Nox4 inhibitors and methods of using same

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), 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)) 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

NOX4 INHIBITORS AND METHODS OF USING SAME CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This Application claims the benefit of U.S. Application No.63 / 535,235, 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 growthfactor 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 withpoor 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 COVID-19 patients (Wu, C. et al. (2020) JAMA Intern. Med.). 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. Thus, new treatments are desired. Accordingly, there exists a need forNOX4 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), and 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, , , , , , 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 A1is selected from ‒O‒ and ‒CH2‒; wherein L1is selected from C2 alkenyl, C2 alkynyl, *‒NHC(O)‒**, *‒C(O)NH‒**, Ar2, and a structure: ; wherein * denotes a connection to ‒(CH2)n‒ and denotes a connection to Ar1; wherein Ar2, 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 R1a, R1b, R1c, and R1dis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, and ‒NO2; wherein R2is selected from hydrogen and C1-C4 alkyl; wherein each of R3aand R3bis independently C1-C4 alkyl, or wherein each of R3aand R3btogether comprise a C4-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; and wherein Ar1is 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, provided that when m is 0 and R2is hydrogen, then one of R3aand R3bis C1-C4 alkyl and the other of R3aand R3bis the structure, provided that when A1is O, then o is not 0 or 1, and provided that when A1is ‒CH2‒, then m is 1 and L1is a structure selected from:.

[0010] Also disclive amount of a disclosed compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0011] 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.

[0012] Also 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 disclosed compound, or a pharmaceutically acceptable salt thereof.

[0013] 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.

[0014] 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.

[0015] 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.

[0016] 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.

[0017] 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 wayintended 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

[0018] 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.

[0019] 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.

[0020] FIG.2A and FIG.2B show representative data illustrating that senescent ECs exhibit impaired barrier-regulatory responses.

[0021] FIG.3A and FIG.3B show representative data illustrating that redox imbalance in senescent ECs corresponds with elevated Nox4 levels.

[0022] FIG.4 shows representative data illustrating that age-dependent severe pre-clinical ARDS is associated with sustained Nox4 levels and excessive ROS production.

[0023] FIG.5A-F show representative data illustrating that aged Nox4-eKO mice demonstrate striking protection from ALI.

[0024] FIG.6A-D shows representative data pertaining to the identification of novel Nox4 inhibitors.

[0025] FIG.7A and FIG.7B show representative data illustrating that Nox4 inhibitors reverse established pro-fibrotic phenotypes in human IPF lung myofibroblasts.

[0026] FIG.8A-G show representative data illustrating that Nox4 inhibitor UANOX48 protects from pre-clinical ARDS.

[0027] FIG.9 shows representative structures of Nox4 inhibitors for IV delivery.

[0028] FIG.10A and FIG.10B show representative diagrams of the efficacy testing protocols.

[0029] 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 beunderstood 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

[0030] The present invention can be understood more readily by reference to the following detailed description of the invention and the Examples included therein.

[0031] 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.

[0032] 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.

[0033] 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 independentconfirmation. A. DEFINITIONS

[0034] 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.

[0035] As used in the specification and in the claims, the term “comprising” can include the aspects “consisting of” and “consisting essentially of.”

[0036] 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.

[0037] 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.

[0038] References in the specification and concluding claims to parts by weight of aparticular 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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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 beendiagnosed 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.).

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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; thetime 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.

[0047] 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 apreservative.

[0048] 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.

[0049] 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.

[0050] 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 (14thedition), the Physicians' Desk Reference (64thedition), and The Pharmacological Basis of Therapeutics (12thedition) , 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 antibioticsand 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.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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 apolyester 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.

[0055] 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).

[0056] 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.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] 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,” isnot meant to imply that the general term does not also include the specific term.

[0061] 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.

[0062] The term “polyalkylene group” as used herein is a group having two or more CH2groups 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.

[0063] 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 —OA1where A1is 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—OA2or — OA1—(OA2)a—OA3, where “a” is an integer of from 1 to 200 and A1, A2, and A3are alkyl and / or cycloalkyl groups.

[0064] 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.

[0065] 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 doublebound, 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, aldeyhyde, −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.

[0066] 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.

[0067] 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.

[0068] 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 πclouds 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.

[0069] 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.

[0070] 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.

[0071] The terms “amine” or “amino” as used herein are represented by the formula — NA1A2, where A1and A2can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. A specific example of amino is ─NH2.

[0072] 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.

[0073] 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)aminogroup, 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.

[0074] The term “carboxylic acid” as used herein is represented by the formula —C(O)OH.

[0075] The term “ester” as used herein is represented by the formula —OC(O)A1or — C(O)OA1, where A1can 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 A1and A2can 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.

[0076] The term “ether” as used herein is represented by the formula A1OA2, where A1and A2can 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 A1and A2can 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.

[0077] The terms “halo,” “halogen,” or “halide” as used herein can be used interchangeably and refer to F, Cl, Br, or I.

[0078] 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.

[0079] 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.

[0080] 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 heteroatomsinclude, 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.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] The term “hydroxy” or “hydroxyl” as used herein is represented by the formula — OH.

[0085] The term “ketone” as used herein is represented by the formula A1C(O)A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0086] The term “azide” or “azido” as used herein is represented by the formula —N3.

[0087] The term “nitro” as used herein is represented by the formula —NO2.

[0088] The term “nitrile” or “cyano” as used herein is represented by the formula —CN or — C≡N.

[0089] The term “silyl” as used herein is represented by the formula —SiA1A2A3, where A1, A2, and A3can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0090] 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 A1can 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 A1can 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 A1and A2can 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 A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0091] The term “thiol” as used herein is represented by the formula —SH.

[0092] “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 R1is 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.

[0093] 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).

[0094] 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.

[0095] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH2)0–4R ^; –(CH2)0–4OR ^; -O(CH2)0-4Ro, – 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; –(C1–4straight or branched alkylene)O–N(R ^)2; or –(C1–4 straight or branched alkylene)C(O)O–N(R ^)2, wherein each R ^ may be substituted as defined below and is independently hydrogen, C1– 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.

[0096] 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^,–(C1–4straight 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 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. Suitable divalent substituents on a saturated carbon atom of R ^ include =O and =S.

[0097] 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*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R*2))2–3O–, or –S(C(R*2))2–3S–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic 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, 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.

[0098] 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 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.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] 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).

[0103] 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.

[0104] 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 thiazolidinedioneprepare 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.

[0105] “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.

[0106] “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.

[0107] 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.

[0108] 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.

[0109] 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 bereferred 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.

[0110] 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 as2H,3H,13C,14C,15N,18O,17O,35S,18F and36Cl, 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 as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H, and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e.,2H, 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.

[0111] The compounds described in the invention can be present as a solvate. In somecases, 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.

[0112] 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.

[0113] 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.

[0114] 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-A3and N1-unsubstituted, 5-A3as shown below.

[0115] Unless stated to the contrary, the invention includes all such possible tautomers.

[0116] 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. Thecompounds 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.

[0117] In some aspects, a structure of a compound can be represented by a formula: , which is understood to be equivalent to aormu a: , wherein n is typically an integer. Thatis, Rnis understood to represent five independent substituents, Rn(a), Rn(b), Rn(c), Rn(d), Rn(e). By “independent substituents,” it is meant that each R substituent can be independently defined. For example, if in one instance Rn(a)is halogen, then Rn(b)is not necessarily halogen in that instance.

[0118] 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).

[0119] 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 tobe 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.

[0120] 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.

[0121] 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

[0122] In one aspect, the invention relates to compounds that inhibit 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)).

[0123] 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

[0124] 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 A1is selected from ‒O‒ and ‒CH2‒; wherein L1is selected from C2 alkenyl, C2 alkynyl, *‒NHC(O)‒**, *‒C(O)NH‒**,Ar2, and a structure:; wherein * denotes a connection to ‒(enotes a connection to Ar1; wherein Ar2, 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 R1a, R1b, R1c, and R1dis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, and ‒NO2; wherein R2is selected from hydrogen and C1-C4 alkyl; wherein each of R3aand R3bis independently C1-C4 alkyl, or wherein each of R3aand R3btogether comprise a C4-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; and wherein Ar1is 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, provided that when m is 0 and R2is hydrogen, then one of R3aand R3bis C1-C4 alkyl and the other of R3aand R3bis the structure, provided that when A1is O, then o is not 0 or 1, and provided that when A1is ‒CH2‒, then m is 1 and L1is a structure selected from: .

[0125] In various aspects, the compound has a structure represented by a formula: ,or a pharmaceutically acceptable salt thereof.

[0126] In various aspects, the compound has a structure represented by a formula selected from: , or a.

[0127] In various aspects, the compound has a structure represented by a formula: , or apharmaceutically acceptable salt thereof.

[0128] In various aspects, the compound has a structure represented by a formula: ,or a pharmaceutically acceptable salt thereof.

[0129] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically acceptabe sa e eo .

[0130] In various aspects, the compound has a structure represented by a formula: ,or a pharmaceutically acceptable salt thereof.

[0131] In various aspects, the compound has a structure represented by a formula: ,or a pharmaceutically acceptable salt thereof.

[0132] In various aspects, the compound has a structure represented by a formula: ,or a pharmaceutically acceptable salt thereof.

[0133] In various aspects, the compound has a structure represented by a formula: , or a pharmaceutically acceptae sa ereo .

[0134] In various aspects, the compound has a structure represented by a formula: ,wherein o is selected from 2, 3, and 4, or a pharmaceutically acceptable salt thereof.

[0135] In various aspects, the compound has a structure represented by a formula: ,or a pharmaceutically acceptable salt thereof.

[0136] In various aspects, the compound has a structure represented by a formula: R1a1bQ q ,wherein q is selected from 0 and 1; and wherein Q is selected from ‒O‒, ‒N(R20)‒, and ‒ C(R21a)(R21b)‒, or a pharmaceutically acceptable salt thereof.

[0137] In various aspects, the compound has a structure represented by a formula: R1aR1b3a, or a pharmaceutically acceptab e sa t t ereo .

[0138] In various aspects, the compound is selected from: , ,,,,,,,, , ,,, , ,, or a pharmaceutica

[0139] In one aspect, n is selected from 0, 1, 2, 3, 4, and 5, and m is selected from 0 and 1, provided that when n is 0 then m is 0.

[0140] 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.

[0141] 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 1. In an even yet further aspect, n is 5. In an even still further aspect, n is 4. In a further aspect, n is 3. In a still further aspect, n is 2. In a yet further aspect, n is 1. In an even further aspect, n is 0.

[0142] In various aspects, n is 1 and m is 1.

[0143] In one aspect, 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 a yet further aspect, o is selected from 0, 1, 2, 3, 4, and 5. In an even further aspect, o is selected from 0, 1, 2, 3, and 4. In an even still further aspect, o is selected from 0, 1, 2, and 3. In an even yet further aspect, o is selected from 0, 1, and 2. In a further aspect, o is selected from 0 and 1. In a still further aspect, o is 0. In a yet further aspect, o is 1. In an even further aspect, o is 2. In an even still further aspect, o is 3. In an even yet further aspect, o is 3. In a further aspect, o is 4. In a still further aspect, o is 5. In a yet further aspect, o is 6. In an even further aspect, o is 7. In an even still further aspect, o is 8.

[0144] In various aspects, o is selected from 2, 3, and 4. In a further aspect, o is selected from 2 and 3. In a still further aspect, o is selected from 3 and 4. In yet a further aspect, o is selected from 2 and 4.

[0145] In one aspect, q is selected from 0 and 1. In a further aspect, q is 0. In a still further aspect, q is 1. a. A1GROUPS

[0146] In one aspect, A1is selected from ‒O‒ and ‒CH2‒. In a further aspect, A ‒O‒ . In a yet further aspect, A is ‒CH2‒. b. L1GROUPS

[0147] In one aspect, L1is selected from C2 alkenyl, C2 alkynyl, *‒NHC(O)‒**, *‒ C(O)NH‒**, Ar2, and a structure: ; wherein * denotes a connection to ‒(C 2)n‒ an denotes a connection to Ar1.

[0148] In various aspects, L1is selected from C2 alkenyl and C2 alkynyl. In a further aspect, L is C2 alkenyl. In a yet further aspect, L1is C2 alkynyl.

[0149] In various aspects, L1is selected from *‒NHC(O)‒** and *‒C(O)NH‒**. In a further aspect, L is *‒NHC(O)‒**. In a yet further aspect, L1is *‒C(O)NH‒**.

[0150] In various aspects, L1is Ar2. In a further aspect, Ar2is 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, Ar2is selected from triazolyl, oxadiazolyl, thiazolyl, tetrazolyl, oxazolyl, and thiadiazolyl, and is unsubstituted. In yet a further aspect, Ar2is a structure selected from: ,wherein * denotes a connection to ‒(CH2)n‒ and ** denotes a connection to Ar1.

[0151] In various aspects, L1is a structure: ;wherein * denotes a connection to ‒(CH2)n‒ and ** denotes a connection to Ar1.a. Q GROUPS

[0152] In one aspect, Q is selected from ‒O‒, ‒N(R20)‒, and ‒C(R21a)(R21b)‒. In a further aspect, is selected from ‒O‒ and ‒N(R20)‒. In a yet further aspect, Q is selected from ‒O‒ and ‒C(R21a)(R21b)‒. In a still further aspect, Q is selected from ‒N(R20)‒ and ‒ C(R21a)(R21b)‒. In an even further aspect, Q is ‒O‒. In an even yet further aspect, Q is ‒ N(R20)‒. In an even still further aspect, Q is ‒C(R21a)(R21b)‒. b. R1A, R1B, R1C, AND R1DGROUPS

[0153] In one aspect, each of R1a, R1b, R1c, and R1dis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, and ‒NO2. In a further aspect, each of R1a, R1b, R1c, and R1dis independently selected from hydrogen, fluorine, chlorine, bromine, ‒CN, ‒NH2, ‒ OH, and ‒NO2. In a still further aspect, each of R1a, R1b, R1c, and R1dis independently selected from hydrogen, fluorine, chlorine, ‒CN, ‒NH2, ‒OH, and ‒NO2. In a yet further aspect, each of R1a, R1b, R1c, and R1dis independently selected from hydrogen fluorine, ‒CN, ‒NH2, ‒OH, and ‒NO2.

[0154] In various aspects, each of R1a, R1b, R1c, and R1dis independently selected from hydrogen and halogen. In a further aspect, each of R1a, R1b, R1c, and R1dis independently selected from hydrogen, fluorine, chlorine, and bromine. In a still further aspect, each of R1a, R1b, R1c, and R1dis independently selected from hydrogen, fluorine, and chlorine. In a yet further aspect, each of R1a, R1b, R1c, and R1dis independently selected from hydrogen and fluorine.

[0155] In various aspects, each of R1a, R1b, R1c, and R1dis hydrogen. c. R2GROUPS

[0156] In one aspect, R2, when present, is selected from hydrogen and C1-C4 alkyl. In a further aspect, R2, when present, is selected from hydrogen, methyl, ethyl, propyl, and isopropyl. In a yet further aspect, R2, when present, is selected from hydrogen, methyl, and ethyl. In a still further aspect, R2, when present, is selected from hydrogen and methyl.

[0157] In various aspect, R2, when present, is C1-C4 alkyl. In a further aspect, R2, when present, is selected from methyl, ethyl, propyl, and isopropyl. In a yet further aspect, R2, when present, is selected from methyl and ethyl. In a still further aspect, R2, when present, is methyl.

[0158] In various aspects, R2, when present, is hydrogen. d. R3A ANDR3BGROUPS

[0159] In one aspect, each of R3aand R3bis independently C1-C4 alkyl, or each of R3aand R3btogether comprise a C4-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.

[0160] In various aspects, each of R3aand R3bis independently C1-C4 alkyl. In a futher aspect, each of R3aand R3bis independently selected from methyl, ethyl, propyl, and isopropyl. In a yet further aspect, each of R3aand R3bis independently selected from methyl and ethyl. In an even further aspect, each of R3aand R3bis methyl.

[0161] In various aspects, each of R3aand R3btogether comprise a C4-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. Examples of C4-C5 heterocycloalkyls include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl. In a further aspect, each of R3aand R3btogether comprise a C4-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 R3aand R3btogether comprise a C4-C5 heterocycloalkyl 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 a still further aspect, each of R3aand R3btogether comprise a C4-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 further aspect, each of R3aand R3btogether comprise an unsubstituted C4-C5 heterocycloalkyl.

[0162] In various aspects, each of R3aand R3btogether comprise a pyrrolidinyl,piperidinyl, piperazinyl, or a morpholinyl ring, 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, each of R3aand R3btogether comprise a pyrrolidinyl, piperidinyl, piperazinyl, or a morpholinyl ring, 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, each of R3aand R3btogether comprise a pyrrolidinyl, piperidinyl, piperazinyl, or a morpholinyl ring, 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 a still further aspect, each of R3aand R3btogether comprise a pyrrolidinyl, piperidinyl, piperazinyl, or a morpholinyl ring, 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, each of R3aand R3btogether comprise a pyrrolidinyl, piperidinyl, piperazinyl, or a morpholinyl ring, and is unsubstituted.

[0163] In various aspects, each of R3aand R3btogether comprise a pyrrolidinyl, piperidinyl, piperazinyl, or a morpholinyl ring, and is substituted with 0 or 1 group selected from ‒OH and C1-C4 alkyl. In a futher aspect, each of R3aand R3btogether comprise a pyrrolidinyl, piperidinyl, piperazinyl, or a morpholinyl ring, and is monosubstituted a group selected from ‒OH and C1-C4 alkyl. In a yet further aspect, each of R3aand R3btogether comprise a pyrrolidinyl, piperidinyl, piperazinyl, or a morpholinyl ring, and is substituted with 0 or 1 group selected from ‒OH, methyl, ethyl, propyl and isopropyl. In a still further aspect, each of R3aand R3btogether comprise a pyrrolidinyl, piperidinyl, piperazinyl, or a morpholinyl ring, and is substituted with 0 or 1 group selected from ‒OH, methyl, and ethyl. In a even further aspect, each of R3aand R3btogether comprise a pyrrolidinyl, piperidinyl, piperazinyl, or a morpholinyl ring, and is substituted with 0 or 1 group selected from ‒OH and methyl. In an even yet further aspect, each of R3aand R3btogether comprise a pyrrolidinyl, piperidinyl, piperazinyl, or a morpholinyl ring, and is unsubstituted.e. R20GROUPS

[0164] In one aspect, R20, when present, is selected from hydrogen and C1-C4 alkyl. In a further aspect, R20, when present, is selected from hydrogen, methyl, ethyl, propyl, and isopropyl. In a yet further aspect, R20, when present, is selected from hydrogen, methyl, and ethyl. In a still further aspect, R2, when present, is selected from hydrogen and methyl.

[0165] In various aspect, R20, when present, is C1-C4 alkyl. In a further aspect, R20, when present, is selected from methyl, ethyl, propyl, and isopropyl. In a yet further aspect, R20, when present, is selected from methyl and ethyl. In a still further aspect, R20, when present, is methyl.

[0166] In various aspects, R20, when present, is hydrogen. f. R21AND R21BGROUPS

[0167] In one aspect, R21aand R21b, when present, is independently selected from hydrogen and C1-C4 alkyl. In a further aspect, R21aand R21b, when present, is independently selected from hydrogen, methyl, ethyl, propyl, and isopropyl. In a yet further aspect, R21aand R21b, when present, is independently selected from hydrogen, methyl, and ethyl. In a still further aspect, R21aand R21b, when present, is independently selected from hydrogen and methyl.

[0168] In various aspect, R21aand R21b, when present, is C1-C4 alkyl. In a further aspect, R21aand R21b, when present, is independently selected from methyl, ethyl, propyl, and isopropyl. In a yet further aspect, R2, when present, is independently selected from methyl and ethyl. In a still further aspect, R21aand R21b, when present, is methyl.

[0169] In various aspects, R21aand R21b, when present, is hydrogen. g. AR1GROUPS

[0170] In one aspect, 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, Ar1is 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-C4cyanoalkyl, 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, Ar1is 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 a yet further aspect, Ar1is 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, Ar1is 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.

[0171] In various aspects, Ar1is 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- C14 aryls include, but are not limited to, phenyl and naphthyl. In a further aspect, Ar1is 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, Ar1is 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 a yet further aspect, Ar1is 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, Ar1is C6-C10 aryl 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.

[0172] In various aspects, Ar1is 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, Ar1is 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, Ar1is 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 a yet further aspect, Ar1is 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, and C1-C4 aminoalkyl. In an even further aspect, Ar1is 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.

[0173] In various aspects, Ar1is 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, Ar1is 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, Ar1is 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 a yet further aspect, Ar1is phenyl monosubstituted with a group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar1is phenyl 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.

[0174] In various aspects, Ar1is naphthyl 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, Ar1is naphthyl 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, Ar1is naphthyl 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 a yet further aspect, Ar1is naphthyl 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, Ar1is naphthyl 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.

[0175] In various aspects, Ar1is 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, Ar1is 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, Ar1is 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 a yet further aspect, Ar1is 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, Ar1is 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. h. AR2GROUPS

[0176] In one aspect, Ar2, 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. 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, Ar2, when present, is 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, Ar2, when present, is 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 a yet further aspect, Ar2, when present, is 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, Ar2, when present, is an unsubstituted C2-C9 heteroaryl.

[0177] In various aspects, Ar2, when present, 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, Ar2, when present, 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 still further aspect, Ar2, when present, is selected from triazolyl, oxadiazolyl, thiazolyl, tetrazolyl, oxazolyl, and thiadiazolyl, 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 a yet further aspect, Ar2, when present, 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, Ar2, when present, is selected from triazolyl, oxadiazolyl, thiazolyl, tetrazolyl, oxazolyl, and thiadiazolyl, and is unsubstituted.

[0178] In various aspects, Ar2is a structure selected from: ,wherein * denotes a connection to ‒(CH2)n‒ and ** denotes a connection to Ar1.

[0179] In various aspects, Ar2is a structure: ,wherein * denotes a connection to ‒(CH2)n‒ and ** denotes a connection to Ar1.

[0180] In various aspects, Ar2is a structure: , wherein * denotes a connection to ‒(Cn denotes a connection to Ar1. 2. EXEMPLARY COMPOUNDS

[0181] In one aspect, a compound can be present as one or more of the following structures: , , , ,,, , ,,, , , ,,, ,or a pharmaceutically acceptable salt thereof.

[0182] It is contemplated that one or more compounds can optionally be omitted from the disclosed invention.

[0183] It is understood that the disclosed compounds can be used in connection with the disclosed methods, compositions, kits, and uses.

[0184] 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

[0185] 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.

[0186] 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 A1is selected from ‒O‒ and ‒CH2‒; wherein L1is selected from C2 alkenyl, C2 alkynyl, *‒NHC(O)‒**, *‒C(O)NH‒**, Ar2, and a structure: ;wherein * denotes a connection to ‒(CH2)n‒ and ** denotes a connection to Ar1; wherein Ar2, 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 R1a, R1b, R1c, and R1dis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, and ‒NO2;wherein R2is selected from hydrogen and C1-C4 alkyl; wherein each of R3aand R3bis independently C1-C4 alkyl, or wherein each of R3aand R3btogether comprise a C4-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; and wherein Ar1is 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, provided that when m is 0 and R2is hydrogen, then one of R3aand R3bis C1-C4 alkyl and the other of R3aand R3bis the structure, provided that when A1is O, then o is not 0 or 1, and provided that when A1is ‒CH2‒, then m is 1 and L1is a structure selected from: , and a pharmaceutically acceptable carrier.

[0187] 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., intravenous, topical, or oral administration.

[0188] 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.

[0189] 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.

[0190] 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.

[0191] 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.

[0192] 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 aspowders, 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

[0193] 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.

[0194] 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.

[0195] 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.

[0196] 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.

[0197] 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.

[0198] 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.

[0199] 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.

[0200] 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.

[0201] 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, acute respiratory distress syndrome (ARDS), or cancer. 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.

[0202] 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

[0203] In various aspects, the compounds and compositions disclosed herein are useful for inhibiting NADPH Oxidase 4 (NOX4) signaling in a cell.

[0204] 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 from0, 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 A1is selected from ‒O‒ and ‒CH2‒; wherein L1is selected from C2 alkenyl, C2 alkynyl, *‒NHC(O)‒**, *‒C(O)NH‒**,Ar2, and a structure: ;wherein * denotes a connection to ‒(CH2)n‒ and ** denotes a connection to Ar1; wherein Ar2, 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 R1a, R1b, R1c, and R1dis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, and ‒NO2; wherein R2is selected from hydrogen and C1-C4 alkyl; wherein each of R3aand R3bis independently C1-C4 alkyl, or wherein each of R3aand R3btogether comprise a C4-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; and wherein Ar1is selected from C6-C10 aryl and C2- C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, ‒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, provided that when m is 0 and R2is hydrogen, then one of R3aand R3bis C1-C4 alkyl and the other of R3aand R3bis the structure, provided that when A1is O, then o is not 0 or 1, and provided that when A1is ‒CH2‒, then m is 1 and L1is a structure selected from: .

[0205] In vari, .

[0206] In various aspects, the cell is a human.

[0207] In various aspects, the cell has been isolated from a mammal prior to the contacting step.

[0208] In various aspects, contacting is ex vivo.

[0209] In various aspects, contacting is in vitro.

[0210] 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 an even further aspect, the disorder is cancer. 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

[0211] 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.

[0212] 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, , , , , , 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 A1is selected from ‒O‒ and ‒CH2‒; wherein L1is selected from C2 alkenyl, C2 alkynyl, *‒NHC(O)‒**, *‒C(O)NH‒**, Ar2, and a structure: ; wherein * denotes a connection to ‒(CH2)n‒ and denotes a connection to Ar1; wherein Ar2, 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 R1a, R1b, R1c, and R1dis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, and ‒NO2; wherein R2is selected from hydrogen and C1-C4 alkyl; wherein each of R3aand R3bis independently C1-C4 alkyl, or wherein each of R3aand R3btogether comprise a C4-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; and wherein Ar1is 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, provided that when m is 0 and R2is hydrogen, then one of R3aand R3bis C1-C4 alkyl and the other of R3aand R3bis the structure, provided that when A1is O, then o is not 0 or 1, and provided that when A1is ‒CH2‒, then m is 1 and L1is a structure selected from:.

[0213] In vari

[0214] In various aspects, the subject is a human.

[0215] In various aspects, the subject has been diagnosed with a need for inhibiting NOX4 signaling to the administering step.

[0216] In various aspects, the method further comprises identifying a subject in need of inhibition of NOX4 signaling as further described herein. F. METHODS OFTREATING AFIBROTICDISORDER IN ASUBJECT

[0217] 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.

[0218] 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 A1is selected from ‒O‒ and ‒CH2‒; wherein L1is selected from C2 alkenyl, C2 alkynyl, *‒NHC(O)‒**, *‒C(O)NH‒**, Ar2, and a structure:; wherein * denotes a connection to ‒(enotes a connection to Ar1; wherein Ar2, 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 R1a, R1b, R1c, and R1dis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, and ‒NO2; wherein R2is selected from hydrogen and C1-C4 alkyl; wherein each of R3aand R3bis independently C1-C4 alkyl, or wherein each of R3aand R3btogether comprise a C4-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; and wherein Ar1is 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, provided that when m is 0 and R2is hydrogen, then one of R3aand R3bis C1-C4 alkyl and the other of R3aand R3bis the structure, provided that when A1is O, then o is not 0 or 1, and provided that when A1is ‒CH2‒, then m is 1 and L1is a structure selected from: .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.

[0219] In various aspects, the fibrotic disorder is pulmonary fibrosis. In a further aspect, the pulmonary fibrosis is idiopathic pulmonary fibrosis.

[0220] In various aspects, the subject is a mammal.

[0221] In various aspects, the subject is a human.

[0222] In various aspects, the subject has been diagnosed with the fibrotic disorder prior to the administering step.

[0223] In various aspects, the method further comprises the step of identifying a subject in need of treatment of the fibrotic disorder.

[0224] 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

[0225] 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.

[0226] 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.

[0227] Further, as noted above, a substantial body of evidence has implicated oxidative stress as a major contributor to the pathogenesis of ARDS. Numerous studies havedemonstrated 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 therapeutic, which targets the critical pathological features of ARDS: excessive ROS production, barrier dysfunction, and inflammatory injury.

[0228] 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 ofARDS (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 therapeutic strategy to correct age-dependent dysfunction associated with severe ARDS in the elderly.

[0229] 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 A1is selected from ‒O‒ and ‒CH2‒; wherein L1is selected from C2 alkenyl, C2 alkynyl, *‒NHC(O)‒**, *‒C(O)NH‒**, Ar2, and a structure: ;wherein * denotes a connection to ‒(CH2)n‒ and ** denotes a connection to Ar1; wherein Ar2, 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 R1a, R1b, R1c, and R1dis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, and ‒NO2; wherein R2is selected from hydrogen and C1-C4 alkyl; wherein each of R3aand R3bis independently C1-C4 alkyl, or wherein each of R3aand R3btogether comprise a C4-C5heterocycloalkyl 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 Ar1is 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, provided that when m is 0 and R2is hydrogen, then one of R3aand R3bis C1-C4 alkyl and the other of R3aand R3bis the structure, provided that when A1is O, then o is not 0 or 1, and provided that when A1is ‒CH2‒, then m is 1 and L1is a structure selected from: .

[0230] In various aspects, a m n sterng s va ora a mnstrat on, ntraperitoneal administration, or intravenous (IV) administration.

[0231] In various aspects, the subject is a mammal.

[0232] In various aspects, the subject is a human.

[0233] In various aspects, the subject has been diagnosed with ARDS prior to the administering step.

[0234] 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).

[0235] In various aspects, the method further comprises the step of identifying a subject in need of treatment of ARDS.

[0236] In various aspects, the method further comprises 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 a corticosteroid. In a further aspect, the corticosteroid is selected from cortisone, hydrocortisone, and prednisone.H. METHODS OF TREATING CANCER IN A SUBJECT

[0237] 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 occurance 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.

[0238] Thus, 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 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 A1is selected from ‒O‒ and ‒CH2‒; wherein L1is selected from C2 alkenyl, C2 alkynyl, *‒NHC(O)‒**, *‒C(O)NH‒**,Ar2, and a structure: ;wherein * denotes a connection to ‒(CH2)n‒ and ** denotes a connection to Ar1; wherein Ar2, 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 R1a, R1b, R1c, and R1dis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, and ‒NO2; wherein R2is selected from hydrogen and C1-C4 alkyl; wherein each of R3aand R3bis independently C1-C4 alkyl, or wherein each of R3aand R3btogether comprise a C4-C5heterocycloalkyl 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 Ar1is 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, provided that when m is 0 and R2is hydrogen, then one of R3aand R3bis C1-C4 alkyl and the other of R3aand R3bis the structure, provided that when A1is O, then o is not 0 or 1, and provided that when A1is ‒CH2‒, then m is 1 and L1is a structure selected from: .

[0239] In various aspects, treat ng srupts tumor-promot ng esmopas a.

[0240] In various aspects, treating inhibits desmoplastic tumor growth.

[0241] 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.

[0242] In various aspects, the subject is a mammal.

[0243] In various aspects, the subject is a human.

[0244] In various aspects, the subject has been diagnosed with cancer prior to the administering step.

[0245] In various aspects, the subject has been diagnosed with desmoplasia prior to the administering step.

[0246] In various aspects, the method further comprising the step of identifying a subject in need of treatment of cancer.

[0247] In various aspects, the method further comprising the step of identifying a subject in need of treatment of desmoplasia.

[0248] In various aspects, the method further comprising administering to the subject anagent 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.

[0249] 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.

[0250] 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.

[0251] 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.

[0252] 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.

[0253] 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.

[0254] In various aspects, the compound and the agent are administered sequentially. In various further aspects, the compound and the agent are administered simultaneously.

[0255] 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, endometrialcancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma).

[0256] In various aspects, the cancer is breast cancer or pancreatic cancer. I. ADDITIONAL METHODS OF USING THE COMPOUNDS

[0257] 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)).

[0258] 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.

[0259] 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, andsubcutaneous 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.

[0260] 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

[0261] 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.

[0262] 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.

[0263] 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 examplesinclude anti-fibrotic agents (e.g., nintedanib, pirfenidone), agents known to treat ARDS (e.g., nitric oxide, corticosteroids), and chemotherapeutic agents, as further described herenin.

[0264] 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 OFCOMPOUNDS ANDCOMPOSITIONS

[0265] 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, acute respiratory distress syndrome (ARDS), or cancer. 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)).

[0266] The compounds and pharmaceutical compositions of the invention are useful in treating or controlling disorders associated with over-activation of NOX4.

[0267] 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 pharmaceuticallyacceptable salt, hydrate, solvate, or polymorph thereof. In a further aspect, the compound used is a product of a disclosed method of making.

[0268] 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.

[0269] 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.

[0270] 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

[0271] 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.

[0272] 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 A1is selected from ‒O‒ and ‒CH2‒; wherein L1is selected from C2 alkenyl, C2 alkynyl, *‒NHC(O)‒**, *‒C(O)NH‒**, Ar2, and a structure: ; wherein * denotes a connection to ‒(notes a connection to Ar1; wherein Ar2, 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 R1a, R1b, R1c, and R1dis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, and ‒NO2; wherein R2is selected from hydrogen and C1-C4 alkyl; wherein each of R3aand R3bis independently C1-C4 alkyl, or wherein each of R3aand R3btogether comprise a C4-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; and wherein Ar1is 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, provided that when m is 0 and R2is hydrogen, then one of R3aand R3bis C1-C4 alkyl and the other of R3aand R3bis the structure, provided that when A1is O, then o is not 0 or 1, and provided that when A1is ‒CH2‒, then m is 1 and L1is a structure selected from: ,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.

[0273] In various aspects, the kit includes the anti-fibrotic agent. Exemplary anti-fibrotic agents include, but are not limited to, nintedanib and pirfenidone.

[0274] 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.

[0275] 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.

[0276] 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.

[0277] In various aspects, the kit includes the agent known to treat cancer such as, for example, a chemotherapeutic agent as further described herein.

[0278] 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.

[0279] 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.

[0280] 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.

[0281] 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.

[0282] 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

[0283] 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.

[0284] 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

[0285] 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.

[0286] 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 beused 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.

[0287] 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.

[0288] 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 OFADMINISTRATION

[0289] 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 ofadministration, 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.

[0290] 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).

[0291] In various aspects, the modes of administration described above may be combined in any order. J. EXAMPLES

[0292] 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.

[0293] The Examples are provided herein to illustrate the invention, and should not be construed as limiting the invention in any way. 1. INSILICOPROPOSEDCOMPOUNDS

[0294] A list of compounds generated in silico is shown in Table 1 below.TABLE 1. Compound NumberStructureCompound NumberStructureCompound NumberStructureCompound NumberStructureCompound NumberStructureCompound NumberStructureCompound NumberStructureCompound NumberStructure2. PROP

[0295] A proposed synthetic route to access the compounds modeled in silico (see Table 1) is shown in Schemes 1 and 2 below. Briefly, the synthesis is envisioned starting from the commercially available compound 1 (Cas # 343773-72-8), 1-(7-hydroxynaphthalen-2- yl)ethan-1-one.1-(7-hydroxynaphthalen-2-yl)ethan-1-one will be treated with 2-bromo-N,N- dimethylethanamine hydrobromide in CH3CN in the presences of K2CO3 at room temperature to provide 2a . Similarly, 1-(7-hydroxynaphthalen-2-yl)ethan-1-one will be treated with 1,3- dibromopropane in CH3CN in the presences of K2CO3 at room temperature followed by the reaction of the resulting intermediate with Me2NH in DMSO in the presence of Hunig’s base at 80 °C to provide 2b. The ketones 2a-b will be reduced to the corresponding alcohols by asymmetric reduction or by non-stereoselective reduction followed by chiral resolution of the racemic mixture by forming tartrate salts or Mosher's ester or esterification with chiral DMAP catalyst to provide chiral secondary alcohols 3a-b and 4a-b. Examples of stereoselective esterification with chiral DMAP catalyst can be found in Molecules 2014, 19, 14273-14291. Alcohols 3a-b and 4a-b will be combined with TsCl in CH2Cl2 in the presences of Et3N at room temperature followed by reaction with indoline in DMF in the presences of K2CO3 at 100 °C to provide requisite compounds BW-008, BW-002, BW-007, and BW-001 respectively.SCHEME 1.

[0296] Compounds av ng met yene and am no groups that are different from those of BW-001, BW-002, BW-007 and BW-008 will be accessed by using appropriate dihalides and secondary amines as shown above in Scheme 2. Compounds for which the starting methyl ketones are not commercially available will be prepared from an appropriate Grignard reagent and Weinreb amide (Tet Lett 1981, 22 (39): 3815–3818) synthesized from acetyl chloride. Grignard reagents that are not commercially available will be synthesized by methods known to those skilled in the art from appropriate aryl halides and magnesium metal. Once synthesized, the methyl ketones will be used in the synthesis of other compounds in the BW series adapting the scheme described for the synthesis of BW-001, BW-002, BW- 007 and BW-008 as needed. 3. DEVELOPMENT OF ARDS THERAPEUTIC STRATEGIES

[0297] A Novel 2-Hit Pre-Clinical Aging Murine Model of Severe ARDS Better Recapitulates 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.

[0298] 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.

[0299] 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).

[0300] 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.

[0301] 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.

[0302] 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.

[0303] Selective Nox4 Inhibitors Have Not Been Previously Identified. There are no commercially available Nox4 inhibitors. Diphenylene iodonium (DPI) remains the only well-validated pan-Nox inhibitor; no selective Nox4 inhibitors have been identified. Drawbacks of DPI have prevented its therapeutic development including lack of specificity, off-target inhibition of other ROS-producing systems, irreversible binding, and toxicity in vivo. Nonetheless, DPI remains a powerful tool for Nox therapeutic development programs. 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.

[0304] An additional challenge to the field are reports of putative “Nox inhibitors,” which have been subsequently challenged and disproven. The most well-studied putative “Nox1 / 4 inhibitor” is Setanaxib (also known as GKT136901), originally developed by Genkyotex (Geneva, Switzerland). However, a recent in-depth evaluation of putative Nox inhibitors demonstrated that “GKT136901 is, in fact, inactive as Nox inhibitor, but rather interferes with peroxidase-dependent assays” (Augsburger et. al. (2019) Redox Biol 26:101272). GKT136901 showed similar 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 general reducing agent. Thus, 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. Although Setanaxib remains marketed as a Nox1 / 4 inhibitor (now being developed by Calliditas Therapeutics), it has been definitively shown that its mechanism of action is not via direct Nox inhibition. 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; cautionis 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 generation. 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). 4. PRELIMINARY STUDIES a. NOX4 TARGET VALIDATION

[0305] 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. Control Senescent yb. AGED EC-TARGETED NOX4 KO MICE DEMONSTRATE STRIKING PROTECTION FROM ALI

[0306] 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.5A), 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.5B). 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.5C), decreased BAL ROS levels (FIG.5D), decreased BAL protein (FIG. 5E), and decreased lung albumin (FIG.5F). 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.

[0307] Referring to FIG.5A-F, validates that aged Nox4-eKO mice demonstrate striking protection from ALI. FIG.5A 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. 5B shows data of lung ECs from WT and Nox4-eKO mice were isolated via FACS and evaluated for Nox4 expression via WB. FIG.5C-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.5C), BAL H2O2(FIG.5D), BAL protein (FIG.5E),and BAL albumin (FIG.5F). 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 OFNOX4 SMALL-MOLECULEINHIBITORCANDIDATES FOR FIBROSIS INDICATIONS VIA ORAL DELIVERY

[0308] 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 (UANOX048) emerged. See Table 1.

[0309] UANOX048 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. UANOX048 passed false-positive screening: demonstrated no scavenger activity (does not act as an antioxidant) (FIG.6A and FIG.6B), does not interfere with assay reagents (FIG.6A), and has no effect on cellular viability (FIG.6C). Predicted docking / binding simulations were also performed on the two enantiomers of UANOX048 using Autodock Vina (J Comput Chem.2010, 31(2):455-61. doi: 10.1002 / jcc.21334. PMID: 19499576), using a predicted homology model of Nox4. It was observed that R- and S- enantiomers of UANOX048 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.

[0310] UANOX048 demonstrated high selectivity for Nox4 over Nox2 or xanthine oxidase (Nox-independent ROS generation) (FIG.6D). 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 screeningcascade. 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.

[0311] Referring to FIG.6A-D, shows assays associated with identification of a Nox4 inhibitor. FIG.6A-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 H2O2was assessed by ROS-Glo (HRP- independent assay) (FIG.6A) and Amplex Red (HRP-dependent assay) (FIG.6B). FIG.6C 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.6D 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. H2O2production 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.

[0312] In lung myofibroblasts isolated from IPF patients, treatment with UANOX048 promoted the reversal of established pro-fibrotic myofibroblast phenotypes: inhibited H2O2production (IC5025.7 nM) (FIG.7A), and collagen production (FIG.7B). Importantly, in vivo efficacy was evaluated in an aging model of persistent lung fibrosis; treatment with UANOX048 promotes the reversal of age-dependent established fibrosis, which resulted in improved lung function. In vivo efficacy was demonstrated for UANOX048 for inhibiting cardiac fibrosis, which led to improvement in cardiac function.

[0313] Referring to FIG.7A and FIG.7B, Nox4 inhibition reverses established pro- fibrotic phenotypes in human IPF lung myofibroblasts. FIG.7A shows myofibroblasts isolated from the lungs of IPF patients treated with UANOX48 (10 µM or as indicated) or vehicle (DMSO). H2O2levels were evaluated at 24h by Amplex Red assay. FIG.7B 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

[0314] UANOX048 was utilized to demonstrate proof-of-concept for targeting Nox4 in an animal model of ARDS. Treatment with UANOX048 led to reduced ROS levels in senescent ECs (FIG.8A) and increased proliferation of non-senescent ECs (FIG.8B).

[0315] The PK profile and lung distribution of UANOX048 via IV delivery was evaluated in mice; half-life (t1 / 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 UANOX048 demonstrated reduced blood ROS levels (FIG.8C) and significant protection from ALI including significantly reduced lung albumin (FIG.8D) and inflammation inflammatory (specifically decreased neutrophil influx) (FIG.8E-G)). These results demonstrate efficacy and provide rationale for the continued development of Nox4 inhibitors for ARDS.

[0316] Referring to FIG.8A-G, Nox4 inhibitors protect from pre-clinical ARDS. FIG. 8A 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.8B 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.8C-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.8C) 4h post-injury and plasma H2O2was evaluated by Amplex red. Severity of ALI was assessed at 24h post-injury by lung albumin (FIG.8D), total BAL cells (FIG.8E), neutrophil influx (FIG.8F), and histopathology (FIG.8G). (n = 3-6 mice / group; *p<0.05, **p<0.01, ***p<0.001, ns = not statistically significant). e. NOX4 INHIBITOR CANDIDATES IDENTIFIED FOR IV DELIVERY

[0317] The studies with UANOX048 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, UANOX048 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 UANOX048. Two representative candidates are shown in FIG.9.

[0318] These combined efforts led to the identification of Nox4 inhibitor candidates (APV235197A, APV235973A, UANOX108, UANOX107; FIG.9 – 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. 5. LINKINGEXCESSIVENOX4-DERIVEDROSANDAGE-RELATEDDISEASE

[0319] 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.

[0320] 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 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 indeveloping 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 therapy to reduce susceptibility and mortality from age-dependent severe ARDS. 6. RESEARCHDESIGN ANDMETHODSa. DIRECTED MEDICINAL CHEMISTRY TO OPTIMIZE ADME PROPERTIES OFTOPCANDIDATES FORIV DELIVERY

[0321] UANOX048 was used to demonstrate proof-of-concept for targeting Nox4 in an animal model of ARDS. However, as detailed above, this candidate is not ideal for IV delivery, particularly due to low solubility. Herein, four Nox4 inhibitor candidates favorable for IV delivery have been described, which candidates exhibit significantly improved solubility (FIG.9). In pursuit of a lead development candidate for subsequent clinical use, this study will initially utilize the IV candidates as a starting point for medicinal chemistry efforts and further optimization. Subsequent studies will utilize IV candidates identified (FIG.9) and / or synthesized analogs to design and synthesize a series of lung-targeting Nox4 inhibitors with improved lung distribution. The overall goal of this study is to develop analogs with optimized properties for IV delivery and to expand the chemical space around these inhibitors for patentability and commercialization. i. DIRECTEDMEDICINALCHEMISTRYEFFORTS TOIMPROVEADME PROFILE

[0322] Medicinal chemistry efforts will focus on optimization of four previously identified IV candidates to achieve the optimal physiochemical profile: cLogP = 3-4, polar surface area (PSA) = 45-70, water solubility at pH 7.4 = >10 µM, mol weight <500, non- ionic molecule, comparable or improved potency to UANOX048. Table 3 shows the molecular weight, ClogP, LogS and Nox4 Score of the prepared analogs. Improving potency and metabolic stability are metrics that will also enhance the profile. Overall, this study is focused on optimizing the profile of the emerging leads in pursuit of a development candidate for subsequent clinical development for ARDS via IV delivery. Molecular simulations used to predict the binding affinity of the BW compounds were performed using Autodock Vina (JComput Chem.2010, 31(2):455-61. doi: 10.1002 / jcc.21334. PMID: 19499576). For this docking study, a homology model of Nox4 was used and the binding orientation of UANOX048 was used as a reference to which those of the BW compounds were compared. TABLE3. NOX4 Score Compound M. Weight CLogP LogS (Kcal / mol)NOX4 Score Compound M. Weight CLogP LogS (Kcal / mol)NOX4 Score Compound M. Weight CLogP LogS (Kcal / mol)TION OFTOPCANDIDATES FOR IV DELIVERY

[0323] Here, the overall goal is to identify top candidates for IV delivery. Continued screening of the candidates identified for IV delivery (FIG.9) and candidates developed as detailed above will be performed. i. SCREENING CASCADE

[0324] Compounds were assay 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. ii. POTENCY FOR NOX4 AND FALSE-POSITIVE SCREENING:

[0325] 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 H2O2will be measured by Amplex red fluorescence assay.

[0326] 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.

[0327] 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 H2O2in 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.

[0328] Assay Interference. Analogs will be incubated in 96-well-plates containing exogenous H2O2(5 µM) and ROS-GLO (an HRP-independent H2O2detection 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.

[0329] Xanthine Oxidase (XO) Assay. XO generates superoxide and H2O2 independent of Nox activity. This assay will be used to eliminate non-specific ROS scavengers.

[0330] 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. iii. FUNCTIONAL SCREENING FOR IN VITRO EFFICACY

[0331] Proliferation. ECs will be evaluated for BrdU incorporation (by ELISA).

[0332] Inflammatory Responses. Senescent EC supernatant will be evaluated to assess changes in inflammatory cytokines using a Multiplex kit (Human Magnetic 65-Plex, ThermoFisher).

[0333] 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):

[0334] 3D Bioengineered Tissue Model to Evaluate Barrier Function. A 3D bioengineered tissue model has been developed, which exhibits synergistic barrier function when endothelial and epithelial cells are co-cultured as measured by trans- epithelial / endothelial electrical resistance (TEER). These 3D cultured tissues are transitioned to an air-liquid-interface in 48 hours. The model recapitulates key air-blood barrier features including low permeability, high TEER, epithelial–endothelial communication, and loss of barrier function in response to inflammatory stimuli. Leveraging the convenient placement of the epithelium facing downward, immune transmigration with neutrophils, monocytes orother immune cells is feasible in this model. Bioengineered tissues will be pre-treated with Nox4 inhibitor followed by LPS challenge. Neutrophil influx and TEER will be evaluated. iv. IN VITRO ADME (ABSORBTION, DISTRIBUTION, METABOLISM, EXCRETION)

[0335] 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.

[0336] 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.

[0337] 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.

[0338] 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.

[0339] Polar Surface Area. Polar surface area will be calculated.

[0340] 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. v. IN VIVOPKAND TISSUE DISTRIBUTION

[0341] 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 atgrams quantities with minimal or no batch-to-batch variations.

[0342] Dosing. C57BL / 6 male mice will be administered candidates in a single dose (10 mg / kg) via IV administration. Mice will be sacrificed by CO2inhalation at various time points (0, 5m, 10m, 15m, 30m, 1, 2, 4, 8, and 24h). 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 ^l 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).

[0343] 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.

[0344] Specific Measured Endpoints. Standard PK parameters of clearance, drug half-life (T1 / 2), Tmax, Cmax, Cmin, drug elimination constant (ke), drug absorption constant (ka), 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 TREATMENT FOR AGE-ASSOCIATEDARDS

[0345] 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. EVALUATION OF IN VIVO DOSE-RANGING TOLERABILITY

[0346] To match efficacy models, TD must be determined in mice. The goal of this study is to calculate the TD of the top 2-3 candidates.

[0347] 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. Dailyin-life measurements will include mortality / moribundity, body weight, and food consumption. Upon death, a full necropsy including weight and clinical observations of major organs will be performed, and major organ tissues will be collected for histological analysis. The resulting toxicity dose-response curves will be used to calculate Toxic Dose (TD50), which will be used (along with Effective Dose (ED50)) for deriving the Therapeutic Index (TI). ii. EVALUATION OF THE EFFICACY OF OPTIMIZED LEAD CANDIDATE FORMULATIONS VIA IV DELIVERY IN A 2-HIT AGING MODEL OF SEVERE PRE-CLINICAL ARDS

[0348] The studies herein provide important target identification and validation data implicating Nox4 as a viable target for age-associated severe ARDS. Preliminary studies with a novel eNox4 KO mouse model demonstrated that selective genetic ablation of endothelial Nox4 in aged mice (when Nox4 is persistently expressed) led to striking protection, as compared to modest protection in young cohorts (FIG.5C-F). The overall goal of this study is to evaluate the most promising candidates optimized for IV delivery (as detailed above) for their efficacy in a rigorous 2-hit murine model of severe pre-clinical ARDS; the ED50of the top two candidates will be determined. Further, both prevention and therapeutic testing protocols will be employed to determine if interventions can: 1) prevent the onset of age-dependent severe ARDS, and / or 2) reduce susceptibility or mortality in age- dependent severe ARDS.

[0349] 2-hit aging model of severe ARDS. Aged (18m) 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 (0.2 mg / kg in PBS in 50 μl) 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). Candidates will be assessed using the protocols described below (FIG. 10A and FIG.10B). For all studies, analogs will be administered via IV delivery through tail vein injection; 5 different dose concentrations will be used for each candidate to determine ED curves. Mice will be sacrificed at 24h after initial injury by exsanguination and bilateral thoracotomy for endpoint analyses.

[0350] Preventative dosing protocol. Referring to FIG.10A, aged mice will receive IV delivery of Nox4 inhibitor 10 minutes prior to LPS-induced injury. At 20h post-LPS inducedinjury, mice will be subjected to VILI for 4h. Mice will be sacrificed at 24h and evaluated for endpoints.

[0351] Curative dosing protocol. Referring to FIG.10B, aged mice will be subjected to LPS-induced injury. At 4h post-injury, mice will receive IV delivery of Nox4 inhibitor. At 20h-post LPS injury, mice will receive a second dose of Nox4 inhibitor. Mice will then be subjected to VILI for 4h and sacrificed at 24h-post initial injury for endpoints analyses including lung injury, oxidative stress and physiological assessments.

[0352] Lung injury (barrier dysfunction and inflammatory responses). Total BAL cells will be evaluated by Coulter counter and total BAL protein will be evaluated by BCA assay. To determine neutrophil influx, cytospin preparations of cellular BAL fraction will be stained with Hema 3 solution and % neutrophils will be quantified. To determine albumin influx, non-cellular BAL fraction will be evaluated by albumin assay kit. To determine lung permeability, mice will be given Evans Blue dye via tail vein injection and lung tissue evaluated by extravasation assay. Pro-inflammatory mediators will be assessed by Multiplex kit (Mouse Magnetic 65-Plex, ThermoFisher). To determine lung injury score, H&E lung sections will be blindly evaluated and scored (HistoWiz) using a previously defined scoring system.

[0353] Oxidative stress. Lung BAL will be evaluated for ROS (Amplex Red assay).

[0354] Physiological assessments. Lung compliance will be evaluated by FlexiVent. Lung weight, body weight, and survival will be monitored / recorded d. SCIENTIFIC RIGOR AND STATISTICAL ANALYSES

[0355] 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. REFERENCES

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[0481] It will be apparent to those skilled in the art that various modifications and variations can be made without departing from the scope or spirit of this disclosure. Other embodiments will be apparent to those skilled in the art from consideration of the specification and practice disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit being indicated by the following claims.

Claims

CLAIMS What is claimed is:

1. A compound having a structure represented by a formula: , wherein n is selected from , , , , , an , an w ere n 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 A1is selected from ‒O‒ and ‒CH2‒; wherein L1is selected from C2 alkenyl, C2 alkynyl, *‒NHC(O)‒**, *‒C(O)NH‒**, Ar2, and a structure: ;wherein * denotes a connection to ‒(CH2)n‒ and ** denotes a connection to Ar1; wherein Ar2, 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 R1a, R1b, R1c, and R1dis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, and ‒NO2; wherein R2is selected from hydrogen and C1-C4 alkyl; wherein each of R3aand R3bis independently C1-C4 alkyl,or wherein each of R3aand R3btogether comprise a C4-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; and wherein Ar1is 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, provided that when m is 0 and R2is hydrogen, then one of R3aand R3bis C1-C4 alkyl and the other of R3aand R3bis the structure, provided that when A1is O, then o is not 0 or 1, and provided that when A1is ‒CH2‒, then m is 1 and L1is a structure selected from: .

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 A1is O.

7. The compound of any one of claims 1 to 5, wherein A1is ‒CH2‒.

8. The compound of any one of claims 1 to 7, wherein L1is C2 alkenyl or C2 alkynyl.

9. The compound of any one of claims 1 to 7, wherein L1is *‒NHC(O)‒**.

10. The compound of any one of claims 1 to 7, wherein L1is Ar2.

11. The compound of any one of claims 1 to 10, wherein Ar2is 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 any one of claims 1 to 10, wherein Ar2is selected from triazolyl, oxadiazolyl, thiazolyl, tetrazolyl, oxazolyl, and thiadiazolyl, and is unsubstituted.

13. The compound of any one of claims 1 to 10, wherein Ar2is a structure selected from: , wherein * denoes a co ec o o ‒ 2 n‒ a e o es a co ec o o Ar1.

14. The compound of any one of claims 1 to 13, wherein each of R1a, R1b, R1c, and R1dis independently selected from hydrogen and halogen.

15. The compound of any one of claims 1 to 13, wherein each of R1a, R1b, R1c, and R1dis hydrogen.

16. The compound of any one of claims 1 to 15, wherein R2is hydrogen.

17. The compound of any one of claims 1 to 15, wherein R2is methyl.

18. The compound of any one of claims 1 to 17, wherein each of R3aand R3bis C1-C4 alkyl.

19. The compound of any one of claims 1 to 17, wherein each of R3aand R3bis methyl.

20. The compound of any one of claims 1 to 17, wherein each of R3aand R3btogether comprise a C4-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.

21. The compound of any one of claims 1 to 17, wherein each of R3aand R3btogether comprise a pyrrolidinyl, piperidinyl, piperazinyl, or a morpholinyl ring, and is substitutedwith 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.

22. The compound of any one of claims 1 to 17, wherein each of R3aand R3btogether comprise a pyrrolidinyl, piperidinyl, piperazinyl, or a morpholinyl ring, 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.

23. The compound of any one of claims 1 to 17, wherein each of R3aand R3btogether comprise a pyrrolidinyl, piperidinyl, piperazinyl, or a morpholinyl ring, and is substituted with 0 or 1 group selected from ‒OH and C1-C4 alkyl.

24. The compound of any one of claims 1 to 23, wherein Ar1is 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.

25. The compound of any one of claims 1 to 23, wherein Ar1is 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.

26. The compound of any one of claims 1 to 23, wherein Ar1is 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.

27. The compound of any one of claims 1 to 23, wherein Ar1is 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.

28. The compound of claim 1, wherein the compound has a structure represented by a formula: , or a pharmaceutically accepta e sa t t ereo .

29. The compound of claim 1, wherein the compound has a structure represented by a formula selected from: , 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: R1aR1b3a, or a pharmaceutically accepta e sa t t ereo .

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 accepa e sa e eo .

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:, wherein o is selected from, , , 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: ,wherein q is selected from 0 and 1; and wherein Q is selected from ‒O‒, ‒N(R20)‒, and ‒C(R21a)(R21b)‒, or a pharmaceutically acceptable salt thereof.

40. The compound of claim 1, wherein the compound has a structure represented by a formula:, or a pharmaceutically accepa e sa eeo.

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 any one of claims 1 to 41, 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 claim 43, wherein the cell has been isolated from a mammal prior to the contacting step.

47. The method of claim 43, wherein the contacting is ex vivo.

48. The method of claim 43, 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 any one of claims 1 to 41, 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 claim 54, 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 41 or 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 41 or 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 for treating ARDS are co-formulated.

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

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

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

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