halogen, ‒CN, ‒NH₂, ‒OH, and ‒NO₂; wherein R² is selected from hydrogen and C1-C4 alkyl; wherein one of R^3a and R^3b is C1-C4 alkyl and one of R^3a and R^3b is a structure selected from: ^; wherein R¹³ is selected from hydrogen and ‒OH; and wherein Ar¹ is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof. [00307] In one aspect, disclosed are methods of treating a fibrotic disorder in a subject, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula: , wherein r is selected from 1, 2, 3, 4, 5, 6, 7, and 8; wherein one of R^3a and R^3b is C1-C4 alkyl and one of R^3a and R^3b is a structure selected from: ^; wherein R¹³ is selected from hydrogen and ‒OH; wherein each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and wherein R¹⁰ is selected from hydrogen and a structure: ; wherein s is selected from 0 and 1; wherein A² is selected from ‒C(O)‒ and ‒SO2‒; wherein L² is ‒(CR^11aR^11b)₂‒; wherein each occurrence of R^11a and R^11b is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl, or wherein each of R^11a and R^11b together comprise =O; wherein R⁵, when present, is selected from hydrogen and C1-C4 alkyl; wherein R⁶ is selected from ‒NR^12aR^12b and Ar²; wherein R^12a is selected from hydrogen, C1-C4 alkyl, and Ar³; wherein Ar³ is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and wherein R^12b is selected from C1-C4 alkyl, ‒CH₂Ar⁴, and Ar⁴; wherein Ar⁴ is selected from C6- C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or wherein each of R^12a and R^12b together comprise a C2-C5 heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein Ar² is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒C(O)NH₂, ‒NHC(O)(C1-C4 alkyl), Cy¹, ‒OCy¹, and ‒NH(CH₂)_tCy¹; wherein t is selected from 0, 1, and 2; and wherein Cy¹ is selected from C3- C6 cycloalkyl, C3-C6 heterocycloalkyl, C6-C14 aryl, and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof. Examples of fibrotic disorders include, but are not limited to, pulmonary fibrosis, heart fibrosis, kidney fibrosis, liver fibrosis, skin fibrosis, mediastinal fibrosis, retroperitoneal cavity fibrosis, bone marrow fibrosis, or scleroderma or systemic sclerosis. [00308] In various aspects, the fibrotic disorder is pulmonary fibrosis. In a further aspect, the pulmonary fibrosis is idiopathic pulmonary fibrosis. [00309] In various aspects, the subject is a mammal. [00310] In various aspects, the subject is a human. [00311] In various aspects, the subject has been diagnosed with the fibrotic disorder prior to the administering step. [00312] In various aspects, the method further comprises the step of identifying a subject in need of treatment of the fibrotic disorder. [00313] In various aspects, the method further comprises administering to the subject an anti-fibrotic agent. Examples of anti-fibrotic agents include, but are not limited to, nintedanib and pirfenidone. G. METHODS OF TREATING ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS) IN A SUBJECT [00314] In one aspect, disclosed are methods treating acute respiratory distress syndrome (ARDS) in a subject in need thereof, the method comprising administering to the subject an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof. Oxidative stress has been implicated as a major contributor to the pathogenesis of ARDS. In addition, aged mice with severe ARDS exhibited sustained upregulation of Nox4 and elevated ROS levels. As such, strategies that block the source of ROS production are more specific and effective in comparison to antioxidant strategies because the damage from highly reactive ROS molecules occur rapidly. [00315] Pulmonary endothelial cells (ECs) line the surface of the lung vasculature and are a critical regulator of vascular homeostasis. Located at the interface between the bloodstream and lung tissue, the endothelium serves as a barrier that regulates the influx of inflammatory cells and fluid into the interstitial space. A key pathological feature of ARDS is EC barrier disruption, which results in increased vascular permeability and inflammatory influx. The accumulation of inflammatory cells and protein-rich fluid into the alveolar space can result in alveolar filling, hypoxemia, and ultimately respiratory failure. Autopsy reports from COVID-19 patients revealed severe injury to lung ECs accompanied by significant inflammatory cell influx, and transcriptomics are consistent with EC dysregulation. Thus, it is theorized that a successful treatment for ARDS and COVID-19-associated ARDS would combat EC barrier dysfunction and inflammatory injury to circumvent pulmonary edema and reduce the risk of respiratory failure and death. [00316] Further, as noted above, a substantial body of evidence has implicated oxidative stress as a major contributor to the pathogenesis of ARDS. Numerous studies have demonstrated high levels of ROS in the lungs following acute lung injury (ALI) in animal models and in ARDS patients. Excessive ROS production has been shown to promote EC barrier dysfunction and increased vascular permeability, which amplifies tissue damage, capillary leak, and pulmonary edema. Elevated ROS levels in ARDS patients have also been linked to increased oxidatively modified proteins, which perpetuate barrier dysfunction and inflammation leading to lung injury. ARDS patients with greater levels of oxidative molecular damage have increased mortality rates; thus, minimizing oxidative stress is a promising approach to mitigate lung damage and improve survival. Unfortunately, despite the well-recognized role of oxidative stress in ARDS pathogenesis, the mechanisms that drive ARDS-associated redox imbalance are largely unknown. Thus, the ability to precisely target key mediators of this process has proved challenging. Moreover, although studies evaluating the effectiveness of antioxidants in animal models of ALI have been promising, clinical trials with antioxidant therapies have failed to reduce ARDS mortality. One potential explanation is that while antioxidants function to scavenge existing ROS (that has already been produced), they do not block the source of ROS production. Oxidants are highly reactive molecules, and once generated, can rapidly induce damage to cells and surrounding tissues and induce inflammatory responses. Thus, strategies that directly block the source of ROS production are likely to be more specific and effective in comparison to antioxidant strategies because the damage from highly reactive ROS molecules may occur rapidly. The proposed treatment method seeks to develop a novel therapeutic, which targets the critical pathological features of ARDS: excessive ROS production, barrier dysfunction, and inflammatory injury. [00317] As life expectancy continues to increase, there is a demographic shift toward a growing elderly population, including the U.S. elderly veteran population. ARDS disproportionately affects the elderly population; higher incidence and mortality are associated with advancing age. ARDS incidence is 16/100,000 persons for adolescents (15-19 years) vs. 306/100,000 among the elderly (75-84 years). ARDS mortality increases with age; 24% in adolescents vs.60% in elderly. ARDS mortality is 2-fold higher in patients >70 years vs. under 70, and elderly survivors have more difficulties recovering. Older age is also a significant risk factor for COVID-19-associated hospitalization, including the development of ARDS and progression from ARDS to death; 75% of hospitalized COVID-19 patients were ≥50 years. Of those who required intensive care, mechanical ventilation, or died, the median age was 63. COVID-19 mortality rate is also highly correlated to older age: 42% (80-89 years), 32% (70-79), 8% (60-69), and 2% (50-59). Importantly, the key pathologic features of ARDS (oxidative stress, barrier dysfunction, and inflammation – discussed above) are increased in elderly patients. Despite overwhelming epidemiologic studies that increased susceptibility and poor outcomes among the elderly, therapeutic targeting of age-dependent pathological mechanisms has yet to be explored in the development of ARDS treatments. This may explain the lack of successful treatment options for ARDS, which primarily afflicts the elderly. Data herein suggests that targeting age-dependent pathological mechanisms may be the key to improving survival outcomes for elderly ARDS patients. The proposed treatment method seeks to develop a novel therapeutic strategy to correct age-dependent dysfunction associated with severe ARDS in the elderly. [00318] Thus, in one aspect, disclosed are methods of treating acute respiratory distress syndrome (ARDS) in a subject, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula: , wherein n is selected from 0, 1, 2, 3, 4, and 5, and wherein m is selected from 0 and 1, provided that when n is 0 then m is 0; wherein o is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8; wherein A¹ is selected from ‒O‒ and ‒CH₂‒, provided that when A¹ is O, then o is not 0 or 1; wherein L¹ is selected from C2 alkenyl, C2 alkynyl, ‒NHSO2‒, ‒SO2NH‒, ‒NHC(O)‒, ‒C(O)NH‒, and Ar⁵; wherein Ar⁵, when present, is a C2-C9 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R^1a, R^1b, R^1c, and R^1d is independently selected from hydrogen, halogen, ‒CN, ‒NH₂, ‒OH, and ‒NO₂; wherein R² is selected from hydrogen and C1-C4 alkyl; wherein one of R^3a and R^3b is C1-C4 alkyl and one of R^3a and R^3b is a structure selected from: ^; wherein R¹³ is selected from hydrogen and ‒OH; and wherein Ar¹ is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof. [00319] In one aspect, disclosed are methods of treating acute respiratory distress syndrome (ARDS) in a subject, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula: , wherein r is selected from 1, 2, 3, 4, 5, 6, 7, and 8; wherein one of R^3a and R^3b is C1-C4 alkyl and one of R^3a and R^3b is a structure selected from:

^; wherein R¹³ is selected from hydrogen and ‒OH; wherein each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and wherein R¹⁰ is selected from hydrogen and a structure: ; wherein s is selected from 0 and 1; wherein A² is selected from ‒C(O)‒ and ‒SO2‒; wherein L² is ‒(CR^11aR^11b)₂‒; wherein each occurrence of R^11a and R^11b is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl, or wherein each of R^11a and R^11b together comprise =O; wherein R⁵, when present, is selected from hydrogen and C1-C4 alkyl; wherein R⁶ is selected from ‒NR^12aR^12b and Ar²; wherein R^12a is selected from hydrogen, C1-C4 alkyl, and Ar³; wherein Ar³ is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and wherein R^12b is selected from C1-C4 alkyl, ‒CH₂Ar⁴, and Ar⁴; wherein Ar⁴ is selected from C6- C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or wherein each of R^12a and R^12b together comprise a C2-C5 heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein Ar² is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒C(O)NH₂, ‒NHC(O)(C1-C4 alkyl), Cy¹, ‒OCy¹, and ‒NH(CH₂)_tCy¹; wherein t is selected from 0, 1, and 2; and wherein Cy¹ is selected from C3- C6 cycloalkyl, C3-C6 heterocycloalkyl, C6-C14 aryl, and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof. [00320] In various aspects, administering is via oral administration, intraperitoneal administration, or intravenous (IV) administration. In a further aspect, administering is via oral administration. In a still further aspect, administering is via intraperitoneal administration. In a yet further aspect, administering is via intravenous (IV) administration. [00321] In various aspects, the subject is a mammal. [00322] In various aspects, the subject is a human. [00323] In various aspects, the subject has been diagnosed with ARDS prior to the administering step. [00324] In various aspects, the subject has been diagnosed with coronavirus disease (COVID) prior to the administering step. In a further aspect, COVID is coronavirus disease 2019 (COVID-19). [00325] In various aspects, the method further comprising the step of identifying a subject in need of treatment of ARDS. [00326] In various aspects, the method further comprising administering to the subject an agent known to treat ARDS. Examples of agents known to treat ARDS include, but are not limited to, nitric oxide and corticosteroids (e.g., cortisone, hydrocortisone, and prednisone). H. METHODS OF TREATING CANCER IN A SUBJECT [00327] In one aspect, disclosed are methods treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof. Reactive oxygen species play a crucial role in the regulation of the tumor occurrence and development. Furthermore, Nox4 is the most frequently expressed member of the Nox members reported to be dysregulated in a wide variety of tumors (Gong et. al., (2022) Frontier in Cell and Developmental Biology 10: 1-7). As such, strategies that modulate Nox4 can be useful in the treatment of cancer. [00328] Thus, in one aspect, disclosed are treating cancer in a subject, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula: , wherein n is selected from 0, 1, 2, 3, 4, and 5, and wherein m is selected from 0 and 1, provided that when n is 0 then m is 0; wherein o is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8; wherein A¹ is selected from ‒O‒ and ‒CH₂‒, provided that when A¹ is O, then o is not 0 or 1; wherein L¹ is selected from C2 alkenyl, C2 alkynyl, ‒NHSO2‒, ‒SO2NH‒, ‒NHC(O)‒, ‒C(O)NH‒, and Ar⁵; wherein Ar⁵, when present, is a C2-C9 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R^1a, R^1b, R^1c, and R^1d is independently selected from hydrogen, halogen, ‒CN, ‒NH₂, ‒OH, and ‒NO₂; wherein R² is selected from hydrogen and C1-C4 alkyl; wherein one of R^3a and R^3b is C1-C4 alkyl and one of R^3a and R^3b is a structure selected from:

^; wherein R¹³ is selected from hydrogen and ‒OH; and wherein Ar¹ is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof. [00329] In one aspect, disclosed are methods of treating cancer in a subject, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula: , wherein r is selected from 1, 2, 3, 4, 5, 6, 7, and 8; wherein one of R^3a and R^3b is C1-C4 alkyl and one of R^3a and R^3b is a structure selected from:

^; wherein R¹³ is selected from hydrogen and ‒OH; wherein each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and wherein R¹⁰ is selected from hydrogen and a structure: ; wherein s is selected from 0 and 1; wherein A² is selected from ‒C(O)‒ and ‒SO2‒; wherein L² is ‒(CR^11aR^11b)₂‒; wherein each occurrence of R^11a and R^11b is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl, or wherein each of R^11a and R^11b together comprise =O; wherein R⁵, when present, is selected from hydrogen and C1-C4 alkyl; wherein R⁶ is selected from ‒NR^12aR^12b and Ar²; wherein R^12a is selected from hydrogen, C1-C4 alkyl, and Ar³; wherein Ar³ is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and wherein R^12b is selected from C1-C4 alkyl, ‒CH₂Ar⁴, and Ar⁴; wherein Ar⁴ is selected from C6- C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or wherein each of R^12a and R^12b together comprise a C2-C5 heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein Ar² is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒C(O)NH₂, ‒NHC(O)(C1-C4 alkyl), Cy¹, ‒OCy¹, and ‒NH(CH₂)_tCy¹; wherein t is selected from 0, 1, and 2; and wherein Cy¹ is selected from C3- C6 cycloalkyl, C3-C6 heterocycloalkyl, C6-C14 aryl, and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof. [00330] In various aspects, treating disrupts tumor-promoting desmoplasia. [00331] In various aspects, treating inhibits desmoplastic tumor growth. [00332] In various aspects, administering is via oral administration, intraperitoneal administration, or intravenous (IV) administration. In a further aspect, administering is via oral administration. In a still further aspect, administering is via intraperitoneal administration. In a yet further aspect, administering is via intravenous (IV) administration. [00333] In various aspects, the subject is a mammal. [00334] In various aspects, the subject is a human. [00335] In various aspects, the subject has been diagnosed with cancer prior to the administering step. [00336] In various aspects, the subject has been diagnosed with desmoplasia prior to the administering step. [00337] In various aspects, the method further comprising the step of identifying a subject in need of treatment of cancer. [00338] In various aspects, the method further comprising the step of identifying a subject in need of treatment of desmoplasia. [00339] In various aspects, the method further comprising administering to the subject an agent known to treat cancer. In a further aspect, the agent known to treat cancer is a chemotherapeutic agent. Examples of chemotherapeutic agents include, but are not limited to alkylating agents, antimetabolite agents, antineoplastic antibiotic agents, mitotic inhibitor agents, and mTor inhibitor agents. [00340] In various aspects, the chemotherapeutic agent is an antineoplastic antibiotic agent. Examples of antineoplastic antibiotic agents include, but are not limited to, doxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, and valrubicin, or a pharmaceutically acceptable salt thereof. [00341] In various aspects, the chemotherapeutic agent is an antimetabolite agent. Examples of antimetabolite agents include, but are not limited to, gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt thereof. [00342] In various aspects, the chemotherapeutic agent is an alkylating agent. Examples of alkylating agents include, but are not limited to, carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide, thiotepa, bendamustine, and streptozocin, or a pharmaceutically acceptable salt thereof. [00343] In various aspects, the chemotherapeutic agent is a mitotic inhibitor agent. Examples of mitotic inhibitor agents include, but are not limited to, irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etopside, vincristine, ixabepilone, vinorelbine, vinblastine, and teniposide, or a pharmaceutically acceptable salt thereof. [00344] In various aspects, the chemotherapeutic agent is a mTOR inhibitor agent. Examples of mTOR inhibitor agents include, but are not limited to, everolimus, siroliumus, and temsirolimus, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. [00345] In various aspects, the compound and the agent are administered sequentially. In various further aspects, the compound and the agent are administered simultaneously. [00346] In various aspects, the cancer is selected from a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma). [00347] In various aspects, the cancer is breast cancer or pancreatic cancer. I. ADDITIONAL METHODS OF USING THE COMPOUNDS [00348] The compounds and pharmaceutical compositions of the invention are useful in treating or controlling disorders associated with over-activation of NOX4. Examples of such disorders include, but are not limited to, fibrotic disorders (e.g., pulmonary fibrosis, heart fibrosis, kidney fibrosis, liver fibrosis, skin fibrosis, mediastinal fibrosis, retroperitoneal cavity fibrosis, bone marrow fibrosis, scleroderma or systemic sclerosis), acute respiratory distress syndrome (ARDS), and cancer (e.g., a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, plasma cell neoplasm (myeloma)). [00349] To treat or control the condition, the compounds and pharmaceutical compositions comprising the compounds are administered to a subject in need thereof, such as a vertebrate, e.g., a mammal, a fish, a bird, a reptile, or an amphibian. The subject can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. The subject is preferably a mammal, such as a human. Prior to administering the compounds or compositions, the subject can be diagnosed with a need for treatment of a disorder associated with associated with over-activation of NOX4. [00350] The compounds or compositions can be administered to the subject according to any method. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. A preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. A preparation can also be administered prophylactically; that is, administered for prevention of a disorder associated with over-activation of NOX4. [00351] The therapeutically effective amount or dosage of the compound can vary within wide limits. Such a dosage is adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 Kg or more, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, as a continuous infusion. Single dose compositions can contain such amounts or submultiples thereof of the compound or composition to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. 1. MANUFACTURE OF A MEDICAMENT [00352] In one aspect, the invention relates to a method for the manufacture of a medicament for the treatment associated with over-activation of NOX4 in a subject in need thereof, the method comprising combining a therapeutically effective amount of a disclosed compound or product of a disclosed method with a pharmaceutically acceptable carrier or diluent. [00353] Also disclosed herein is the use of the disclosed compounds or a pharmaceutically acceptable salt thereof, together with a compound or agent known for treating or controlling disorders associated with over-activation of NOX4, in the manufacture of a medicament. In one aspect, for example, when the subject has a fibrotic disorder, ARDS, or cancer, disclosed is the use of the disclosed compounds or a pharmaceutically acceptable salt thereof along with a compound known for treating or controlling disorders associated with over-activation of NOX4. [00354] In one aspect, the manufacture of the medicament can comprise co-formulating or co-packaging the disclosed compounds, or a pharmaceutically acceptable salt thereof, together with a therapy targeting a fibrotic disorder, ARDS, or cancer. Non-limiting examples include anti-fibrotic agents (e.g., nintedanib, pirfenidone), agents known to treat ARDS (e.g., nitric oxide, corticosteroids), and chemotherapeutic agents. [00355] In various aspects, the method for the manufacture of a medicament comprises combining a therapeutically effective amount of the disclosed compounds, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier or diluent and/or with a compound known for treating the fibrotic disorder, ARDS, or cancer. In a further aspect, disclosed is a method for the manufacture of a medicament for treating syndrome fibrotic disorder, ARDS, or cancer, the method comprising combining a therapeutically effective amount of a disclosed compounds or a pharmaceutically acceptable salt thereof with a therapeutically effective amount of a compound known for treating the fibrotic disorder, ARDS, or cancer, together with a pharmaceutically acceptable carrier or diluent. 2. USE OF COMPOUNDS AND COMPOSITIONS [00356] In one aspect, the invention relates to the use of a disclosed compound, a disclosed composition, or a product of a disclosed method. In a further aspect, a use relates to the manufacture of a medicament for treating or controlling disorders associated with over- activation of NOX4. In a still further aspect, a use relates to the manufacture of a medicament for treating a disorder that is a fibrotic disorder or acute respiratory distress syndrome (ARDS). Examples of such disorders include, but are not limited to, fibrotic disorders (e.g., pulmonary fibrosis, heart fibrosis, kidney fibrosis, liver fibrosis, skin fibrosis, mediastinal fibrosis, retroperitoneal cavity fibrosis, bone marrow fibrosis, scleroderma or systemic sclerosis), acute respiratory distress syndrome (ARDS), and cancer (e.g., a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, plasma cell neoplasm (myeloma)). [00357] The compounds and pharmaceutical compositions of the invention are useful in treating or controlling disorders associated with over-activation of NOX4. [00358] Also provided are the uses of the disclosed compounds and products. In one aspect, the invention relates to use of at least one disclosed compound; or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In a further aspect, the compound used is a product of a disclosed method of making. [00359] In a further aspect, the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, for use as a medicament. [00360] In a further aspect, the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of the compound or the product of a disclosed method of making. [00361] It is understood that the disclosed uses can be employed in connection with the disclosed compounds, products of disclosed methods of making, methods, compositions, and kits. In a further aspect, the invention relates to the use of a disclosed compound or a disclosed product in the manufacture of a medicament for the treatment of a disorder associated with over- activation of NOX4. 3. KITS [00362] In a further aspect, disclosed are kits comprising a disclosed compound, or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an anti-fibrotic agent; (b) instructions for treating a fibrotic disorder; (c) an agent known to treat ARDS; (d) instructions for treating ARDS; (e) an agent known to treat cancer; and (f) instructions for treating cancer. [00363] Thus, in one aspect, disclosed are kits comprising a compound having a structure represented by a formula: , wherein n is selected from 0, 1, 2, 3, 4, and 5, and wherein m is selected from 0 and 1, provided that when n is 0 then m is 0; wherein o is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8; wherein A¹ is selected from ‒O‒ and ‒CH₂‒, provided that when A¹ is O, then o is not 0 or 1; wherein L¹ is selected from C2 alkenyl, C2 alkynyl, ‒NHSO₂‒, ‒SO₂NH‒, ‒NHC(O)‒, ‒C(O)NH‒, and Ar⁵; wherein Ar⁵, when present, is a C2-C9 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R^1a, R^1b, R^1c, and R^1d is independently selected from hydrogen, halogen, ‒CN, ‒NH₂, ‒OH, and ‒NO₂; wherein R² is selected from hydrogen and C1-C4 alkyl; wherein one of R^3a and R^3b is C1-C4 alkyl and one of R^3a and R^3b is a structure selected from: ^; wherein R¹³ is selected from hydrogen and ‒OH; and wherein Ar¹ is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an anti-fibrotic agent; (b) instructions for treating a fibrotic disorder; (c) an agent known to treat ARDS; (d) instructions for treating ARDS; (e) an agent known to treat cancer; and (f) instructions for treating cancer. [00364] In one aspect, disclosed are kits comprising a compound having a structure represented by a formula: , wherein r is selected from 1, 2, 3, 4, 5, 6, 7, and 8; wherein one of R^3a and R^3b is C1-C4 alkyl and one of R^3a and R^3b is a structure selected from: ^; wherein R¹³ is selected from hydrogen and ‒OH; wherein each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and wherein R¹⁰ is selected from hydrogen and a structure: ; wherein s is selected from 0 and 1; wherein A² is selected from ‒C(O)‒ and ‒SO2‒; wherein L² is ‒(CR^11aR^11b)₂‒; wherein each occurrence of R^11a and R^11b is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl, or wherein each of R^11a and R^11b together comprise =O; wherein R⁵, when present, is selected from hydrogen and C1-C4 alkyl; wherein R⁶ is selected from ‒NR^12aR^12b and Ar²; wherein R^12a is selected from hydrogen, C1-C4 alkyl, and Ar³; wherein Ar³ is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and wherein R^12b is selected from C1-C4 alkyl, ‒CH₂Ar⁴, and Ar⁴; wherein Ar⁴ is selected from C6- C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or wherein each of R^12a and R^12b together comprise a C2-C5 heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein Ar² is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒C(O)NH₂, ‒NHC(O)(C1-C4 alkyl), Cy¹, ‒OCy¹, and ‒NH(CH₂)_tCy¹; wherein t is selected from 0, 1, and 2; and wherein Cy¹ is selected from C3- C6 cycloalkyl, C3-C6 heterocycloalkyl, C6-C14 aryl, and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an anti-fibrotic agent; (b) instructions for treating a fibrotic disorder; (c) an agent known to treat ARDS; (d) instructions for treating ARDS; (e) an agent known to treat cancer; and (f) instructions for treating cancer. [00365] In various aspects, kit includes the anti-fibrotic agent. Exemplary anti-fibrotic agents include, but are not limited to, nintedanib and pirfenidone. [00366] In various aspects, the kit includes the agent known to treat ARDS. Exemplary agents known to treat ARDS include, but are not limited to, nitric oxide and corticosteroid. [00367] In various aspects, the kit includes the agent known to treat cancer such as, for example, a chemotherapeutic agent as further described herein. [00368] In various aspects, the compound and the anti-fibrotic agent are co-formulated. In various further aspects, the compound and the anti-fibrotic agent are co-packaged. [00369] In various aspects, the compound and the agent known to treat ARDS are co- formulated. In various further aspects, the compound and the agent known to treat cancer are co- packaged. [00370] In various aspects, the compound and the agent known to treat cancer are co- formulated. In various further aspects, the compound and the agent known to treat cancer are co- packaged. [00371] In various further aspects, a disclosed compound or a pharmaceutically-acceptable salt thereof, the instructions for the use thereof (when present) and/or a combination therapy including a compound known for treating the target condition can be co-packaged and/or co- formulated. In a still further aspect, the compound or pharmaceutically-acceptable salt thereof, the instructions (when present), and/or the compound known for treating the target condition are not co-packaged. [00372] The kits can also comprise compounds and/or products co-packaged, co- formulated, and/or co-delivered with other components. For example, a drug manufacturer, a drug reseller, a physician, a compounding shop, or a pharmacist can provide a kit comprising a disclosed compound and/or product and another component for delivery to a patient. [00373] It is understood that the disclosed kits can be prepared from the disclosed compounds and pharmaceutical formulations. It is also understood that the disclosed kits can be employed in connection with the disclosed methods of using the compounds and pharmaceutical formulations. [00374] In a further aspect, the kit further comprises a plurality of dosage forms, the plurality comprising one or more doses; wherein each dose comprises an effective amount of the compound and the agent. In an even further aspect, each dose of the compound and the agent are co-packaged. In a still further aspect, each dose of the compound and the agent are co- formulated. 4. SUBJECTS [00375] In various aspects, the subject of the herein disclosed methods is a vertebrate, e.g., a mammal. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. A patient refers to a subject afflicted with a disease or disorder. The term “patient” includes human and veterinary subjects. [00376] In some aspects of the disclosed methods, the subject has been diagnosed with a need for treatment prior to the administering step. In some aspects of the disclosed method, the subject has been diagnosed with a disorder of uncontrolled cellular proliferation prior to the administering step. In some aspects of the disclosed methods, the subject has been identified with a need for treatment prior to the administering step. In one aspect, a subject can be treated prophylactically with a compound or composition disclosed herein, as discussed herein elsewhere. a. DOSAGE [00377] Toxicity and therapeutic efficacy of the agents and pharmaceutical compositions described herein can be determined by standard pharmaceutical procedures, using either cells in culture or experimental animals to determine the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD₅₀/ED₅₀. [00378] Data obtained from cell culture assays and further animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED₅₀ with little or no toxicity, and with little or no adverse effect on a human's ability to hear. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any agents used in the methods described herein, the therapeutically effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC₅₀ (that is, the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Exemplary dosage amounts of a differentiation agent are at least from about 0.01 to 3000 mg per day, e.g., at least about 0.00001, 0.0001, 0.001, 0.01, 0.1, 1, 2, 5, 10, 25, 50, 100, 200, 500, 1000, 2000, or 3000 mg per kg per day, or more. [00379] The formulations and routes of administration can be tailored to the disease or disorder being treated, and for the specific human being treated. For example, a subject can receive a dose of the agent once or twice or more daily for one week, one month, six months, one year, or more. The treatment can continue indefinitely, such as throughout the lifetime of the human. Treatment can be administered at regular or irregular intervals (once every other day or twice per week), and the dosage and timing of the administration can be adjusted throughout the course of the treatment. The dosage can remain constant over the course of the treatment regimen, or it can be decreased or increased over the course of the treatment. [00380] In various aspects, the dosage facilitates an intended purpose for both prophylaxis and treatment without undesirable side effects, such as toxicity, irritation or allergic response. Although individual needs may vary, the determination of optimal ranges for effective amounts of formulations is within the skill of the art. Human doses can readily be extrapolated from animal studies (Katocs et al., (1990) Chapter 27 in Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA). In general, the dosage required to provide an effective amount of a formulation, which can be adjusted by one skilled in the art, will vary depending on several factors, including the age, health, physical condition, weight, type and extent of the disease or disorder of the recipient, frequency of treatment, the nature of concurrent therapy, if required, and the nature and scope of the desired effect(s) (Nies et al., (1996) Chapter 3, In: Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th Ed., Hardman et al., eds., McGraw-Hill, New York, NY). b. ROUTES OF ADMINISTRATION [00381] Also provided are routes of administering the disclosed compounds and compositions. The compounds and compositions of the present invention can be administered by direct therapy using systemic administration and/or local administration. In various aspects, the route of administration can be determined by a patient's health care provider or clinician, for example following an evaluation of the patient. In various aspects, an individual patient's therapy may be customized, e.g., the type of agent used, the routes of administration, and the frequency of administration can be personalized. Alternatively, therapy may be performed using a standard course of treatment, e.g., using pre-selected agents and pre-selected routes of administration and frequency of administration. [00382] Systemic routes of administration can include, but are not limited to, parenteral routes of administration, e.g., intravenous injection, intramuscular injection, and intraperitoneal injection; enteral routes of administration e.g., administration by the oral route, lozenges, compressed tablets, pills, tablets, capsules, drops (e.g., ear drops), syrups, suspensions and emulsions; rectal administration, e.g., a rectal suppository or enema; a vaginal suppository; a urethral suppository; transdermal routes of administration; and inhalation (e.g., nasal sprays). [00383] In various aspects, the modes of administration described above may be combined in any order. J. EXAMPLES [00384] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the methods and products claimed herein are made and evaluated, and are intended to be purely exemplary and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric. [00385] The Examples are provided herein to illustrate the invention, and should not be construed as limiting the invention in any way. 1. CHEMISTRY EXPERIMENTALS a. PREPARATION OF COMPOUND 7 i. STEP 1 [00386] A mixture of 4-(chloromethyl)benzoic acid (0.2 g 1 equiv.) and EDCI.HCl (0.247 g, 1.1 equiv.) in dry CH₂Cl₂ (6 mL) was kept stirring at 0 °C under an argon atmosphere for 30 min.2-(Indolin-1-yl)ethan-1-amine(0.152 g, 0.8 equiv.) and DMAP (21 mg, 0.15 equiv.) were added and the reaction mixture was stirred at rt for 15 h. The completion of the reaction was indicated by TLC. The reaction mixture was quenched with water (50 mL), extracted with CH₂Cl₂ (2×20 mL), and the combined organic layer was sequentially washed with a saturated solution of NaHCO₃ and brine (30 mL). The organic layer was dried over Na₂SO_4, and then filtered. The solvent was removed using a rotary evaporator and the crude material was purified on silica gel column chromatography, eluting with Hexane: ethyl acetate (7:3), v/v, to afford the desired product (4-(chloromethyl)-N-(2-(indolin-1-yl) ethyl)benzamide) as a light brown solid; yield: 254 mg (86 %).¹H NMR (400 MHz, CDCl₃) δ 7.70 – 7.65 (d, J = 8.3 Hz, 2H), 7.35 – 7.30 (d, J = 8.3 Hz, 2H), 7.10 – 7.04 (m, 2H), 6.71 – 6.66 (t, J = 6.9 Hz, 1H), 6.61 – 6.57 (t, J = 5.5 Hz, 1H), 4.43 – 4.36 (s, 2H), 3.51 – 3.46 (t, J = 6.1 Hz, 2H), 3.46 – 3.39 (d, J = 8.3 Hz, 2H), 3.32 – 3.26 (d, J = 12.2 Hz, 2H), 3.03 – 2.96 (d, J = 8.3 Hz, 2H). [00387] A mixture of desmethylazithromycin (226 mg, 1 equiv.) and DIPEA (0.142 mL, 3 equiv.) in dry DMSO (5 mL) was stirred for 10 min at rt. 4-(Chloromethyl)-N-(2-(indolin-1-yl) ethyl)benzamide (88 mg, 1.1 equiv.) was added to the reaction and the resulting mixture was stirred for 15 h at 80 °C. The completion of the reaction was indicated by TLC. The reaction was quenched with water (10 mL) and extracted with CH₂Cl₂ (2×20 mL). The organic layers were combined, dried over Na₂SO₄, and then filtered. The solvent was removed using a rotary evaporator, and the crude material was purified using preparative TLC, eluting with Acetone: Hexane: MeOH (3:4:0.2),v/v. to afford Compound 7 as a white solid (yield = 130 mg, 62 %).¹H NMR (400 MHz, CDCl₃) δ 7.70 – 7.65 (d, J = 8.3 Hz, 2H), 7.35 – 7.30 (d, J = 8.3 Hz, 2H), 7.10 – 7.04 (m, 2H), 6.71 – 6.66 (t, J = 6.9 Hz, 1H), 6.61 – 6.57 (t, J = 5.5 Hz, 1H), 5.13 – 5.07 (s, 1H), 4.75 – 4.65 (d, J = 8.7 Hz, 1H), 4.43 – 4.36 (s, 1H), 4.26 – 4.21 (s, 1H), 4.10 – 3.96 (m, 1H), 3.89 – 3.30 (m, 7H), 3.22 – 2.87 (m, 6H), 2.76 – 2.65 (d, J = 14.8 Hz, 1H), 2.60 – 2.40 (d, J = 8.9 Hz, 1H), 2.40 – 2.26 (s, 3H), 2.26 – 2.14 (s, 3H), 2.12 – 1.82 (m, 4H), 1.81 – 1.65 (s, 1H), 1.56 – 1.40 (m, 1H), 1.36 – 1.05 (m, 21H), 1.00 – 0.83 (s, 6H).¹³C NMR (176 MHz, CDCl₃) δ 178, 167, 152, 136, 133, 130 , 128 , 127.59 , 127 , 124 , 122 , 121 , 119 , 118 , 109, 107 , 103 , 101, 94, 83, 78, 77, 74, 74, 73, 73, 71, 70, 68, 65, 64 , 65, 62, 57, 53, 45.7, 45, 42, 38, 37, 36, 29, 28, 27, 26, 22, 18, 16, 14, 11.63, 11, 9,7. [M + H]⁺ Expected 1013.32, Found = 1013.60. b. PREPARATION OF COMPOUND 8 i. STEP 1 [00388] A solution of indoline (0.150 g, 1.23 mmol) in DMF (5 mL) was treated with NaH (0.062 g, 1.5 mmol) at rt for 30 min.6-Azidohexyl 4-methylbenzenesulfonate (0.44 g, 1.48 mmol) was added and stirring continued at rt for about 20 h. The reaction was partitioned between CH₂Cl₂ (40 mL) and brine (25 mL). The two layers were separated, the aqueous layer was extracted with CH₂Cl₂ (20 mL) and the combined organic layer was dried over Na₂SO₄. The crude was purified using prep-TLC, eluting with EtOAc/Hexanes 1:7 to give the requisite 1-(6- azidohexyl)indoline, after eluting off silica gel with CH₂Cl₂/MeOH 14:1, as a clear oil. Yield = 0.125 g (42 %). ii. STEP 2 [00389] 1-(6-Azidohexyl)indoline (0.12 g, 0.49 mmol), alkyneazithromycin (0.25 g, 0.33 mmol) and CuI (0.015 g, 0.08 mmol) were dissolved in THF (2 mL) and DMSO (2 mL). The mixture was kept stirring at rt and fluxed with argon. DIPEA (Hunig’s base) (0.04 mL) was added and stirring continued under argon at rt overnight (about 20 h). The reaction was partitioned between CH₂Cl₂ (40 mL) and conc. NH₄OH/NH₄Cl 1:1 (30 mL), the two layers separated and the organic layer was washed sequentially with conc. NH₄OH/NH₄Cl 1:1 (2 x 30 mL), brine (30 mL) and dried over Na₂SO₄. The crude was purified using prep-TLC, eluting with EtOAc/Hexanes/Et₃N 3:2:0.2 to give Compound 8, after eluting off silica gel with CH₂Cl₂/MeOH/ NH₄OH 14:1:0.1, as a white solid or foam. Yield = 0.168 g (47 %).¹H NMR (400 MHz, CDCl₃) δ 7.78 – 7.74 (s, 2H), 7.65 – 7.63 (s, 1H), 7.36 – 7.32 (s, 2H), 7.23 – 7.13 (m, 1H), 7.13 – 6.99 (m, 1H), 6.48 – 6.44 (d, J = 4.0 Hz, 1H), 4.68 (d, J = 12.6 Hz, 1H), 4.47 (d, J = 14.9 Hz, 2H), 4.30 (s, 2H), 4.24 (s, 1H), 4.1 (S, 3H), 4.0 (m, 1H), 3.83 – 3.75 (d, J = 13.1 Hz, 1H), 3.68 – 3.58 (s, 3 H), 3.50 – 3.40 (s, 3H), 3.38 – 3.32 (m, 1H), 3.14 – 3.08 (s, 3H), 2.82 – 2.68 (m, 2H), 2.54 – 2.45 (s, 1H), 2.34 – 2.16 (s, 6H), 2.10 – 1.89 (s, 810H), 2.16 – 1.64 (m, 12H), 1.63 – 1.36 (s, 8H), 1.35 – 0.91 (m, 8H), 0.99 – 0.81 (d, J = 3.6 Hz, 6H).¹³C NMR (176 MHz, CDCl₃) δ 178, 171, 152, 147, 139, 135, 132, 130, 129, 128, 127, 125, 124, 123, 122, 121, 119, 118, 117, 109, 108, 106, 102, 97, 94, 83, 78, 77, 74, 73, 72, 70, 68, 65, 64, 62, 60, 57, 53, 50, 49, 46, 44, 37, 36, 34, 30, 29, 28, 27, 26.72, 26, 22, 21, 20, 18, 16, 15, 14, 11, 11, 9, 7. [M + H]⁺ Expected 1093.45, Found = 1093.64. c. PREPARATION OF COMPOUND 9 i. STEP 1 [00390] The reaction of indoline (0.150 g, 1.23 mmol), 5-azidopentyl 4- methylbenzenesulfonate (0.248g, 0.88 mmol), NaH (0.051 g, 1.23 mmol) in DMF (4 mL), as described for the synthesis of 1-(6-azidohexyl)indoline, furnished the desired 1-(5- azidopentyl)indoline. Yield = 0.061 g (30 %). ii. STEP 2 [00391] The reaction of 1-(5-azidopentyl)indoline (0.06 g, 0.26 mmol), alkyneazithromycin (0.12 g, 0.16 mmol), CuI (0.0075 g, 0.04 mmol), and DIPEA (0.03 mL) in THF (1.5 mL)/DMSO (1.5 mL), as described for the synthesis of Compound 8, furnished the desired Compound 9 as a white solid or foam. Yield = 0.074 g (44 %).¹H NMR (400 MHz, CDCl₃) δ 7.77 – 7.68 (d, J = 7.8 Hz, 2H), 7.58 – 7.54 (s, 1H), 7.39 – 7.33 (d, J = 8.0 Hz, 2H), 7.22 – 7.18 (s, 1H), 7.12 – 7.08 (s, 1H), 7.05 – 7.02 (d, J = 3.0 Hz, 2H), 6.49 – 6.41 (d, J = 3.1 Hz, 1H), 5.08 – 5.01 (s, 1H), 4.68 (d, J = 12.6 Hz, 1H), 4.47 (d, J = 14.9 Hz, 2H), 4.30 (s, 2H), 4.24 (s, 1H), 4.1 (S, 3H), 4.0 (m, 1H), 3.83 – 3.75 (d, J = 13.1 Hz, 1H), 3.68 – 3.58 (s, 3 H), 3.50 – 3.40 (s, 3H), 3.38 – 3.32 (m, 1H), 3.14 – 3.08 (s, 3H), 2.82 – 2.68 (m, 3H), 2.54 – 2.45 (s, 2H), 2.34 – 2.16 (s, 6H), 2.10 – 1.89 (s, 8 H), 2.16 – 1.64 (m, 10H), 1.63 – 1.36 (s, 8H), 1.35 – 0.91 (m, 8H), 0.99 – 0.81 (d, J = 3.6 Hz, 6H).¹³C NMR (176 MHz, CDCl₃) δ 178, 171, 162, 139, 135, 129, 128, 127, 125, 121, 119, 109, 102, 101, 97, 94, 83, 78, 74, 73, 72, 70 ,69, 68, 65, 64, 62, 60, 57, 50, 49, 46, 45, 42, 41, 37, 36, 34, 30, 29, 27, 23, 22, 21, 18, 16, 15, 14, 11, 9, 7. [M + H]⁺ Expected 1079.43, Found = 1079.39. d. PREPARATION OF COMPOUND 10 i. STEP 1 [00392] Imidazole-1-sulfonyl azide hydrogen sulfate (0.126 g 1.1 equiv.) was added to the amine substrate (0.1 g 1.0 equiv.), K₂CO₃ (0.117 g, 2 equiv.), and CuSO₄.5H₂O (1 mg, 1 mol%) in MeOH (5 mL) and the mixture stirred at room temperature for 15 h. After completion of the reaction, the mixture was diluted with H₂O (15 mL), and extracted with EtOAc (3 × 15 mL). The combined organic layer was dried (MgSO₄), filtered, and concentrated to afford the desired 1-(2- Azidoethyl) indoline as liquid (yield =74 mg, 92 %), which was used for the next step without purification.¹H NMR (400 MHz, CDCl₃) δ 7.13 – 7.07 (d, J = 6.5 Hz, 2H), 6.73 – 6.61 (m, 1H), 6.52 – 6.44 (d, J = 7.7 Hz, 1H), 3.51 – 3.46 (t, J = 6.1 Hz, 2H), 3.46 – 3.39 (d, J = 8.3 Hz, 2H), 3.32 – 3.26 (d, J = 12.2 Hz, 2H), 3.03 – 2.96 (d, J = 8.3 Hz, 2H).

ii. STEP 2 [00393] 1-(2-Azidoethyl)indoline (66 mg, 1.5 equiv.) and alkyneazithromycin (0.2 g, 1 equiv.) were dissolved in the dry DMSO under an argon atmosphere. Additionally, argon was bubbled through the solution for 10 min before and after the addition of Copper (I) iodide (33 mg, 0.75 equiv.). Diisopropyl ethyl amine (0.060 mL, 1.5 equiv.) was added and the reaction mixture was stirred at rt for 15 h. The completion of the reaction was indicated by TLC. The reaction mixture was quenched with water (50 mL), extracted with CH₂Cl₂ (2×20 mL), and the organic layer was sequentially washed with a 4:1 mixture of NH₄Cl: conc. NH₄OH, (15 mL), water (15 mL), and brine (10 mL). The organic layer was dried over Na₂SO₄, and then filtered. The solvent was removed using a rotary evaporator, and the crude material was purified preparative TLC, using Ethyl acetate: Hexane: Et₃N (3:2:0.2), to afford Compound 10 as a white solid (yield = 0.210 g, 86 %).¹H NMR (700 MHz, CDCl₃) δ 7.85 – 7.77 (s, 1H), 7.79 – 7.64 (d, 2H), 7.39 – 7.26 (d, 2H), 7.16 – 6.93 (m, 2H), 6.75 – 6.57 (s, 1H), 6.50 – 6.29 (s, 1H), 5.15 – 4.90 (s, 1H), 4.76 – 4.54 (m, 4H), 4.48 – 4.38 (s, 1H), 4.32 – 4.19 (s, 1H), 4.08 – 3.93 (s, 1H), 3.86 – 3.24 (m, 10 H), 3.17 – 2.81 (m, 6H), 2.81 – 2.59 (s, 2H), 2.61 – 2.48 (s, 2H), 2.42 – 2.19 (S, 6H), 2.16 – 1.76 (m, 7H), 1.53 – 1.40 (s, 2H), 1.37 – 0.92 (m, 26H), 0.94 – 0.80 (s, 6H).¹³C NMR (176 MHz, CDCl₃) δ 178, 151, 147, 139, 129, 127, 125, 124,120 ,119, 117, 106, 103, 94, 83, 78, 74, 73, 72, 70, 68, 65, 64, 62, 57, 54 , 50, 49, 48 , 43, 42, 41, 37, 36, 34, 29, 28, 27, 26, 22, 21, 18, 16, 14, 11, 9, 7. [M + H]⁺ Expected 1037.35, Found = 1037.65. e. PREPARATION OF COMPOUND 11 i. STEP 1 [00394] A mixture of 4-(chloromethyl)benzoic acid (0.2 g 1 equiv.) and EDCI.HCl (0.247 g,1.1 equiv.) in dry CH₂Cl₂ (6mL) was stirred at 0 °C under an argon atmosphere for 30 min. Tryptamine (0.150 g, 0.8 equiv.) and DMAP (21 mg, 0.15 equiv.) were added and the reaction was stirred at rt for 15 h. The completion of the reaction was indicated by TLC. The reaction was quenched with water (50 mL), extracted with CH₂Cl₂ (2×20 mL), and the combined organic layer was sequentially washed with a saturated solution of NaHCO₃ and brine (30 mL). The organic layer was dried over Na₂SO₄, and then filtered. The solvent was removed using a rotary evaporator and the crude material was purified on silica gel column chromatography, eluting with Hexane: ethylacetate (6:4), v/v, to afford solid the desired product (N-(2-(1H-Indol-3-yl) ethyl)-4-(chloromethyl)benzamide); yield: 210 mg (72 %).¹H NMR (400 MHz, CDCl₃) δ 7.65 – 7.58 (t, J = 8.0 Hz, 3H), 7.41 – 7.36 (d, J = 8.0 Hz, 1H), 7.32 – 7.28 (d, J = 8.2 Hz, 2H), 7.23 – 7.16 (d, J = 7.0 Hz, 1H), 7.14 – 7.08 (t, J = 7.5 Hz, 1H), 7.08 – 7.03 (s, 1H), 4.6 (S, 2H), 3.46 – 3.39 (d, J = 8.3 Hz, 2H),3.03 – 2.96 (d, J = 8.3 Hz, 2H). ii. STEP 2 [00395] A mixture of desmethylazithromycin (250 mg, 1 equiv.) and DIPEA (0.173 mL, 3 equiv.) in dry DMSO (5 mL) was stirred for 10 min at rt. N-(2-(1H-Indol-3-yl) ethyl)-4- (chloromethyl)benzamide (116 mg, 1.1 equiv.) was added to the reaction, and the resulting mixture was stirred for 15 h at 80 °C. The completion of the reaction was indicated by TLC. The reaction was quenched with water (10 mL) and extracted with CH₂Cl₂ (2×20 mL). The organic layers were combined, dried over Na₂SO₄, and then filtered. The solvent was removed using a rotary evaporator, and the crude material was purified by using preparative TLC, eluting with Acetone: Hexane: MeOH (3:4:0.2), v/v, to furnish Compound 11 as a white solid (yield = 185 mg, 53 %).¹H NMR (400 MHz, CDCl₃) δ 8.52 – 8.28 (s, 1H), 7.65 – 7.58 (t, J = 8.0 Hz, 2H), 7.41 – 7.36 (d, J = 8.0 Hz, 1H), 7.32 – 7.28 (d, J = 8.2 Hz, 2H), 7.23 – 7.16 (d, J = 7.0 Hz, 1H), 7.14 – 7.08 (t, J = 7.5 Hz, 1H), 7.08 – 7.03 (s, 1H), 6.37 – 6.12 (s, 1H), 5.15 – 5.09 (s, 1H), 4.75 – 4.65 (d, J = 8.7 Hz, 1H), 4.43 – 4.36 (s, 1H), 4.26 – 4.21 (s, 1H), 4.10 – 3.96 (m, 1H), 3.89 – 3.30 (m, 7H), 3.22 – 2.87 (m, 6H), 2.76 – 2.65 (d, J = 14.8 Hz, 1H), 2.60 – 2.40 (d, J = 8.9 Hz, 1H), 2.40 – 2.26 (s, 3H), 2.26 – 2.14 (s, 3H), 2.12 – 1.82 (m, 4H), 1.81 – 1.65 (s, 1H), 1.56 – 1.40 (m, 1H), 1.36 – 1.05 (m, 21H), 1.00 – 0.83 (s, 6H).¹³C NMR (176 MHz, CDCl₃) δ 178, 167, 152, 136, 133, 133, 130, 128, 127.59, 127, 124, 122, 121, 119, 118, 109, 107, 103, 101, 94, 83, 78, 77, 74, 74 , 73, 73, 71, 70, 68, 65, 64, 65, 62, 57, 53, 45.7, 45, 42, 38, 37, 36, 29, 28, 27, 26, 22, 18, 16, 14, 11.63, 11, 9, 7. [M + H]⁺ Expected 1011.30, Found = 1011.60. f. PREPARATION OF COMPOUND 12 i. STEP 1 [00396] A mixture of 2-(indolin-1-yl)ethan-1-amine (50 mg, 1 equiv.) and Et₃N (72 mg, 3 equiv.) in dry CH₂Cl₂ (5 mL) was stirred under an argon atmosphere and cooled to 0 °C. Subsequently, 4-(chloromethyl)benzenesulfonyl chloride, was added to the mixture. The solution was stirred at room temperature for 15 h. The completion of the reaction was indicated by TLC. The reaction was quenched with water (50 mL), extracted with CH₂Cl₂ (3×20 mL), and the combined organic layer was sequentially washed with a saturated solution of NaHCO3 and brine (30 mL). The organic layer was dried over Na₂SO₄, and then filtered. The solvent was removed using a rotary evaporator, and the crude product (4-(Chloromethyl)-N-(2-(indolin-1- yl)ethyl)benzenesulfonamide) was used for the next reaction without further purification. ii. STEP 2 [00397] A mixture of desmethylazithromycin (0.2 g, 1 equiv.) and DIPEA (0.174 mL, 3 equiv.) in dry DMSO (5 mL) was stirred for 10 min at rt. 4-(Chloromethyl)-N-(2-(indolin-1- yl)ethyl)benzenesulfonamide (0.105 g, 1.1 equiv.) was added to the reaction and the resulting mixture was stirred for 15 h at 80 °C. The completion of the reaction was indicated by TLC. The reaction was quenched with water (10 mL) and extracted with CH₂Cl₂ (2×20 mL). The organic layers were combined, dried over Na₂SO₄, and then filtered. The solvent was removed using a rotary evaporator, and the crude material was purified using preparative TLC, eluting with Acetone: Hexane: MeOH (3:4:0.2),v/v, to furnish Compound 12 as a white solid (yield = 218 mg, 76 %).¹H NMR (700 MHz, CDCl₃) δ 7.86 – 7.81 (s, 2H), 7.51 – 7.47 (d, J = 8.4 Hz, 2H), 7.11 – 7.08 (d, J = 8.3 Hz, 1H), 7.06 – 7.01 (s, 1H), 6.73 – 6.68 (d, J = 7.2 Hz, 1H), 6.39 – 6.35 (s, 1H), 5.18 – 5.12 (d, J = 4.9 Hz, 1H), 4.94 – 4.87 (t, J = 5.9 Hz, 2H), 4.74 – 4.67 (s, 1H), 4.48 – 4.44 (s, 1H), 4.30 – 4.26 (s, 1H), 4.10 – 4.02 (s, 1H), 3.93 – 3.83 (s, 1H), 3.74 – 3.65 (s, 2H), 3.60 – 3.51 (s, 2H), 3.45 – 3.38 (s, 1H), 3.27 – 3.12 (d, J = 15.7 Hz, 7H), 3.11 – 3.02 (m, 1H), 2.98 – 2.86 (t, 3H), 2.80 – 2.51 (m, 4H), 2.31 – 2.21 (s, 6H), 2.13 – 2.11 (d, 1H), 2.04 – 1.83 (m, 3H), 1.85 – 1.68 (d, J = 14.6 Hz, 2H), 1.65 – 1.53 (d, J = 15.3 Hz, 1H), 1.54 – 1.43 (s, 3H), 1.43 – 1.16 (m, 12H), 1.19 – 0.98 (s, 6H), 0.97 – 0.78 (s, 6H).¹³C NMR (176 MHz, CDCl₃) δ 179, 152, 144, 138, 127, 124, 118, 109, 102, 94, 78, 77, 74, 73.7, 73, 70, 68, 65.67, 65, 57, 53, 49.61, 49, 45, 42, 41, 37, 36, 34, 30, 29, 28, 26, 22, 21.71, 21, 18, 16, 14, 11, 9, 7. [M + H]⁺ Expected 1049.37, Found = 1049.59. g. PREPARATION OF COMPOUND 13 i. STEP 1 [00398] To a solution of 2-(indolin-1-yl) ethan-1-amine (0.2 g, 1 equiv.) in CH₂Cl₂ (10 mL) was added triethyl amine (0.207 mL, 1.2 equiv.). The resulting mixture was cooled to 0 °C and stirred for 10 min at the same temperature.4-Methoxybenzenesulfonyl chloride (0.279 g 1.1 equiv.) was added and the mixture was warmed to rt and stirred overnight at rt. The completion of the reaction was indicated by TLC. The reaction was quenched with water (50 mL), extracted with CH₂Cl₂ (3×20 mL), and sequentially washed with a saturated solution of NaHCO₃ and brine (30 mL). The organic layers were combined, dried over Na₂SO₄, and then filtered. The solvent was removed using a rotary evaporator, and the crude product was used for the next reaction without further purification. [00399] The crude product from above, N-(2-(indolin-1-yl)ethyl)-4-methoxy benzenesulfonamide (0.410 g., 1 equiv.), was dissolved in dry CH₂Cl₂ (10 mL) in a 100-mL round bottom flask under argon atmosphere and the flask is placed in an acetone-dry ice bath at −80 °C. A solution of boron tribromide (1.947 g, 6 equiv.) was added carefully to the stirred solution. The reaction was allowed to attain room temperature overnight with stirring when a clear, brownish-yellow solution was obtained. The reaction was carefully quenched with water (approx.20 mL), resulting in the precipitation of a white solid which was dissolved by the addition of ether (50 mL). The organic layer was separated and extracted with 2N sodium hydroxide (25 mL); the alkaline extract was neutralized with dilute hydrochloric acid, extracted with ether (30 mL), and the ether extract was dried over MgSO₄. On the removal of the ether under reduced pressure, a brownish-yellow oil remains which soon crystallizes to give an off- white solid. The crude material was purified on silica gel column chromatography, eluting with Hexane: ethylacetate (7:3), v/v], to furnish the desired 4-hydroxy-N-(2-(indolin-1- yl)ethyl)benzenesulfonamide, yield: 316 mg (80 % after two steps).¹H NMR (400 MHz, CDCl₃) δ 7.97 – 7.70 (d, 2H), 7.11 – 7.00 (d, J = 12.1 Hz, 2H), 6.98 – 6.96 (d , 2H), 6.73 – 6.61 (m, 1H), 6.36 – 6.34 (d, J = 7.8 Hz, 1H), 3.20 – 3.04 (m, 6H), 2.96 – 2.86 (t, J = 8.1 Hz, 2H). ii. STEP 2 [00400] A solution of 4-hydroxy-N-(2-(indolin-1-yl)ethyl)benzenesulfonamide (300 mg, 1 equiv.) in dry acetonitrile (10 mL) was stirred under an argon atmosphere and cooled to 0 °C. K₂CO₃ (867 mg, 2 equiv.) was added and the mixture was allowed to warm up to rt and kept stirring at rt for 30 min. Subsequently, 1, 3-dibromopropane (1.91 mL, 6 equiv.) was added dropwise to the mixture, and the solution was stirred at rt for 24 h. After completion of the reaction as indicated by TLC, the reaction was quenched with water (50 mL) and extracted with CH₂Cl₂ (3×20 mL). The combined organic layer was dried over Na₂SO₄ and then filtered. The solvent was removed using a rotary evaporator, and the crude was purified by silica gel chromatography, eluting with Hexane: ethylacetate (6:4), v/v, to furnish the desired 4-(3- bromopropoxy)-N-(2-(indolin-1-yl) ethyl)benzenesulfonamide, yield: 281 mg (68 %).¹H NMR (400 MHz, CDCl₃) δ 7.84 – 7.78 (d, 2H), 7.11 – 7.00 (m, 3H), 7.00 – 6.95 (d, J = 11.9 Hz, 2H), 6.72 – 6.67 (t, J = 7.8 Hz, 1H), 6.38 – 6.32 (d, J = 7.9 Hz, 1H), 4.19 – 4.15 (t, 2H), 3.64 – 3.59 (t, 2H), 3.20 – 3.09 (m, J = 8.1 Hz, 6H), 2.96 – 2.85 (t, J = 8.3 Hz, 2H), 2.39 – 2.32 (m, J = 6.9 Hz, 2H). iii. STEP 3 [00401] A mixture of desmethylazithromycin (0.2 g, 1 equiv.) and DIPEA (0.174 mL, 3 equiv.) in dry DMSO (5 mL) was stirred for 10 min at rt. 4-(3-Bromopropoxy)-N-(2-(indolin-1- yl) ethyl)benzenesulfonamide (0.150 g, 1.1 equiv.) was added to the reaction and the resulting mixture was stirred for 15 h at 80 °C. The completion of the reaction was indicated by TLC. The reaction mixture was quenched with water (10 mL) and extracted with CH₂Cl₂ (3×20 mL). The organic layers were combined, dried over Na₂SO_4, and then filtered. The solvent was removed using a rotary evaporator, and the crude material was purified using preparative TLC, eluting with Acetone: Hexane: MeOH (3:4:0.2),v/v; to furnish Compound 13 as a white solid (yield = 280 mg, 75 %).¹H NMR (400 MHz, CDCl₃) δ 7.81 – 7.73 (d, J = 12.0 Hz, 2H), 7.10 – 7.00 (m, 2H), 6.98 – 6.93 (s, 2H), 6.74 – 6.61 (m, 1H), 6.40 – 6.32 (s, 1H), 5.11 – 4.94 (s, 1H), 4.73 – 4.60 (s, 1H), 4.51 – 4.39 (s, 1H), 4.32 – 4.21 (s, 1H), 4.09 – 3.91 (s, 2H), 3.74 – 3.59 (s, 4H), 3.44 – 3.29 (m, 12H), 3.04 – 2.83 (s, 5H), 2.9 – 2.62 (m, 3H), 2.61 – 2.36 (s, 3H), 2.41 – 2.23 (s, 7H), 2.20-2.18 (d,1H) 2.10-1.40 (m, 6 H), 1.39 – 1.15 (m, 12H), 1.14 – 0.97 (m, 8H), 0.97 – 0.71 (s, 6H).¹³C NMR (176 MHz, CDCl₃) δ 179, 152, 144, 138, 127, 124, 118, 109, 102, 94, 78, 77, 74, 73.7, 73, 70, 68, 65, 57, 53, 49.61, 49, 45, 42, 41, 37, 36, 34, 30, 29, 28, 26, 22, 21.71, 21, 18, 16, 14, 11, 9, 7. [M + H]⁺ Expected 1093.42, Found = 1093.64. h. PREPARATION OF COMPOUND 14 i. STEP 1 [00402] A mixture of 4-hydroxybenzoic acid (0.2 g 1 equiv.) and EDCI.HCl (0.304 g,1.1 equiv.) in dry CH₂Cl₂ (10 mL) was stirred under an argon atmosphere for 30 min.2-(Indolin-1- yl) ethan-1-amine (0.187 mg, 0.8 equiv.) and DMAP (35 mg, 0.15 equiv.) were added and the reaction mixture was stirred at rt for 15 h. The completion of the reaction was indicated by TLC. The reaction was quenched with water (50 mL), extracted with CH₂Cl₂ (2×20 mL), and the combined organic layer was sequentially washed with a saturated solution of NaHCO3 and brine (30 mL). The organic layers were combined, dried over Na₂SO₄, and then filtered. The solvent was removed using a rotary evaporator. The crude was purified by silica gel column chromatography, eluting with Hexane: ethyl acetate (7:3), v/v, to afford 4-hydroxy-N-(2- (indolin-1-yl)ethyl)benzamide as a white solid; yield: 280 mg (86 %).¹H NMR (400 MHz, CDCl₃) δ 7.59 (d, J = 9.0 Hz, 2H), 7.15 – 7.00 (m, 2H), 6.82 (d, J = 9.0 Hz, 2H), 6.74 – 6.67 (m, 1H), 6.64 – 6.58 (broad s, 1H), 6.57 – 6.50 (d, J = 7.2 Hz, 1H), 3.75 – 3.63 (t, 2H), 3.43 – 3.25 (m, 4H), 3.04 – 2.89 (t, J = 8.3 Hz, 2H). ii. STEP 2 [00403] A solution of 4-hydroxy-N-(2-(indolin-1-yl)ethyl)benzamide (0.2 g, 1 equiv.) in dry acetone (10 mL) was cooled to 0 °C under an argon atmosphere. K₂CO₃ (195 mg, 2 equiv.) was added and the mixture was stirred at rt for 30 min. Subsequently, 1,3-dibromopropane (0.431 mL, 6 equiv.) was added dropwise to the reaction and the mixture was stirred at room temperature for 24 h. After completion of the reaction as indicated by TLC, the reaction was quenched with water (50 mL) and extracted with CH₂Cl₂ (3×20 mL). The combined organic layer was dried over Na₂SO₄ and then filtered. The solvent was removed using a rotary evaporator, and the crude was purified by silica gel chromatography, eluting with Hexane: ethylacetate (6:4), v/v, to furnish the desired 4-(3-bromopropoxy)-N-(2-(indolin-1- yl)ethyl)benzamide, yield: 230 mg (80 %).¹H NMR (400 MHz, CDCl₃) δ 7.75 – 7.67 (d, J = 9.0 Hz, 2H), 7.14 – 7.03 (m, 2H), 6.91 – 6.87 (s, 2H), 6.73 – 6.66 (d, J = 8.4 Hz, 1H), 6.57 – 6.52 (d, J = 7.8 Hz, 1H), 4.16 – 4.06 (t, 2H), 3.71 – 3.65 (d, J = 5.3 Hz, 2H), 3.63 – 3.57 (t, 2H), 3.43 – 3.34 (t, 2H), 3.33 – 3.23 (t, J = 6.1 Hz, 2H), 3.03 – 2.89 (t, J = 8.3 Hz, 2H), 2.35 – 2.23 (m, J = 12.1 Hz, 2H). iii. STEP 3 [00404] Desmethylazithromycin (0.219 g, 0.8 equiv.) and DIPEA (0.190 ml, 3 equiv.) were dissolved in dry DMSO (5 mL) and the mixture was stirred for 10 min at rt.4-(3- Bromopropoxy)-N-(2-(indolin-1-yl)ethyl)benzamide (0.150 g, 1 equiv.) was added to the reaction and the resulting mixture was stirred for 15 h at 80 °C. The completion of the reaction was indicated by TLC. The reaction was quenched with water (10 mL) and extracted with CH₂Cl₂ (2×20 mL). The organic layers were combined, dried over Na₂SO₄, and then filtered. The solvent was removed using a rotary evaporator, and the crude material was purified using preparative TLC, eluting with Acetone: Hexane: MeOH (3:4:0.2), v/v, to furnish Compound 14 as a white solid (yield = 265 mg, 75 %).¹H NMR (400 MHz, CDCl₃) δ 7.71 – 7.65 (dd, J = 8.8, 3.1 Hz, 2H), 7.12 – 7.04 (m, 2H), 6.90 – 6.83 (dd, J = 8.7, 1.7 Hz, 2H), 6.73 – 6.67 (tdd, J = 7.4, 3.2, 1.0 Hz, 1H), 6.58 – 6.53 (d, J = 7.8 Hz, 1H), 6.49 – 6.43 (t, J = 5.3 Hz, 1H), 5.11 – 4.94 (s, 1H), 4.73 – 4.60 (s, 1H), 4.51 – 4.39 (s, 1H), 4.32 – 4.21 (s, 1H), 4.09 – 3.91 (s, 2H), 3.74 – 3.59 (s, 4H), 3.44 – 3.29 (m, 12H), 3.04 – 2.83 (s, 5H), 2.9 – 2.62 (m, 3H), 2.61 – 2.36 (s, 3H), 2.41 – 2.23 (s, 7H), 2.20-2.18 (d,1H) 2.10-1.40 (m, 6 H), 1.39 – 1.15 (m, 12H), 1.14 – 0.97 (m, 8H), 0.97 – 0.71 (s, 6H).¹³C NMR (176 MHz, CDCl₃) δ 179, 152, 144, 138, 127, 124, 118, 109, 102, 94, 78, 77, 74, 73, 70, 68, 65, 57 , 53, 49.61, 49, 45, 42, 41, 37, 36, 34, 30, 29, 28, 26, 22, 21.71, 21, 18, 16, 14, 11, 9, 7. [M + H]⁺ Expected 1057.37, Found = 1057.66. i. PREPARATION OF COMPOUND 15 [00405] A mixture of desmethylclarithromycin (257 mg, 1 equiv.) and DIPEA (0.162 mL, 3 equiv.) in dry DMSO (5 mL) was stirred for 10 min at rt. 4-(Chloromethyl)-N-(2-(indolin-1- yl) ethyl)benzamide (100 mg, 1.1 equiv.) was added to the reaction mixture, and the resulting solution was stirred for 15 h at 80 °C. The completion of the reaction was indicated by TLC. The reaction was quenched with water (10 mL) and extracted with CH₂Cl₂ (2× 30 mL). The organic layers were combined, dried over Na₂SO₄, and then filtered. The solvent was removed using a rotary evaporator, and the crude material was purified using preparative TLC, eluting with Acetone: Hexane: MeOH (3:4:0.1), v/v/v, to afford Compound 15 as a white solid (yield = 192 mg, 54.4 %).¹H NMR (400 MHz, CDCl₃) δ 7.72 – 7.66 (d, J = 8.3 Hz, 2H), 7.36 – 7.32 (d, J = 8.4 Hz, 2H), 7.13 – 7.04 (m, 2H), 6.74 – 6.67 (t, J = 7.4 Hz, 1H), 6.59 – 6.49 (m, 2H), 5.08 – 4.99 (d, J = 11.3 Hz, 1H), 4.92 – 4.86 (s, 1H), 4.43 – 4.37 (d, J = 7.3 Hz, 1H), 3.99 – 3.97 (s, 1H), 3.97 – 3.90 (s, 1H), 3.78 – 3.68 (d, J = 13.1 Hz, 3H), 3.66 – 3.58 (d, J = 7.3 Hz, 1H), 3.48 – 3.37 (m, 3H), 3.20 – 3.14 (s, 3H), 3.02 – 2.93 (s, 3H), 2.91 – 2.80 (s, 1H), 2.63 – 2.45 (m, 2H), 2.35 – 2.23 (d, J = 15.1 Hz, 1H), 2.24 – 2.20 (s, 3H), 2.11 – 2.02 (s, 1H), 1.94 – 1.79 (m, 3H), 1.73 – 1.61 (m, 3H), 1.57 – 1.43 (m, 2H), 1.40 – 1.33 (s, 3H), 1.29 – 1.20 (m, 9H), 1.21 – 1.14 (d, J = 7.1 Hz, 3H), 1.13 – 1.03 (m, 16H), 0.86 – 0.79 (t, 3H). [M + H]⁺ Expected 1012.29, Found = 1012.64. j. PREPARATION OF COMPOUND 16 [00406] A mixture of 1-(2-azidoethyl)indoline (48 mg, 1.2 equiv.) and alkyneclarithromycin (0.180 g, 1 equiv.) in dry DMSO (4 mL) was kept under an argon atmosphere and stirred at rt for 10 min before Copper (I) iodide (37 mg, 0.75 equiv.) was add. Diisopropyl ethyl amine (DIPEA) (0.067 mL, 1.5 equiv.) was added and the reaction was stirred at rt for 15 h. The completion of the reaction was indicated by TLC. The reaction was quenched with water (50 mL), extracted with CH₂Cl₂ (2×20 mL), and the combined organic layer was sequentially washed with a mixture of NH₄Cl: conc. NH₄OH (4:1) (15 mL), water (15 mL), and brine (20 mL). The organic layers were combined, dried over Na₂SO₄, and then filtered. The solvent was removed using a rotary evaporator, and the crude material was purified using preparative TLC, eluting with Acetone: Hexane: MeOH (3:4:0.1, to afford Compound 16 as a white solid (yield = 190 mg, 90 %). ¹H NMR (400 MHz, CDCl₃) δ 7.82 – 7.81 (s, 1H), 7.37 – 7.30 (d, J = 8.3 Hz, 2H), 7.12 – 7.01 (m, 2H), 6.72 – 6.65 (t, J = 7.9 Hz, 1H), 6.44 – 6.29 (d, J = 7.8 Hz, 1H), 5.10 – 4.99 (d, J = 13.5 Hz, 1H), 4.94 – 4.83 (s, 1H), 4.65 – 4.57 (s, 2H), 4.45 – 4.33 (s, 1H), 4.00 – 3.95 (s, 1H), 3.96 – 3.87 (s, 1H), 3.79 – 3.69 (m, 3H), 3.65 – 3.59 (s, 3H), 3.55 – 3.38 (m, 3H), 3.38 – 3.29 (s, 3H), 2.91 – 2.77 (s, 2H), 2.60 – 2.46 (m, 2H), 2.26 – 2.20 (s, 3H), 2.10 – 1.98 (d, J = 10.2 Hz, 1H), 1.98 – 1.84 (s, 3H), 1.77 – 1.64 (t, J = 16.1 Hz, 3H), 1.52 – 1.43 (d, J = 15.0 Hz, 2H), 1.42 – 1.37 (s, 3H), 1.30 – 1.20 (m, 9H), 1.20 – 1.15 (d, J = 7.3 Hz, 3H), 1.14 – 1.10 (d, J = 4.3 Hz, 10H), 1.10 – 1.02 (d, J = 8.7 Hz, 6H), 0.88 – 0.78 (t, 3H). [M + H]⁺ Expected 1036.31, Found = 1036.77. k. PREPARATION OF COMPOUND 21 i. STEP 1 [00407] The reaction of indoline (0.2 g, 1 equiv.), 5-azidopentyl 4- methylbenzenesulfonate (0.284 g, 1 equiv.), NaH (0.060 g, 1.5 equiv) in DMF (4 mL), as described for the synthesis of 1-(6-azidohexyl)indoline, furnished the desired 1-(5- azidopentyl)indoline. Yield = 0.140 g (36 %). ii. STEP 2 [00408] The reaction of 1-(5-azidopentyl)indoline (0.069 g, 0.26 mmol), and alkyneclarithromycin (0.255 g, 0.16 mmol), CuI (0.042 g, 0.75 equiv.), and DIPEA (0.03 mL) in THF (1.5 mL)/DMSO (1.5 mL), as described for the synthesis of DW-343, furnished the desired DW-334 as a white solid or foam. Yield = 0.181 g (56 %).¹H NMR (400 MHz, CDCl₃) δ 7.80 – 7.75 (d, J = 1.7 Hz, 2H), 7.74 – 7.69 (s, 1H), 7.38 – 7.31 (d, J = 6.5 Hz, 2H), 7.08 – 7.02 (d, J = 7.7 Hz, 2H), 6.65 – 6.59 (d, J = 4.9 Hz, 1H), 6.46 – 6.40 (s, 1H), 5.07 – 5.01 (d, J = 13.6 Hz, 1H), 4.91 – 4.86 (s, 1H), 4.45 – 4.38 (s, 3H), 3.99 – 3.96 (s, 1H), 3.96 – 3.90 (s, 1H), 3.80 – 3.69 (m, 4H), 3.64 – 3.59 (s, 1H), 3.49 – 3.40 (s, 2H), 3.33 – 3.24 (s, 3H), 3.20 – 3.16 (s, 1H), 3.13 – 3.09 (s, 4H), 3.04 – 2.85 (m, 11H), 2.61 – 2.51 (s, 2H), 2.28 – 2.21 (s, 4H), 2.10 – 1.98 (m, 3H), 1.93 – 1.63 (m, 10H), 1.52 – 1.41 (d, J = 4.3 Hz, 5H), 1.41 – 1.37 (d, J = 1.6 Hz, 4H), 1.29 – 1.05 (m, 26H), 0.89 – 0.77 (s, 3H).¹³C NMR (176 MHz, CDCl₃) δ 219, 178, 162, 139, 135, 129, 128, 127, 125, 121, 119, 109, 102, 101, 97, 94, 83, 78, 74, 73, 72, 70 ,69, 68, 65, 64, 62, 60, 57, 50, 49, 46, 45, 42, 41, 37, 36, 34, 30, 29, 27, 23, 22, 21, 18, 16, 15, 14, 11, 9, 7. HPLC-MS: [M + H]⁺ Expected 1077.6613; Found =1078.68. l. PREPARATION OF COMPOUND 22 [00409] 1-(4-Azidobutyl)indoline (0.060 g, 1 equiv.) and alkyneazithromycin (0.235 g, 1 equiv.) and CuI (0.039 g, 0.75 equiv.) were dissolved in THF (2 mL) and DMSO (2 mL). The mixture was kept stirring at rt and flushed with argon. DIPEA (Hunig’s base) (0.070 mL) was added and stirring continued under argon at rt overnight (about 20 h). The reaction was partitioned between CH₂Cl₂ (40 mL) and conc. NH₄OH/NH₄Cl 1:1 (30 mL), the two layers separated, and the organic layer was washed sequentially with conc. NH₄OH/NH₄Cl 1:1 (2 × 30 mL), brine (30 mL) and dried over Na₂SO₄. The crude was purified using prep-TLC, eluting with Acetone/Hexanes/MeOH: 3:4:0.2 to give Compound 22, after eluting off silica gel with CH₂Cl₂/MeOH/ NH₄OH 14:1:0.1, as a white solid. Yield = 0.144 g (49 %).¹H NMR (400 MHz, CDCl₃) δ 7.81 – 7.72 (m, 3H), 7.37 – 7.32 (s, 2H), 7.07 – 7.02 (m, 2H), 6.67 – 6.61 (s, 1H), 6.47 – 6.41 (d, J = 7.8 Hz, 1H), 5.19 – 5.11 (s, 1H), 4.73 – 4.66 (s, 1H), 4.48 – 4.36 (s, 4H), 4.25 – 4.14 (s, 2H), 4.06 – 3.99 (s, 1H), 3.85 – 3.74 (s, 1H), 3.70 – 3.64 (s, 1H), 3.62 – 3.55 (s, 2H), 3.51 – 3.41 (s, 3H), 3.32 – 3.21 (s, 3H), 3.15 – 2.82 (s, 15H), 2.75 – 2.63 (s, 3H), 2.62 – 2.52 (s, 3H), 2.34 – 2.27 (s, 4H), 2.28 – 2.23 (s, 4H), 2.11 – 2.04 (s, 5H), 1.95 – 1.84 (s, 3H), 1.80 – 1.66 (m, 4H), 1.34 – 1.28 (s, 9H), 1.27 – 1.18 (s, 8H), 1.15 – 1.07 (s, 11H), 1.06 – 1.00 (s, 3H), 0.93 – 0.78 (s, 7H).¹³C NMR (176 MHz, CDCl₃) δ 178, 171, 152, 147, 139, 135, 132, 130, 129, 128, 127, 125, 124, 123, 122, 121, 119, 118, 117, 109, 108, 106, 102, 97, 94, 83, 78, 77, 74, 73, 72, 70, 68, 65, 64, 62, 60, 57, 53, 50, 49, 46, 44, 37, 36, 34, 30, 29, 28, 27, 26, 22, 21, 20, 18, 16, 15, 14, 11, 9, 7. HPLC-MS: [M + H]⁺ Expected 1064.67; Found = 1064.66. m. PREPARATION OF COMPOUND 23 i. STEP 1 [00410] A solution of indoline (0.176 g, 1 equiv.) in DMF (5 mL) was treated with NaH (0.053 g, 1.5 equiv.) at rt for 30 min.4-azidobutyl 4-methylbenzenesulfonate (0.400 g, 1 equiv.) was added, and stirring continued at rt for about 20 h. The reaction was partitioned between CH₂Cl₂ (40 mL) and brine (25 mL). The two layers were separated, the aqueous layer was extracted with CH₂Cl₂ (20 mL) and the combined organic layer was dried over Na₂SO₄. The crude was purified using prep-TLC, eluting with EtOAc/Hexanes 1:7 to give the requisite 1-(4- azidobutyl)indoline, after eluting off silica gel with CH₂Cl₂/MeOH 14:1, as a clear oil. Yield = 0.140 g (43.9 %). ii. STEP 2 [00411] 1-(4-azidobutyl)indoline (0.070 g, 1 equiv.), and alkyneclarithromycin (0.275 g, 1 equiv.) and CuI (0.046 g, 0.75 equiv.) were dissolved in THF (2 mL) and DMSO (2 mL). The mixture was kept stirring at rt and fluxed with argon. DIPEA (Hunig’s base) (0.082 mL) was added and stirring continued under argon at rt overnight (about 20 h). The reaction was partitioned between CH₂Cl₂ (40 mL) and conc. NH₄OH/NH₄Cl 1:1 (30 mL), the two layers separated, and the organic layer was washed sequentially with conc. NH₄OH/NH₄Cl 1:1 (2 x 30 mL), brine (30 mL) and dried over Na₂SO₄. The crude was purified using prep-TLC, eluting with EtOAc/Hexanes/Et₃N 3:2:0.2 to give Compound 23, after eluting off silica gel with CH₂Cl₂/MeOH/ NH₄OH 14:1:0.1, as a white solid or foam. Yield = 0.085 g (56 %).¹H NMR (400 MHz, CDCl₃) δ 7.78 – 7.77 (s, 1H), 7.76 – 7.73 (d, 2H), 7.35 – 7.30 (d, J = 8.4 Hz, 2H), 7.08 – 7.01 (d, J = 11.3 Hz, 2H), 6.66 – 6.59 (m, 1H), 6.45 – 6.41 (d, J = 7.8 Hz, 1H), 5.08 – 4.98 (s, 1H), 4.90 – 4.84 (s, 1H), 4.46 – 4.38 (s, 3H), 4.02 – 3.90 (s, 2H), 3.79 – 3.65 (d, J = 18.0 Hz, 3H), 3.64 – 3.57 (s, 1H), 3.53 – 3.42 (s, 2H), 3.36 – 3.21 (s, 4H), 3.11 – 2.97 (m, 10H), 2.97 – 2.86 (s, 5H), 2.59 – 2.48 (s, 2H), 2.31 – 2.20 (s, 5H), 2.16 – 1.87 (m, 6H), 1.90 – 1.59 (m, 3H),1.52– 1.03 (m, 26H), 0.84 – 0.73 (s, 3H).¹³C NMR (176 MHz, CDCl₃) δ 220, 179, 161 ,139, 134, 129 , 128 , 127, 125 , 121, 119, 102, 94, 83 , 78, 77, 74, 73, 72, 70, 68 , 65, 64, 62 , 57, 53 , 49, 45, 42, 42, 36, 36, 34, 29, 27, 26, 18, 17, 16, 14, 11, 8, 7. HPLC-MS: [M + H]⁺ Expected 1064.37; Found = 1064.65. n. PREPARATION OF COMPOUND 24 i. STEP 1 [00412] The reaction of indoline (0.08 g, 1 equiv.), 6-azidohexyl 4- methylbenzenesulfonate (0.2 g, 1 equiv.), NaH (0.040 g, 1.5 equiv) in DMF (4 mL), as described for the synthesis of 1-(4-azidobutyl)indoline, furnished the desired 1-(6-azidohexyl)indoline. Yield = 0.080 g (42 %). ii. STEP 2 [00413] The reaction of 1-(5-azidopentyl)indoline (0.050 g,1 equiv.), and alkyneclarithromycin (0.174 g, 1 equiv.), CuI (0.042 g, 0.75 equiv.), and DIPEA (0.052 mL) in THF (1.5 mL)/DMSO (1.5 mL), as described for the synthesis of Compound 23, furnished the desired Compound 24 as a white solid. Yield = 0.083 g (37 %).¹H NMR (400 MHz, CDCl₃) δ 7.81 – 7.78 (d, 2H), 7.74 – 7.70 (s, 1H), 7.37 – 7.33 (d, J = 8.4 Hz, 3H), 7.09 – 7.03 (d, J = 8.0 Hz, 2H), 6.65 – 6.59 (t, J = 6.8 Hz, 1H), 6.45 – 6.41 (d, J = 8.1 Hz, 1H), 5.10 – 4.99 (d, J = 13.5 Hz, 1H), 4.92 – 4.84 (s, 1H), 4.44 – 4.34 (m, 3H), 4.02 – 3.91 (m, 2H), 3.83 – 3.69 (m, 3H), 3.65 – 3.59 (d, J = 7.2 Hz, 1H), 3.56 – 3.53 (s, 1H), 3.47 – 3.40 (d, J = 13.0 Hz, 2H), 3.32 – 3.25 (d, J = 8.2 Hz, 3H), 3.21 – 3.16 (s, 1H), 3.12 – 3.09 (s, 4H), 3.04 – 3.00 (s, 7H), 2.97 – 2.91 (t, J = 8.9 Hz, 4H), 2.90 – 2.84 (s, 1H), 2.65 – 2.50 (d, J = 12.6 Hz, 2H), 2.28 – 2.22 (d, J = 7.1 Hz, 5H), 2.12 – 1.80 (m, 7H), 1.80 – 1.66 (m, 4H), 1.62 – 1.54 (s, 2H), 1.46 – 1.37 (d, J = 15.0 Hz, 10H), 1.29 – 1.23 (s, 10H), 1.21 – 1.16 (s, 5H), 1.14 – 1.05 (s, 22H), 0.86 – 0.81 (t, J = 7.4 Hz, 4H). ). ¹³C NMR (176 MHz, CDCl₃) δ 219, 178, 162, 139, 135, 129, 128, 127, 125, 121, 119, 109, 102, 101, 97, 94, 83, 78, 74, 73, 72, 70, 69, 68, 65, 64, 62, 60, 57, 50, 49, 46, 45, 42, 41, 37, 36, 34, 30, 29, 27, 23, 22, 21, 18, 16, 15, 14, 11, 9, 7. HPLC-MS: [M + H]⁺ Expected 1091.67; Found =1092.69[M+H]. o. PREPARATION OF COMPOUND 25

i. STEP 1 [00414] Imidazole-1-sulfonyl azide hydrogen sulfate (0.307 g 1.1 equiv.) was added to the amine substrate (0.2 g 1.0 equiv.), K₂CO₃ (0.312 g, 2 equiv.), and CuSO₄.5H₂O (3 mg, 1 mol%) in MeOH (5 mL) and the mixture stirred at room temperature for 15 h. After completion of the reaction, the mixture was diluted with H₂O (15 mL), and extracted with EtOAc (3 × 15 mL). The combined organic layer was dried (MgSO₄), filtered, and concentrated to afford the desired 1-(3- azidopropyl)indoline as liquid (yield =0.201 mg, 87 %), which was used for the next step without purification.¹H NMR (400 MHz, CDCl₃) δ 7.11 – 7.03 (d, J = 4.1 Hz, 2H), 6.70 – 6.64 (s, 1H), 6.52 – 6.48 (d, J = 9.3 Hz, 1H), 3.48 – 3.41 (t, 2H), 3.37 – 3.31 (t, 2H), 3.20 – 3.13 (t, 2H), 3.02 – 2.95 (t, 2H), 1.94 – 1.84 (m, 2H). ii. STEP 2 [00415] 1-(3-azidopropyl)indoline (50 mg, 1 equiv.) and alkyneclarithromycin (0.210 g, 1 equiv.) were dissolved in the dry THF (2 mL) and DMSO (2 mL) under an argon atmosphere. Additionally, argon was bubbled through the solution for 10 min before and after the addition of Copper (I) iodide (35 mg, 0.75 equiv.). Diisopropyl ethyl amine (0.062 mL, 1.5 equiv.) was added and the reaction mixture was stirred at rt for 15 h. TLC indicated the completion of the reaction. The reaction mixture was quenched with water (50 mL), extracted with CH₂Cl₂ (2 × 20 mL), and the organic layer was sequentially washed with a 4:1 mixture of NH₄Cl: conc. NH₄OH, (15 mL), water (15 mL), and brine (10 mL). The organic layer was dried over Na₂SO₄, and then filtered. The solvent was removed using a rotary evaporator, and the crude material was purified preparative TLC, using Ethyl acetate: Hexane: Et₃N (3:2:0.2), to afford Compound 25 as a white solid (yield = 0.163 g, 63 %).¹H NMR (400 MHz, CDCl₃) δ 7.78 – 7.73 (d, J = 8.2 Hz, 2H), 7.74 – 7.69 (s, 1H), 7.35 – 7.30 (d, , J = 8.2 Hz, 2H), 7.09 – 7.05 (d, J = 7.1 Hz, 1H), 7.04 – 6.98 (t, J = 7.7 Hz, 1H), 6.73 – 6.54 (t, J = 7.3 Hz, 1H), 6.41 – 6.27 (d, J = 7.8 Hz, 1H), 5.06 – 4.97 (d, J = 13.5 Hz, 1H), 4.91 – 4.83 (s, 1H), 4.55 – 4.49 (t, J = 6.7 Hz, 2H), 4.44 – 4.38 (d, J = 7.1 Hz, 1H), 3.99 – 3.91 (s, 2H), 3.79 – 3.68 (m, 3H), 3.63 – 3.57 (d, J = 7.1 Hz, 1H), 3.46 – 3.39 (m, 2H), 3.33 – 3.26 (s, 3H), 3.23 – 3.17 (s, 1H), 3.12 – 3.00 (m, 9H), 2.90 – 2.83 (s, 1H), 2.60 – 2.45 (m, 3H), 2.29 – 2.16 (s, 8H), 2.16 – 2.07 (d, J = 10.2 Hz, 1H), 1.89 – 1.80 (m, 3H), 1.78 – 1.67 (m, 2H), 1.51 – 1.45 (s, 2H), 1.41 – 1.34 (s, 3H), 1.30 – 1.20 (d, J = 13.1 Hz, 8H), 1.18 – 0.97 (m, 21H), 0.85 – 0.78 (t, J = 7.4 Hz, 3H).¹³C NMR (176 MHz, CDCl₃) δ 178, 151, 147, 139, 129, 127, 125, 124,120 ,119, 117, 106, 103, 94, 83, 78, 74, 73, 72, 70, 68, 65, 64, 62, 57 , 54 , 50 49 , 48 , 43, 42, 41, 37, 36 , 34 , 29 , 28 , 27, 26 , 22 , 21 , 18 16,14, 11, 9, 7. HPLC-MS: [M + H]⁺ Expected 1049.63; Found = 1050.64. p. PREPARATION OF COMPOUND 26 [00416] 1-(3-azidopropyl)indoline (50 mg, 1 equiv.) and alkyneazithromycin (0.209 g, 1 equiv.) were dissolved in the dry THF (2 mL) and DMSO (2 mL) under an argon atmosphere. Additionally, argon was bubbled through the solution for 10 min before and after the addition of Copper (I) iodide (35 mg, 0.75 equiv.). Diisopropyl ethyl amine (0.062 mL, 1.5 equiv.) was added and the reaction mixture was stirred at rt for 15 h. TLC indicated the completion of the reaction. The reaction mixture was quenched with water (50 mL), extracted with CH₂Cl₂ (2 × 20 mL), and the organic layer was sequentially washed with a 4:1 mixture of NH₄Cl: conc. NH4OH, (15 mL), water (15 mL), and brine (10 mL). The organic layer was dried over Na₂SO₄, and then filtered. The solvent was removed using a rotary evaporator, and the crude material was purified preparative TLC, using Acetone/Hexanes/MeOH: 3:4:0.2 to afford Compound 26 as a white solid (yield = 0.220 g, 84 %).¹H NMR (400 MHz, CDCl₃) δ 7.77 – 7.66 (d, J = 10.2 Hz, 3H), 7.36 – 7.30 (d, J = 11.2 Hz, 2H), 7.08 – 6.93 (m, 2H), 6.69 – 6.60 (t, J = 7.4 Hz, 1H), 6.40 – 6.29 (d, J = 7.8 Hz, 1H), 5.17 – 5.06 (s, 1H), 4.70 – 4.64 (s, 1H), 4.55 – 4.50 (s, 1H), 4.42 – 4.36 (s, 1H), 4.21 – 4.18 (s, 1H), 4.09 – 4.00 (s, 1H), 3.79 – 3.69 (s, 1H), 3.64 – 3.52 (m, 3H), 3.48 – 3.29 (m, 5H), 3.15 – 3.05 (s, 4H), 3.06 – 2.86 (m, 5H), 2.79 – 2.67 (s, 1H), 2.60 – 2.49 (s, 2H), 2.31 – 2.20 (s, 8H), 2.17 – 2.06 (s, 1H), 2.10 –1.68 (s, 6H), 1.53 – 1.46 (s, 2H), 1.47 – 0.95 (m, 26H), 0.89 – 0.76 (s, 6H).¹³C NMR (176 MHz, CDCl₃) δ 178, 171, 152, 147, 139, 135, 132, 130, 129, 128, 127, 125, 124, 123, 122, 121, 119, 118, 117, 109, 108, 106, 102, 97, 94, 83, 78, 77, 74, 73, 72, 70, 68, 65, 64, 62, 60, 57, 53, 50, 49, 46, 44, 37, 36, 34, 30, 29, 28, 27, 26.72, 26, 22, 21, 20, 18, 16, 15, 14, 11, 11, 9, 7. HPLC-MS: [M + H]⁺ Expected 1050.66; Found = 1051.67. q. PREPARATION OF COMPOUND 27 i. STEP 1 [00417] A mixture of 4-(chloromethyl)benzoic acid (0.176 g 1 equiv.) and EDCI.HCl (0.198 g,1.1 equiv.) in dry CH₂Cl₂ (6mL) was stirred at 0 ^oC in an argon atmosphere for 30 min. 2-(1H-indol-1-yl)ethan-1-amine (0.150 g, 0.8 equiv.) and DMAP (12 mg, 0.15 equiv.) were added and the reaction was stirred at rt for 15 h. TLC indicated the completion of the reaction. The reaction was quenched with water (50 mL), extracted with CH₂Cl₂ (2 × 30 mL), and the combined organic layer was sequentially washed with a saturated solution of NaHCO₃ and brine (30 mL). The organic layer was dried over Na₂SO₄, and then filtered. The solvent was removed using a rotary evaporator and the crude material was purified on silica gel column chromatography, eluting with Hexane: ethylacetate (6:4), v/v, to afford solid the desired product N-(2-(1H-indol-1-yl)ethyl)-4-(chloromethyl)benzamide; yield: 175 mg (60 %).¹H NMR (400 MHz, CDCl₃) δ 7.63 – 7.57 (d, J = 6.4 Hz, 1H), 7.53 – 7.48 (d, J = 8.5 Hz, 2H), 7.34 – 7.27 (t, J = 8.8 Hz, 3H), 7.20 – 7.13 (m, 1H), 7.12 – 7.07 (m, 1H), 7.01 – 6.97 (d, J = 3.2 Hz, 1H), 6.50 – 6.45 (d, J = 3.1 Hz, 1H), 6.44 – 6.37 (d, J = 6.3 Hz, 1H), 4.57 – 4.45 (s, 2H), 4.31 – 4.21 (t, 2H), 3.71 – 3.59 (t, J = 6.0 Hz, 2H). [00418] A mixture of desmethylazithromycin (226 mg, 1.1 equiv.) and DIPEA (0.142 mL, 3 equiv.) in dry DMSO (5 mL) was stirred for 10 min at rt. N-(2-(1H-indol-1-yl)ethyl)-4- (chloromethyl)benzamide (0.087 g, 1 equiv.) was added to the reaction, and the resulting mixture was stirred for 15 h at 80 °C. TLC indicated the completion of the reaction. The reaction was quenched with water (10 mL) and extracted with CH₂Cl₂ (2 × 20 mL). The organic layers were combined, dried over Na₂SO₄, and then filtered. The solvent was removed using a rotary evaporator, and the crude material was purified by using preparative TLC, eluting with Acetone: Hexane: MeOH (3:4:0.2), v/v, to furnish Compound 27 as a white solid (yield = 225 mg, 72 %). ¹H NMR (400 MHz, CDCl₃) δ 7.64 – 7.60 (d, J = 8.0 Hz, 1H), 7.57 – 7.50 (d, J = 6.4 Hz, 2H), 7.43 – 7.35 (d, J = 8.2 Hz, 1H), 7.33 – 7.27 (d, J = 8.4 Hz, 2H), 7.20 – 7.14 (m, 1H), 7.13 – 7.04 (d, J = 17.8 Hz, 2H), 6.52 – 6.46 (s, 1H), 6.33 – 6.27 (s, 1H), 5.00 – 4.92 (s, 1H), 4.69 – 4.59 (s, 1H), 4.42 – 4.35 (s, 3H), 4.28 – 4.22 (s, 1H), 4.04 – 3.94 (s, 1H), 3.83 – 3.74 (s, 4H), 3.68 – 3.62 (s, 2H), 3.51 – 3.44 (s, 2H), 3.43 – 3.32 (d, J = 17.5 Hz, 1H), 3.22 – 3.10 (s, 3H), 2.98 – 2.88 (d, J = 4.3 Hz, 1H), 2.85 – 2.73 (s, 1H), 2.72 – 2.66 (s, 2H), 2.56 – 2.40 (m, 2H), 2.36 – 2.21 (d, J = 8.8 Hz, 6H), 2.15 – 2.01 (m, 2H), 1.88 – 1.74 (s, 2H), 1.58 – 1.45 (m, 2H), 1.28 – 1.10 (m, 15H), 1.13 – 0.99 (d, J = 4.4 Hz, 10H), 0.95 – 0.78 (d, J = 9.6 Hz, 6H).¹³C NMR (101 MHz, CDCl₃) δ 178, 167, 143, 136, 133, 129, 128, 127, 122, 121, 119109, 103, 102, 95, 84, 79, 78, 77, 75, 74, 73, 72, 71, 69, 68, 65, 64, 62, 57, 49, 45, 44, 42, 41 , 40 , 37, 36, 35, 30, 27, 26, 22, 21, 21,20, 18, 16, 15, 11, 9, 7. HPLC-MS: [M + H]⁺ Expected 1010.62; Found = 1011.63. r. PREPARATION OF COMPOUND 28 [00419] A mixture of desmethylclarithromycin (259 mg, 1.1 equiv.) and DIPEA (0.163 mL, 3 equiv.) in dry DMSO (5 mL) was stirred for 10 min at rt. N-(2-(1H-indol-1-yl)ethyl)-4- (chloromethyl)benzamide (0.1 g, 1 equiv.) was added to the reaction, and the resulting mixture was stirred for 15 h at 80 °C. TLC indicated the completion of the reaction. The reaction was quenched with water (10 mL) and extracted with CH₂Cl₂ (2×20 mL). The organic layers were combined, dried over Na₂SO₄, and then filtered. The solvent was removed using a rotary evaporator, and the crude material was purified by using preparative TLC, eluting with Acetone: Hexane: MeOH (3:4:0.2), v/v, to furnish Compound 28 as a white solid (yield = 200 mg, 62 %).  ¹H NMR (400 MHz, CDCl₃) δ 7.65 – 7.61 (s, 1H), 7.57 – 7.53 (d, J = 6.4 Hz, 2H), 7.42 – 7.35 (d, J = 9.1 Hz, 1H), 7.33 – 7.28 (d, J = 10.6 Hz, 2H), 7.22 – 7.17 (m, 1H), 7.14 – 7.11 (d, J = 6.0 Hz, 1H), 7.09 – 7.07 (s, 1H), 6.53 – 6.50 (d, J = 3.9 Hz, 1H), 6.19 – 6.15 (s, 1H), 5.08 – 5.00 (d, J = 11.2 Hz, 1H), 4.91 – 4.88 (s, 1H), 4.44 – 4.37 (s, 3H), 4.01 – 3.92 (s, 2H), 3.84 – 3.71 (m, 5H), 3.64 – 3.61 (d, J = 7.2 Hz, 1H), 3.50 – 3.41 (s, 2H), 3.33 – 3.28 (s, 1H), 3.20 – 3.14 (d, J = 9.6 Hz, 4H), 3.04 – 2.99 (s, 3H), 3.00 – 2.94 (s, 2H), 2.90 – 2.82 (s, 1H), 2.62 – 2.45 (s, 2H), 2.34 – 2.27 (d, J = 15.1 Hz, 1H), 2.23 – 2.14 (s, 3H), 2.11 – 2.05 (d, J = 10.4 Hz, 1H), 1.95 – 1.80 (m, 3H), 1.77 – 1.66 (t, J = 14.9 Hz, 2H), 1.56 – 1.50 (d, J = 10.0 Hz, 1H), 1.41 – 1.37 (s, 3H), 1.29 – 1.1 (m, 26 H), 0.85 – 0.79 (t, 3H).¹³C NMR (101 MHz, CDCl₃) δ 175, 167.65, 143, 136, 133, 129, 128, 127, 122, 121, 119, 109, 103, 81, 78, 7874, 72, 71, 66, 64, 51, 49, 45, 45, 40, 3937, 21, 19, 18, 17, 16, 12, 10, 9. HPLC-MS: [M + H]⁺ Expected 1009.58 ; Found = 1010.60. s. PREPARATION OF COMPOUND 29 [00420] A mixture of desmethylclarithromycin (0.2 g, 1.2 equiv.) and DIPEA (0.174 mL, 3 equiv.) in dry DMSO (5 mL) was stirred for 10 min at rt. 4-(3-Bromopropoxy)-N-(2-(indolin- 1-yl) ethyl)benzenesulfonamide (0.1 g, 1 equiv.) was added to the reaction and the resulting mixture was stirred for 15 h at 80 °C. TLC indicated the completion of the reaction. The reaction mixture was quenched with water (10 mL) and extracted with CH₂Cl₂ (3 × 20 mL). The organic layers were combined, dried over Na₂SO_4, and then filtered. The solvent was removed using a rotary evaporator, and the crude material was purified using preparative TLC, eluting with EtOAc/Hexanes/Et3N (3:2:0.2) v/v; to furnish Compound 29 as a white solid (yield = 70 mg, 24 %).¹H NMR (400 MHz, CDCl₃) δ 7.74 – 7.65 (d, 2H), 7.07 – 7.00 (d, J = 7.5 Hz, 2H), 6.95 – 6.89 (d, J = 8.9 Hz, 2H), 6.67 – 6.58 (t, J = 7.4 Hz, 1H), 6.45 – 6.38 (d, J = 7.8 Hz, 0H), 5.06 – 4.99 (d, J = 11.0 Hz, 1H), 4.91 – 4.88 (s, 1H), 4.45 – 4.37 (d, J = 7.2 Hz, 1H), 4.06 – 3.99 (s, 1H), 3.75 – 3.70 (s, 2H), 3.68 – 3.59 (s, 1H), 3.53 – 3.40 (s, 1H), 3.31 – 3.15 (m, 7H), 3.04 – 2.89 (s, 6H), 2.58 – 2.41 (s, 3H), 2.36 – 2.28 (d, J = 15.1 Hz, 2H), 2.29 – 2.15 (m, 4H), 1.98 – 1.75 (s, 4H), 1.70 – 1.49 (m, 3H), 1.45 – 1.35 (s, 3H), 1.32 – 1.26 (d, J = 9.4 Hz, 3H), 1.26 – 0.98 (m, 22H), 0.86 – 0.75 (d, J = 7.4 Hz, 3H).¹³C NMR (176 MHz, CDCl₃) δ 179, 152, 144, 138, 127, 124, 118, 109, 102, 94 , 78 , 77 , 74, 73.7, 73 , 70 , 68 , 65 , 57 , 53, 49.61 , 49 , 45 , 42 , 41 , 37 , 36 , 34 , 30 , 29 , 28 , 26 , 22, 21.71, 21, 18, 16, 14, 11, 9, 7. HPLC-MS: [M + H]⁺ Expected 1091.59 Found = 1092.60. 2. EXEMPLARY COMPOUNDS [00421] A list of exemplary compounds is shown in Table 1 below. Compounds 1-16 and 21-31 were prepared using the synthetic methods described herein. Additional methods of synthesizing Nox4 inhibitors are described in U.S. Patent No.10,654,802. Compound nos.17- 20 were designed in silico only and were used for computational studies as further described herein. TABLE 1.

3. DEVELOPMENT OF ARDS THERAPEUTIC STRATEGIES [00422] A Novel 2-Hit Pre-Clinical Aging Murine Model of Severe ARDS Better Reccapitulates the Clinical Features of ARDS in Elderly Patients. Pre-clinical animal models that more accurately reproduce the clinical features of ARDS are critical to better understanding pathogenesis and developing therapeutic interventions. A key limitation is the overwhelming utilization of young animals to evaluate the pathogenesis and therapeutic interventions of this age-related disease. A novel 2-hit pre-clinical aging murine model of severe ARDS was developed previously (Palumbo et al. (2017) American Journal of Physiology-Lung Cellular and Molecular Physiology 312.3: L297-L308). In this model, aged (18 month) mice are subjected to combined exposure to both LPS and VILI (FIG.1A). It was shown that, compared to young (2m) cohorts, only aged mice develop severe ARDS; demonstrated by significantly increased: lung injury score (FIG.1B), vascular permeability (bronchoalveolar lavage protein, cellular, neutrophil, and albumin influx), oxidative damage, and mortality. These findings support the concept that synergistic lung inflammatory and injury responses are acquired with advanced age. Overall, this 2-hit pre-clinical aging model of severe ARDS more accurately recapitulates the clinical features of ARDS in elderly patients (regardless of etiology). This model is in line with elderly patients at risk for ARDS and provides the ability to implement more clinically relevant therapeutic testing protocols. [00423] Senescent ECs Exhibit Defective Barrier-Regulatory Responses. The increased presence of senescent cells at sites of age-associated pathologies supports a role for senescence in the pathogenesis (Vasile E, et al. (2001) FASEB 15(2):458-66). The impact of senescence in EC barrier-regulatory responses was evaluated using an in vitro cellular model of replicative senescence using characterized human ECs characterized. In response to insult, senescent cells exhibit significantly increased permeability (FIG.2B), as compared to control “young” ECs (FIG.2A). Without wishing to be bound by theory, these studies indicate that EC senescence leads to impaired barrier function. [00424] Nox4: An ROS-Generating Enzyme that Mediates EC Permeability. Numerous studies have demonstrated that excessive ROS production plays a major role in EC barrier dysfunction resulting in pulmonary edema. It has been demonstrated that although both young and senescent ECs generate ROS in response to insult, senescent ECs with defective barrier- regulatory responses generated significantly greater ROS levels compared to young ECs (FIG. 3A) (Palumbo et al. (2017) American Journal of Physiology-Lung Cellular and Molecular Physiology 312.3: L297-L308). [00425] The NADPH oxidase (Nox) enzymes are an evolutionarily conserved gene family linked to host defense mechanisms. The only known role of Nox enzymes is the production of ROS, which is important for cellular homeostasis and stress-induced repair-responses. NADPH oxidase-4 (Nox4) is a constitutively active enzyme, which specifically generates H₂O₂, a relatively stable oxidant compared to other ROS types. Nox4 is the most abundantly expressed Nox isoform in ECs, and Nox4 is the primary enzymatic source of ROS in ECs. It has been demonstrated that Nox4-dependent ROS mediates EC permeability. Importantly, in response to insult, expression levels of other Nox isoforms remained unchanged (only Nox4 was increased). These findings have been validated further confirming the Nox4-specific role in mediating EC permeability (ruling out the role of other Nox isoforms). Further, a number of stimuli (ex. LPS and P. aeruginosa) have been shown to induce Nox4-dependent ROS, which mediates increased permeability responses in various types of ECs and promotes pro-inflammatory responses. It has been demonstrated that in response to insult, senescent ECs generate excessive ROS levels due to persistently elevated Nox4 expression (FIG.3A and FIG.3B), whereas control ECs exhibit rapid and transient expression of Nox4 with lower ROS levels (FIG.3A and FIG.3B). It has been demonstrated that targeting Nox4 in senescent ECs attenuated ROS production and restored barrier function. Nox4 has also been shown to mediate senescence; Nox4 overexpression increased ROS production and induced EC senescence, whereas Nox4 knockdown inhibited the induction of EC senescence. Overall, Nox4-dependent ROS plays a critical in mediating EC barrier regulatory responses, and aberrant/sustained upregulation of Nox4 in senescent ECs promotes persistently elevated ROS levels resulting in exacerbated permeability and inflammatory responses. [00426] Aged Mice with Severe ARDS Exhibit Sustained Upregulation of Nox4 and Elevated ROS. It was previously demonstrated that aged mice with severe ARDS (FIG.1B) exhibited significantly elevated Nox4 protein levels in the lungs, which corresponded with increased ROS levels in lung BAL (FIG.4) (Palumbo et al. (2017) American Journal of Physiology-Lung Cellular and Molecular Physiology 312.3: L297-L308). In contrast, young/injured mice that demonstrated mild injury exhibited only a modest increase in Nox4 and had significantly lower BAL/ROS levels than aged/injured mice (FIG.4). These results demonstrate an age-dependent divergent induction of Nox4 in the lungs following ALI. [00427] Novel Age-Dependent Mechanism of Nox4 Dysregulation. Although Nox4 is primarily known to be regulated at the transcriptional level, It has been demonstrated that Nox4 expression can be rapidly induced (within 5 min) in both young control ECs and senescent ECs. A novel post-translational mechanism has been established by which expression of Nox4 can be rapidly altered in ECs (via the proteasome-ubiquitin system). Importantly, in young ECs (with intact permeability responses) this rapid increase in Nox4 expression returned to baseline levels within 1h. In contrast, senescent ECs exhibit deficient ubiquitination of Nox4, which promotes its sustained expression and excessive ROS production. Without wishing to be bound by theory, these studies provide novel mechanistic insight that may in part explain the persistent upregulation of Nox4 following acute insult/injury in the context of aging, and further validate the rationale to develop ARDS therapeutic strategies that aim to correct age-dependent Nox4 dysfunction. [00428] Selective Nox4 Inhibitors Have Not Been Successfully Developed. There are no commercially available Nox4 inhibitors. Nox4 drug development has proven challenging for several reasons. The crystal structure of Nox4 is unknown, which precludes traditional rational drug design approaches. Screening methods for Nox inhibitors typically utilize ROS detection- based screening assays that have limited specificity. Thus, it may be difficult to discern whether a putative inhibitor is acting directly on Nox versus regulation of upstream signaling pathway(s). Accordingly, one study reported that of >350 “Nox inhibitors” described, a majority of these did not directly block Nox enzymatic activity, but rather showed interference with upstream signaling pathways or demonstrated antioxidant activity. An additional challenge to the field is reports of putative “Nox inhibitors,” which have been subsequently challenged and disproven. [00429] The most well-studied putative “Nox1/4 inhibitor” is Setanaxib (also known as GKT137831), originally developed by Genkyotex (Geneva, Switzerland) and now being developed by Calliditas Therapeutics. However, a recent in-depth evaluation of putative Nox inhibitors demonstrated that “GKT136901 is inactive as Nox inhibitor, but rather interferes with peroxidase-dependent assays” (Augsburger et. al. (2019) Redox Biol 26:101272). Setanaxib showed significant inhibitory activity in the presence of H₂O₂ alone using a cell-free assay system (Augsburger et. al. (2019) Redox Biol 26:101272), suggesting it acts as an anti-oxidant rather than via direct Nox4 inhibition. Recent data further validate these findings: in a cell-free assay with exogenous H₂O₂, Setanaxib showed 63% inhibition at 10mM (Fig.5A), and 100% inhibition at higher concentrations >30mM. Although Setanaxib remains marketed as a Nox1/4 inhibitor, it has been definitively shown that its mechanism of action is not via direct Nox inhibition. [00430] APX-115 is a “putative Nox1,2,4 inhibitor” (Aptabio Therapeutics Inc) that is currently in a clinical trial for Type 2 diabetic nephropathy. Although this candidate has been evaluated in pre-clinical efficacy studies with animal models, it is important to note that its characterization as a “Nox inhibitor” is limited to only one published report. Further, the rigor of published characterization studies with APX-115 is below currently accepted standards. Shortcomings of APX-115 characterization include: (1) Lucigenin was used for ROS detection, which detects O₂ (not H₂O₂, the primary ROS produced by Nox4). Further, NADPH + lucigenin generates a bioluminescent signal, which is not Nox dependent; caution is advised for the use of lucigenin for ROS detection. (2) False-positive screening for H₂O₂ scavenger activity also utilized Lucigenin (which only detects O₂). Further, 1 mM H₂O₂ was evaluated in this assay; this concentration is likely to denature the system such that results are not reliable (5-10 µM H₂O₂ is appropriate for such assays). (3) ROS generation was evaluated by dichlorodihydrofluorescein (DCF); however, DCF is photoactivated and known to be artifact prone. (4) The Drosophila membrane assay utilized lacks validation; no data is provided to confirm Nox expression and no controls were used. (5) Studies lack the addition of subunits for Nox1 and Nox2, which are essential to have a functional ROS generating Nox1 and 2 membrane assays. In summary, although APX-115 and Setanaxib might be interesting non-toxic pharmacological agents, their Nox inhibitory activity has either been disproven (Setanaxib) or is not convincing (APX-115). Current data demonstrate that APX-115 is an antioxidant: in a cell-free assay with exogenous H₂O₂, APX- 115 showed 56% inhibition at 10 μM, and 100% inhibition at higher concentrations >30 μM (FIG.5A). [00431] GLX351322: is a putative Nox inhibitor developed by Glucox Biotech, which was initially identified via a high-throughput approach using a Nox4 overexpressing cell line and an Amplex Red assay (similar to our primary screening assay). This candidate is still in pre-clinical development and has not reached clinical trials. Pre-clinical studies have evaluated GLX351322 as a therapeutic strategy for type 2 diabetes. However, similar to APX-115, published studies are primarily focused on its therapeutic effects and rigorous validation studies for its potency and selectivity for Nox4 are lacking. Data indicates that GLX351322 has toxic effects; treatment 10mM led to 66% cell death, as compared to vehicle (Fig.5B). This calls into question the validity of this candidate, as decreased cell number resulting from cell death is a false-positive result in the primary screen. [00432] Diphenylene iodonium (DPI) remains the only well-validated pan-Nox inhibitor; however, drawbacks including lack of specificity individual, off-target inhibition of other ROS- producing systems, irreversible binding and toxicity in vivo have prevented its therapeutic development of this non-drug-like molecule. Nonetheless DPI remains a powerful tool for Nox therapeutic development programs and will be used as a positive control in our proposed studies. [00433] In summary, no bona fide Nox inhibitors are clinically available. Importantly, Setanaxib, APX-115, and GLX351322 did not pass the false-positive screening at the earliest stage of our screening pipeline, which is required for any of our candidates to advance. Although APX-115 and Setanaxib might be interesting non-toxic pharmacological agents (both currently in clinical trials), their Nox inhibitory activity has either been disproven or is not convincing. The observed protective effects of these candidates reported in pre-clinical in vivo studies do not stem from direct inhibition of Nox, but rather from a non-specific redox mechanism and/or downstream effects on Nox4 activity. A bona fide Nox4 inhibitor needs to fulfill several criteria: limited antioxidant activity, lack of effect on other sources of ROS upstream of Nox4 signaling, demonstrated direct inhibition of Nox4 activity, and high selectivity for Nox4. The development of novel biochemical assays and progress in other therapeutic Nox programs will be monitored in order to maintain the highest standards of rigor and reproducibility. [00434] Other putative Nox inhibitors failed the screening pipeline. Referring to FIG.5A and FIG.5B, APX-115, Setanaxib, and GLX exemplified the failed false-positive screening of the putative Nox4 inhibitors. FIG.5A shows compounds at (10mM), Vehicle (DMSO), or Catalase (750U/mL; positive control for antioxidant activity) were incubated with H₂O₂ (5µM) for 1h. H₂O₂ was assessed by ROS-Glo Amplex Red (HRP-dependent assay); these data demonstrate that other putative Nox inhibitors act as antioxidants. FIG.5B shows data of HEK cells stably transfected to overexpress Nox4 (HEK-Nox4 cells) were treated with compounds (10µM), vehicle control (DMSO), or digitonin (positive control cell death) and incubated for 1h. Cellular viability was evaluated by CellTiter-Glo® Assay. These data demonstrate that GLX treatment leads to significant cell death. 4. PRELIMINARY STUDIES a. NOX4 TARGET VALIDATION [00435] Previous studies have demonstrated that Nox4 mediates EC barrier responses, and that Nox4 is upregulated in senescent ECs. Microarray data further corroborated these findings at the transcriptional level (Table 2). Importantly, no other Nox isoforms are upregulated. Overall, these data further support a Nox4-specific role in mediating EC permeability. TABLE 2. b. AGED EC-TARGETED NOX4 KO MICE DEMONSTRATE STRIKING PROTECTION FROM ALI [00436] Although several studies have demonstrated in vivo proof-of-concept for systemic targeting of Nox4-mediated barrier dysfunction, evidence for selective targeting of Nox4 specifically in ECs in vivo has not been performed previously due to the lack of available research tools. Further, genetic targeting of Nox4 in age-dependent severe pre-clinical ARDS has not been evaluated previously. In a mouse model of brain ischemia, EC-targeted genetic ablation of Nox4 led to significant protection from blood-brain barrier breakdown, supporting an EC- specific role for Nox4 in mediating permeability responses in vivo. Another study demonstrated that EC-specific targeting of Nox activation (via PECAM-conjugated liposome containing MJ33, an indirect inhibitor of Nox activity) resulted in greater protection from ALI, as compared to systemic delivery. In order to more specifically evaluate the role of EC-Nox4 in ALI in vivo, particularly in the context of aging, endothelial targeted Nox4 knockout (Nox4-eKO) mice were developed (FIG.6A), and mice were aged to 18m. To confirm EC-Nox4 knockdown in vivo, ECs were isolated from wild-type (WT) and Nox4-eKO mice via FACS. Indeed, ECs isolated from Nox4-eKO mice demonstrated significant knockdown of Nox4, as compared to WT isolated ECs (FIG.6B). Young (2m) and aged (18m) WT and Nox4-eKO mice were then subjected to ALI (LPS via IT delivery). Although preliminary data suggested that young Nox4- eKO mice exhibit some protection from ALI, only aged Nox4-eKO mice exhibited striking protection from ALI, as demonstrated by decreased lung BAL cells (FIG.6C), decreased BAL ROS levels (FIG.6D), decreased BAL protein (FIG.6E), and decreased lung albumin (FIG. 6F). Overall, these studies support the concept that specifically targeting mechanisms that become defective in aging (ex. persistently elevated Nox4/ROS) offers the most significant therapeutic benefit, and may be the key to improving outcomes for elderly ARDS patients. [00437] Referring to FIG.6A-F, validates that aged Nox4-eKO mice demonstrate striking protection from ALI. FIG.6A shows Nox4-eKO mice were generated by crossing Nox4 floxed mouse (gift from Dr. Sadoshima, Rutgers University) with EC specific promoter-driven Cre (EC- targeted Cre) mouse (Jackson Laboratory); confirmed by genotyping. FIG.6B shows data of lung ECs from WT and Nox4-eKO mice were isolated via FACS and evaluated for Nox4 expression via WB. FIG.6C-F show young and aged mice were subjected to intratracheal instillation of LPS (0.2mg/kg) via IT delivery for 24h. Severity of ALI assessed by total BAL cells (FIG.6C), BAL H₂O₂ (FIG.6D), BAL protein (FIG.6E), and BAL albumin (FIG.6F). Values shown are injured mice compared to respective uninjured control. (n = 3-16 mice/group; *p < 0.05, **p < 0.01 using Student’s 2-tailed t-test). c. IDENTIFICATION OF NOVEL NOX4 SMALL-MOLECULE INHIBITOR CANDIDATES FOR FIBROSIS INDICATIONS VIA ORAL DELIVERY [00438] Previous studies demonstrated feasibility of successful pre-clinical development of Nox4 inhibitors. A high-throughput screening (HTS) approach was employed to screen for Nox4 inhibitor candidates, utilizing HEK293 cells that stably over-express Nox4 (HEK/Nox4 cells) which generate high levels of Nox4-dependent H₂O₂.30,000 compounds were screened, which led to the identification of “hits” which were subjected to false-positive screening; those that passed served as a starting point for medicinal chemistry efforts. A putative lead candidate (UANOX48) emerged. See Table 1. [00439] UANOX48 has a low molecular weight (384.4 g/mole) and a relatively high solid-to-liquid melting phase transition (Tonset 89.72˚C, Tpeak 92.3°C), indicating high stability at both room and body temperatures (32-37°C); this is important from a pharmaceutical standpoint, as these data indicate high stability at drug manufacturing/processing and delivery temperatures. UANOX48 passed false-positive screening: demonstrated no scavenger activity (does not act as an antioxidant) (FIG.7A and FIG.7B), does not interfere with assay reagents (FIG.7A), and has no effect on cellular viability (FIG.7C). Predicted docking/binding simulations were also performed on the two enantiomers of UANOX48 using Autodock Vina (J Comput Chem.2010, 31(2):455-61. doi: 10.1002/jcc.21334. PMID: 19499576). For this docking study, a homology model of Nox4 was used with the binding orientation of UANOX048 as a reference. It was observed that R- and S-enantiomers of UANOX48 adopt identical docked poses having the same dock score (-9.0 kcal/mol), with their methyl moiety oriented in opposite directions in regions where they form no interaction with the active site residues. This in silico observation strongly indicates direct binding with high binding affinity and a lack of preference for either enantiomer. [00440] UANOX48 demonstrated high selectivity for Nox4 over Nox2 or xanthine oxidase (Nox-independent ROS generation) (FIG.7D). In vitro absorption, distribution, metabolism, and excretion (ADME) indicate an acceptable profile, with low lipophilicity (calculated logD = 3.85) and high Caco-2 permeability no efflux pump susceptibility (54.6 ×10cm/sec). The inducibility of Nox4-dependent H₂O₂ by TGF-β1 is a highly specific and unique function of Nox4. This unique feature of Nox4 was exploited in the screening cascade. In human lung fibroblasts, treatment with UANOX048 inhibited TGF-β1-induced H₂O₂ production, which blocked induction of pro-fibrotic myofibroblast phenotypes, including myofibroblast differentiation and collagen production. [00441] Referring to FIG.7A-D, shows assays associated with identification of a novel Nox4 inhibitor. FIG.7A-C show results for false-positive screening: UANOX48 (10 µM), Vehicle (DMSO), or Catalase (750U/mL; positive control for scavenger activity) were incubated with H₂O₂ (5 µM) for 1h. Scavenger activity of H₂O₂ was assessed by ROS-Glo (HRP- independent assay) (FIG.7A) and Amplex Red (HRP-dependent assay) (FIG.7B). FIG.7C shows HEK cells stably transfected to overexpress Nox4 (HEK-Nox4 cells) were treated with UANOX48 (10 µM), vehicle control (DMSO), or digitonin (positive control cell death) and incubated for 1h. Cellular viability was evaluated by CellTiter-Glo® Assay. FIG.7D shows selectivity assay data: IC₅₀ evaluation was performed in cell-based assays. Nox4: HEK-Nox4 cells were treated with varying concentrations of UANOX48 or vehicle (DMSO) and incubated for 1h. H₂O₂ production was evaluated by Amplex Red assay. Nox2: RAW 264.7 cells were stimulated with PMA to induce Nox2 activity. Xanthine oxidase (XO): XO was evaluated by XO activity assay. All values represent means ± SEM (n=3-6); *p<0.05; ***p<0.001; using students t-test or one-way ANOVA multiple comparisons with a Tukey’s post-test. [00442] In lung myofibroblasts isolated from IPF patients, treatment with UANOX48 promoted the reversal of established pro-fibrotic myofibroblast phenotypes: inhibited H₂O₂ production (IC5025.7 nM) (FIG.8A), and collagen production (FIG.8B). Importantly, in vivo efficacy was evaluated in an aging model of persistent lung fibrosis; treatment with UANOX48 promotes the reversal of age-dependent established fibrosis, which resulted in improved lung function. In vivo efficacy was demonstrated for UANOX48 for inhibiting cardiac fibrosis, which led to improvement in cardiac function. [00443] Referring to FIG.8A and FIG.8B, Nox4 inhibition reverses established pro- fibrotic phenotypes in human IPF lung myofibroblasts. FIG.8A shows myofibroblasts isolated from the lungs of IPF patients treated with UANOX48 (10 µM or as indicated) or vehicle (DMSO). H₂O₂ levels were evaluated at 24h by Amplex Red assay. FIG.8B shows collagen levels determined by quantitative Sircol assay (n=3-6); *p<0.05;**p<0.01; using one-way ANOVA multiple comparisons with a Tukey’s post-test or Student’s two-tailed t-test to compare the means between two groups. d. TARGETING NOX4-DEPENDENT REDOX IMBALANCE AS A THERAPEUTIC APPROACH FOR ARDS [00444] UANOX48 was utilized to demonstrate proof-of-concept for targeting Nox4 in an animal model of ARDS. Treatment with UANOX48 led to reduced ROS levels in senescent ECs (FIG.9A) and increased proliferation of non-senescent ECs (FIG.9B). [00445] The PK profile and lung distribution of UANOX048 via IV delivery was evaluated in mice; half-life (t_1/2) 3h (plasma), and 2.9h (lung). The efficacy of UANOX048 was evaluated in a murine model of ALI. Mice were pre-treated with inhibitor or vehicle via IV administration and subjected to ALI. Mice treated with UANOX48 demonstrated reduced blood ROS levels (FIG.9C) and significant protection from ALI including significantly reduced lung albumin (FIG.9D) and inflammation inflammatory (specifically decreased neutrophil influx) (FIG.9E-G)). These results demonstrate efficacy and provide rationale for the continued development of Nox4 inhibitors for ARDS. [00446] Referring to FIG.9A-G, Nox4 inhibitors protect from pre-clinical ARDS. FIG. 9A shows senescent ECs were treated with Nox4 inhibitor (20 µM), vehicle (DMSO), or DPI (10 µM) for 2h; H₂O₂ was assesed by Amplex Red. FIG.9B shows ECs were treated with Nox4 inhibitor (0.1 nM) or DMSO and incubated for 5 days. Proliferation was evaluated by Cell Viability Assay. (n = 3-5; *p < 0.05, ****p < 0.0001) FIG.9C-G show young (2m) C57BL/6 mice were treated with UANOX48 (50 mg/kg) or vehicle via IV followed by IT instillation of LPS (0.2 mg/kg). (FIG.9C) 4h post-injury and plasma H₂O₂ was evaluated by Amplex red. Severity of ALI was assessed at 24h post-injury by lung albumin (FIG.9D), total BAL cells (FIG.9E), neutrophil influx (FIG.9F), and histopathology (FIG.9G). (n = 3-6 mice/group; *p<0.05, **p<0.01, ***p<0.001, ns = not statistically significant). e. NOVEL NOX4 INHIBITOR CANDIDATES IDENTIFIED FOR IV DELIVERY [00447] The studies with UANOX48 showcase the development of Nox4 small molecule inhibitors and the performance of pre-clinical efficacy studies, which inform and strongly support the experimental plan detailed herein. Although these studies provide proof-of-concept for the continued pre-clinical development of Nox4 inhibitors for ARDS, UANOX48 is not an ideal candidate for IV delivery; it has relatively low water solubility (high solubility is a key metric for IV delivered drugs) and higher clearance (Clint >200 µL/min/mg) in human and mouse liver microsomes as well as oral or IV dosing in rodents. The ideal Nox4 inhibitor should meet optimal physicochemical selection criteria for IV delivery leads: cLogP = 3-4, polar surface area (PSA) = 45-70, water solubility at pH 7.4 = >10 µM, mol weight <500, non-ionic molecule, and potency similar to UANOX48. Two representative candidates are shown in FIG.10. [00448] These combined efforts led to the identification of Nox4 inhibitor candidates (APV235197A, APV235973A, UANOX108, UANOX107; FIG.10 – two of these are shown) that meet optimal physiochemical criteria for IV delivery and are predicted to have highly favorable profiles for IV delivery in humans. Without wishing to be bound by theory, these candidates will be the starting point for medicinal chemistry efforts proposed to further optimize and expand the chemical space around these candidates. f. DEVELOPMENT OF NOVEL LUNG-TARGETING NOX4 INHIBITORS FOR ENHANCED LUNG DISTRIBUTION [00449] Macrolides are a class of antibiotics, which commonly used to treat various respiratory conditions. Their use in respiratory indications is advantageous due to a unique property of macrolide-based compounds: they have a high affinity for the lung and are able to effectively penetrate lung tissue. Significant distribution of macrolides in the lung occurs within 2h of IV delivery, and sustained lung levels are detectable for up to 8.5 days. Pre-clinical and clinical data have demonstrated that 24h after systemic administration, concentrations of macrolides are 400-800 times greater in the alveolar compared to serum levels. Treatment with macrolide antibiotics, specifically azithromycin, is associated with improved outcomes in the ALI/ARDS arena. In patients with ALI, treatment with azithromycin led to increased survival and decreased time to successful discontinuation of mechanical ventilation. Further, a retrospective cohort evaluation of hospitalized patients with sepsis-associated ARDS assessed the impact of azithromycin on clinical outcomes; azithromycin treatment was associated with decreased mortality and ventilator dependency in patients with sepsis-associated ARDS. [00450] A macrocycle is a molecule that contains a cyclic framework of >12 atoms that can encapsulate drugs, thereby being used as a drug delivery vehicle, particularly to exploit a key property of macrolides: lung-targeting. It has been shown that the tissue accumulation property of macrocycle is tolerant of changes to their key moieties, resulting in compounds and nano- conjugates, which accumulate in the lung. This class of bioconjugate serves as an effective platform for intracellular drug delivery in the context of pulmonary disease and is highly amenable to IV delivery (vs. other delivery routes). A significant number of macrocycle-based IV drugs are currently on the market, as they are well-tolerated, with no serious adverse events reported in clinical trials. Treprostinil and Macitentan are two examples of FDA-approved macrocycle drugs specifically utilized for pulmonary indications (pulmonary hypertension). [00451] A Lung-Targeting Nox4 inhibitor (LT-Nox4i) series was developed in an effort to improve distribution and concentration of candidate inhibitors within the lung. We utilized a structure-based design tool to develop several macrocycle-based Nox4 inhibitors and evaluate docking simulations in silico (FIG.11A and FIG.11B). Docking simulations predicted that compared to parent Nox4 inhibitors, LT-Nox4_i’s designed demonstrated either similar binding affinity to Nox4 (-8.6--9 kcal/mol) and some LT-Nox4_i’s demonstrated significantly increased binding affinity for Nox4 (up to -9.7--10.4 kcal/mol) vs parent inhibitor alone; these data suggest that the medicinal chemistry features of LT-Nox4i’s may exhibit improved binding to Nox4. Artificial intelligence (AI) platform was utilized to perform blinded screening of two LT-Nox4_i structures; as compared to 50 of our top parent Nox4 inhibitors, LT-Nox4i’s were predicted to have up to ~30-fold increased distribution within the lungs, as compared to parent Nox4 inhibitors alone (Table 3). TABLE 3. [00452] Further, docking simulations predicted significantly increased binding affinity for Nox4 for macrocycle-Nox4 inhibitors (up to -10.4 kcal/mol) vs parent inhibitor alone (-8.6 kcal/mol) (Table 4). Macrocycles are an ideal vehicle to develop lung-targeted Nox4 inhibitors intended for IV delivery. Without being bound by theory, this directed approach will increase availability of Nox4 inhibitor within the lungs and will increase efficacy at significantly lower concentrations while reducing the toxicity risk. TABLE 4. [00453] Based on promising in silico and AI predictive data, additional macrocycle-based LT-Nox4_i for continued screening were prepared. Given that azithromycin treatment alone has already demonstrated positive outcomes in ALI/ARDS patients, azithromycin was selected as the macrolide-based linker to attach to Nox4 inhibitors. Importantly, azithromycin alone showed no potency for inhibiting Nox4-dependent ROS, while Compound 7 LT-Nox4_i-1 (Nox4 inhibitor attached to azithromycin) showed nearly identical potency for Nox4/ROS inhibition compared to parent Nox4 inhibitors compounds 1 and 2 (FIG.12A). The efficacy of LT-Nox4i analogs were also evaluated for inhibiting Nox4-dependent ROS in senescent ECs; LT-Nox4_i’s also showed similar potency to parent Nox4_i’s for inhibiting ROS in senescent ECs (FIG.12B). [00454] Referring to FIG.12A and FIG.12B, comparisons of IC50 evaluation of LT- Nox4i vs parent Nox4 inhibitors or macrolide (azithromycin) alone are shown. FIG.12A shows stable Nox4 overexpressing HEK (HEK-Nox4) cells were treated with varying concentrations of azithromycin (macrolide alone), parent Nox4 inhibitors (shown as compounds 1 and 2), or Lung- Targeting-Nox4 inhibitor (LT-Nox4i-1; shown as compound 7 in graph). and incubated for 1h in HEK-Nox4 cells. H₂O₂ production was evaluated by Amplex Red assay. Values = means ±SEM (n=3). Lung-Targeting-Nox4 inhibitors (LT-Nox4_i-1; shown as compound 7 or LT- Nox4i-7; shown as compound 13 in graph) vs parent Nox inhibitors (compounds 3 and 6). These data demonstrate that adding the linker does not interfere with Nox4 inhibitory activity. [00455] Lung-targeting approach in vivo, was to be evaluated by performing PK studies with parent Nox4 inhibitor versus LT-Nox4i. The LT-Nox4i demonstrated significantly increased maximal concentrations (Cmax) within the lung (up to ~65-fold higher than parent) which remain elevated in the lungs even at 24h post-administration (vs. parent which drop to zero within the lung within ~1h pos-administration (FIG.13A-C). This is likely also due to the fact that LT-Nox4i demonstrated significantly decreased clearance within the lung vs. parent Nox4 inhibitors (FIG.13B). The area under the curve (AUC) gives insight into the extent of drug exposure and its clearance rate. Importantly, compared to parent Nox4 inhibitors the LT-Nox4i demonstrated significantly increased AUC levels in the lung (up to ~1,000-fold increased; FIG. 13B) and significantly decreased plasma AUC levels (FIG.13A); these data indicate that LT- Nox4i exhibits a tremendous improvement in lung exposure accompanied by reduced systemic exposure in vivo. [00456] Referring to FIG.13A-C, Lung-targeting Nox4 inhibitor demonstrated significantly elevated concentrations within the lung in vivo vs. parent Nox4 inhibitor. C57/Bl6 male mice (2m) were administered Lung-targeting Nox4 inhibitor (LT-Nox4i-1) or parent Nox4 inhibitors via IV delivery (1mg/kg). Plasma and lung tissues were harvested at various time points following administration and assessed by LC-MS/MS. Analysis was performed using Pksolver 2.0 and one-compartment model. Blood plasma PK (FIG.13A) and lung PK (FIG.13B and FIG.13C) parameters are shown. [00457] LPS (1mg/kg) was administered to mice followed by treatment vehicle, parent Nox4i, or LT-Nox4i-1 (5.7mg/kg;days 0-3) and endpoints were assessed 4 days post-injury. Treatment with LT-Nox4i-1 significantly reduced lung BAL cells (FIG.15). In contrast, parent Nox4i showed no efficacy. To evaluate this lung-targeting approach in vivo, we performed PK studies with IV delivery of LT-Nox4i-1 vs. parent Nox4 inhibitor (UANOX48) via IV and inhaled delivery. The area under the curve (AUC) is used to assess the extent of drug exposure (AUC accounts for C_max, t_1/2, and clearance rate). Importantly, compared to parent Nox4i at the same dose (1mg/kg), IV delivery of LT-Nox4i-1 resulted in 40-fold increased AUC levels in the lung (this represents a 4,000% increase) (FIG.16B and Table 6). Even when compared to inhaled delivery of parent Nox4i at 10x the dose (10mg/kg), IV delivery of LT-Nox4_i-1 (1mg/kg) resulted in 11-fold increased lung AUC levels (FIG.16B and Table 6). Further, LT-Nox4_i-1 drug concentration remained elevated in the lungs 24 hours post administration, whereas concentrations of parent Nox4i (via both IV and inhaled delivery) were negligible within 1h post administration (FIG.16A and Table 5). Finally, compared to parent Nox4i, LT-Nox4_i-1 resulted in a 50% decrease in plasma AUC levels (FIG.16A and Table 5), indicating significantly reduced systemic exposure and decreased toxicity risk. In summary, this directed approach dramatically improves drug exposure within the lungs and simultaneously decrease systemic exposure, which reduce the potential for off-target effects and/or toxicity. TABLE 5. TABLE 6. [00458] Referring to FIG.17A-D, FIG.17A demonstrates that LT-Nox4i-1 inhibits ROS production in a stable cell line overexpressing Nox4. FIG.17B demonstrates that LT-Nox4i-1 does not induce cell death in a viability assay (Digitonin is a positive control for cell death). FIG.17C demonstrates that LT-Nox4i-1 does not inhibit Nox-independent ROS production (via xanthine oxidase). FIG.17D demonstrates that LT-Nox4i-1 shows no antioxidant activity in a cell-free assay with exogenous ROS (catalase is a positive control for antioxidant activity). [00459] Overall, these data suggest that macrocycles are an ideal vehicle to develop lung- targeted Nox4 inhibitors intended for IV delivery. The proposed studies will exploit a well- known property of macrocycles: they “home” to the lung following systemic delivery. This directed approach will increase availability of Nox4 inhibitor within the lungs and will increase efficacy at significantly lower concentrations while reducing the toxicity risk. Without wishing to be bound by theory, these linkers can be attached to a variety of different Nox4 inhibitors as further described herein. 5. LINKING EXCESSIVE NOX4-DERIVED ROS AND AGE-RELATED DISEASE [00460] The only known physiologic role of Nox4 is ROS production; importantly, redox- signaling events depend on spatially confined and tightly regulated Nox4-dependent ROS production. In contrast, persistent expression of Nox4 and sustained ROS production leads to oxidative stress (that is no longer compartmentalized) and detrimental effects. Preliminary data and a growing body of evidence supports a link between excessive Nox4-derived ROS and numerous age-related diseases. Nox4 represents an “antagonistically pleiotropic” enzyme – it confers a reproductive advantage early in life but can have detrimental effects in late life (during post-reproductive age). This makes Nox4 an attractive target from a drug targeting perspective. Further, it is important to note that Nox4 knockout mice are viable with no appreciable phenotype in the unstressed (uninjured) state; suggesting lower risk for toxicity or off-target effects from Nox4 inhibition in unaffected tissues. [00461] Extensive epidemiological data demonstrates that susceptibility, severity, hospitalization, and mortality from ARDS is significantly higher in the elderly population. It is therefore hypothesized that therapeutic strategies targeting age-associated pathologic mechanisms offer the greatest potential for developing successful ARDS treatments; targeting the persistent upregulation of Nox4 (a major source of excessive oxidant generation) represents one plausible strategy. Published studies have identified novel age-dependent mechanisms of Nox4 dysregulation, leading to excessive ROS production and increased severity and mortality of ARDS in aging. Collectively, these studies suggest that targeting Nox4 in aging provides the greatest therapeutic benefit. It is important to note that Nox inhibitors are not clinically available, but substantial progress has been made recently in developing Nox4 inhibitors for oral delivery. However, ARDS patients often require mechanical ventilation for life support, where oral delivery is not optimal. As IV administration is the ideal delivery route for critically ill patients, a key objective is to optimize Nox4 inhibitors for IV delivery as a novel therapy to reduce susceptibility and mortality from age-dependent severe ARDS. 6. RESEARCH DESIGN AND METHODS a. DIRECTED MEDICINAL CHEMISTRY TO EXPAND LUNG-TARGETING NOX4 INHIBITOR SERIES AND SCREEN FOR NOX4 INHIBITION [00462] UANOX48 was used to demonstrate proof-of-concept for targeting Nox4 in an animal model of ARDS. However, UANOX48 is not ideally suited for subsequent clinical development for ARDS primarily due to poor bioavailability within the lung; this is largely attributed to poor metabolic stability (high liver microsomal clearance, 349 μL/min/mg) and relatively high logD (4.05). [00463] To overcome this major liability, lung-targeting Nox4-inhibitors (LT-Nox4_is) were developed using a macrocycle-based approach; proof-of-concept that for the development of LT-Nox4is using a macrocycle-based approach was demonstrated (FIG.13A-C). The initial data demonstrate that compared to parent Nox4 inhibitor alone, this approach results in significantly increased drug exposure (>1,000-fold) within the lung, with significantly reduced systemic exposure. This directed approach dramatically boosts bioavailability of Nox4 inhibitor within the lung while reducing the risk of systemic toxicity. During proof-of-concept studies, several synthesized LT-Nox4_i candidates were prepared. It was found that some lung-targeting Nox4-inhibitors have identical or somewhat improved potency as compared to parent Nox4 inhibitor alone (FIG.12A and FIG.12B). Without wishing to be bound by theory, this data helps to inform SAR of Nox4 inhibitors and understanding the optimal locations to attach the macrolide-based lung linker to Nox4 inhibitors without altering potency. Additionally, preliminary data (see above) suggests that attachment of the macrolide-lung linker may also alter predicted binding to Nox4, some indicating enhanced binding as compared to parent alone. i. DESIGN OF NOVEL LT-NOX4_I SERIES [00464] LT-Nox4i candidates will be designed by integrating novel macrocycle lung- targeted linkers into the molecular architecture of previously identified top Nox4 inhibitor candidates. Candidates will be evaluated via in silico docking/binding simulations. ii. DEVELOP A LUNG-TARGETING NOX4 INHIBITOR SERIES AIMED TO ENHANCE DISTRIBUTION AND CONCENTRATION IN THE LUNG. [00465] Preliminary data suggests that macrocycle-based Nox4 inhibitors could significantly improve binding to Nox4 and selective distribution to the lung. If successfully validated, this will significantly advance the goal of improved Nox4 inhibitor distribution and bioavailability within the lung, which could potentially reduce toxicity risk. The ultimate goal of this study is to develop candidates that would increase drug efficacy in the lung, and mitigate potential systemic toxic effects. [00466] In order to validate a lung-targeting Nox4 inhibitor approach, macrolide-based Nox4 inhibitors will be designed and synthesized, integrating novel “lung-targeted linker” into the molecular architecture of top IV candidates. Previously identified top candidates (FIG.10) and/or top candidates developed as detailed above will be used as the starting point for these medicinal chemistry efforts. To date, a series of >50 lung-targeting Nox4 inhibitors have been developed around the UANOX048 series (FIG.11A and FIG.11B; representative example is shown); similar approaches will be employed under this study focusing on top candidates identified for IV delivery. iii. SCREENING CASCADE [00467] Compounds will be assessed as described below. Controls for all studies: DPI (pan-Nox inhibitor) will be used as a positive control for Nox inhibition; GKT136901 will be used as a positive control for scavenger activity; APX-115 (a putative competitor Nox inhibitor) will also be evaluated in parallel to compare performance. iv. POTENCY FOR NOX4 AND FALSE-POSITIVE SCREENING: [00468] Potency for Nox4. Synthesized analogs will be subjected to IC50 evaluation in a 96-well format with HEK/Nox4 cells, which generate high levels of H₂O₂. Efficacy for inhibition of H₂O₂ will be measured by Amplex red fluorescence assay. [00469] Cytotoxicity Assay. Ensuring that Nox4 inhibitors are not cytotoxic is a key parameter that requires assessment. Cell Titer Glo assay is an industry-standard that measures cellular ATP levels. Analogs will be evaluated in this assay relative to vehicle control. Digitonin (200 µg/ml) will be used as a positive control for cell death. [00470] Antioxidant Activity. Analogs will be incubated in 96-well-plates containing exogenous H₂O₂ (5 µM) and Amplex Red (a HRP-dependent assay mechanism to detect H₂O₂). Compounds that inhibit H₂O₂ in the absence of cells will be considered scavengers and will be eliminated. Catalase (750 U/ml) will also be used as a positive control for scavenger activity. [00471] Assay Interference. Analogs will be incubated in 96-well-plates containing exogenous H₂O₂ (5 µM) and ROS-GLO (an HRP-independent H₂O₂ detection system) to rule out false positives from potential compound interference with HRP. Catalase (750 U/ml) will be used as a positive control for scavenger activity. [00472] Xanthine Oxidase (XO) Assay. XO generates superoxide and H₂O₂ independent of Nox activity. This assay will be used to eliminate non-specific ROS scavengers. [00473] Potency for Nox2. A screening assay using RAW264.7 cells was utilized, which exhibit high Nox2-dependent H₂O₂ production upon stimulation with PMA (1 μM); H₂O₂ production will be measured by Amplex red assay. v. FUNCTIONAL SCREENING FOR IN VITRO EFFICACY [00474] Proliferation. ECs will be evaluated for BrdU incorporation (by ELISA). [00475] Inflammatory Responses. Senescent EC supernatant will be evaluated to assess changes in inflammatory cytokines using a Multiplex kit (Human Magnetic 65-Plex, ThermoFisher). [00476] Permeability. Senescent ECs will be plated in a confluent monolayer in electric cell-substrate impedance sensing (ECIS) array plates coated with 0.1% gelatin. Cells will be treated with Nox4 inhibitor and stimulated with LPS. Trans-endothelial electrical resistance (TEER) will be evaluated using an electrical cell substrate impedance sensing system (Applied Biophysics): b. EVALUATE IN VITRO ADME AND IN VIVO PK/PD OF LUNG-TARGETING NOX4 INHIBITORS [00477] Functional screening will be performed to confirm that placement/attachment of the linker to Nox4 inhibitors does not detrimentally impact in vitro efficacy. i. IN VITRO ADME (ABSORBTION, DISTRIBUTION, METABOLISM, EXCRETION) [00478] Determination of aqueous stability. As an IV route of administration for acute conditions is being targeted, assessment of compounds in aqueous media is an important factor to consider in identifying a lead. [00479] Kinetic and thermodynamic solubility. Adequate aqueous solubility is a pre- requisite for a drug designed for IV route of administration, to this end, it is important to track and optimize solubility, in order to develop a successful candidate. Goals will be to achieve thermodynamic solubility >200 µM at physiological pH in 0.5% aqueous DMSO, and aqueous solubility >10 µM at physiological pH. [00480] LogD. LogD is a measure of compound lipophilicity. The distribution coefficient is determined between octanol and an aqueous phase buffered to physiological pH. The value is an important metric and most typically marketed small molecule drug molecules have a LogD between 1-3. [00481] PPB (Plasma Protein Binding). Binding of compounds to human serum albumin will be measured. This assay will provide the information required to determine that bioavailability of free compound for interaction with Nox4 to elicit inhibitory effect. Compounds that are highly protein bound, have little or no free fraction to elicit a response and this often requires optimization. [00482] Polar Surface Area. Polar surface area will be calculated. [00483] Cytochrome P450 (CYP) Inhibition. The potential for a compound to inhibit CYP oxidative enzymes is indicative of the potential for undesirable drug-drug interactions. Compounds will be tested against selected CYP isoforms. These studies will also identify metabolism products, including reactive metabolites. ii. IN VIVO PK AND TISSUE DISTRIBUTION [00484] Scale-up: Scale-up of selected lead analogs to gram quantities will be required for in vivo studies. Successful and reproducible scale-up of analogs from 200 mg to 8 g quantities has been previously demonstrated. Analogs will be tailored to 3-4 step synthesis protocols using commercially available materials. This approach will allow synthesis of molecules at grams quantities with minimal or no batch-to-batch variations. [00485] C57BL/6 male mice will be administered candidates in a single dose (1 mg/kg) via IV administration. Mice will be sacrificed by CO₂ inhalation at various time points (0, 30m, 1, 2, 4, 6, 8, 24h) following drug administration. Blood plasma will be isolated, and tissues (lung, heart, liver, kidney, and spleen) will be harvested and snap frozen in liquid nitrogen. Tissues will be then homogenized in 300 ul of acetonitrile with a mechanical homogenizer, centrifuged, and supernatant will be used for analyses. Plasma and tissue concentration over time will be determined by liquid chromatography/mass spectroscopy (LC/MS). [00486] It is recognized that gender-dependent differences in metabolism are known to exist, which may lead to PK profiles that are different between males and females. However, industry standard at this stage of pre-clinical development is to perform PK profiling in one gender; at this stage of development the priority is to evaluate the greatest number of analogs. ARDS is more prevalent in males (>60% of ARDS patients are male), and COVID-19-ARDS mortality is 2.4 times greater in males compared to females. Thus, initial efforts will utilize male mice only. However, the top 2 candidates will also be evaluated for their PK profile in female mice. [00487] Specific Measured Endpoints. Standard PK parameters of clearance, drug half- life (T_1/2), T_max, C_max, C_min, drug elimination constant (k_e), drug absorption constant (k_a), and area under the curve (AUC), bioavailability, and lung/plasma ratio will be calculated. c. DETERMINATION OF THE THERAPEUTIC INDEX OF TOP CANDIDATE AS A NOVEL TREATMENT FOR AGE-ASSOCIATED ARDS [00488] The top candidates (as determined above) will be advanced to determine the Therapeutic Index (TI), the window of safe and effective dosing, which must be established for IND-enabling studies will be established for the compounds. TI is calculated as TD₅₀/ED₅₀ (TD = toxic dose; ED = effective dose) within the same species. TD and ED will be evaluated. i. EVALUATE EFFICACY OF OPTIMIZED LEAD CANDIDATE FORMULATIONS VIA IV DELIVERY IN 2 MURINE MODELS OF PRE- CLINICAL ARDS [00489] Important target identification and validation data implicating Nox4 as a viable target for age-associated severe ARDS has been shown in various studies.2 murine models that have previously validated Nox4 upregulation following injury will be utilized. Genetic targeting of Nox4 in a CLP model led to reduced lung ROS levels and improved survival, whereas knockdown of Nox1, Nox2 or p47phox had no effects. Preliminary studies with a novel eNox4 KO mouse model demonstrate that selective genetic ablation of endothelial Nox4 leads to striking protection in aged mice (when Nox4 is persistently expressed), as compared to modest protection in young cohorts (FIG.6). The significantly elevated Nox4/ROS in this aging model offers a larger therapeutic window to evaluate the extent of Nox4 inhibitor efficacy and to identify the most promising candidates that can reduce Nox4-dependent pathological effects to the greatest extent. Evaluation of the efficacy of the top 2 most promising candidates using 2 murine model of pre-clinical ARDS will be performed; the ED₅₀ of the top two candidates will be determined in each model. [00490] Candidates will be assessed using the murine models described below. For all studies, candidates will be administered via IV delivery through tail vein injection at 4h post- initial injury (for both models), 5 different dose concentrations will be used for each candidate to determine ED curves, and mice will be sacrificed at 24h after initial injury by exsanguination and bilateral thoracotomy for endpoint analyses. [00491] Cecal Ligation Puncture (CLP) model: C57BL/6 mice (2m) will be anesthetized with isoflurane. Skin will be disinfected and a 1 cm incision will be made in the middle of the abdomen, allowing the cecum to be exposed. A braided silk suture will be passed through the midpoint between the colon root and cecum terminal to ligate the cecum. A 21-gauge needle will be inserted into the ligated cecum and a small drop of the intestinal content will be squeezed out to induce infection. The cecum will then be repositioned, and the incision closed. [00492] 2-hit aging model of severe ARDS: Aged (20m) C57BL/6 mice will be anesthetized by intraperitoneal (IP) injection of ketamine (80 mg/kg; anesthetic) and xylazine (5 mg/kg; analgesic) and subjected to LPS (0.2mg/kg in PBS in 50μl) via IT administration. At 20h post-LPS, anesthetized mice will be subjected to VILI by high tidal volume ventilation for 4h (room air, 20 ml/kg tidal volume, 85 breaths/min; Inspira rodent ventilator, Harvard Apparatus). [00493] Specific Measured Endpoints: [00494] Lung injury (barrier dysfunction and inflammatory responses): i) Total BAL cells: evaluated by Coulter counter, ii) Total BAL protein: evaluated by BCA assay. iii) Neutrophil influx: cytospin preparations of cellular BAL fraction will be stained with Hema 3 solution, and % neutrophils will be quantified. iv) Albumin influx: non-cellular BAL fraction will be evaluated by albumin assay kit, v) Lung permeability: Mice will be given Evans Blue dye via tail vein injection and lung tissue evaluated by extravasation assay. vi) Pro-inflammatory mediators: assessed by Multiplex kit (Mouse Magnetic 65-Plex, ThermoFisher). vii) Lung injury score: H&E lung sections will be blindly evaluated and scored (HistoWiz) using a previously defined scoring system. [00495] Oxidative stress: Lung BAL will be evaluated for ROS (Amplex Red assay). [00496] Physiological assessments: i) lung compliance will be evaluated by FlexiVent. ii) Lung weight, iii) body weight, and iv) survival will be monitored/recorded. ii. EVALUATE DOSE TOLERABILITY AND SAFETY IN A RODENT MODEL [00497] The information obtained will establish the safety/tolerance of the top two candidates in healthy mice, as a precursor to IND-enabling studies. Without wishing to be bound by theory, one objective is to identify the Maximum Tolerated Dose (MTD) and the no- observed-adverse-effect level (NOAEL), the highest dose with no detected effects. [00498] Assess the acute repeated-dose tolerance in healthy mice: Candidates will be evaluated in rising dose tolerance studies conducted in healthy aged (24m) mice. Preliminary data with the parent compound from various studies (at 50mg/kg) will be used as the starting point, the “safety margin” above that dose will be further interrogated in an increasing repeat dose study (dose will increase each day until side-effects are observed). The safety margin is the difference between the NOAEL dose in non-clinical species and the starting clinical dose, aiming at approximately 3-10-fold above the proposed clinical dose. Mice will be dosed daily via IV delivery with increasing concentrations of candidates until evidence of toxicity; vehicle will be administered as a control group. The resulting toxicity dose-response curves will be used to calculate TD₅₀, which will be used (along with ED₅₀) for deriving the TI. [00499] Specific Measured Endpoints: Animals will be assessed for clinical signs of tolerance, body weight, gross pathology, hematology, clinical chemistry and by histopathology to assign the NOAEL for both acute and repeated dosing. Body weight will be measured prior to test article dosing, at necropsy and at any interval where clinical signs of toxicity are observed. Food consumption will be monitored. Detailed clinical observations will be conducted according to standard operating procedure (SOP) with special attention paid to signs associated with the respiratory tract. These include but are not limited to apnea, labored breathing, malaise, marked nasal discharge, etc. Gross pathology will consist of a complete external and internal examination including body orifices (ears, nostrils, mouth, anus, etc.) and cranial, thoracic, and abdominal organs and tissues. All gross findings will be recorded, including size, shape, color, and consistency. Organs with lesions will be fixed for histopathologic evaluation. Blood will be collected at regular intervals during treatment to correlate drug levels with toxicity results. Hematology will be conducted by an Advia 120 Series Hematology System. Clinical chemistry will be performed to quantify endpoints (e.g. albumin, calcium, chloride, creatinine, glucose, potassium, protein, triglycerides). Blood and lung tissue will be collected at terminal necropsy for quantification of drug and correlation to biological finding of tolerance. TD will be determined by clinical observations, chiefly the side effects can range from mild effects such as reduced weight gain, moderate effects such as weight loss up to 20% or substantial effects such as unresponsiveness. d. SCIENTIFIC RIGOR AND STATISTICAL ANALYSES [00500] Statistical significance will be analyzed using Prism 7 (GraphPad Software) and p < 0.05 will be considered significant. Student’s t-tests will be used when comparing two groups. When comparing 3 or more groups, 2-way analysis of variance (ANOVA) with Bonferroni post- test will be performed. p<0.05 will be considered significant. A power analysis was performed to calculate the number of mice needed per experimental arm. The minimal number of rodents to obtain reliable scientific results will be used; the numbers in each group were estimated based on a power analysis using α=0.05. To control potential bias, all murine studies proposed will be randomized into the groups and assessors will be blinded to treatment groups. 7. EVALUATION OF NOX4 INHIBITORS HAVING A LUNG-TARGETED LINKER a. BIOLOGICAL ASSAYS [00501] Potency for Nox4. Analogs were subjected to IC₅₀ evaluation in a 96-well format with HEK/Nox4 cells, which generate high levels of H₂O₂. Efficacy for inhibition of H₂O₂ will be measured by Amplex red fluorescence assay. [00502] Cytotoxic Assay. Ensuring that Nox4 inhibitors are not cytotoxic is a key parameter that requires assessment. Cell Titer Glo assay is an industry-standard that measures cellular ATP levels. Analogs were evaluated in this assay relative to vehicle control. Digitonin (200 µg/ml) was used as a positive control for cell death. [00503] Antioxidant Activity. Analogs were incubated in 96-well-plates containing exogenous H₂O₂ (5 µM) and Amplex Red (a HRP-dependent assay mechanism to detect H₂O₂). Compounds that inhibit H₂O₂ in the absence of cells were considered scavengers and eliminated. Catalase (750 U/ml) was also be used as a positive control for scavenger activity. [00504] Assay Interference. Analogs were incubated in 96-well-plates containing exogenous H₂O₂ (5 µM) and ROS-GLO (an HRP-independent H₂O₂ detection system) to rule out false positives from potential compound interference with HRP. Catalase (750 U/ml) were used as a positive control for scavenger activity. [00505] Xanthine Oxidase (XO) Assay. XO generates superoxide and H₂O₂ independent of Nox activity. This assay will be used to eliminate non-specific ROS scavengers. [00506] Potency for Nox2. A screening assay using RAW264.7 cells, which exhibit high Nox2-dependent H₂O₂ production upon stimulation with PMA (1 μM), was employed. H₂O₂ production was measured by Amplex red assay. b. EVALUATION OF MACROLIDE-NOX4 CONJUGATES [00507] Exemplary macrolide-Nox4 conjugates as shown in Table 1 were evaluated using the assays detailed above, and the results are shown in Table 7 below. TABLE 7.

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Claims

CLAIMS What is claimed is: 1. A compound having a structure represented by a formula: , wherein n is selected from 0, 1, 2, 3, 4, and 5, and wherein m is selected from 0 and 1, provided that when n is 0 then m is 0; wherein o is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8; wherein A¹ is selected from ‒O‒ and ‒CH₂‒, provided that when A¹ is O, then o is not 0 or 1; wherein L¹ is selected from C2 alkenyl, C2 alkynyl, ‒NHSO₂‒, ‒SO₂NH‒, ‒NHC(O)‒, ‒ C(O)NH‒, and Ar⁵; wherein Ar⁵, when present, is a C2-C9 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R^1a, R^1b, R^1c, and R^1d is independently selected from hydrogen, halogen, ‒ CN, ‒NH₂, ‒OH, and ‒NO₂; wherein R² is selected from hydrogen and C1-C4 alkyl; wherein one of R^3a and R^3b is C1-C4 alkyl and one of R^3a and R^3b is a structure selected from:

wherein R¹³ is selected from hydrogen and ‒OH; and wherein Ar¹ is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein n is 0.

3. The compound of claim 1, wherein n is 1.

4. The compound of any one of claims 1 to 3, wherein m is 1.

5. The compound of any one of claims 1 to 3, wherein m is 0.

6. The compound of any one of claims 1 to 5, wherein A¹ is O.

7. The compound of any one of claims 1 to 5, wherein A¹ is ‒CH₂‒.

8. The compound of any one of claims 1 to 7, wherein L¹ is C2 alkenyl or C2 alkynyl.

9. The compound of any one of claims 1 to 7, wherein L¹ is ‒NHC(O)‒.

10. The compound of any one of claims 1 to 7, wherein L¹ is Ar⁵.

11. The compound of claim 10, wherein Ar⁵ is selected from triazolyl, oxadiazolyl, thiazolyl, tetrazolyl, oxazolyl, and thiadiazolyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.

12. The compound of claim 10, wherein Ar⁵ is selected from triazolyl, oxadiazolyl, thiazolyl, tetrazolyl, oxazolyl, and thiadiazolyl, and is unsubstituted.

13. The compound of claim 10, wherein Ar⁵ is a structure selected from: ^, wherein * denotes a connection to ‒(CH₂)_n‒ and ** denotes a connection to Ar¹.

14. The compound of any one of claims 1 to 13, wherein each of R^1a, R^1b, R^1c, and R^1d is independently selected from hydrogen and halogen.

15. The compound of any one of claims 1 to 13, wherein each of R^1a, R^1b, R^1c, and R^1d is hydrogen.

16. The compound of any one of claims 1 to 15, wherein R² is hydrogen.

17. The compound of any one of claims 1 to 15, wherein R² is methyl.

18. The compound of any one of claims 1 to 17, wherein one of R^3a and R^3b is methyl.

19. The compound of any one of claims 1 to 17, wherein one of R^3a and R^3b is a structure selected from:

^.

20. The compound of any one of claims 1 to 17, wherein one of R^3a and R^3b is a structure selected from: ^.

21. The compound of any one of claims 1 to 17, wherein one of R^3a and R^3b is a structure selected from: ^.

22. The compound of any one of claims 1 to 17, wherein one of R^3a and R^3b is a structure selected from:

^.

23. The compound of any one of claims 1 to 22, wherein Ar¹ is C6-C10 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.

24. The compound of any one of claims 1 to 22, wherein Ar¹ is C6-C10 aryl with 0 groups selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.

25. The compound of any one of claims 1 to 22, wherein Ar¹ is selected from phenyl and naphthyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.

26. The compound of any one of claims 1 to 22, wherein Ar¹ is selected from phenyl and naphthyl, and is substituted with 0 groups selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1- C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.

27. The compound of claim 1, wherein the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.

28. The compound of claim 1, wherein the compound has a structure represented by a formula selected from: ^, or a pharmaceutically acceptable salt thereof.

29. The compound of claim 1, wherein the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.

30. The compound of claim 1, wherein the compound has a structure represented by a formula:

, or a pharmaceutically acceptable salt thereof.

31. The compound of claim 1, wherein the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.

32. The compound of claim 1, wherein the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.

33. The compound of claim 1, wherein the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.

34. The compound of claim 1, wherein the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.

35. The compound of claim 1, wherein the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.

36. The compound of claim 1, wherein the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.

37. The compound of claim 1, wherein the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.

38. The compound of claim 1, wherein the compound has a structure represented by a formula:

, or a pharmaceutically acceptable salt thereof.

39. The compound of claim 1, wherein the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.

40. The compound of claim 1, wherein the compound is selected from:

, ,

, ,

, ,

,

,

,

,

or a pharmaceutically acceptable salt thereof.

41. The compound of claim 1, wherein the compound is selected from:

, ,

,

,

, ,

, or a pharmaceutically acceptable salt thereof.

42. A pharmaceutical composition comprising an effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

43. A method of inhibiting NADPH Oxidase 4 (NOX4) signaling in a cell, the method comprising contacting the cell with an effective amount of the compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof.

44. The method of claim 43, wherein the cell is mammalian.

45. The method of claim 43, wherein the cell is human.

46. The method of any one of claims 43 to 45, wherein the cell has been isolated from a mammal prior to the contacting step.

47. The method of any one of claims 43 to 46, wherein the contacting is ex vivo.

48. The method of any one of claims 43 to 46, wherein the contacting is in vitro.

49. The method of claim 43, wherein contacting is via administration to a mammal.

50. The method of claim 49, wherein the mammal has been diagnosed with a need for inhibiting NOX4 signaling prior to the administering step.

51. The method of claim 49, wherein the mammal has been diagnosed with a need for treatment of a disorder associated with over-activation of NOX4 signaling prior to the administering step.

52. The method of claim 51, wherein the disorder is a fibrotic disorder or acute respiratory distress syndrome (ARDS).

53. The method of claim 49, wherein the mammal has been diagnosed with a need for inhibition of NOX4 signaling prior to the administering step.

54. A method of inhibiting NADPH Oxidase 4 (NOX4) signaling in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof.

55. The method of claim 54, wherein the subject is a mammal.

56. The method of claim 54, wherein the subject is a human.

57. The method of any one of claims 54 to 56, wherein the subject has been diagnosed with a need for inhibiting NOX4 signaling to the administering step.

58. The method of claim 54, further comprising identifying a subject in need of inhibition of NOX4 signaling.

59. A method of treating a fibrotic disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof.

60. The method of claim 59, wherein the fibrotic disorder is pulmonary fibrosis, heart fibrosis, kidney fibrosis, liver fibrosis, skin fibrosis, mediastinal fibrosis, retroperitoneal cavity fibrosis, bone marrow fibrosis, or scleroderma or systemic sclerosis.

61. The method of claim 59, wherein the fibrotic disorder is pulmonary fibrosis.

62. The method of claim 61, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.

63. The method of claim 59, wherein the subject is a mammal.

64. The method of claim 59, wherein the mammal is a human.

65. The method of claim 59, wherein the subject has been diagnosed with the fibrotic disorder prior to the administering step.

66. The method of claim 59, further comprising the step of identifying a subject in need of treatment of the fibrotic disorder.

67. The method of claim 59, further comprising administering to the subject an anti-fibrotic agent.

68. The method of claim 67, wherein the anti-fibrotic agent is selected from nintedanib and pirfenidone.

69. A method of treating acute respiratory distress syndrome (ARDS) in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any one of claims 1 to 41or a pharmaceutically acceptable salt thereof.

70. The method of claim 69, wherein administering is via oral administration, intraperitoneal administration, or intravenous (IV) administration.

71. The method of claim 69, wherein the subject is a mammal.

72. The method of claim 69, wherein the mammal is a human.

73. The method of claim 69, wherein the subject has been diagnosed with ARDS prior to the administering step.

74. The method of claim 69, wherein the subject has been diagnosed with coronavirus disease (COVID) prior to the administering step.

75. The method of claim 74, wherein COVID is coronavirus disease 2019 (COVID-19).

76. The method of claim 69, further comprising the step of identifying a subject in need of treatment of ARDS.

77. The method of claim 69, further comprising administering to the subject an agent known to treat ARDS.

78. The method of claim 77, wherein the agent is selected from nitric oxide and a corticosteroid.

79. The method of claim 78, wherein the corticosteroid is selected from cortisone, hydrocortisone, and prednisone.

80. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any one of claims 1 to 41or a pharmaceutically acceptable salt thereof.

81. The method of claim 80, wherein treating disrupts tumor-promoting desmoplasia.

82. The method of claim 80, wherein treating inhibits desmoplastic tumor growth.

83. The method of claim 80, wherein administering is via oral administration, intraperitoneal administration, or intravenous (IV) administration.

84. The method of claim 80, wherein the subject is a mammal.

85. The method of claim 80, wherein the mammal is a human.

86. The method of claim 80, wherein the subject has been diagnosed with cancer prior to the administering step.

87. The method of claim 80, wherein the subject has been diagnosed with desmoplasia prior to the administering step.

88. The method of claim 80, further comprising the step of identifying a subject in need of treatment of cancer.

89. The method of claim 80, further comprising the step of identifying a subject in need of treatment of desmoplasia.

90. The method of claim 80, further comprising administering to the subject an agent known to treat cancer.

91. The method of claim 90, wherein the agent known to treat cancer is a chemotherapeutic agent.

92. The method of claim 91, wherein the chemotherapeutic agent is selected from an alkylating agent, an antimetabolite agent, an antineoplastic antibiotic agent, a mitotic inhibitor agent, and a mTor inhibitor agent.

93. The method of claim 92, wherein the antineoplastic antibiotic agent is selected from doxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, and valrubicin, or a pharmaceutically acceptable salt thereof.

94. The method of claim 92, wherein the antimetabolite agent is selected from gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt thereof.

95. The method of claim 92, wherein the alkylating agent is selected from carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide, thiotepa, bendamustine, and streptozocin, or a pharmaceutically acceptable salt thereof.

96. The method of claim 92, wherein the mitotic inhibitor agent is selected from irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etopside, vincristine, ixabepilone, vinorelbine, vinblastine, and teniposide, or a pharmaceutically acceptable salt thereof.

97. The method of claim 92, wherein the mTor inhibitor agent is selected from everolimus, siroliumus, and temsirolimus, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

98. The method of claim 90, wherein the compound and the agent are administered sequentially.

99. The method of claim 90, wherein the compound and the agent are administered simultaneously.

100. The method of claim 80, wherein the cancer is selected from a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma).

101. The method of claim 80, wherein the cancer is breast cancer or pancreatic cancer.

102. A kit comprising the compound of any one of claims 1 to 41or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an anti-fibrotic agent; (b) instructions for treating a fibrotic disorder; (c) an agent known to treat ARDS; (d) instructions for treating ARDS; (e) an agent known to treat cancer; and (f) instructions for treating cancer.

103. The kit of claim 102, wherein the anti-fibrotic agent is selected from nintedanib and pirfenidone.

104. The kit of claim 102, wherein the agent is selected from nitric oxide, a corticosteroid, and an anti-inflammatory agent.

105. The kit of claim 102, wherein the compound and the anti-fibrotic agent are co- formulated.

106. The kit of claim 102, wherein the compound and the anti-fibrotic agent are co-packaged.

107. The kit of claim 102, wherein the compound and the agent known to treat ARDS are co- formulated.

108. The kit of claim 102, wherein the compound and the agent known to treat ARDS are co- packaged.

109. The kit of claim 102, wherein the compound and the agent known to treat cancer are co- formulated.

110. The kit of claim 102, wherein the compound and the agent known to treat cancer are co- packaged.

111. A compound having a structure represented by a formula: , wherein r is selected from 1, 2, 3, 4, 5, 6, 7, and 8; wherein one of R^3a and R^3b is C1-C4 alkyl and one of R^3a and R^3b is a structure selected from: ^; wherein R¹³ is selected from hydrogen and ‒OH; wherein each of R^4a, R^4b, R^4c, and R^4d is independently selected from hydrogen, halogen, ‒ CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1- C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and wherein R¹⁰ is selected from hydrogen and a structure: ; wherein s is selected from 0 and 1; wherein A² is selected from ‒C(O)‒ and ‒SO₂‒; wherein L² is ‒(CR^11aR^11b)2‒; wherein each occurrence of R^11a and R^11b is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl, or wherein each of R^11a and R^11b together comprise =O; wherein R⁵, when present, is selected from hydrogen and C1-C4 alkyl; wherein R⁶ is selected from ‒NR^12aR^12b and Ar²; wherein R^12a is selected from hydrogen, C1-C4 alkyl, and Ar³; wherein Ar³ is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1- C4 aminoalkyl; and wherein R^12b is selected from C1-C4 alkyl, ‒CH₂Ar⁴, and Ar⁴; wherein Ar⁴ is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1- C4 aminoalkyl, or wherein each of R^12a and R^12b together comprise a C2-C5 heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒ NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein Ar² is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒ NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒C(O)NH₂, ‒ NHC(O)(C1-C4 alkyl), Cy¹, ‒OCy¹, and ‒NH(CH₂)_tCy¹; wherein t is selected from 0, 1, and 2; and wherein Cy¹ is selected from C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C6-C14 aryl, and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1- C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.

112. The compound of claim 111, wherein s is 0.

113. The compound of claim 111 or claim 112, wherein A² is ‒SO₂‒.

114. The compound of any one of claims 111 to 113, wherein each of R^4a, R^4b, R^4c, and R^4d is hydrogen.

115. The compound of any one of claims 111 to 114, wherein R⁵, when present, is hydrogen.

116. The compound of any one of claims 111 to 115, wherein R⁶ is Ar².

117. The compound of any one of claims 111 to 116, wherein Ar² is selected from C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.

118. The compound of any one of claims 111 to 116, wherein Ar² is selected from C6-C14 aryl and C2-C10 heteroaryl, and is monosubstituted with a C1-C4 haloalkyl group.

119. The compound of any one of claims 111 to 116, wherein Ar² is phenyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH₂, ‒OH, ‒NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.

120. The compound of any one of claims 111 to 116, wherein Ar² is phenyl monosubstituted with a C1-C4 haloalkyl group.

121. The compound of claim 111, wherein the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.

122. The compound of claim 111, wherein the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.

123. The compound of claim 111, wherein the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.

124. The compound of claim 111, wherein the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.

125. The compound of claim 111, wherein the compound has a structure represented by a formula:

, or a pharmaceutically acceptable salt thereof.

126. The compound of claim 111, wherein the compound is selected from: ,

,

,

,

,

, or a pharmaceutically acceptable salt thereof.

127. The compound of claim 111, wherein the compound is: , or a pharmaceutically acceptable salt thereof.

128. A pharmaceutical composition comprising an effective amount of the compound of claim 111, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

129. A method of inhibiting NADPH Oxidase 4 (NOX4) signaling in a cell, the method comprising contacting the cell with an effective amount of the compound of any one of claims 111 to 127, or a pharmaceutically acceptable salt thereof.

130. A method of inhibiting NADPH Oxidase 4 (NOX4) signaling in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any one of claims 111 to 127, or a pharmaceutically acceptable salt thereof.

131. A method of treating a fibrotic disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any one of claims 111 to 127, or a pharmaceutically acceptable salt thereof.

132. A method of treating acute respiratory distress syndrome (ARDS) in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any one of claims 111 to 127or a pharmaceutically acceptable salt thereof.

133. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any one of claims 111 to 127or a pharmaceutically acceptable salt thereof.

134. A kit comprising the compound of any one of claims 111 to 127or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an anti-fibrotic agent; (b) instructions for treating a fibrotic disorder; (c) an agent known to treat ARDS; (d) instructions for treating ARDS; (e) an agent known to treat cancer; and (f) instructions for treating cancer.