Niclosamide prodrugs for treating cancers

Abstract

Methods of treating cancer in a subject in need thereof are provided. The methods include administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or derivative thereof. Compounds and compositions are also provided.

Description

[0001] Attorney Docket No.103361-522WO1 NICLOSAMIDE PRODRUGS FOR TREATING CANCERS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to United States Provisional Patent Application No. 63 / 655,643, filed June 4, 2024, the disclosure of which is incorporated herein by reference in its entirety. BACKGROUND Hepatocellular carcinoma (HCC) is currently the second leading cause of cancer- related mortality globally. Its incidence has been increasing globally, and in the United States it is currently the fastest growing cause of cancer-related mortality. Despite recent advances in front-line therapeutic options for advanced HCC, which comprises the majority of HCC cases, the five-year survival rate for HCC in the US is less than 12% [1,2]. HCC exhibits sexual dimorphism with men having an increased rate of both incidence and mortality [3]. Additionally, HCC precursors including steatosis, hepatitis, cirrhosis, and non-alcoholic fatty liver disease (NAFLD), now called metabolic dysfunction-associated steatotic liver disease (MASLD), have higher incidence in men [4]. The androgen receptor (NR3C4 / AR) has been implicated in HCC progression and provides a potential explanation for the sexual dimorphism exhibited in both its incidence and mortality. The AR, like other nuclear hormone receptors, functions as a transcription factor. It is bound by androgens leading to receptor activation, nuclear localization, and dimerization. It then binds to a variety of cofactors and androgen response elements (AREs) within the cellular genome to regulate a diverse set of target genes [4]. While androgens play a role in AR activation, AR rather than androgens are implicated in HCC progression and alternative mechanisms for AR activation including mTOR crosstalk, lipogenesis driven AR activity, CCRK-mediated activity, FAK-mediated signaling, and most notably AR splice variant (AR-SV) expression in HCC [3]. AR-SV expression has been described in 78% of HCC patients within The Cancer Genome Atlas (TCGA) cohort [5]. These results, in conjunction with the clinical failure of anti-androgen therapy, enzalutamide, in HCC emphasize Attorney Docket No.103361-522WO1 the need for HCC therapeutics directly addressing AR protein levels and AR activity [6]. Current front-line therapeutic options for advanced HCC have long included sorafenib, a multikinase inhibitor, and more recently expanded to include lenvatinib, another multikinase inhibitor, and the combination atezolizumab / bevacizumab, a combination immune checkpoint inhibitor (ICI) and anti-VEGF-A antibody. The atezolizumab / bevacizumab combination offers a median overall survival (mOS) improvement of 19.2 months and current efforts are being directed toward determining appropriate second-line approaches for patients who fail ICI therapies [2]. Most recently, the combination of durvalumab, an anti-PD-L1 ICI, and tremelimumab, an anti-CTLA-4 ICI, successfully completed a phase III trial in unresectable HCC and were approved for front line use with a mOS increase of 16.4 months [7]. Considering the significant mortality of the disease and modest overall survival improvements offered by current front-line systemic therapies, exploration of additional therapeutic options for use alone and in combination with existing therapies is warranted. Due to the role of AR activity in HCC, there have been several calls for AR therapeutics in HCC that address both AR / AR-SV protein levels and AR activity [8-10]. Niclosamide is an anthelmintic drug approved by the FDA in 1982 for the treatment of tapeworm infections and is included in the World Health Organization’s (WHO) essential medicines list

[0011] . Niclosamide’s activity against tapeworms is largely credited to its ability to uncouple oxidative phosphorylation. However, more recent studies investigating niclosamide’s mechanism of action have demonstrated its involvement in targeting a variety of oncogenic pathways [12-14]. For this reason, niclosamide has been investigated for a variety of alternative indications including Parkinson’s disease, diabetes, bacterial infections, viral infections, and cancer

[0011] . For one particular use case, AR-SV(+) HCC, niclosamide was highlighted in two drug screens for its ability both to reverse HCC gene expression patterns and for its ability to lower AR-V7 protein, a dominant prostate cancer AR-SV [15,16]. These activities, in addition to niclosamide’s activity against NF-κB, STAT3, KRAS, Myc, and mTOR among many other oncogenic pathways and its ability to both upregulate p53 and enhance PD-1 / PD-L1 blockade, position it well as an oncological multitool [17-28]. While niclosamide’s anti-cancer activities provide strong rationale for cancer Attorney Docket No.103361-522WO1 indications, its pitfalls as an oral therapeutic serve as the primary hurdle to utilizing niclosamide as a systemic therapy in the clinic. Niclosamide is poorly soluble and poorly orally bioavailable. In a prostate cancer clinical trial, niclosamide was tested due to its activity against AR-SVs, but failed to show therapeutic efficacy due to its inability to reach therapeutic plasma levels without dose limiting toxicities

[0029] . Various attempts to improve niclosamide’s bioavailability have been made including development of a more soluble niclosamide ethanolamine salt, a self-microemulsion of niclosamide, niclosamide-loaded nanoparticles, and various analogs of niclosamide [15,17,30-34]. SUMMARY The present disclosure provides compounds, compositions comprising said compounds, and methods of treating medical disorders using said compounds. In particular, the present disclosure provides valine analogs of niclosamide that provide improved oral bioavailability while avoiding dose-limiting toxicity. Use of these compounds in the treatment of medical disorders such as cancer, for example, in androgen receptor positive cancers, is also provided. In one aspect, method of treating cancer in a subject in need thereof is provided. In some aspects, the method can include administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or derivative thereof, wherein all variables are as defined herein. In some aspects, the compound can be selected from Attorney Docket No.103361-522WO1 or a pharmaceutically acceptable salt or derivative thereof. In some aspects, the subject can be a human. In some aspects, the cancer can be selected from prostate cancer, colon cancer, acute myeloid leukemia, or hepatocellular carcinoma. In some aspects, the cancer can be androgen receptor positive. In some aspects, the cancer can be androgen receptor positive hepatocellular carcinoma. In another aspect, a compound is provided selected from: or a pharmaceutically acceptable salt or derivative thereof. In another aspect, a pharmaceutical composition is provided. In some aspects, the pharmaceutical composition can include a compound described herein, or a pharmaceutically acceptable salt or derivative thereof, and a pharmaceutically acceptable carrier or excipient. Attorney Docket No.103361-522WO1 The details of one or more aspects of the disclosure are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the disclosure will be apparent from the description, the drawings, and the claims. DESCRIPTION OF DRAWINGS FIGs.1A-1E provides data regarding the importance and role of AR-SV signaling in LIHC primary samples and HCC cell lines as described in the examples. (FIG. 1A) AR-SV expression of patients in the LIHC TCGA cohort (n=372) broken down into four quartiles. Statistical significance was evaluated using the Mann-Whitney test. *, P<0.05 for Q1 vs Q4. (FIG. 1B) HCCLM3 and SNU475 cells were transfected with either a non-specific siRNA control or an siRNA targeting both AR-FL and AR-SVs. AR status of siAR transfected cells was confirmed by western blot with anti-AR-NT (CS#5153, Cell Signaling) and GAPDH (CS#5174, Cell Signaling). RNA sequencing revealed 8,479 differentially expressed genes in the HCCLM3 line and 8,152 differentially expressed genes in the SNU475 line with an intersection of 3,701 genes. (FIGs. 1C-1D) GSEA analyses HCCLM3 and SNU475 ranked gene lists featuring intersecting up and down regulated Hallmark gene sets. FDR<25% (FIG.1E) Highest ranking up and down regulated intersecting Hallmark gene sets from GSEA analyses on HCC cell lines. FIGs. 2A-2C depict and provide data regarding the characterization of CRISPR AR KO HCC cell lines as described in the examples. (FIG. 2A) AR-FL and AR-SV expressing HCCLM3 (left) and AR-SV expressing SNU475 (right) CRISPR AR KO clones were generated and validated by Western blot with a N-terminal AR (CS#5153, Cell Signaling) and GAPDH antibodies (CS#5174, Cell Signaling). (FIG. 2B) AR KO status was additionally validated by AR ELISA. (FIG.2C) Cellular invasion assay was performed on HCCLM3 (left) and SNU475 (right) AR KO clones. One way ANOVA with Dunnett’s multiple comparisons test. ns, P>0.05; *, P<0.05; **, P<0.01; ***, P<0.001; **** P<0.0001 versus wild type (FIGs.2B and 2C). FIGs.3A-3D depict and provide data regarding the biological activity of niclosamide analogs as described in the examples. (FIG.3A) Chemical structures of niclosamide analogs. Niclosamide is labeled with A and B rings to denote typical structural reference conventions. (FIG. 3B) Niclosamide activity against AR determined by dose-response AR ELISA in AR-FL expressing SNU423 (left) and AR-SV expressing Attorney Docket No.103361-522WO1 SNU475 (right) HCC cell lines. (FIG. 3C) Compound #7 activity against AR determined by dose-response AR ELISA in AR-FL expressing SNU423 (left) and AR- SV expressing SNU475 (right) HCC cell lines. (FIG. 3D) Compound #11 activity against AR determined by dose-response AR ELISA in AR-FL expressing SNU423 (left) and AR-SV expressing SNU475 (right) HCC cell lines. Curve fit and EC50 determined by three parameter nonlinear regression fit by least squares (FIGs. 3B- 3D). FIGs. 4A-4B provide data regarding the pharmacokinetic parameters and solubility of niclosamide analogs as described in the examples. (FIG. 4A) Single dose IV clearance (left) and single dose PO AUCall for niclosamide analogs. One way ANOVA with Šidák’s multiple comparisons test. *, P<0.05; ***, P<0.001. (FIG.4B) Solubility of niclosamide analogs in fasted state simulated intestinal fluid (FaSSIF). Solubility of niclosamide analogs in simulated gastric fluid (SGF) not shown as all were below the LLOQ. Lower limit of quantification (LLOQ) <1.56 µM. FIGs.5A-5C depict and provide data regarding the pharmacokinetic parameters and solubility of valine conjugated niclosamide analogs as described in the examples. (FIG. 5A) Chemical structures of valine conjugated niclosamide analogs. Valine- niclosamide is labeled with A and B rings to denote typical structural reference conventions. (FIG.5B) Single dose IV clearance (left) and single dose PO AUCall for niclosamide analogs and their respective valine conjugates. Niclosamide analogs given at 2 mg / kg IV or 40 mg / kg PO with molar equivalent doses for respective valine conjugates. One way ANOVA with Šidák’s multiple comparisons test. ns, P>0.05; *, P<0.05; ***, P<0.001; **** P<0.0001. (FIG. 5C) Solubility of valine conjugated niclosamide analogs in simulated gastric fluid (SGF) (left) and fasted state simulated intestinal fluid (FaSSIF) (right). Lower limit of quantification (LLOQ) <1.56 µM. FIGs. 6A-6B provide data regarding a hollow fiber assay as a model of HCC in vivo efficacy as described in the examples. (FIG. 6A) Hollow fibers were filled with SNU475 cells (3x106cells / mL). Three nude mice were implanted with two fibers each. Fibers were implanted subcutaneously on the left flank. After a two-week growth period, mice were treated with either vehicle or 25 mg / kg IP paclitaxel every other day for one week. Fibers were explanted and MTT assay was performed to determine cell viability. Unpaired t-test. **, P<0.01. (FIG. 6B) Hollow fibers were filled with SNU475 cells (3x106cells / mL). Three nude mice were implanted with Attorney Docket No.103361-522WO1 three fibers each. Fibers were implanted subcutaneously on the left flank. After a two- week growth period, mice were treated with either vehicle or niclosamide (75 mg / kg), valine-niclosamide (106.1 mg / kg, 75 mg / kg molar equivalent), valine-compound #7 (87.3 mg / kg, 75 mg / kg molar equivalent multiplied by a factor of 0.78 to exposure match to valine-niclosamide), or compound #7 (62.9 mg / kg, 87.3 mg / kg valine- compound #7 molar equivalent) twice daily for one week. Fibers were explanted and MTT assay was performed to determine cell viability. FIGs. 7A-7C depict and provide data regarding the conversion of valine-conjugated niclosamide analogs to parent drug as described in the examples. (FIG. 7A) Flow chart of pharmacokinetic modeling scheme integrating single IV and PO doses of both parent and valine-conjugated niclosamide. F1, bioavailability of valine conjugate; Ka1, first order absorption rate constant of valine conjugate; V1, volume of depot for valine conjugate; Q1, inter-compartmental clearance; V2, volume of central compartment of valine conjugate; CL, clearance of valine conjugate; Fm, fraction of conjugate metabolized; CLp, clearance of the parent compound; V3, volume of central compartment of valine conjugate; V4, volume of peripheral compartment of parent compound; Q2, inter-compartmental clearance; V5, volume of peripheral compartment of parent compound; F2, bioavailability of parent compound; Ka2, first order absorption rate constant of parent compound; V6, volume of depot for parent compound. (FIG. 7B) Calculated conversion rates and fraction converted of valine prodrug to parent forms. Methodology outlined in Methods. (FIG. 7C) Percent of valine conjugated niclosamide analogs remaining in human and murine plasma following 360 minutes compared to valacyclovir as a control. FIGs.8A-8B provide data regarding the biological activity of niclosamide on SNU475 cells. (FIG.8A) SNU475 cells were treated with 10 µM of each compound for 24 hours before analysis by AR ELISA. (FIG.8B) (Left) Cellular invasion assay was performed on SNU475 cells plated at 2x104cells / well treated with 1 and 10 µM niclosamide for 48 hrs. One way ANOVA with Dunnett’s multiple comparisons test. ****, P<0.0001 versus niclosamide treated cells. (Center) Representative fields of invasion membrane shown with invaded cells indicated by red arrows. (Right) Cell viability was performed under the same conditions as invasion assay, 2x104cells / well treated with either 1 and 10 µM niclosamide for 48 hours. Attorney Docket No.103361-522WO1 FIGs. 9A-9G provide data regarding the cytotoxicity dose response for niclosamide analogs and standard of care drugs as described in the examples. (FIG. 9A) Cytotoxicity dose response of niclosamide against HCC cell lines SNU423, SNU475, HepG2, normal immortalized liver THLE-2, and primary male hepatocytes. (FIG. 9B) Cytotoxicity dose response of compound #7. (FIG. 9C) Cytotoxicity dose response of compound #11 against HCC cell lines SNU423, SNU475, HepG2, normal immortalized liver THLE-2, and primary male hepatocytes. (FIG. 9D) Cytotoxicity dose response of enzalutamide, an antiandrogen drug, against HCC cell lines SNU423, SNU475, HepG2, normal immortalized liver THLE-2, and primary male hepatocytes. (FIG.9E) Cytotoxicity dose response of sorafenib, an HCC standard of care, against HCC cell lines SNU423, SNU475, HepG2, normal immortalized liver THLE-2, and primary male hepatocytes. (FIG. 9F) Cytotoxicity dose response of lenvatinib, an HCC standard of care, against HCC cell lines SNU423, SNU475, HepG2, normal immortalized liver THLE-2, and primary male hepatocytes. (FIG. 9G) Cytotoxicity dose response of regorafenib, an HCC standard of care, against HCC cell lines SNU423, SNU475, HepG2, normal immortalized liver THLE-2, and primary male hepatocytes. FIGs. 10A-10D provide data regarding concentration vs time curves and bioavailability of niclosamide analogs and valine-conjugates as described in the examples. (FIG.10A) Single dose PK of niclosamide at 2 mg / kg IV and 40 mg / kg PO and single dose PK of valine niclosamide at molar equivalent doses shown. (FIG.10B) Single dose PK of compound #7 at 2 mg / kg IV and 40 mg / kg PO and single dose PK of valine-compound #7 at molar equivalent doses shown. (FIG.10C) Single dose PK of compound #11 at 2 mg / kg IV and 40 mg / kg PO and single dose PK of valine- compound #11 at molar equivalent doses shown. (FIG. 10D) Bioavailability of all niclosamide analogs and valine conjugates was determined. One way ANOVA with Šidák’s multiple comparisons test. ns, P>0.05; **, P<0.01; ****, P<0.0001 versus respective parent compound. FIGs. 11A-11C provide data regarding the valine-niclosamide tolerance study as described in the examples. (FIG.11A) Terminal body weights of male C57BL / 6J mice following 2 weeks of daily oral administration of 14.1, 56.4, or 141.0 mg / kg doses of valine-niclosamide (molar equivalents of 10, 40, and 100 mg / kg niclosamide). (FIG. 11B) Liver enzyme panel comprised of alanine aminotransferase (ALT), aspartate Attorney Docket No.103361-522WO1 aminotransferase (AST), and albumin completed post-study. (FIG. 11C) Spleen weights as a percentage of body weight with the only significant difference being an increase at the highest dose level. One way ANOVA with Dunnett’s multiple comparisons test. *, P<0.05 versus vehicle. FIGs. 12A-12B provide concentration vs time curves of parent drug from oral doses of valine-conjugates as described in the examples. (FIG. 12A) Single dose PK of valine-niclosamide at 40 mg / kg PO molar equivalent with measured prodrug and parent (niclosamide) concentrations. (FIG.12B) Single dose PK of valine-compound #7 at 40 mg / kg PO molar equivalent with measured prodrug and parent (compound #7) concentrations. DETAILED DESCRIPTION The following description of the disclosure is provided as an enabling teaching of the disclosure in its best, currently known aspects. Many modifications and other aspects disclosed herein will come to mind to one skilled in the art to which the disclosed compositions and methods pertain, benefiting from the teachings presented in the descriptions herein and the associated drawings. Therefore, it is understood that the disclosures are not limited to the specific aspects disclosed and that modifications and other aspects are intended to be included within the scope of the appended claims. The skilled artisan will recognize many variants and adaptations of the aspects described herein. These variants and adaptations are intended to be included in the teachings of this disclosure and to be encompassed by the claims herein. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation. As apparent to those of skill in the art upon reading this disclosure, each of the individual aspects described and illustrated herein has discrete components and features that may be readily separated from or combined with the features of any of the other several aspects without departing from the scope or spirit of the present disclosure. Any recited method can be carried out in the order of events recited or any other order that is logically possible. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that Attorney Docket No.103361-522WO1 its steps be performed in a specific order. Accordingly, where a method claim does not explicitly state in the claims or descriptions that the steps are to be limited to a particular order, it is in no way intended that an order be inferred in any respect. This holds for any possible non-express basis for interpretation, including logic concerning arrangement of steps or operational flow, meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification. All publications mentioned herein are incorporated by reference to disclose and describe the methods or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure before the filing date of the present application. Further, the dates of publication provided herein can be different from the actual publication dates, which can require independent confirmation. It is also to be understood that the terminology herein describes particular aspects only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed compositions and methods belong. It can be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly defined herein. Before describing the various aspects of the present disclosure, the following definitions are provided and should be used unless otherwise indicated. Additional terms may be defined elsewhere in the present disclosure. Definitions As used herein, “comprising” is interpreted as specifying the presence of the stated features, integers, steps, or components but does not preclude the presence or addition of one or more features, integers, steps, components, or groups thereof. Moreover, each of the terms “by,” “comprising,” “comprises,” “comprised of,” “including,” “includes,” “included,” “involving,” “involves,” “involved,” and “such as” are used in their open, non-limiting sense and may be used interchangeably. Further, the term “comprising” is intended to include examples and aspects encompassed by Attorney Docket No.103361-522WO1 the terms “consisting essentially of” and “consisting of.” Similarly, “consisting essentially of” is intended to include examples encompassed by the term “consisting of.” As used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context dictates otherwise. Ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. Further, the endpoints of each of the ranges are significant both in relation to the other endpoint and independently of the other endpoint. There are many values disclosed herein, and each value is also 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. Ranges can be expressed herein as from “about” one particular value and to “about” another particular value. Similarly, when values are expressed as approximations, using the antecedent “about,” the particular value forms a further aspect. For example, if the value “about 10” is disclosed, then “10” is also disclosed. When a range is expressed, a further aspect includes from the one particular value and to the other particular value. For example, where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, e.g., the phrase “x to y” includes the range from ‘x’ to ‘y’ as well as the range greater than ‘x’ and less than ‘y’. The range can also be expressed as an upper limit, e.g. ‘about x, y, z, or less’ and should be interpreted to include the specific ranges of ‘about x,’ ‘about y,’ and ‘about z’ as well as the ranges of ‘less than x,’ ‘less than y.’ and ‘less than z.’ Likewise, the phrase ‘about x, y, z, or greater’ should be interpreted to include the specific ranges of ‘about x,’ ‘about y,’ and ‘about z’ as well as the ranges of ‘greater than x,’ greater than y,’ and ‘greater than z.’ In addition, the phrase “about ‘x’ to ‘y’,” where ‘x’ and ‘y’ are numerical values, includes “about ‘x’ to about ‘y’.” Such a range format is used for convenience and brevity and thus, should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range but also to include all the individual numerical values or sub- ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. To illustrate, a numerical range of “about 0.1% to 5%” should be Attorney Docket No.103361-522WO1 interpreted to include not only the explicitly recited values of about 0.1% to about 5%, but also include individual values (e.g., about 1%, about 2%, about 3%, and about 4%) and the sub-ranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible sub- ranges) within the indicated range. As used herein, the terms “about,” “approximate,” “at or about,” and “substantially” mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact but may be approximate, larger or smaller, as desired, reflecting tolerances, conversion factors, rounding, measurement error, and the like, and other factors known to those of skill in the art such that equivalent results or effects are obtained. In some circumstances, the value that provides equivalent results or effects cannot be reasonably determined. In such cases, as used herein, “about” and “at or about” mean the nominal value indicated ±10% variation unless otherwise indicated or inferred. In general, an amount, size, formulation, parameter, or other quantity or characteristic is “about,” “approximate,” or “at or about,” whether or not expressly stated to be such. Where “about,” “approximate,” or “at or about” is used before a quantitative value, the parameter also includes the specific quantitative value itself unless expressly stated otherwise. As used herein, the term “therapeutically effective amount” refers to an amount sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms but generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors, including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the particular compound employed and like factors within the knowledge and expertise of the health practitioner and which may be well known in the medical arts. In the case of treating a particular disease or condition, in some instances, the desired response can be inhibiting the progression of the disease or condition. This may involve only slowing Attorney Docket No.103361-522WO1 the progression of the disease temporarily. However, in other instances, it may be desirable to permanently halt the progression of the disease. This can be monitored by routine diagnostic methods known to one of ordinary skill in the art for any particular disease. The desired response to treatment of the disease or condition can also be delaying the onset or even preventing the onset. 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 increase the dosage gradually until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The individual physician can adjust the dosage in the event of any contraindications. It is generally preferred that a maximum dose of the pharmacological agents of the disclosure (alone or in combination with other therapeutic agents) be used, that is, the highest safe dose according to sound medical judgment. However, a patient may insist on a lower or tolerable dose for medical reasons, psychological reasons, or virtually any other reason. A response to a therapeutically effective dose of a disclosed compound or composition can be measured by determining the physiological effects of the treatment or medication, such as the decrease or lack of disease symptoms following the administration of the treatment or pharmacological agent. Other assays will be known to one of ordinary skill in the art and can be employed for measuring the level of the response. The amount of a treatment may be varied, for example, by increasing or decreasing the amount of a disclosed compound or pharmaceutical composition, changing the disclosed compound or pharmaceutical composition administered, changing the route of administration, changing the dosage timing, and so on. 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. As used herein, the term “prophylactically effective amount” refers to an amount effective for preventing the onset or initiation of a disease or condition. As used herein, “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by Attorney Docket No.103361-522WO1 advance action. Where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed. As used herein, “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur. The description includes instances where said event or circumstance occurs and those where it does not. As used interchangeably herein, “subject,” “individual,” or “patient” can refer to a vertebrate organism, such as a mammal (e.g., human). “Subject” can also refer to a cell, a population of cells, a tissue, an organ, or an organism, preferably to a human and constituents thereof. As used herein, “treating” and “treatment” generally refer to obtaining a desired pharmacological or physiological effect. The effect can be but does not necessarily have to be prophylactic in preventing or partially preventing a disease, symptom, or condition. The effect can be therapeutic regarding a partial or complete cure of a disease, condition, symptom, or adverse effect attributed to the disease, disorder, or condition. The term “treatment” as used herein can include any treatment of a disorder in a subject, particularly a human. It can include any one or more of the following: (a) preventing the disease from occurring in a subject who may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., mitigating or ameliorating the disease or its symptoms or conditions. The term “treatment,” as used herein, can refer to both therapeutic treatment alone, prophylactic treatment alone, or both therapeutic and prophylactic treatment. Those in need of treatment (i.e., subjects in need thereof) can include those already with the disorder or those in which the disorder is to be prevented. As used herein, the term “treating” can include inhibiting the disease, disorder, or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder, or condition. Treating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, e.g., such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain. Attorney Docket No.103361-522WO1 As used herein, “dose,” “unit dose,” or “dosage” can refer to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of a disclosed compound or a pharmaceutical composition thereof calculated to produce the desired response or responses in association with its administration. As used herein, “therapeutic” can refer to treating, healing, or ameliorating a disease, disorder, condition, or side effect or decreasing the rate of advancement of a disease, disorder, condition, or side effect. As used herein, the term or phrase “effective,” “effective amount,” or “conditions effective to” refers to such amount or condition that is capable of performing the function or property for which an effective amount or condition is expressed. As will be pointed out below, the exact amount or particular condition required will vary from one aspect to another, depending on recognized variables such as the materials employed and the processing conditions observed. Thus, it is not always possible to specify an exact “effective amount” or “condition effective to.” However, it should be understood that an appropriate effective amount will be readily determined by one of ordinary skill in the art using only routine experimentation. As used herein, the term "substantially" means that the subsequently described event or circumstance completely occurs or that the subsequently described event or circumstance generally, typically, or approximately occurs. Still further, the term “substantially” can, in some aspects, refer to at least about 90 %, at least about 91 %, at least about 92 %, at least about 93 %, at least about 94 %, at least about 95 %, at least about 96 %, at least about 97 %, at least about 98 %, at least about 99 %, or about 100 % of the stated property, component, composition, or other condition for which substantially is used to characterize or otherwise quantify an amount. As used herein, the term “substantially,” in, for example, the context “substantially identical” or “substantially similar,” refers to a method, a system, or a component that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% by similar to the method, system, or component it is compared to. Attorney Docket No.103361-522WO1 Chemical Definitions Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs. The compounds described herein include enantiomers, mixtures of enantiomers, diastereomers, tautomers, racemates, and other isomers, such as rotamers, as if each is specifically described unless otherwise indicated or otherwise excluded by context. It is to be understood that the compounds provided herein may contain chiral centers. Such chiral centers may be of either the (R) or (S) configuration. The compounds provided herein may either be enantiomerically pure or be diastereomeric or enantiomeric mixtures. It is to be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. As such, one of ordinary skill in the art will recognize that administering a compound in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to administering the compound in its (S) form. 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, diastereomer, and meso compound, and a mixture of isomers, such as a racemic or scalemic mixture. Compounds described herein may 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, all such possible isomers are contemplated, as well as mixtures of such isomers. Compounds described herein may also 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. Likewise, amides with an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form. Unless stated to the contrary, all possible tautomers of the compounds described herein are contemplated. A dash that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -(C=O)NH2is attached through the carbon of the keto (C=O) group. The term “substituted,” as used herein, means that any one or more hydrogens on the designated atom or group are replaced with a moiety selected from the indicated Attorney Docket No.103361-522WO1 group, provided that the designated atom’s normal valence is not exceeded and the resulting compound is stable. For example, when the substituent is oxo (i.e., =O), two hydrogens on the atom are replaced. For example, a pyridyl group substituted by oxo is a pyridine. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable active compound refers to a compound that can be isolated and / or can be formulated into a form with a shelf life of at least one month. A stable manufacturing intermediate or precursor to an active compound is stable if it does not degrade within the period needed for reaction or other use. A stable moiety or substituent group is one that does not degrade, react, or fall apart within the period necessary for use. Non-limiting examples of unstable moieties are those that combine heteroatoms in an unstable arrangement, as typically known and identifiable to those of skill in the art. Any suitable group may be present on a “substituted” or “optionally substituted” position that forms a stable molecule and meets the desired purpose of the disclosure and includes, but is not limited to: halo, nitro, cyano, azido, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C7 cycloalkyl)(C0-C3 alkyl)-, (3- to 8- membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, AxO-(C0-C6alkyl)-, AxS-(C0-C6alkyl)-, (AxAyN)-(C0-C6alkyl)-, AzC(O)-(C0-C6 alkyl)-, AzC(N)-(C0-C6 alkyl)-, and AzS(O)-(C0-C6 alkyl)-, and AzS(O)2-(C0-C6alkyl)-, wherein Axand Ayare independently selected at each occurrence from Aa, AzC(O)-, AzC(N)-, AzS(O)-, and AzS(O)2-, each of which may be optionally substituted with one or more B groups as allowed by valency; wherein Azis independently selected at each occurrence from hydrogen, halo, C1-C6alkyl, C1- C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7 cycloalkyl)-(C0-C3 alkyl)-, (4- to 6- membered heterocycle)-(C0-C3alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, -OAa, -SAa, and -NAaAb, each of which may be optionally substituted with one or more B groups as allowed by valency; wherein Aaand Abare independently selected at each occurrence from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7 cycloalkyl)-(C0-C3 alkyl)-, (4- to 6-membered heterocycle)-(C0- C3alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(C0-C3alkyl)-, (5- to 10- Attorney Docket No.103361-522WO1 membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, each of which may be optionally substituted by one or more B groups as allowed by valency; and wherein B is independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C7 cycloalkyl)(C0-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0- C6 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6 alkyl)-, (5- to 10- membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, ApO-, ApS-, ApAqN-, AoC(O)-, AoC(O)-O-, AoC(O)-NAq-, AoS(O)2-, AoS(O)2-O-, and AoS(O)2-NAq-, wherein Aois independently selected at each occurrence from Ap, halo, ApO-, and ApAqN-, and wherein Apand Aqare independently selected at each occurrence from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)(C0-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0- C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, and (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6 alkyl)-. The terms for various functional groups as used herein are not intended to be limited to monovalent radicals and may include polyvalent radical groups as appropriate, such as divalent, trivalent, tetravalent, pentavalent, and hexavalent groups, and the like, based on the position and location of such groups in the compounds described herein as would be readily understood by the skilled person in the context in which said functional groups are recited.As used herein, the symbol “ ” (which hereinafter can be referred to as “a pointof attachment bond”) denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which is not depicted as being attached to the point XY of attachment bond. For example, “ ” indicates that the chemical entity “XY” is bonded to another chemical entity via the point of attachment bond. Furthermore, the specific point of attachment to the non-depicted chemical entity can be specified nd CH3-R3XY by inference. For example, the compou , wherein R3is H or “ ” infers that when R3is “XY”, the point of attachment bond is the same bond as the bond by which R3is depicted as being bonded to CH3. “Halo” or “halogen” independently indicates any fluoro, chloro, bromo or iodo. Attorney Docket No.103361-522WO1 The term “nitro,” as used herein, is represented by the formula —NO2. The term “cyano,” as used herein, is represented by the formula —CN The term “azido,” as used herein, is represented by the formula –N3. The term “oxo,” as used herein, is represented by the formula =O. “Alkyl” is a straight chain or branched saturated aliphatic hydrocarbon group. In certain aspects, the alkyl is C1-C2, C1-C3, or C1-C6 (i.e., the alkyl chain can be 1, 2, 3, 4, 5, or 6 carbons in length). The specified ranges as used herein indicate an alkyl group with the length of each member of the range described as an independent species. For example, C1-C6alkyl, as used herein, indicates an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species, and C1-C4alkyl, as used herein, indicates an alkyl group having 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species. When C0-Cnalkyl is used herein in conjunction with another group, for example (C3-C7 cycloalkyl)C0-C4alkyl, or -C0-C4(C3-C7 cycloalkyl), the indicated group, in this case cycloalkyl, is either directly bound by a single covalent bond (C0alkyl), or attached by an alkyl chain, in this case 1, 2, 3, or 4 carbon atoms. Alkyls can also be attached via other groups such as heteroatoms, such as -O-C0- C4alkyl(C3-C7cycloalkyl). Examples of alkyl include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2- dimethylbutane, and 2,3-dimethylbutane. In some aspects, the alkyl group is optionally substituted as described herein. “Haloalkyl” refers to an alkyl group that is substituted with one or more halo groups, e.g., fluoro, chloro, bromo, iodo, or combinations thereof. “Cycloalkyl” is a saturated or partially unsaturated mono- or multicyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused or bridged fashion. Non-limiting examples of typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some aspects, the cycloalkyl group is optionally substituted as described herein. “Alkenyl” is a straight or branched chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds, each of which is independently either cis or trans, that may occur at a stable point along the chain. Non-limiting examples include C2- Attorney Docket No.103361-522WO1 C4alkenyl and C2-C6alkenyl (i.e., having 2, 3, 4, 5, or 6 carbons). The specified ranges as used herein indicate an alkenyl group, with each member of the range described as an independent species, as described above for the alkyl moiety. Examples of alkenyl include, but are not limited to, ethenyl and propenyl. In one aspect, the alkenyl group is optionally substituted as described herein. “Alkynyl” is a straight or branched chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that may occur at any stable point along the chain, for example, C2-C4alkynyl or C2-C6alkynyl (i.e., having 2, 3, 4, 5, or 6 carbons). The specified ranges as used herein indicate an alkynyl group, with each member of the range described as an independent species, as described above for the alkyl moiety. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2- butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2- hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl. In one aspect, the alkynyl group is optionally substituted as described herein. “Aryl” indicates an aromatic group containing only carbon in the aromatic ring or rings. In one aspect, the aryl group contains 1 to 3 separate or fused rings and is 6 to 14 or 18 ring atoms, without heteroatoms as ring members. When indicated, such aryl groups may be further substituted with carbon or non-carbon atoms or groups. Such substitution may include the fusion to a 4- to 7- or 5- to 7-membered saturated or partially unsaturated cyclic group that optionally contains 1, 2, or 3 heteroatoms independently selected from N, O, B, P, Si, and S, to form, for example, a 3,4- methylenedioxyphenyl group. Aryl groups include, for example, phenyl and naphthyl, including 1-naphthyl and 2-naphthyl. In one aspect, aryl groups are pendant. An example of a pendant ring is a phenyl group substituted with a phenyl group. In one aspect, the aryl group is optionally substituted as described herein. The term “heterocycle” refers to saturated and partially saturated heteroatom- containing ring radicals, where the heteroatoms may be selected from N, O, and S. The term heterocycle includes monocyclic 3-12 members rings, as well as bicyclic 5- 16 membered ring systems (which can include fused, bridged, or spiro bicyclic ring systems). It does not include rings containing -O-O-, -O-S-, and -S-S- portions. Examples of saturated heterocycle groups, including saturated 4- to 7-membered monocyclic groups containing 1 to 4 nitrogen atoms [e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, azetidinyl, piperazinyl, and pyrazolidinyl]; Attorney Docket No.103361-522WO1 saturated 4- to 6-membered monocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g., morpholinyl]; and saturated 3- to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocycle radicals include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocycle groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2- dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4- a]isoquinolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl, 2,3,- dihydro-1H-benzo[d]isothazol-6-yl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Bicyclic heterocycle includes groups wherein the heterocyclic radical is fused with an aryl radical, and the point of attachment is the heterocycle ring. Bicyclic heterocycle also includes heterocyclic radicals that are fused with a carbocyclic radical. Representative examples include but are not limited to, partially unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, for example, indoline and isoindoline, partially unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, partially unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, and saturated condensed heterocyclic groups containing 1 to 2 oxygen or sulfur atoms. In one aspect, the heterocycle group is optionally substituted as described herein. “Heteroaryl” refers to a stable monocyclic, bicyclic, or multicyclic aromatic ring that contains from 1 to 4, or in some aspects 1, 2, or 3 heteroatoms selected from N, O, S, B, and P (and typically selected from N, O, and S) with remaining ring atoms being carbon, or a stable bicyclic or tricyclic system containing at least one 5, 6, or 7 membered aromatic ring which contains from 1 to 4, or in some aspects from 1 to 3 or from 1 to 2, heteroatoms selected from N, O, S, B, or P, with remaining ring atoms being carbon. In one aspect, the only heteroatom is nitrogen. In one aspect, the only heteroatom is oxygen. In one aspect, the only heteroatom is sulfur. Monocyclic Attorney Docket No.103361-522WO1 heteroaryl groups typically have from 5 to 6 ring atoms. In some aspects, bicyclic heteroaryl groups are 8- to 10-membered heteroaryl groups, that is groups containing 8 or 10 ring atoms in which one 5-, 6-, or 7-membered aromatic ring which contains from 1 to 4 heteroatoms selected from N, O, S, B, or P is fused to a second aromatic or non-aromatic ring, wherein the point of attachment is an aromatic ring. When the total number of S and O atoms in the heteroaryl ring exceeds 1, these heteroatoms are not adjacent to one another within the ring. In one aspect, the total number of S and O atoms in the heteroaryl ring is not more than 2. In another aspect, the total number of S and O atoms in the heteroaryl ring is not more than 1. Examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, triazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. In one aspect, the heteroaryl group is optionally substituted as described herein. A “pharmaceutically acceptable salt” is a derivative of the disclosed compound in which the parent compound is modified by making inorganic and organic, pharmaceutically acceptable, acid or base addition salts thereof. The salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like) or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water, an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, where practicable. Salts of the present compounds further include solvates of the compounds and of the compound salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and Attorney Docket No.103361-522WO1 the like. The pharmaceutically acceptable salts include salts which are acceptable for human consumption and the quaternary ammonium salts of the parent compound formed, for example, from inorganic or organic salts. Example of such salts include, but are not limited to, those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2)1-4-COOH, and the like, or using a different acid that produced the same counterion. Suitable counterions found in pharmaceutically acceptable salts described herein include, but are not limited to, cations such as calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, meglumine, potassium, procaine, sodium, triethylamine, and zinc, and anions such as acetate, aspartate, benzenesulfonate, besylate, bicarbonate, bitartrate, bromide, camsylate, carbonate, chloride, citrate, decanoate, edetate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, sulfate, tartrate, teoclate, and tosylate. Lists of additional suitable salts may be found, e.g., in Remington’s Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, PA, p.1418 (1985). 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 compound. Exemplary derivatives include but are not limited to, salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound. Attorney Docket No.103361-522WO1 The present disclosure also includes compounds described herein with at least one desired isotopic substitution of an atom at an amount above the natural abundance of the isotope, i.e., enriched. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as2H,3H,11C,13C,15N,17O,18O,18F,31P, 32P,35S,36Cl, and125I, respectively. In one aspect, isotopically labeled compounds can be used in metabolic studies (with14C), reaction kinetic studies (with, for example,2H or3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug and substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an18F-labeled compound may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed herein by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. By way of general example and without limitation, isotopes of hydrogen, for example, deuterium (2H) and tritium (3H), may optionally be used anywhere in described structures that achieve the desired result. Alternatively, or in addition, isotopes of carbon, e.g., and14C, may be used. In one aspect, the isotopic substitution is replacing hydrogen with deuterium at one or more locations on the molecule to improve the performance of the molecule as a drug, for example, the pharmacodynamics, pharmacokinetics, biodistribution, half-life, stability, AUC, Tmax, Cmax, etc. For example, the deuterium can be bound to carbon in the allocation of bond breakage during metabolism (an alpha-deuterium kinetic isotope effect) or next to or near the site of bond breakage (a beta-deuterium kinetic isotope effect). Isotopic substitutions, for example deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium. In certain aspects, the isotope is 80, 85, 90, 95, or 99% or more enriched in an isotope at any location of interest. In some aspects, deuterium is 80, 85, 90, 95, or 99% enriched at a desired location. Unless otherwise stated, enrichment at any point is above natural abundance and, in an aspect, is enough to alter a detectable property of the compounds as a drug in a human. Attorney Docket No.103361-522WO1 The compounds of the present disclosure may form a solvate with solvents (including water). Therefore, in one aspect, the disclosure includes a solvated form of the active compound. The term “solvate” refers to a molecular complex of a compound of the present disclosure (including a salt thereof) with one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term “hydrate” refers to a molecular complex comprising a disclosed compound and water. Pharmaceutically acceptable solvates in accordance with the disclosure include those wherein the solvent of crystallization may be isotopically substituted, e.g., D2O, d6-acetone, or d6-DMSO. A solvate can be in a liquid or solid form. It is known that chemical substances may form solids present in different states of order term polymorphic forms or modifications. The different forms of a polymorphic substance can differ greatly in their physical properties. The compounds disclosed herein can be present in different polymorphic forms, with it possible for particular forms to be metastable. Unless stated to the contrary, the present disclosure includes all such polymorphic forms. 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 Sigma-Aldrich (formally MilliporeSigma, Burlington, MA) or Thermo Fisher Scientific Inc. (Waltham, MA), 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 (John Wiley and Sons, 2007); Organic Reactions (John Wiley and Sons, 2004); March's Advanced Organic Chemistry, (John Wiley and Sons, 8thEdition); and Larock's Comprehensive Organic Transformations (John Wiley and Sons, 3rdedition, 2017). Methods of Use The present disclosure also provides methods for treating or preventing cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound or composition disclosed herein. The methods can further comprise administering one or more additional therapeutic agents, for example, anticancer Attorney Docket No.103361-522WO1 agents or anti-inflammatory agents. Additionally, the method can further comprise administering a therapeutically effective amount of ionizing radiation to the subject. Methods of killing a cancer or tumor cell are also provided, comprising contacting the cancer or tumor cell with an effective amount of a compound or composition as described herein. The methods can further include administering one or more additional therapeutic agents or administering an effective amount of ionizing radiation. The disclosed methods can optionally include identifying a patient who is or can be in need of treatment of an oncological disorder. The patient can be a human or another mammal, such as a primate (monkey, chimpanzee, ape, etc.), dog, cat, cow, pig, or horse, or other animals having an oncological disorder. In some aspects, the subject can receive the therapeutic compositions prior to, during, or after surgical intervention to remove part or all of a tumor. The term “neoplasia” or “cancer” is used throughout this disclosure to refer to the pathological process that results in the formation and growth of a cancerous or malignant neoplasm, i.e., abnormal tissue (solid) or cells (non-solid) that grow by cellular proliferation, often more rapidly than normal and continues to grow after the stimuli that initiated the new growth cease. Malignant neoplasms show partial or complete lack of structural organization and functional coordination with the normal tissue, and most invade surrounding tissues, can metastasize to several sites, are likely to recur after attempted removal, and may cause the death of the patient unless adequately treated. As used herein, the term neoplasia is used to describe all cancerous disease states and embraces or encompasses the pathological process associated with malignant, hematogenous, ascitic, and solid tumors. The cancers which may be treated by the compounds and compositions disclosed herein may comprise carcinomas, sarcomas, lymphomas, leukemias, germ cell tumors, or blastomas. Carcinomas which may be treated by the compounds and compositions of the present disclosure include, but are not limited to, acinar carcinoma, acinous carcinoma, alveolar adenocarcinoma, carcinoma adenomatosum, adenocarcinoma, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellular, basaloid carcinoma, basosquamous cell carcinoma, breast Attorney Docket No.103361-522WO1 carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedocarcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epibulbar carcinoma, epidermoid carcinoma, carcinoma epitheliate adenoids, carcinoma exulcere, carcinoma fibrosum, gelatinform carcinoma, gelatinous carcinoma, giant cell carcinoma, gigantocellulare, glandular carcinoma, granulose cell carcinoma, hair matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma,hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher’s carcinoma, Kulchitzky‐cell carcinoma, lentivular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma mastotoids, carcinoma medullare, medullary carcinoma, carcinoma melanodes, melanotonic carcinoma, mucinous carcinoma, carcinoma muciparum, carcinoma mucocullare, mucoepidermoid carcinoma, mucous carcinoma, carcinoma myxomatodes, masopharyngeal carcinoma, carcinoma nigrum, oat cell carcinoma, carcinoma ossificans, osteroid carcinoma, ovarian carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prostate carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, scheinderian carcinoma, scirrhous carcinoma, carcinoma scrota, signet‐ring cell carcinoma, carcinoma simplex, small cell carcinoma, solandoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberrosum, tuberous carcinoma, verrucous carcinoma, and carcinoma vilosum. Representative sarcomas which may be treated by the compounds and compositions of the present disclosure include, but are not limited to, liposarcomas (including myxoid liposarcomas and pleomorphic liposarcomas), leiomyosarcomas, rhabdomyosarcomas, neurofibrosarcomas, malignant peripheral nerve sheath tumors, Ewing’s tumors (including Ewing’s sarcoma of bone, extraskeletal or non‐ bone) and primitive neuroectodermal tumors (PNET), synovial sarcoma, Attorney Docket No.103361-522WO1 hemangioendothelioma, fibrosarcoma, desmoids tumors, dermatofibrosarcoma protuberance (DFSP), malignant fibrous histiocytoma(MFH), hemangiopericytoma, malignant mesenchymoma, alveolar soft‐part sarcoma, epithelioid sarcoma, clear cell sarcoma, desmoplastic small cell tumor, gastrointestinal stromal tumor (GIST) and osteosarcoma (also known as osteogenic sarcoma) skeletal and extraskeletal, and chondrosarcoma. The compounds and compositions of the present disclosure may be used in the treatment of a lymphoma. Lymphomas which may be treated include mature B cell neoplasms, mature T cell and natural killer (NK) cell neoplasms, precursor lymphoid neoplasms, Hodgkin lymphomas, and immunodeficiency-associated lymphoproliferative disorders. Representative mature B cell neoplasms include, but are not limited to, B-cell chronic lymphocytic leukemia / small cell lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma (such as Waldenström macroglobulinemia), splenic marginal zone lymphoma, hairy cell leukemia, plasma cell neoplasms (such as plasma cell myeloma / multiple myeloma, plasmacytoma, monoclonal immunoglobulin deposition diseases, and heavy chain diseases), extranodal marginal zone B cell lymphoma (MALT lymphoma), nodal marginal zone B cell lymphoma, follicular lymphoma, primary cutaneous follicular center lymphoma, mantle cell lymphoma, diffuse large B cell lymphoma, diffuse large B-cell lymphoma associated with chronic inflammation, Epstein-Barr virus-positive DLBCL of the elderly, lyphomatoid granulomatosis, primary mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, ALK+ large B-cell lymphoma, plasmablastic lymphoma, primary effusion lymphoma, large B-cell lymphoma arising in HHV8-associated multicentric Castleman’s disease, and Burkitt lymphoma / leukemia. Representative mature T cell and NK cell neoplasms include, but are not limited to, T-cell prolymphocytic leukemia, T-cell large granular lymphocyte leukemia, aggressive NK cell leukemia, adult T-cell leukemia / lymphoma, extranodal NK / T-cell lymphoma, nasal type, enteropathy- associated T-cell lymphoma, hepatosplenic T-cell lymphoma, blastic NK cell lymphoma, lycosis fungoides / Sezary syndrome, primary cutaneous CD30-positive T cell lymphoproliferative disorders (such as primary cutaneous anaplastic large cell lymphoma and lymphomatoid papulosis), peripheral T-cell lymphoma not otherwise specified, angioimmunoblastic T cell lymphoma, and anaplastic large cell lymphoma. Attorney Docket No.103361-522WO1 Representative precursor lymphoid neoplasms include B-lymphoblastic leukemia / lymphoma not otherwise specified, B-lymphoblastic leukemia / lymphoma with recurrent genetic abnormalities, or T-lymphoblastic leukemia / lymphoma. Representative Hodgkin lymphomas include classical Hodgkin lymphomas, mixed cellularity Hodgkin lymphoma, lymphocyte-rich Hodgkin lymphoma, and nodular lymphocyte-predominant Hodgkin lymphoma. The compounds and compositions of the present disclosure may be used in the treatment of a leukemia. Representative examples of leukemias include but are not limited to, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), hairy cell leukemia (HCL), T-cell prolymphocytic leukemia, adult T-cell leukemia, clonal eosinophilias, and transient myeloproliferative disease. The compounds and compositions of the present disclosure may be used in the treatment of a germ cell tumor, for example, germinomatous (such as germinoma, dysgerminoma, and seminoma), nongerminomatous (such as embryonal carcinoma, endodermal sinus tumor, choriocarcinoma, teratoma, polyembryoma, and gonadoblastoma) and mixed tumors. The compounds and compositions of the present disclosure may be used in the treatment of blastomas, for example, hepatoblastoma, medulloblastoma, nephroblastoma, neuroblastoma, pancreatoblastoma, pleuropulmonary blastoma, retinoblastoma, and glioblastoma multiforme. Representative cancers which may be treated include, but are not limited to: bone and muscle sarcomas such as chondrosarcoma, Ewing’s sarcoma, malignant fibrous histiocytoma of bone / osteosarcoma, osteosarcoma, rhabdomyosarcoma, and heart cancer; brain and nervous system cancers such as astrocytoma, brainstem glioma, pilocytic astrocytoma, ependymoma, primitive neuroectodermal tumor, cerebellar astrocytoma, cerebral astrocytoma, glioma, medulloblastoma, neuroblastoma, oligodendroglioma, pineal astrocytoma, pituitary adenoma, and visual pathway and hypothalamic glioma; breast cancers including invasive lobular carcinoma, tubular carcinoma, invasive cribriform carcinoma, medullary carcinoma, male breast cancer, Phyllodes tumor, and inflammatory breast cancer; endocrine system cancers such as adrenocortical carcinoma, islet cell carcinoma, multiple endocrine neoplasia Attorney Docket No.103361-522WO1 syndrome, parathyroid cancer, phemochromocytoma, thyroid cancer, and Merkel cell carcinoma; eye cancers including uveal melanoma and retinoblastoma; gastrointestinal cancers such as anal cancer, appendix cancer, cholangiocarcinoma, gastrointestinal carcinoid tumors, colon cancer, extrahepatic bile duct cancer, gallbladder cancer, gastric cancer, gastrointestinal stromal tumor, hepatocellular cancer, pancreatic cancer, and rectal cancer; genitourinary and gynecologic cancers such as bladder cancer, cervical cancer, endometrial cancer, extragonadal germ cell tumor, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, penile cancer, renal cell carcinoma, renal pelvis and ureter transitional cell cancer, prostate cancer, testicular cancer, gestational trophoblastic tumor, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms tumor; head and neck cancers such as esophageal cancer, head and neck cancer, nasopharyngeal carcinoma, oral cancer, oropharyngeal cancer, paranasal sinus and nasal cavity cancer, pharyngeal cancer, salivary gland cancer, and hypopharyngeal cancer; hematopoietic cancers such as acute biphenotypic leukemia, acute eosinophilic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, acute myeloid dendritic cell leukemia, AIDS-related lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt’s lymphoma, chronic lymphocytic leukemia, chronic myelogenous leukemia, cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, hepatosplenic T-cell lymphoma, Hodgkin’s lymphoma, hairy cell leukemia, intravascular large B-cell lymphoma, large granular lymphocytic leukemia, lymphoplasmacytic lymphoma, lymphomatoid granulomatosis, mantle cell lymphoma, marginal zone B-cell lymphoma, Mast cell leukemia, mediastinal large B cell lymphoma, multiple myeloma / plasma cell neoplasm, myelodysplastic syndroms, mucosa-associated lymphoid tissue lymphoma, mycosis fungoides, nodal marginal zone B cell lymphoma, non-Hodgkin lymphoma, precursor B lymphoblastic leukemia, primary central nervous system lymphoma, primary cutaneous follicular lymphoma, primary cutaneous immunocytoma, primary effusion lymphoma, plasmablastic lymphoma, Sezary syndrome, splenic marginal zone lymphoma, and T-cell prolymphocytic leukemia; skin cancers such as basal cell carcinoma, squamous cell carcinoma, skin adnexal tumors (such as sebaceous carcinoma), melanoma, Merkel cell carcinoma, sarcomas of primary cutaneous origin (such as dermatofibrosarcoma protuberans), and lymphomas of primary cutaneous origin Attorney Docket No.103361-522WO1 (such as mycosis fungoides); thoracic and respiratory cancers such as bronchial adenomas / carcinoids, small cell lung cancer, mesothelioma, non-small cell lung cancer, pleuropulmonary blastoma, laryngeal cancer, and thymoma or thymic carcinoma; HIV / AIDs-related cancers such as Kaposi sarcoma; epithelioid hemangioendothelioma; desmoplastic small round cell tumor; and liposarcoma. In particular aspects, the cancer is selected from prostate cancer, colon cancer, acute myeloid leukemia, or hepatocellular carcinoma. In some aspects, the cancer to be treated is an androgen receptor-associated cancer. Thus, a method of treating androgen receptor-associated cancer in a subject in need thereof is also provided, the method comprising administering to the subject a therapeutically effective amount of a compound or composition described herein. As used herein, an “androgen receptor-associated cancer” refers to a cancer having a dysregulation of the androgen receptor via an associated gene, an associated protein, or expression or activity or level of the same. Representative examples of dysregulation of the androgen receptor include, but are not limited to: overexpression of the wildtype androgen receptor or overexpression or underexpression of an associated protein, including any proteins downstream or upstream of the androgen receptor in an associated signaling or regulatory pathway; and insertions, deletions, or other mutations (such as expression of a fusion protein) in the androgen receptor or other associated protein, including any proteins downstream or upstream of the androgen receptor in an associated signaling or regulatory pathway. In some aspects, an assay can be used to determine whether the subject has dysregulation of the androgen receptor via an associated gene, an associated protein, or expression or activity, or level of the same, using a sample (e.g., a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from a subject. Representative examples of such assays can include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR). As is well-known in the art, the assays are typically performed, e.g., with at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof. Assays can utilize other Attorney Docket No.103361-522WO1 detection methods known in the art for detecting dysregulation of the androgen receptor. In particular aspects, the cancer is androgen receptor-positive. In particular aspects, the cancer is androgen receptor-positive hepatocellular carcinoma. Compounds and compositions disclosed herein can be locally administered at one or more anatomical sites, such as sites of unwanted cell growth (such as a tumor site or benign skin growth, e.g., injected or topically applied to the tumor or skin growth), optionally in combination with a pharmaceutically acceptable carrier such as an inert diluent. Compounds and compositions disclosed herein can also be systemically administered, such as intravenously or orally, optionally in combination with a pharmaceutically acceptable carrier, such as an inert diluent or an assimilable edible carrier for oral delivery. In addition, the active compound can be incorporated into sustained-release preparations and / or devices. For the treatment of an oncological disorder, compounds, agents, and compositions disclosed herein can be administered to a patient in need of treatment prior to, subsequent to, or in combination with other antitumor or anticancer agents or substances (e.g., chemotherapeutic agents, immunotherapeutic agents, radiotherapeutic agents, cytotoxic agents, etc.) and / or with radiation therapy and / or with surgical treatment to remove a tumor. For example, compounds, agents, and compositions disclosed herein can be used in methods of treating cancer wherein the patient is to be treated or is or has been treated with mitotic inhibitors such as taxol or vinblastine, alkylating agents such as cyclophosphamide or ifosfamide, antimetabolites such as 5-fluorouracil or hydroxyurea, DNA intercalators such as adriamycin or bleomycin, topoisomerase inhibitors such as etoposide or camptothecin, antiangiogenic agents such as angiostatin, antiestrogens such as tamoxifen, and / or other anticancer drugs or antibodies, such as, for example, imatinid or trastuzumab. These other substances or radiation treatments can be given at the same time as or at different times from the compounds disclosed herein. Examples of other suitable chemotherapeutic agents include but are not limited to, altretamine, bleomycin, bortezomib, busulphan, calcium folinate, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, crisantaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, docetaxel, doxorubicin, epirubicin, etoposide, fludarabine, fluorouracil, gefitinib, gemcitabine, Attorney Docket No.103361-522WO1 hydroxyurea, idarubicin, ifosfamide, imatinib, irinotecan, liposomal doxorubicin, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitoxantrone, oxaliplatin, paclitaxel, pentostatin, procarbazine, raltitrexed, streptozocin, tegafur- uraxil, temozolomide, thiotepa, tioguanine / thioguanine, topotexan, treosulfan, vinblastine, vincristine, vindesine, and vinorelbine. Examples of suitable immunotherapeutic agents include but are not limited to, alemtuzumab, cetuximab, gemtuzumab, iodine 131 tositumomab, rituximab, and trastuzumab. Cytotoxic agents include, for example, radioactive isotopes and toxins of bacterial, fungal, plant, or animal origin. Also disclosed are methods of treating an oncological disorder comprising administering an effective amount of a compound described herein prior to, subsequent to, and / or in combination with administration of a chemotherapeutic agent, an immunotherapeutic agent, a radiotherapeutic agent, or radiotherapy. The active ingredient may be administered in such amounts, time, and route deemed necessary in order to achieve the desired result. The exact amount of the active ingredient will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the medical disorder, the particular active ingredient, its mode of administration, its mode of activity, and the like. The active ingredient, whether the active compound itself or the active compound in combination with an agent, is preferably formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the active ingredient will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend upon a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the active ingredient employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts. The active ingredient may be administered by any route. In some aspects, the active ingredient is administered via a variety of routes, including oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, Attorney Docket No.103361-522WO1 topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, bucal, enteral, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. In general, the most appropriate route of administration will depend upon a variety of factors, including the nature of the active ingredient (e.g., its stability in the environment of the gastrointestinal tract), the condition of the subject (e.g., whether the subject is able to tolerate oral administration), etc. The exact amount of an active ingredient required to achieve a therapeutically or prophylactically effective amount will vary from subject to subject, depending on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound(s), mode of administration, and the like. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult. Useful dosages of the active agents and pharmaceutical compositions disclosed herein can be determined by comparing their in vitro activity and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans, are known to the art. The dosage ranges for the administration of the compositions are those large enough to produce the desired effect in which the symptoms or disorder are affected. The dosage should not be so large as to cause adverse side effects, such as unwanted cross- reactions, anaphylactic reactions, and the like. Generally, the dosage will vary with the age, condition, sex, and extent of the disease in the patient and can be determined by one of skill in the art. The dosage can be adjusted by the individual physician in the event of any counterindications. Dosage can vary and can be administered in one or more dose administrations daily for one or several days. Compounds In some aspects, a compound as used in the methods described herein is of Formula I: Attorney Docket No.103361-522WO1 or a pharmaceutically acceptable salt or derivative thereof, wherein all variables are as defined further herein. In some aspects of Formula In some aspects of Formula I, m can be an integer from 0 to 4. In some aspects of Formula I, m is 0. In some aspects of Formula I, m is 1. In some aspects of Formula I, m is 2. In some aspects of Formula I, m is 3. In some aspects of Formula I, m is 4. Attorney Docket No.103361-522WO1 In some aspects of Formula I, n can be an integer from 0 to 5. In some aspects of Formula I, n is 0. In some aspects of Formula I, n is 1. In some aspects of Formula I, n is 2. In some aspects of Formula I, n is 3. In some aspects of Formula I, n is 4. In some aspects of Formula I, n is 5. , In some aspects of Formula I, R1can be independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6 alkynyl, (C3-C7 cycloalkyl)(C0-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)- Attorney Docket No.103361-522WO1 (C0-C6 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6 alkyl)-, RpO-, RpS-, RpRqN-, RoC(O)-, RoC(O)-O-, RoC(O)-NRq-, RoS(O)2-, RoS(O)2-O-, and RoS(O)2-NRq-. In some occurrences, R1can be hydrogen, In some occurrences, R1can be selected from fluoro, chloro, bromo, and iodo. In some occurrences, R1can be nitro. In some occurrences, R1can be cyano. In some occurrences, R1can be azido. In some occurrences, R1can be selected from methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane. In some occurrences, R1can be selected from trifluoromethyl, trifluoroethyl, and hexafluoroisopropyl. In some occurrences, R1can be selected from ethenyl and propenyl. In some occurrences, R1can be ethynyl, propynyl, and propargyl. In some occurrences, R1can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some occurrences, R1can be selected from pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, azetidinyl, piperazinyl, pyrazolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, indolinyl, and isoindolinyl. In some occurrences, R1can be selected from phenyl, 1-naphthyl, and 2-naphthyl. In some occurrences, R1can be selected from pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Attorney Docket No.103361-522WO1 In some occurrences, R1can be RpO-, wherein Rpis selected from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. In some occurrences, R1can be RpS-, wherein Rpis selected from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. In some occurrences, R1can be RpRqN-, wherein Rpand Rqare independently selected from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. In some occurrences, R1can be RoC(O)-, wherein Rois selected from hydrogen, chloro, bromo, -OH, -NH2, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. In some occurrences, R1can be RoC(O)-O-, wherein Rois selected from hydrogen, chloro, bromo, -OH, -NH2, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. In some occurrences, R1can be RoC(O)-NRq-, wherein Rois selected from hydrogen, chloro, bromo, -OH, -NH2, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl, and wherein Rqis selected from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. In some occurrences, R1can be RoS(O)2-, wherein Rois selected from hydrogen, chloro, bromo, -OH, -NH2, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. In some occurrences, R1can be RoS(O)2-O-, wherein Rois selected from hydrogen, chloro, bromo, -OH, -NH2, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. In some occurrences, R1can be RoS(O)2-NRq-, wherein Rois selected from hydrogen, chloro, bromo, -OH, -NH2, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl, and wherein Rqis selected from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. Attorney Docket No.103361-522WO1 In some aspects of Formula I, R1can be independently selected at each occurrence from hydrogen, halo, nitro, cyano, C1-C6alkyl, C1-C6haloalkyl, and RpO-. In some aspects of Formula I, R1can be independently selected at each occurrence from hydrogen, fluoro, chloro, bromo, iodo, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, trifluoroethyl, hexafluoroisopropyl, and RpO-, wherein Rpis selected from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. In some aspects of Formula I, R1can be independently selected at each occurrence from hydrogen, halo, nitro, and C1-C6haloalkyl. In some aspects of Formula I, R1can be independently selected at each occurrence from hydrogen, fluoro, chloro, bromo, iodo, nitro, trifluoromethyl, trifluoroethyl, and hexafluoroisopropyl. In some aspects of Formula can In some aspects of Formula I, R2can be independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)- (C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RpO-, RpS-, RpRqN-, RoC(O)-, RoC(O)-O-, RoC(O)-NRq-, RoS(O)2-, RoS(O)2-O-, and RoS(O)2-NRq-. In some occurrences, R2can be hydrogen, In some occurrences, R2can be selected from fluoro, chloro, bromo, and iodo. In some occurrences, R2can be nitro. In some occurrences, R2can be cyano. In some occurrences, R2can be azido. In some occurrences, R2can be selected from methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane. Attorney Docket No.103361-522WO1 In some occurrences, R2can be selected from trifluoromethyl, trifluoroethyl, and hexafluoroisopropyl. In some occurrences, R2can be selected from ethenyl and propenyl. In some occurrences, R2can be ethynyl, propynyl, and propargyl. In some occurrences, R2can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some occurrences, R2can be selected from pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, azetidinyl, piperazinyl, pyrazolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, indolinyl, and isoindolinyl. In some occurrences, R2can be selected from phenyl, 1-naphthyl, and 2-naphthyl. In some occurrences, R2can be selected from pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. In some occurrences, R2can be RpO-, wherein Rpis selected from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. In some occurrences, R2can be RpS-, wherein Rpis selected from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. In some occurrences, R2can be RpRqN-, wherein Rpand Rqare independently selected from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. In some occurrences, R2can be RoC(O)-, wherein Rois selected from hydrogen, chloro, bromo, -OH, -NH2, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. Attorney Docket No.103361-522WO1 In some occurrences, R2can be RoC(O)-O-, wherein Rois selected from hydrogen, chloro, bromo, -OH, -NH2, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. In some occurrences, R2can be RoC(O)-NRq-, wherein Rois selected from hydrogen, chloro, bromo, -OH, -NH2, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl, and wherein Rqis selected from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. In some occurrences, R2can be RoS(O)2-, wherein Rois selected from hydrogen, chloro, bromo, -OH, -NH2, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. In some occurrences, R2can be RoS(O)2-O-, wherein Rois selected from hydrogen, chloro, bromo, -OH, -NH2, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. In some occurrences, R2can be RoS(O)2-NRq-, wherein Rois selected from hydrogen, chloro, bromo, -OH, -NH2, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl, and wherein Rqis selected from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. In some aspects of Formula I, R2can be independently selected at each occurrence from hydrogen, halo, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, and RpO-. In some aspects of Formula I, R2can be independently selected at each occurrence from hydrogen, fluoro, chloro, bromo, iodo, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, trifluoroethyl, hexafluoroisopropyl, and RpO-, wherein Rpis selected from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. In some aspects of Formula I, R2can be independently selected at each occurrence from hydrogen, halo, nitro, and C1-C6 haloalkyl. In some aspects of Formula I, R2can be independently selected at each occurrence from hydrogen, fluoro, chloro, bromo, iodo, nitro, trifluoromethyl, trifluoroethyl, and hexafluoroisopropyl. Attorney Docket No.103361-522WO1 In some aspects of R1or R2, Rocan be independently selected at each occurrence from Rp, halo, RpO-, and RpRqN-. In some aspects of R1, R2, or Ro, Rpand Rqcan be independently selected at each occurrence from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7 cycloalkyl)(C0-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, and (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-. In some aspects, the compound of Formula I is selected from: or a pharmaceutically acceptable salt or derivative thereof. In one aspect, a compound is provided selected from: Attorney Docket No.103361-522WO1 or a pharmaceutically acceptable salt or derivative thereof. Pharmaceutical Compositions The compounds as described herein can be administered by any suitable method and technique presently or prospectively known to those skilled in the art. For example, the active components described herein can be formulated in a physiologically- or pharmaceutically-acceptable form and administered by any suitable route known in the art, including, for example, oral and parenteral routes of administering. As used herein, the term “parenteral” includes subcutaneous, intradermal, intravenous, intramuscular, intraperitoneal, and intrasternal administration, such as by injection. Administration of the active components of their compositions can be a single administration or at continuous and distinct intervals as can be readily determined by a person skilled in the art. Compositions, as described herein, comprising an active compound and a pharmaceutically acceptable carrier or excipient of some sort, may be useful in a variety of medical and non-medical applications. “Pharmaceutically acceptable carrier” (sometimes referred to as a “carrier”) means a carrier or excipient that is useful in preparing a pharmaceutical or therapeutic composition that is generally safe and nontoxic and includes a carrier that is acceptable for veterinary and / or human pharmaceutical or therapeutic use. The terms “carrier” or “pharmaceutically acceptable carrier” can include, but are not limited to, phosphate-buffered saline solution, water, emulsions (such as an oil / water or water / oil emulsion) and / or various types of wetting agents. As used herein, the term “carrier” encompasses, but is not limited to, any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, stabilizer, or other material well-known in the art for use in pharmaceutical formulations and as described further herein. Attorney Docket No.103361-522WO1 “Excipients” include any and all solvents, diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like, as suited to the particular dosage form desired. General considerations in formulation and / or manufacture can be found, for example, in Remington’s Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005). Exemplary excipients include but are not limited to, any nontoxic, inert solid, semisolid, or liquid filler, diluent, encapsulating material, or formulation auxiliary of any type. Some examples of materials which can serve as excipients include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; detergents such as Tween 80; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; and phosphate buffer solutions, as well as other nontoxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. As would be appreciated by one of skill in this art, the excipients may be chosen based on what the composition is useful for. For example, with a pharmaceutical composition or cosmetic composition, the choice of the excipient will depend on the route of administration, the agent being delivered, time course of delivery of the agent, etc., and can be administered to humans and / or to animals, orally, rectally, parenterally, intracisternally, intravaginally, intranasally, intraperitoneally, topically (as by powders, creams, ointments, or drops), buccally, or as an oral or nasal spray. In some aspects, the active compounds disclosed herein are administered topically. Attorney Docket No.103361-522WO1 Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, etc., and combinations thereof. Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl- pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross- linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, etc., and combinations thereof. Exemplary surface active agents and / or emulsifiers include natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxy vinyl polymer), carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylene sorbitan monolaurate [Tween 20], polyoxyethylene sorbitan [Tween 60], polyoxyethylene sorbitan monooleate [Tween 80], sorbitan monopalmitate [Span 40], sorbitan monostearate [Span 60], sorbitan tristearate [Span 65], glyceryl monooleate, sorbitan monooleate [Span 80]), polyoxyethylene esters (e.g. polyoxyethylene monostearate [Myrj 45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, Attorney Docket No.103361-522WO1 polyethylene glycol fatty acid esters (e.g. Cremophor), polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether [Brij 30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and / or combinations thereof. Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, etc., and / or combinations thereof. Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives. Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite. Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal. Attorney Docket No.103361-522WO1 Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid. Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol. Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta- carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid. Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl. In certain aspect, the preservative is an antioxidant. In others, the preservative is a chelating agent. Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen- free water, isotonic saline, Ringer’s solution, ethyl alcohol, etc., and combinations thereof. Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, etc., and combinations thereof. Attorney Docket No.103361-522WO1 Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, chamomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof. Additionally, the composition may further comprise a polymer. Exemplary polymers contemplated herein include, but are not limited to, cellulosic polymers and copolymers, for example, cellulose ethers such as methylcellulose (MC), hydroxyethylcellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), methylhydroxyethylcellulose (MHEC), methylhydroxypropylcellulose (MHPC), carboxymethyl cellulose (CMC) and its various salts, including, e.g., the sodium salt, hydroxyethylcarboxymethylcellulose (HECMC) and its various salts, carboxymethylhydroxyethylcellulose (CMHEC) and its various salts, other polysaccharides and polysaccharide derivatives such as starch, dextran, dextran derivatives, chitosan, and alginic acid and its various salts, carageenan, varoius gums, including xanthan gum, guar gum, gum arabic, gum karaya, gum ghatti, konjac and gum tragacanth, glycosaminoglycans and proteoglycans such as hyaluronic acid and its salts, proteins such as gelatin, collagen, albumin, and fibrin, other polymers, for example, polyhydroxyacids such as polylactide, polyglycolide, polyl(lactide-co-glycolide) and poly(.epsilon.- caprolactone-co-glycolide)-, carboxyvinyl polymers and their salts (e.g., carbomer), polyvinylpyrrolidone (PVP), polyacrylic acid and its salts, polyacrylamide, polyacrylic acid / acrylamide copolymer, polyalkylene oxides such as polyethylene oxide, polypropylene oxide, poly(ethylene oxide- propylene oxide), and a Pluronic polymer, polyoxy ethylene (polyethylene glycol), polyanhydrides, polyvinylalchol, Attorney Docket No.103361-522WO1 polyethyleneamine and polypyrridine, polyethylene glycol (PEG) polymers, such as PEGylated lipids (e.g., PEG-stearate, l,2-Distearoyl-sn-glycero-3- Phosphoethanolamine-N-[Methoxy(Polyethylene glycol)-1000], 1,2-Distearoyl-sn- glycero-3-Phosphoethanolamine-N-[Methoxy(Polyethylene glycol)-2000], and 1,2- Distearoyl-sn-glycero-3-Phosphoethanolamine-N-[Methoxy(Polyethylene glycol)- 5000]), copolymers and salts thereof. Additionally, the composition may further comprise an emulsifying agent. Exemplary emulsifying agents include, but are not limited to, a polyethylene glycol (PEG), a polypropylene glycol, a polyvinyl alcohol, a poly-N-vinyl pyrrolidone and copolymers thereof, poloxamer nonionic surfactants, neutral water-soluble polysaccharides (e.g., dextran, Ficoll, celluloses), non-cationic poly(meth)acrylates, non-cationic polyacrylates, such as poly (meth) acrylic acid, and esters amide and hydroxy alkyl amides thereof, natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxy vinyl polymer), carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylene sorbitan monolaurate [Tween 20], polyoxyethylene sorbitan [Tween 60], polyoxyethylene sorbitan monooleate [Tween 80], sorbitan monopalmitate [Span 40], sorbitan monostearate [Span 60], sorbitan tristearate [Span 65], glyceryl monooleate, sorbitan monooleate [Span 80]), polyoxyethylene esters (e.g. polyoxyethylene monostearate [Myrj 45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g. Cremophor), polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether [Brij 30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68, Attorney Docket No.103361-522WO1 Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and / or combinations thereof. In certain aspects, the emulsifying agent is cholesterol. Liquid compositions include emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid composition may contain inert diluents commonly used in the art, such as for example, water or other solvents, solubilizing agents, and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Injectable compositions, for example, injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be an injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents for pharmaceutical or cosmetic compositions that may be employed are water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any bland fixed oil can be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. In certain aspects, the particles are suspended in a carrier fluid comprising 1% (w / v) sodium carboxymethyl cellulose and 0.1% (v / v) Tween 80. The injectable composition can be sterilized, for example, by filtration through a bacteria- 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 medium prior to use. Compositions for rectal or vaginal administration may be in the form of suppositories which can be prepared by mixing the particles with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are Attorney Docket No.103361-522WO1 solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the particles. Solid compositions include capsules, tablets, pills, powders, and granules. In such solid compositions, the particles are mixed with at least one excipient and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar- agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. Tablets, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. Compositions for topical or transdermal administration include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active compound is admixed with an excipient and any needed preservatives or buffers as may be required. The ointments, pastes, creams, and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffins, Attorney Docket No.103361-522WO1 starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, and zinc oxide, or mixtures thereof. Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons. Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the nanoparticles in a proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate-controlling membrane or by dispersing the particles in a polymer matrix or gel. Additional Aspects In view of the described compounds, compositions, and methods, certain more particular aspects of the disclosure are described below. These particularly recited aspects should not, however, be interpreted to have any limiting effect on any different claims containing different or more general teachings described herein, or that the “particular” aspects are somehow limited in some way other than the inherent meanings of the language and formulae literally used therein. Aspect 1. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or derivative thereof, wherein: m is an integer from 0 to 4; Attorney Docket No.103361-522WO1 n is an integer from 0 to 5; R1is independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C7 cycloalkyl)(C0- C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6 alkyl)-, RpO-, RpS-, RpRqN-, RoC(O)-, RoC(O)-O-, RoC(O)-NRq-, RoS(O)2-, RoS(O)2-O-, and RoS(O)2-NRq-; R2is independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)(C0- C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6 alkyl)-, RpO-, RpS-, RpRqN-, RoC(O)-, RoC(O)-O-, RoC(O)-NRq-, RoS(O)2-, RoS(O)2-O-, and RoS(O)2-NRq-; Rois independently selected at each occurrence from Rp, halo, RpO-, and RpRqN-; and Rpand Rqare independently selected at each occurrence from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C7 cycloalkyl)(C0-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, and (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6 alkyl)-. Aspect 2. The method of aspect 1, wherein Aspect 3. The method of aspect 1 or aspect 2, wherein m is 1. Aspect 4. The method of any one of aspects 1-3, wherein Attorney Docket No.103361-522WO1 Aspect 5. The method of any one of aspects 1-4, wherein R1is independently selected at each occurrence from hydrogen, halo, nitro, cyano, C1-C6alkyl, C1-C6haloalkyl, and RpO-. Aspect 6. The method of any one of aspects 1-4, wherein R1is independently selected at each occurrence from hydrogen, fluoro, chloro, bromo, iodo, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, trifluoroethyl, hexafluoroisopropyl, and RpO-, wherein Rpis selected from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. Aspect 7. The method of any one of aspects 1-4, wherein R1is independently selected at each occurrence from hydrogen, halo, nitro, and C1-C6haloalkyl. Aspect 8. The method of any one of aspects 1-4, wherein R1is independently selected at each occurrence from hydrogen, fluoro, chloro, bromo, iodo, nitro, trifluoromethyl, trifluoroethyl, and hexafluoroisopropyl. Aspect 9. The method of any one of aspects 1-8, wherein Aspect 10. The method of any one of aspects 1-9, wherein n is 1 or 2. Aspect 11. The method of any one of aspects 1-10, wherein Aspect 12. The method of any one of aspects 1-11, wherein R2is independently selected at each occurrence from hydrogen, halo, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, and RpO-. Aspect 13. The method of any one of aspects 1-11, wherein R2is independently selected at each occurrence from hydrogen, fluoro, chloro, bromo, iodo, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, trifluoroethyl, Attorney Docket No.103361-522WO1 hexafluoroisopropyl, and RpO-, wherein Rpis selected from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. Aspect 14. The method of any one of aspects 1-11, wherein R2is independently selected at each occurrence from hydrogen, halo, nitro, and C1-C6 haloalkyl. Aspect 15. The method of any one of aspects 1-11, wherein R2is independently selected at each occurrence from hydrogen, fluoro, chloro, bromo, iodo, nitro, trifluoromethyl, trifluoroethyl, and hexafluoroisopropyl. Aspect 16. The method of any one of aspects 1-15, wherein selected from or a pharmaceutically acceptable salt or derivative thereof. Aspect 18. The method of any one of aspects 1-17, wherein the subject is a human. Attorney Docket No.103361-522WO1 Aspect 19. The method of any one of aspects 1-18, wherein the cancer is selected from prostate cancer, colon cancer, acute myeloid leukemia, or hepatocellular carcinoma. Aspect 20. The method of any one of aspects 1-19, wherein the cancer is androgen receptor positive. Aspect 21. The method of aspect 20, wherein the cancer is androgen receptor positive hepatocellular carcinoma. Aspect 22. A compound selected from: or a pharmaceutically acceptable salt or derivative thereof. Aspect 23. A pharmaceutical composition comprising a compound of aspect 22, or a pharmaceutically acceptable salt or derivative thereof, and a pharmaceutically acceptable carrier or excipient. A number of aspects of the disclosure have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the disclosure. Accordingly, other aspects are within the scope of the following claims. By way of non-limiting illustration, examples of certain aspects of the present disclosure are given below. EXAMPLES The following examples are set forth below to illustrate the compounds, compositions, and methods claimed herein, along with associated methods and results according to the disclosed subject matter. These examples are not intended to be inclusive of all aspects of the subject matter disclosed herein, but rather to illustrate representative methods and results. These examples are not intended to Attorney Docket No.103361-522WO1 exclude equivalents and variations of the present disclosure, which are apparent to one skilled in the art. 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. There are numerous variations and combinations of reaction conditions, e.g., component concentrations, temperatures, pressures, and other reaction ranges and conditions that can be used to optimize the product purity and yield obtained from the described process. Only reasonable and routine experimentation will be required to optimize such process conditions. Valine-Niclosamide for Treatment of AR-SV(+) Hepatocellular Carcinoma Hepatocellular carcinoma (HCC) is the predominant form of liver cancer and a leading cause of global cancer related mortality. At present, current front-line therapies for advanced hepatocellular carcinoma offer limited improvements to overall survival. In this example, we repurposed niclosamide, an anti-tapeworm therapeutic, for use in HCC by utilizing an amino-acid conjugate, valine-niclosamide. This example provides further evidence of the role of the androgen receptor (AR) and its truncated splice variants (SVs) in HCC and offers valine-niclosamide as a candidate therapeutic that address not only AR signaling in HCC but also other known pro-cancer signaling pathways. We believe that this data provides rationale for use of valine conjugated niclosamide as a broad anti-cancer therapeutic that addresses, in part, niclosamide’s poor oral bioavailability and describes AR-SV positive advanced HCC as a potential use case for valine-niclosamide. Hepatocellular carcinoma (HCC) is the predominant form of liver cancer and currently is the second leading cause of cancer-related mortality globally. Current front-line therapies for advanced HCC offer only modest improvements in patient overall survival. HCC is a sexually dimorphic disease and cancer progression is driven in part by AR activity. Here we present niclosamide prodrugs for use in advanced HCC based upon niclosamide’s known anti-AR activity and additional anti-cancer pathway efficacy. Niclosamide analogs were evaluated for their impact on AR protein Attorney Docket No.103361-522WO1 in two HCC cell lines with different AR phenotypes. Pharmacokinetic (PK) analyses were conducted to determine improvements in clearance and oral exposure. Amino- acid conjugates of niclosamide were developed to improve oral exposure and pharmacokinetic analyses were conducted to determine improvements. Finally, niclosamide analogs and amino-acid conjugates were evaluated in an in vivo model of HCC. Niclosamide analogs maintain anti-AR properties in HCC. Valine conjugated niclosamide showed improved oral exposure positioning it as a potential therapeutic in advanced HCC. Valine-niclosamide improves upon niclosamide’s poor solubility and oral bioavailability increasing its utility for a variety of therapeutic uses. In this example, we repurpose the anthelmintic drug niclosamide for use in liver cancer due to its desirable anti-HCC properties and ability to lower AR / AR-SVs protein. Here we demonstrate that niclosamide analogs maintain AR activity against HCC cell lines and that amino-acid conjugation of niclosamide is an effective means of increasing bioavailability and solubility improving its pharmacokinetic profile for a variety of uses. Materials and Methods Synthetic Chemistry Niclosamide analogs and amino-acid conjugate compounds were synthesized as detailed below: Scheme 1: JFR-I-51-01 Synthesis of 4-chloro-2-((2-chloro-4-nitrophenyl)carbamoyl)phenyl L-valinate.Hydrochloride (JFR-I-51-01): Attorney Docket No.103361-522WO1 To the solution of 5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide in THF, was added EDCI (1.5 eq), DMAP (0.1 Eq), and stirred for 15 min. Then, Boc-L- valine (1.5 Eq) was added to the reaction mixture and stirred for overnight. The reaction mixture was evaporated and diluted with EtOAc and water. The compound extracted with EtOAC (3×50 mL) and dried on Na2SO4and concentrated on reduced vapor pressure. The compound was purified by combi flash using 0-15% EtOAc in Hexanes gradient. The pure fractions concentrated and converted as a HCl salt using 4 equivalent of HCl in dioxane (42% yield, Colorless solid):1HNMR (400 MHz, DMSO-d6) δ 11.98 (s, 1H), 10.18 (s, 1H), 8.97 (d, J = 8.0 Hz, 1H), 8.37 (d, J = 2.5 Hz, 1H), 8.24 - 8.21 (m, 2H), 7.99 (d, J = 2.6 Hz, 1H), 7.45 (dd, J = 8.7, 2.6 Hz, 1H), 6.99 (d, J = 8.7 Hz, 1H), 4.85 (t, J = 6.9 Hz, 1H), 2.33 - 2.23 (m, 1H), 1.04 - 0.89 (m, 6H); LC-MS (ESI) m / z calculated for [M+H] C18H18Cl2N3O5: 426.03. Scheme 2: Synthesis of Val-Compound 11 R= H; Val-Compound 11 R= Cl, Val-Compound 7 Attorney Docket No.103361-522WO1 Procedure A: To the solution of corresponding carboxylic acids (1.0 eq) in m-xylene was added corresponding anilines (1.1 eq) and heated to 110oC. After 20 min, PCl3(0.4 mmol) was added to reaction mixture and raised the temperature to 120 °C and stirred for another 3 hours. The reaction mixture was brought to 80°C and diluted with water. Major of the compounds are precipitated and filtered off, washed with Hexane and pet-ether and dried. The compounds which are not precipitated, followed the Combi flash purification by using EtOAc in Hexane system. Procedure B: To the solution of corresponding salicylanilides in THF, was added EDCI (1.5 eq), DMAP (0. 1 Eq), and stirred for 15 min. Then, Boc-L-valine (1.5 Eq) was added to the reaction mixture and stirred for overnight. The reaction mixture was evaporated and diluted with EtOAc and water. The compound extracted with EtOAC (3×50 mL) and dried on Na2SO4 and concentrated on reduced vapor pressure. The compound was purified by combi flash using 0-15% EtOAc in Hexanes gradient. The pure fractions concentrated and converted as a HCl salt using 4 equivalents of HCl in dioxane 5-chloro-2-hydroxy-N-(4-(trifluoromethyl)phenyl)benzamide (SOH-I-158, Compound 11) Compound 11(White solid, 58% yield):1HNMR (400 MHz, DMSO-d6) δ 11.5 (s, 1H), 10.6 (s, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.88 (d, J = 2.6 Hz, 1H), 7.74 (d, J = 8.6 Hz, 2H), 7.47 (dd, J = 8.8 Hz, 2.7 Hz, 1H), 7.03 (d, J = 8.7 Hz, 1H); LC-MS (ESI); [M-H]: 313.9 Synthesis of 4-chloro-2-((4-(trifluoromethyl)phenyl)carbamoyl)phenyl L-valinate.Hydrochloride (JFR-I-58-01, Val-Compound 11): Val-Compound 11 was prepared as previously described in: Pauk, K., et al., “New derivatives of salicylamides: Preparation and antimicrobial activity against various bacterial species.” Bioorg Med Chem 2013, 21, 6574-6851. Attorney Docket No.103361-522WO1 Val-Compound 11Colorless solid, 55% yield,:1HNMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.73 (brs, 2H), 7.93 - 7.87 (m, 3H), 7.76 - 7.72 (m, 3H), 7.47 (d, J = 9.9 Hz, 1H), 4.12 (brs, 1H), 3.51 - 3.50 (brs, 1H), 2.33 - 2.26 (m, 1H), 0.99 - 0.96 (m, 6H);13CNMR (100 MHz, DMSO-d6) δ 167.8, 163.4, 146.0, 142.8, 132.0, 131.6, 131.2, 129.2, 126.5, 126.4, 125.6, 120.1, 57.9, 29.6, 18.2; LC-MS (ESI) m / z calculated for [M+ H] C19H19ClF3N2O3: 415.3 5-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-hydroxybenzamide (SOH-I- 167-01, Compound 7) Compound 7(White solid, 51% yield):1HNMR (400 MHz, DMSO-d6) δ 12.4 (s, 1H), 11.17 (s, 1H), 8.73 (d, J = 8.4 Hz, 1H), 8.0 - 7.98 (m, 2H), 7.79 (dd, J = 8.7 Hz, 1.6 Hz, 1H), 7.53 (dd, J = 8.7 Hz, 2.8 Hz, 1H), 7.10 (d, J = 4.3 Hz, 1H); LC-MS (ESI); [M-H]: 348.0 Synthesis of 4-chloro-2-((2-chloro-4-(trifluoromethyl)phenyl)carbamoyl)phenyl L- valinate.Hydrochloride (SOH-III-106-02, Val-Compound 7): Attorney Docket No.103361-522WO1 Val-Compound 7 Colorless solid, 43% yield,:1HNMR (400 MHz, CD3OD) δ 8.08 (b, J = 8.4 Hz, 1H), 7.90 - 7.74 (m, 2H), 7.69 - 7.66 (m, 2H), 7.35 (d, J = 8.7 Hz, 1H), 4.22 (d, J = 4.2 Hz, 1H), 2.55- 2.47 (m, 1H), 1.17 - 1.11 (m, 6H);13CNMR (100 MHz, CD3OD) δ 168.7, 165.4, 147.6, 139.1, 133.5, 130.3, 129.4, 127.9, 127.9, 127.7, 126.0, 125.5, 120.5, 59.5, 30.7, 18.6, 17.9; LC-MS (ESI) m / z calculated for [M+ H] C19H18Cl2F3N2O3: 449.0, observed [M+H]: 449.2 Materials and Methods Cell Culture, Reagents, and Transfections Human hepatocellular carcinoma cell lines SNU-423, SNU-475, and HepG2 along with the immortalized human liver epithelial cell line THLE2 were purchased from the American Type Culture Collection (ATCC, Manassas, VA). Primary male hepatocytes were obtained from Lonza (Basel, CHE). HCCLM3 cells were received from Thomas Schmittgen, University of Florida (Gainsville, FL) and HEK293 cells were received from Dr. Josie Silvaroli and Dr. Navjot Pabla, The Ohio State University (Columbus, OH). All cells were regularly tested for Mycoplasma using PlasmoTest (rep-pt1, InvivoGen, San Diego, CA). Cells were sub-cultured in media based upon the ATCC recommendation, RPMI1640 (SH30027.LS, Cytiva, Marlborough, MA), EMEM (30-2003, ATCC), or BEGM (CC-3170, Lonza, Basel, CHE). Cell media was supplemented with 10% FBS (S1620 (HI), Biowest, Nuaillé, FRA). Cells were incubated at 37°C in a humidified atmosphere with 5% CO2. Primary male hepatocytes were grown, plated, and cultured as directed by Lonza “Suspension and Plateable Cryopreserved Hepatocyte” protocol using Hepatocyte Culture Medium BulletKit (CC-3198, Lonza). Paclitaxel (PTX) and valacyclovir were obtained from MCE (HY-B0015 and HY-17425A, MedChemExpress, Monmouth Junction, NJ). Attorney Docket No.103361-522WO1 siRNA Knockdown siRNA knockdown of the androgen receptor was performed utilizing Lipofectamine 2000 (11668019, Invitrogen, Carlsbad, CA) per manufacturer’s instructions. Small interfering RNAs targeting AR (M-003400-02 and L-003400-00, Dharmacon, Lafayette, CO and CD.Ri.209684.13.5, Integrated DNA Technologies (IDT), Coralville, IA) were purchased and pooled for use. A nonspecific control siRNA duplex (4457287, Ambion, Carlsbad, CA) was utilized as a negative control. Cell protein lysates were collected at 48 hours after transfection and subsequently analyzed via Western blotting. RNA Sequencing and GSEA Analysis RNA was isolated from siRNA knockdown cells and submitted to Nationwide Children’s Steve and Cindy Rasmussen Institute for Genomic Medicine (Columbus, OH) for total RNA sequencing. RNA purity and concentration were measured using a NanoDrop Spectrophotometer (ND2000, Thermo Scientific, Waltham, MA). The ScriptSeq RNA-Seq library preparation method was utilized. Differential gene expression analysis based on androgen receptor status was performed, yielding 8,479 differentially expressed genes (DEGs) for HCCLM3 and 8,152 DEGs for SNU475. Next, gene set enrichment analysis (GSEA) was performed using v.2024.1.Hs molecular signature database (MSigDB) and hallmark gene sets (H) [35,36]. CRISPR AR Knockout Multi-guide sgRNA was rehydrated (1.5 nmol with 15 µL 1xTE for a final concentration of 100 µM). Prior to RNP complex assembly, sgRNA was diluted to 30 µM with 1xTE. RNPs were prepared by mixing 18 µL supplemented Nucleofector solution (Solution SE for SNU475 and HCCLM3), 6 µL 30 µM sgRNA and 1 µL 20 µM Cas9. Cells were centrifuged (1.5x105cells per transfection; 1K, 5 min), cell pellets resuspended in 5 µL of supplemented Nucleofection solution SE and added to 25 µL of RNP solution. Cell / RNP suspensions were transferred into a Nucleocuvette strip and pulsed with program EN-150 for SNU475, or DS-120 for HCCLM3 cells. AR CRISPR-transfected cells were harvested, suspended at 250 cells in 50 mL medium and plated out on five 96-well plates (0.1 mL / well). Individual single clones were isolated, expanded and cell lysates tested by ELISA (PathScan®Total Androgen Attorney Docket No.103361-522WO1 Receptor Sandwich ELISA Kit; #12850, Cell Signaling Technology, Danvers, MA). Genomic DNA was isolated from AR protein-negative clones, PCR-amplified with primers, and subjected to Sanger sequencing. Protein Extraction and Immunoblotting RIPA Lysis & Extraction buffer (89900, Thermo Scientific, Waltham, MA) and Halt Protease and Phosphatase Inhibitor Cocktail (78440, Thermo Scientific, Waltham, MA) were used according to their respective product instructions to prepare all cell lysates. Lysates were stored at -80°C prior to use. Protein amounts were determined by BCA assay (23227, Thermo Scientific, Waltham, MA) and lysate protein quantity was equalized for all samples across a single assay. Samples were loaded on a 4-12% SDS-PAGE gel and gel electrophoresis was used to resolve the samples prior to transfer. Proteins were transferred from the gel onto a nitrocellulose membrane using a Trans-Blot®Turbo™Transfer System (#1704271 and #1704150, Bio-Rad Laboratories, Hercules, CA). Membranes were washed three times with TBST [Tris- buffered saline (TBS) containing 0.1% Tween 20] before blocking with 5% nonfat dry milk in TBST for 1 hour. Following three additional wash streps, membranes were incubated overnight with specific primary antibody in TBST (1:1000) at 4°C. The following day, membranes were washed three times in TBST and then incubated with either goat anti-rabbit or anti-mouse IgG-horseradish peroxidase (HRP) conjugated secondary antibodies (1:5000) for 1 hour at 25°C. Selected proteins were detected with HRP chemiluminescence reagent. The following primary antibodies were used: anti-AR-NT (#5153) and anti-GAPDH (#5174) (Cell Signaling Technology, Beverly, MA). AR Protein ELISA Androgen receptor protein levels were measured by AR ELISA (PathScan® Total Androgen Receptor Sandwich ELISA Kit, #12850, Cell Signaling Technology, Danvers, MA). Cells were plated at 3x105cells / well in 6-well plates and incubated overnight to allow for adherence. After overnight incubation (5% CO2, 37°C), cells were treated with semi-log concentrations of test compound in 10% FBS and 0.1-1% vehicle (DMSO for Nic / Cmp#7 / Cmp#11), depending on solubility of the compound. Cells were placed back in the incubator for 24-hour treatment. Cell lysates were Attorney Docket No.103361-522WO1 prepared with RIPA Lysis & Extraction buffer (89900, Thermo Scientific, Waltham, MA) and Halt Protease and Phosphatase Inhibitor Cocktail (78440, Thermo Scientific, Waltham, MA) according to product instructions. Lysates were stored at - 80°C prior to use. Protein concentrations were determined via Bradford Assay (5000006, Bio-Rad Laboratories, Hercules, CA) using a Biotek Synergy H1 plate reader.80 µg of protein was loaded per ELISA well immediately after estimation. AR ELISA protocol was carried out according to manufacturer’s instructions. Optical densities were measured at 450nm using a Biotek Synergy H1 plate reader. Invasion Assay BioCoat Matrigel Invasion assay was performed according to manufacturer’s instructions (BioCoat Matrigel Invasion Chambers, 354480, Corning, Corning, NY). AR-negative clones and parental lines (SNU475 and HCCLM3) were hormone deprived in phenol red-free RPMI1640 with 5% csFBS (+ Pen-Strep) for 24hrs. 40,000 cells were suspended in a well insert in 0.5 mL of phenol red-free medium without csFBS over a well of 0.75 mL phenol red-free medium with 5% csFBS as a chemoattractant and incubated for 24 hrs. Invaded cells were fixed in 4% paraformaldehyde and stained with 0.1% crystal violet in 20% methanol. Cells in 10 different and non-overlapping fields of each membrane were photographed and counted. Fluorometric QCM™ 24-Well Cell Invasion Assay (ECM 554, MilliporeSigma, Burlington, MA) was executed per manufacturer’s protocol using 1.25x105 cells in 250 μL of serum free medium and incubated for 24 - 72 hours. Following cell lysis and staining with CyQuant GR Dye, fluorescence was measured in plate reader using 480 / 520 nm filter set. Cell Proliferation and Toxicity Assay Cytotoxicity of compounds was determined by CCK-8 assay (Cell Counting Kit-8, CK04, Dojindo Molecular Technologies, Kumamoto, JPN). Cell lines were plated at 10,000 cells / well in 96-well plates and incubated overnight to allow for adherence to wells. After overnight incubation (5% CO2, 37°C), cells were treated in triplicates with semi-log concentrations of test compound in 10% FBS and 0.1-1% vehicle (DMSO for Nic / Cmp#7 / Cmp#11), depending on solubility of the compound. Cells were placed back in the incubator for 72-hour treatment. CCK-8 reagent was added, and plates Attorney Docket No.103361-522WO1 were further incubated 1-4 hrs as directed by supplier instructions. Optical density measurement was measured using a Biotek Synergy H1 plate reader at 450nm. Primary hepatocytes were plated at 30,000 cells or 50,000 cells / well and maintained according to technical information bulletin provided by the supplier. Upon treatment, maintenance media was supplemented with 10% FBS and fresh test compound for all subsequent media changes, as directed. Pharmacokinetic Studies and Parameter Analyses The pharmacokinetics of niclosamide, valine-niclosamide, compound #7, valine- compound #7, compound #11, valine-compound #11 after IV and PO administration were assessed in male C57BL / 6 mice. The in-life study and quantitative analysis of plasma samples were performed at Charles River Laboratories, Inc. (Wilmington, MA). Mice (approximately 30 grams, n = 3 per group) were administered a single dose of niclosamide, compound #7, or compound #11 at 2 mg / kg (IV) or 40 mg / kg (PO), or valine-niclosamide (IV: 2.8 mg / kg; PO: 56.4 mg / kg), valine-compound #7 (IV: 2.77 mg / kg; PO: 55.49 mg / kg), or valine-compound #11 (IV: 2.9 mg / kg; PO: 56.18 mg / kg) at molar equivalent IV and PO doses to their respective parent compounds. Blood samples were collected serially at 0.083, 0.25, 0.5, 1, 2, 6, and 12 h after IV dosing with the exception of valine-compound #7 where collection at 1 h was omitted and 24 h was collected, and at 0.25, 0.5, 1, 2, 4, 8, and 12 h after PO dosing with the exception of compound #7 and valine-compound #7 where collection at 4 h was omitted and 24 h was collected. Thermodynamic Solubility Study The thermodynamic solubility of niclosamide, valine-niclosamide, compound #7, valine-compound #7, compound #11, valine-compound #11 were assessed in simulated gastric fluid (SGF) (0.2% (w / v) sodium chloride in 0.7% (v / v) hydrochloric acid, deionized water, 0.32% pepsin (w / v), pH 1.2 ± 0.05) and in fasted state simulated intestinal fluid (FaSSIF) (0.056% (w / v) lecithin, 0.161% (w / v) sodium taurocholate, 0.39% (w / v) monobasic potassium phosphate, 0.77% (w / v) potassium chloride, deionized water, pH 6.5 ± 0.05). The thermodynamic solubility in biological media and quantitative analysis of samples were performed according to standard protocol at WuXi AppTec (Shanghai, CHN). Attorney Docket No.103361-522WO1 Pharmacokinetic Modeling Methods A total of 36 mice with PK data were available for nonlinear mixed effects analysis using NONMEM, Version 7.5, implementing the first order conditional estimation with interaction (FOCE-I). R (version 4.2.0) was used for visual diagnostics. Analyte (valine conjugate or parent compound) plasma concentration-time data were confirmed to have biphasic distribution and elimination and were therefore fit separately to a linear two compartment model with a depot for oral administration. Each model was parametrized in terms of clearance (CL), volume of distribution of the central compartment (V1), intercompartmental clearance (Q), and volume of the peripheral compartment (V3). Interindividual variability (IIV) for each parameter was assumed to be log-normally distributed, and residual variability (ε) was described with a proportional error model. No covariate analysis was performed. The PK parameter estimates from these independent models (valine conjugate or parent compound) were used as initial estimates for a combined model describing the conversion and disposition of the valine conjugate to parent drug and associated metabolites (FIGs. 5A and 5B). The model estimated fraction of prodrug converted to parent drug (Fm) was used to calculate the first-order rate constant of metabolite formation (Kmet) = Fm* Kel. This rate constant was used to calculate the half-life of the conversion process and the amount of metabolite formed at complete conversion. Rate of metabolite formation was then calculated as the ratio of the amount of metabolite formed to the time required for complete conversion (~ 5 half-lives). Plasma Stability Study Plasma stability of valacyclovir, valine-niclosamide, valine-compound #7, and valine-compound #11 were assessed in human male plasma and male C57BL / 6 murine plasma with K2EDTA as an anticoagulant. Samples were taken at 0, 30, 60, 120, 180, and 360 minutes to quantitate disappearance of the valine-conjugates. The matrix stability assay in plasma and quantitative analysis of samples were performed according to standard protocol at Charles River Laboratories Inc. (Wilmington, MA). Animal Tolerability Study A tolerability study of valine-niclosamide was performed in male C57BL / 6J mice (8- weeks-old, Jackson Laboratories, Bar Harbor, ME) to inform dose selection for Attorney Docket No.103361-522WO1 follow up efficacy studies in a model of HCC. Mice were group‐housed under conditions of constant photoperiod (12‐h light / 12‐h dark), temperature, and humidity with ad libitum access to water and standard pelleted chow. Mice were randomized to treatment groups (n = 5 per group) that received valine-niclosamide at 14.1, 56.4, and 141.0 mg / kg corresponding to a molar equivalent niclosamide doses of 10, 40, and 100 mg / kg. Control mice were treated with vehicle (DMSO:CremophorEL:water, 3:15:82 by volume). Treatments were administered PO by gavage once daily for 14 days. Mouse weights were measured every 2 days. At the study endpoint, mice were euthanized approximately 2-4 hours after the last dose. Blood was collected by cardiac puncture immediately after CO2euthanasia. At necropsy, carcasses were examined for grossly visible lesions and organ weights were measured (liver, kidneys, spleen, urogenital tract, testes, heart, lungs, brain). Whole blood and serum were submitted to the Comparative Pathology and Digital Imaging Shared Resource at The Ohio State Comprehensive Cancer Center (OSUCCC, Columbus, OH) for determinations of complete blood counts and serum chemistry. Hollow Fiber Assay The hollow fiber procedures were based upon those developed by Hollingshead et al

[0037] with technical consultation kindly provided by Joanna Burdette and Dan Lantvit. We modified this technique, based upon literature support, in order to utilize the solely AR-SV expressing SNU475 model which has a low frequency of xenograft take upon subcutaneous injection of cells in nude mice but does show exponential growth in an HFA model

[0038] . In order to utilize a PO dosing approach with the hollow fiber assay (HFA), we extended the traditional HFA timeline to improve angiogenesis as noted in the literature [39,40]. Based upon our own cell density and angiogenesis optimization, we arrived at the following approach. Hollow fibers (KrosFlo Implant Membranes, M138615, Repligen, Waltham, MA) were filled with 3x106SNU475 cells / mL per length and heat-sealed into 2 cm lengths on Day -1. On Day 0, three fibers were implanted into 20-week-old male outbred homozygous athymic nude mice (Foxn1nu / Foxn1nu, The Jackson Laboratory, Bar Harbor, ME) subcutaneously parallel to the spine. Following a 14-day waiting period to allow for angiogenesis around the fibers, treatment was initiated. Mice were randomized to treatment groups (n = 4 per treatment group and n=3 per vehicle Attorney Docket No.103361-522WO1 group) and treated BID PO for 7 days with either niclosamide (75 mg / kg), valine- niclosamide (106.1 mg / kg, 75 mg / kg molar equivalent), valine-compound #7 (87.3 mg / kg, 75 mg / kg molar equivalent multiplied by a factor of 0.78 to exposure match to valine-niclosamide), compound #7 (62.9 mg / kg, 87.3 mg / kg valine-compound #7 molar equivalent) or vehicle (3% DMSO, 15% CremophorEL in water). We performed an additional study (n=3 per group, 2 fibers per mouse) treated with either vehicle (25% ethanol, 25% CremophorEL in physiologic saline) or EOD IP paclitaxel (PTX) (25 mg / kg) as a positive control based upon efficacy shown by Mi et al and efficacy against SNU475 cells [41,42]. On Day 21, mice were sacrificed and hollow fibers were explanted. MTT assay was performed according to KrosFlo Implant Membrane protocol utilizing Thiazolyl Blue Tetrazolium Bromide (M2128, MilliporeSigma, Burlington, MA). Statistical Analyses Statistical tests were performed in GraphPad Prism (version 10; GraphPad Software Inc, La Jolla, CA) and listed as the mean or geometric mean ± confidence interval or coefficient of variation unless otherwise noted. Statistical significance was ascertained through an unpaired t-test for two groups or an analysis of variance (ANOVA) for 3 or more groups. P values of <0.05 were considered statistically significant. Results AR / AR-SV Regulated Oncogenic and Tumor Suppressive Pathways Building upon previous reporting of AR-SV transcript presence and abundance in patients within The Cancer Genome Atlas (TCGA) Liver Hepatocellular Carcinoma (LIHC) cohort [5], we evaluated the relationship between AR-SV transcript abundance and overall survival. AR-SV transcript abundance, expressed as a percentage of AR-FL transcript abundance, were stratified into quartiles with Quartile 1 (Q1) representing the lowest abundance and Quartile 4 (Q4) representing the highest, and analyzed for differences in overall survival (OS) among the quartiles. While the OS of patients represented in Q1 was not significantly different from that of the second or third quartiles, the OS of Q4 was significantly lower than that of Q1 Attorney Docket No.103361-522WO1 (FIG. 1A), indicating that overall survival is negatively correlated with AR-SV transcript abundance. To better understand the impact of AR-SV transcripts on downstream cellular signaling, we analyzed the effect of siRNA-mediated AR depletion on gene expression in two human HCC cell lines, HCCLM3 and SNU475, with differing AR / AR-SV expression status. HCCLM3 cells express both AR-FL and AR-SV, representative of the AR tumor status in most HCC patients, while SNU475 cells solely express AR-SV due to a genomic deletion in the ligand binding domain (LBD) [5]. Upon confirmation of successful siRNA-mediated knockdown of total AR protein compared to nonspecific siRNA-transfected controls, we analyzed the resulting differentially expressed genes (DEGs) between the AR knockdown and control conditions for each cell line. AR knockdown in HCCLM3 cells resulted in 8,479 DEGs, while that in SNU475 cells resulted in 8,152 DEGs with an overlap of 3,701 genes common to both sets of DEGs (FIG.1B). We next used Gene Set Enrichment Analysis (GSEA) and the Hallmark gene set within the Molecular Signature Database (MSigDB) to determine correlation between the AR-dependent HCCLM3 and SNU475 gene sets and various characterized biological signaling pathways. Several pathways were significantly enriched in both gene sets with False Discovery Rates (FDR) below 25%. We found that the presence of siAR downregulated several major cellular regulation and cell proliferation pathways in both cell lines including E2F targets, G2 / M checkpoints, Myc targets, and mitotic spindle signaling (FIGs.1C-1E). These pathways are all likely upregulated by AR / AR-SVs. We also found that in the presence of siAR, TNFα signaling via NF-κB, IL-2 mediated STAT5, IL-6 mediated STAT3, and KRAS signaling were all upregulated (FIGs. 1C-1E). This indicates that AR / AR-SVs likely play a role in suppressing these oncogenic signaling pathways. CRISPR AR KO Downregulates Cellular Invasion We decided to further validate the role of AR / AR-SVs in downstream oncogenic pathways by utilizing CRISPR-Cas9 to produce HCCLM3 and SNU475 AR knockout cell lines. AR KO was confirmed for multiple clones for both HCCLM3 and SNU475 by comparing total AR protein levels in edited clones to parental HCCLM3 or SNU475 (FIGs.2A-2B). Attorney Docket No.103361-522WO1 Based upon our GSEA data suggesting a role for AR in regulating E2F targets, transcription factors regulating cell cycle implicated in cancer progression, invasion, and metastasis, we examined the invasive potential of our AR KO clones. We found that the AR KO clones had decreased invasive potential compared to parental in our invasion assay (FIG.2C). Niclosamide Analogs Decrease AR Expression and Invasion in AR / AR- SV(+) HCC Cells Based upon previous reports supporting niclosamide’s ability to decrease AR / AR-SV protein levels as well as decrease activity of multiple oncogenic pathways, we decided to evaluate niclosamide and two previously reported analogs with anti-AR effects, compound #7 and compound #11, for use in HCC (FIG. 3A)

[0033] . We evaluated the ability of niclosamide, compound #7, and compound #11 to decrease AR protein in two human HCC cell lines, SNU423 and SNU475, with differing AR profiles. SNU423 is a human HCC cell line expressing only AR-FL, while SNU475, as previously mentioned, only expresses AR-SVs [5]. Niclosamide was effective in decreasing AR protein levels after 48 hours of treatment time in SNU423 with an EC50 of roughly 0.2 µM and in decreasing AR-SV protein levels in SNU475 with an EC50 of roughly 0.4 µM (FIG.3B). Compound #7 and compound #11 were also effective in decreasing AR-FL in SNU423 with EC50 of 1.0 µM and 1.1 µM, respectively, and in AR-SV in SNU475 with an EC50of 4.6 µM and 3.4 µM, respectively (FIGs. 3C-3D). We also compared niclosamide, compound #7, and compound #11 to both the AR antagonist enzalutamide and the kinase inhibitor as well as HCC standard of care agent, sorafenib at the clinically relevant concentrations of 10 µM [PMID: 25917876, PMID: 33021346]. We found that all three niclosamide-based compounds were able to more effectively decrease AR protein levels compared to enzalutamide and sorafenib (FIG. 8A). Additionally, we tested the ability of niclosamide to decrease SNU475 invasion, similar to the SNU475 CRISPR AR KO cell lines, and found decreased invasion after 48 hours of treatment at 1 µM and 10 µM (FIG. 8B). Critically, cell viability at 48 hours was not impacted at 1 µM supporting niclosamide’s ability to mitigate SNU- 475 cellular invasion at concentrations less than 10 µM without overt cytoxicity. Attorney Docket No.103361-522WO1 Finally, we determined niclosamide’s antiproliferative impact on SNU423 and SNU475 along with HepG2, a human HCC cell line lacking AR expression, THLE-2, an AR negative immortalized normal human liver cell line, and primary male hepatocytes (Table 1, FIGs. 9A-9G) [5]. Niclosamide demonstrated some cancer selectivity with greater potency in inhibiting SNU423 and SNU475 cell growth after 72 hours of treatment time, 0.25 and 1.3 µM, respectively, as compared to primary male hepatocytes (7.2 µM), while similar anti-proliferative potency was apparent in HepG2 and THLE-2, 0.6 and 0.37 µM, respectively. Compound #7 and Compound #11 showed similar potency to niclosamide against SNU423 cells, 0.28 and 0.58 µM respectively, but were less potent against SNU475 cells, 4.0 and 7.2 µM respectively. Compound #7 and Compound #11 showed anti-proliferative potencies in a similar range to niclosamide against both HepG2 (0.45 µM and 1.9 µM, respectively) and THLE-2 (0.31 µM and 0.56 µM respectively). Like niclosmide, Compound #7 and Compound #11 demonstrated some cancer selectivity with potency against primary male hepatocytes and THLE-2 cell lines of >30 µM and 9.5 µM, respectively. Compared to enzalutamide, a prostate cancer therapeutic, and sorafenib, lenvatinib, and regorafenib, which are standards of care in liver cancer[PMID: 37263081], niclosamide and its analogs showed a higher degree of potency against AR-FL+ SNU423 HCC cells, while only sorafenib and regorafenib had similar degrees of potency against AR-SV+ SNU475 HCC cells at 4.0 µM and 1.6 µM, respectively. Table 1. IC50s of niclosamide amino-acid conjugates and analogs against HCC, liver epithelial, and hepatocyte cell lines.1IC50s in µM Primary Male Compound SNU423 SNU475 HepG2 THLE-2 Hepatocytes IC50 95% CI IC50 95% CI IC50 95% CI IC50 95% CI IC50 95% CI Niclosamide 0.25 0.20-0.32 1.33 0.96-1.9 0.60 0.45-0.81 0.37 0.29-0.48 7.16 3.3-16.3 Compound #7 0.28 0.24-0.34 6.6 3.1-13.9 0.45 0.32-0.63 0.31 0.25-0.40 >30 ND Compound #11 0.58 0.44-0.76 0.89 0.62-1.3 1.86 1.3-2.8 0.56 0.16-2.2 9.47 2.6-37.8 Enzalutamide 16.6 12.1-22.9 14.88 9.0-24.6 >30 ND >30 ND >30 ND Sorafenib 6.1 4.6-8.1 4.20 2.8-6.4 10.76 6.8-16.9 >30 ND 5.10 1.2-20.4 Lenvatinib >30 24.1-50.9 13.00 4.4-23.1 >30 ND 25.13 ND >30 ND Regorafenib 5.5 4.1-7.4 1.63 0.77-3.5 11.90 7.7-18.2 >30 ND >30 ND Attorney Docket No.103361-522WO11IC50 values determined by a three-parameter nonlinear regression fit by nonlinear least squares. Niclosamide Analogs Demonstrate Improved Pharamcokinetics and Solubility Based upon the prior reports of improved rodent pharmacokinetic parameters of compound #7 [PMID: 34272475], we assessed both analogs’ pharmacokinetics in single dose IV and PO studies in mice (FIG. 4A, FIGs. 10A-10D). Consistent with limiting metabolism, both compound #7 and compound #11 showed significant decreases in systemic clearance following an IV dose compared to niclosamide (0.04 and 0.03 L / hr, respectively, versus 0.08 L / hr, Table 2). These apparent reductions in systemic clearance were matched with improvements in oral exposure such that compound #7 and #11 exhibited significant increases in circulating drug levels following an oral dose compared to niclosamide (12.97 and 7.98 hr*µmol / L, respectively, versus 1.79 hr*µmol / L). While none of the niclosamide analogs tested exhibited solubility above 1.5 µM in simulated gastric fluid, compounds #7 and #11 showed increased solubility in simulated intestinal fluid compared to niclosamide (FIG.4B). Table 2. Pharmacokinetic parameters from single IV or single PO doses of niclosamide amino-acid conjugates and analogs.1IV: Clobs (L / hr) AUCallCmaxTmax Geo Geo Geo Geo Geo Geo Geo Geo Geo Geo Dose Route Analyte Mean CV% Mean CV% Mean CV% Mean CV% Mean CV% 2 mg / kg IV Nic 1.79 37.47 0.08 28.44 6.03 26.71 1.33 68.33 0.08 0.00 2 mg / kg IV Val-Nic 7.52 34.60 0.02 35.28 11.20 8.31 1.54 13.02 0.08 0.00 EQV 2 mg / kg IV Cmp #7 3.70 20.93 0.04 22.88 6.98 4.19 4.85 10.04 0.08 0.00 2 mg / kg Val-Cmp IV 13.46 5.07 0.01 2.74 10.08 11.69 4.20 3.78 0.08 0.00 EQV #7 2 mg / kg IV Cmp #11 5.06 27.11 0.03 29.72 11.31 5.36 0.96 21.20 0.08 0.00 2 mg / kg Val-Cmp IV 36.06 55.80 0.004 58.38 20.17 15.32 1.94 10.42 0.39 20.01 EQV #11 2 mg / kg PO Nic 3.25 37.85 0.78 55.85 1.65 56.00 2.74 75.99 0.42 34.64 Attorney Docket No.103361-522WO1 2 mg / kg PO Val-Nic 48.57 8.21 0.05 10.40 11.15 11.00 4.11 58.21 0.67 43.30 EQV 2 mg / kg PO Cmp #7 12.97 8.04 0.21 8.08 5.79 18.79 3.58 3.25 0.25 0.00 2 mg / kg Val-Cmp PO 62.09 1.21 0.05 5.95 7.71 0.94 6.46 14.37 1.26 35.84 EQV #7 2 mg / kg PO Cmp #11 7.98 14.35 0.35 10.15 6.08 16.38 2.68 34.97 0.42 34.64 2 mg / kg Val-Cmp PO 4.17 15.84 0.59 8.82 0.99 3.92 5.77 32.48 1.00 0.00 EQV #111Pharmacokinetic parameters were determined by non-compartmental analysis. Valine-Niclosamide and Valine-Conjugated Niclosamide Analogs Demonstrate Improved Oral Exposure, Solubility and Bioavailability With the goal of sustaining roughly 5 µM plasma levels for 8 hours of a daily dosing interval to achieve anti-HCC effects in subsequent xenograft models, we linearly scaled our pharmacokinetic data and approximated the need for 500 -1,500 mg / kg doses of niclosamide and its analogs. Despite the apparent improvements in pharmacokinetics provided by Compound #7 and #11, the necessary dose size remained prohibitively large. To address this limitation, we pursued an approach to improve on a known limitation of the niclosamide pharmacophore, poor solubility [PMID: 40153934]. To this end, we further modified niclosamide, compound #7, and compound #11 by valine amino acid conjugation (FIG.5A) to determine if a pro-drug approach could improve solubility and subsequent exposure following an oral dose. We determined the impact of this structural modification on pharmacokinetic parameters using single dose IV and PO pharmacokinetic studies of valine conjugated compounds in mice (FIG. 5B) which revealed valine-conjugation decreased systemic IV clearance compared to the parent compounds, with significant reductions for both niclosamide and compound #7 (0.02 versus 0.08 L / hr and 0.01 versus 0.04 L / hr, respectively). Additionally, conjugation resulted in substantial increases in systemic exposure of pro-drug following an equimolar oral dose of valine-niclosamide and valine-compound #7 compared to a 40 mg / kg dose of their respective parental compounds (48.57 versus 3.25 hr*µmol / L and 62.09 versus 3.58 hr*µmol / L, respectively) (FIGs.10A-10D and Table 2). With this dramatic increase in systemic exposure, we were able to significantly increase the bioavailability of valine-niclosamide compared to niclosamide (FIG.10D). Attorney Docket No.103361-522WO1 Surprisingly, while valine-compound #11 had the lowest IV clearance of all the conjugated compounds (0.03 L / hr), it had very poor systemic exposure following an oral dose (4.17 hr*µmol / L), similar to niclosamide (3.25 hr*µmol / L). This was particularly striking as valine-compound #11 and valine-compound #7 differ by a single chlorine atom but showed dramatic discrepancy in the exposures of their prodrug forms following equivalent oral doses. To determine the potential impact of solubility on valine conjugate pharmacokinetics, we conducted thermodynamic solubility studies in simulated gastric and intestinal fluids (FIG. 5C). In simulated gastric fluid, the valine-conjugated forms showed 9.2 to 17.7 µM solubility, a notable improvement over the extremely limited solubility of unconjugated forms (all less than the 1.56 µM LLOQ). However, in simulated intestinal fluid, while all other niclosamide analogs and their respective valine-conjugated forms showed at least a two-fold increase in solubility compared to niclosamide, valine-compound #11’s solubility remained under 1.56 µM LLOQ in intestinal fluid providing a potential explanation for its reduced systemic exposure following an oral dose relative to other analogs. Valine-Niclosamide in an In Vivo Hollow Fiber Assay Model of AR-SV(+) HCC Based upon our pharmacokinetic data showing improved systemic exposure of valine-niclosamide and valine-compound #7 following an oral dose, we decided to move forward with valine-niclosamide and valine-compound #7 for study in vivo. To assess in vivo efficacy of these compounds against AR-SV(+) liver cancer, we utilized a modified hollow fiber assay (HFA), as developed by Hollingshead et al to accommodate the poor subcutaneous take rate of SNU475, our primary AR-SV (+) HCC model of interest

[0037] . We utilized paclitaxel as a positive control due to its prior use as a positive control in HFA models

[0041] . To inform our dose selection, we performed a two-week tolerability study of valine- niclosamide in mice of daily oral doses of 10, 40, and 100 mg / kg molar equivalencies of niclosamide (FIGs. 11A-11C). Based upon valine-niclosamide’s increased oral exposure, we wanted to determine if higher oral exposure led to potentially dose limiting toxicities. We found that valine-niclosamide was tolerated at all tested dose Attorney Docket No.103361-522WO1 levels with no significant impact on body weight, liver enzyme levels or concerning increases in spleen weight. We designed our efficacy study to target 1 to 4 µM circulating levels of agent for 8 hours of the 12 hour BID dosing interval given the previously determined IC50s of niclosamide and compound #7 against SNU475 are 1.3 µM and 4.0 µM, respectively. Based on linearly scaling our pharmacokinetic data, 75 mg / kg niclosamide BID and a molar equivalent dose of valine-niclosamide (105.7 mg / kg BID) would be expected to provide plasma levels of approximately 0.2 µM niclosamide and 3.5 µM valine- niclosamide for up to 8 hours post-dose. In an effort to predict tolerated doses of compound #7 and its valine conjugate, we then calculated a dose for valine- compound #7 exposure matched to a 105.7 mg / kg valine-niclosamide dose (87.3 mg / kg BID valine-compound #7) and then an equimolar dose of compound #7 (62.9 mg / kg BID). Based on our pharmacokinetic data, these dosing regimens were expected to provide plasma levels of 3.7 µM valine-compound #7 and 0.86 µM compound #7 up to 8 hours post-dose. To ensure our subcutaneous fibers were sufficiently vascularized to receive circulating therapy, we performed a positive control experiment by treating mice with 25 mg / kg paclitaxel (PTX) IP every other day for one week (FIG.7A). PTX treatment resulted in a significant decrease in cell viability as determined by MTT assay within our fibers, confirming the validity of our model system. In contrast to our control experiment, one week of BID treatment with niclosamide, compound #7, valine-niclosamide, and valine-compound #7 resulted in no differences in cell viability within the fibers (FIG. 7B). Of note, one mouse was removed early from the valine-niclosamide group due to potential gavage-associated injury and two mice were excluded from the valine-compound #7 group due to apparent toxicity. Assessing Conversion of Valine Conjugated Niclosamide Analogs to Parent To better understand the lack of efficacy in our hollow fiber assay we revisited the cleavage of valine-niclosamide and valine-compound 7 to their parental forms as incomplete conversion could limit the amount of active agent reaching our SNU-475 cells (FIGs.12A-12B, Table 3). When measuring circulating niclosamide following a 56.4 mg / kg oral dose of valine-niclosamide (40 mg / kg EQV of niclosamide) we found Attorney Docket No.103361-522WO1 only 0.87 µM Cmax niclosamide, which is less than the 1.65 µM Cmax resulting from simply dosing 40 mg / kg niclosamide. Likewise, the AUCallof niclosamide following an oral dose of valine-niclosamide was only 0.8 µM*hr which is lower than the AUCall of 3.25 µM*hr following an equivalent dose of niclosamide. Compound #7 followed a similar pattern in that the Cmax of compound #7 following a 55.49 mg / kg oral dose of valine-compound #7 was limited to 0.85 µM which is lower than the Cmax of 5.78 µM resulting from an equivalent dose of compound #7. The AUCallof compound #7 following an oral dose of valine-compound#7 was only 1.31 µM*hr which is lower than the AUCallof 12.97 µM*hr following an equivalent dose of unconjugated compound #7. Table 3. Pharmacokinetic parameters from single PO doses of niclosamide amino-acid conjugates measuring parent drug.1IV: Clobs(L / hr) AUCall Cmax HL_Lambda_z Tmax (hr*µmol / L) PO: Cl_Fobs(µmol / L) (hr) (hr) (L / hr) Geo Geo Geo Geo Geo Geo Geo Geo Geo Geo Dose Route Analyte Mean CV% Mean CV% Mean CV% Mean CV% Mean CV% 40 mg / kg PO Nic 0.80 22.99 3.45 18.79 0.87 18.69 3.52 72.71 0.50 0.00 EQV 40 mg / kg PO Cmp7 1.31 3.47 2.33 4.19 0.85 4.03 4.83 6.56 0.40 17.51 EQV1Pharmacokinetic parameters were determined by non-compartmental analysis. We further evaluated the conversion of valine conjugated pro-drugs utilizing a pharmacokinetic modeling approach whereby the kinetics of both pro-drug and parent could be simultaneously considered (FIG. 7A). We determined two- compartment structural models best described the combined data and allowed us to estimate both the conversion to parent rate and the fraction converted (FIG.7B). The estimated rate of formation of the parent compound from each of the valine conjugates investigated was approximately 0.1 µmoles / hr for niclosamide and compound #11, and 0.2 µmoles / hr for compound #7. The estimated fraction converted was limited to 22.6% for valine-niclosamide, 25% for valine-compound #7, and 39% for valine-compound #11. Operating with the hypothesis that soluble esterases were at least partially responsible for cleaving our pro-drugs, as has been Attorney Docket No.103361-522WO1 suggested for other amino-acid conjugates

[0043] , we performed a plasma stability assay comparing the valine-conjugated niclosamide analogs to valacyclovir, a well characterized valine prodrug [44,45]. Over 6 hours, we found that compared to valacyclovir where 66.4% and 37.7% of the pro-drug remained in human and murine plasma, respectively, 90% or more of the valine-conjugated drugs remained in human and murine plasma (FIG.7C). Discussion As a follow up to prior work characterizing the presence and role of AR-SVs in HCC sexual dimorphism, we sought to better understand downstream AR / AR-SV signaling and evaluate niclosamide, an anthelmintic drug that was recently the focus of repurposing efforts in AR-SV driven PCa, for use as a therapeutic tool for AR-SV(+) HCC [5,33]. GSEA of AR knockdown in HCC cell lines found that AR / AR-SVs play a role in upregulating several cell cycle regulation and cellular proliferation pathways in HCC including E2F targets, G2 / M checkpoint, Myc targets, and mitotic spindle signaling. These pathways have been implicated in increasing HCC aggressiveness and proliferation [46,47]. However, several oncogenic pathways were suppressed by AR / AR-SV expression including TNFα signaling via NF-κB, IL-2 mediated STAT5, IL-6 mediated STAT3, and KRAS signaling (FIGs.1A-1E). We also further solidified the role of AR in cellular invasion in AR+ HCC by showing that AR KO was able to mitigate cellular invasive potential (FIG.2C). As AR has previously been reported to have dual roles in HCC [4], our findings corroborate reports that AR can both contribute to cancer aggressiveness and suppress several oncogenic pathways. In this complex case, identifying a therapeutic that not only addresses AR signaling, but can also suppress rebound signaling that may result from diminished AR activity is key. Niclosamide, due to its ability to inhibit a wide range of oncogenic pathways, has been previously reported as a multitool compound for cancer or other disease indications [11-14]. Niclosamide has already been investigated as an anti-AR-SV therapeutic in prostate cancer [16,29,33,48]. In addition, niclosamide is reported to inhibit IL-6 mediated phosphorylation of STAT3, mitigate the STAT3-AR axis, and inhibit p- STAT3 binding to the PD-L1 promoter allowing niclosamide to enhance PD-1 / PD-L1 blockade [22,23,26]. Niclosamide is also reported to inhibit both NF-kB activation and KRAS as well as reduce cell invasion [13,21,25]. This overlap between AR / AR-SV Attorney Docket No.103361-522WO1 suppressed oncogenic pathways in AR-SV(+) HCC and niclosamide’s anti-AR and anti-cancer activities well positions niclosamide as a potential HCC therapeutic that can address this complex signaling. Additionally, with the recent approval of atezolizumab (PD-L1 inhibitor) and bevacizumab (VEGF inhibitor) as front-line therapeutics in HCC, niclosamide has strong potential as a combination therapeutic improving ICI efficacy. Prior attempts to improve niclosamide’s therapeutic profile included a niclosamide ethanolamine salt (NEN), development of niclosamide analogs, and a self- microemulsion of niclosamide (Nic-SMEDDS) [24,30,31,33,48]. Current research on the niclosamide pharmacophore indicates that the nitro group on the B ring and the hydroxyl group on the A ring (FIG.3A) are critical for anti-cancer activity, however, when the nitro group is substituted with a tri-fluoromethyl group, as in compound #7 and compound #11, activity is maintained and this may allow the compound to bypass first pass metabolism

[0048] . Kang et al also reported that the A ring chlorine is non-critical for activity. We found that the B ring chlorine, while not critical for activity (Table 1) is critical for solubility and maintaining drug-like properties. Prior studies on similar analogs, including compounds #7 and #11, showed clear activity against AR / AR-SVs in PCa, showed activity against Wnt-ß-catenin, mTORC1, STAT3 in ovarian cancer, and activity against NF-κB in breast cancer [24,30,31,33]. While niclosamide and niclosamide analogs have shown anti-AR / AR-SV activity in PCa, it has not yet been shown in HCC

[0033] . We demonstrated that niclosamide decreases AR protein in SNU423 and SNU475 cells with an EC50of 0.2 and 0.4 µM, respectively (FIG.3B). Compound #7 and compound #11 also decreased AR protein with EC50’s of 1.0 and 1.1 µM, respectively, in SNU423 and EC50’s of 4.6 and 3.4 µM respectively in SNU475 (FIGs. 3C_3D). Consistent with its effects on AR protein, niclosamide decreased invasion of SNU475 cells (FIG. 8B). Niclosamide demonstrated favorable activity in AR+ HCC cells in comparison to several front-line advanced HCC therapeutics, sorafenib, lenvatinib, and regorafenib (Table 1). Niclosamide analogs also showed either greater or similar potency to front-line HCC agents in our in vitro proliferation assays. These analogs also show improvements in mouse pharmacokinetics including reduced systemic clearance following an IV dose and increased systemic exposure following an oral dose (FIG. 3B). While these experiments validated the translatability of niclosamide activity in PCa to AR + HCC, Attorney Docket No.103361-522WO1 prior clinical failures driven by poor solubility and absorption called for a further redesign of niclosamide to improve its bioavailability in order to leverage these activities for therapeutic use

[0029] . To further improve niclosamide bioavailability, we adopted an amino acid conjugation strategy based upon prior success in this approach with drugs like acyclovir and its pro-drug valacyclovir

[0044] . The previously reported activity of analogs #7 and #11 provided rationale to move forward with valine-conjugated versions of these agents [24,30,33]. Compound #31, the other lead compound presented by Liu et al, was excluded due to its structural incompatibility with valine conjugation

[0033] . Valine conjugation of niclosamide led to a greater increase in systemic exposure following an oral dose when compared to similar efforts. Chen et al. noted that they observed plasma concentrations of roughly 0.10 µM niclosamide 4 hrs after oral administration of 40 mg / kg dose and NEN improved plasma niclosamide concentration more than 7-fold to roughly 0.72 µM

[0015] . We similarly observed niclosamide levels of 0.22 µM at 4 hrs post oral administration of 40 mg / kg dose, but found that valine conjugation increased plasma levels more than 16-fold to 3.59 µmol / L at 4hrs after a molar equivalent of 40 mg / kg was given orally (FIGs. 10A-10B). The Nic-SMEDDS offered a 1.8-fold Cmaximprovement over orally administered niclosamide

[0032] . However, we found that valine-niclosamide provided a 6.8-fold improvement in Cmaxover orally administered niclosamide and a 14.9-fold increase in systemic exposure (Table 2). We demonstrated that conjugating analogs with valine improved both solubility and bioavailability beyond existing approaches but conversion of these pro-drug forms remained problematic. Given our cellular model of choice, ARSV+ SNU-475 cells, we were limited to an adopted HFA model as opposed to a traditional subcutaneous xenograft. Though our model responded to PTX treatment, we were ultimately unable to demonstrate efficacy with valine-niclosamide and valine-compound #7 (FIG. 6B). While not wishing to be bound by any one theory, this was potentially due to poor conversion of our valine-conjugated pro-drugs and found that our estimated conversion rates of 0.1- 0.2 µmol / hr were likely insufficient to generate enough circulating active agent to generate anti-cancer effects. Consistent with this finding, our estimated fractions converted were limited to 22.6% and 25% for niclosamide and compound #7, respectively (FIG.7B). Our valine-conjugated prodrugs deviated in a surprising way Attorney Docket No.103361-522WO1 from other valine conjugated pharmacophores, such as valacyclovir, which exhibits nearly total conversion to parent

[0045] . As a more direct measure of activation in plasma, our plasma stability assay revealed that 90% or more of the amino acid conjugated forms remained in plasma following a 6-hour incubation in stark contrast to the positive control valacyclovir (FIG.7C). The underlying cause for poor cleavage remains unclear. Conclusions Overall, our findings further demonstrate the clinical relevance of AR / AR-SVs to HCC and their role in upregulating other cell regulation and proliferation pathways such as E2F targets, G2 / M checkpoint, Myc, and mitotic spindle. Compared to current HCC therapies that offer only minimal improvements in overall survival, niclosamide is well positioned as a cancer multitool compound due its ability to decrease AR / AR-SV protein and prevent rebound oncogenic signaling through its activity against NF-κB, STAT3, and KRAS. In response to the clinical hurdle of niclosamide’s poor solubility and bioavailability, we present valine-conjugated niclosamide as a potentially improved therapeutic with improved solubility and absorption when orally administered. By potentially increasing the systemic exposure possible following an oral dose, these improvements provide rationale for further investigation into broad applications of niclosamide to cancer or other disease indications. Abbreviations MDPI Multidisciplinary Digital Publishing Institute HCC Hepatocellular Carcinoma AR Androgen Receptor AR-SV Androgen Receptor Splice Variants NAFLD Non-Alcoholic Fatty Liver Disease MAFLD Metabolic-dysfunction Associated Fatty Liver Disease Attorney Docket No.103361-522WO1 ARE Androgen Response Elements TCGA The Cancer Genome Atlas ICI Immune Checkpoint Inhibitor mOS Median Overall Survival WHO World Health Organization ATCC American Type Culture Collection PTX Paclitaxel IDT Integrated DNA TEch DEG Differentially Expressed Genes GSEA Gene Set Enrichment Analysis MSigDB Molecular Signature Database PK Pharmacokinetic IV Intravenous PO Per Os / By Mouth HFA Hollow Fiber Assay LBD Ligand Binding Domain LIHC Liver Hepatocellular Carcinoma AUCall Total Area Under the Curve Cmax Maximum Concentration Tmax Time at Maximum Concentration SGF Simulated Gastric Fluid FaSSIF Fasted State Simulated Intestinal Fluid ALT Alanine Aminotransferase AST Aspartate Aminotransferase NEN Niclosamide Ethanolamine Salt Attorney Docket No.103361-522WO1 Nic-SMEDDS Self-Microemulsifying Drug Delivery System Encapsulating Niclosamide References The references cited below are hereby incorporated by reference to disclose and describe the methods or materials in connection with which the publications are cited or to provide background for the present disclosure. 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The compositions and methods of the appended claims are not limited in scope by the specific compositions and methods described herein, which are intended as illustrations of a few aspects of the claims and any compositions and methods that are functionally equivalent are intended to fall within the scope of the claims. Various modifications of the compositions and methods in addition to those shown and described herein are intended to fall within the scope of the appended claims. Further, while only certain representative compositions and method steps disclosed herein are specifically described, other combinations of the compositions and method steps also are intended to fall within the scope of the appended claims, even if not specifically recited. Thus, a combination of steps, elements, components, or constituents may be explicitly mentioned herein; however, other combinations of steps, elements, components, and constituents are included, even though not explicitly stated.

Claims

Attorney Docket No.103361-522WO1 WHAT IS CLAIMED IS:

1. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula Ior a pharmaceutically acceptable salt or derivative thereof, wherein: m is an integer from 0 to 4; n is an integer from 0 to 5; R1is independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C7 cycloalkyl)(C0- C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, RpO-, RpS-, RpRqN-, RoC(O)-, RoC(O)-O-, RoC(O)-NRq-, RoS(O)2-, RoS(O)2-O-, and RoS(O)2-NRq-; R2is independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C7 cycloalkyl)(C0- C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6 alkyl)-, RpO-, RpS-, RpRqN-, RoC(O)-, RoC(O)-O-, RoC(O)-NRq-, RoS(O)2-, RoS(O)2-O-, and RoS(O)2-NRq-; Rois independently selected at each occurrence from Rp, halo, RpO-, and RpRqN-; and Rpand Rqare independently selected at each occurrence from hydrogen, C1-C6alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C7 cycloalkyl)(C0-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6alkyl)-, (6- to 10-memberedAttorney Docket No.103361-522WO1 monocyclic or bicyclic aryl)-(C0-C6 alkyl)-, and (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-.

2. The method of claim 1, wherein3. The method of claim 1 or claim 2, wherein m is 1.

4. The method of any one of claims 1-3, wherein5. The method of any one of claims 1-4, wherein R1is independently selected at each occurrence from hydrogen, halo, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, and RpO-.

6. The method of any one of claims 1-4, wherein R1is independently selected at each occurrence from hydrogen, fluoro, chloro, bromo, iodo, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, trifluoroethyl, hexafluoroisopropyl, and RpO-, wherein Rpis selected from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl.

7. The method of any one of claims 1-4, wherein R1is independently selected at each occurrence from hydrogen, halo, nitro, and C1-C6haloalkyl.

8. The method of any one of claims 1-4, wherein R1is independently selected at each occurrence from hydrogen, fluoro, chloro, bromo, iodo, nitro, trifluoromethyl, trifluoroethyl, and hexafluoroisopropyl.

9. The method of any one of claims 1-8, wherein10. The method of any one of claims 1-9, wherein n is 1 or 2.Attorney Docket No.103361-522WO1 11. The method of any one of claims 1-10, whereinselected R2R2fromR2and .

12. The method of any one of claims 1-11, wherein R2is independently selected at each occurrence from hydrogen, halo, nitro, cyano, C1-C6alkyl, C1-C6haloalkyl, and RpO-.

13. The method of any one of claims 1-11, wherein R2is independently selected at each occurrence from hydrogen, fluoro, chloro, bromo, iodo, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, trifluoroethyl, hexafluoroisopropyl, and RpO-, wherein Rpis selected from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl.

14. The method of any one of claims 1-11, wherein R2is independently selected at each occurrence from hydrogen, halo, nitro, and C1-C6 haloalkyl.

15. The method of any one of claims 1-11, wherein R2is independently selected at each occurrence from hydrogen, fluoro, chloro, bromo, iodo, nitro, trifluoromethyl, trifluoroethyl, and hexafluoroisopropyl.

16. The method of any one of claims 1-15, whereinselected17. The method of claim 1, wherein the compound is selected fromAttorney Docket No.103361-522WO1or a pharmaceutically acceptable salt or derivative thereof.

18. The method of any one of claims 1-17, wherein the subject is a human.

19. The method of any one of claims 1-18, wherein the cancer is selected from prostate cancer, colon cancer, acute myeloid leukemia, or hepatocellular carcinoma.

20. The method of any one of claims 1-19, wherein the cancer is androgen receptor positive.

21. The method of claim 20, wherein the cancer is androgen receptor positive hepatocellular carcinoma.

22. A compound selected from:or a pharmaceutically acceptable salt or derivative thereof.

23. A pharmaceutical composition comprising a compound of claim 22, or a pharmaceutically acceptable salt or derivative thereof, and a pharmaceutically acceptable carrier or excipient.

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