Targeting estrogen signaling in the treatment of peripheral neuropathy, aging, & metabolic disease

Abstract

Disclosed are methods for treating age-related disorders, metabolic perturbations, and / or peripheral neuropathic conditions in a subject by targeting estrogen receptors. In some embodiments, the targeting composition comprises an estradiol, such as 17α estradiol, or a carborane or carborane analog. The composition can include a selective ERβ agonist. Also provided are pharmaceutical compositions comprising a therapeutically effective amount of a composition to treat age-related metabolic perturbations and / or peripheral neuropathic conditions.

Description

[0001] Attorney Docket No.: 103362-074WO1 TARGETING ESTROGEN SIGNALING IN THE TREATMENT OF PERIPHERAL NEUROPATHY, AGING, & METABOLIC DISEASE

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims benefit of U. S. Provisional Application No. 63 / 727,711, filed December 4, 2024, incorporated herein by reference in its entirety.

[0004] BACKGROUND

[0005] The National Institute on Aging (NIA’s) intervention testing program (ITP) has tested numerous potential longevity treatments across 3 academic research sites, using the genetically heterogeneous yet reproducible IIET3 strain. HET3 mice have more varied age-related morbidities, more closely mimicking human aging. The majority of ITP -tested compounds that increase lifespan only do so in male mice, but a few have increased lifespan in males and females. Distinct from lifespan extension, ITP compounds may improve health span (the life lived free from disease) in one or both sexes, but few studies have assessed these endpoints. It was previously demonstrated that one ITP-tested compound that does increase lifespan in males and females, rapamycin, actually does not improve health span of the peripheral nervous system (which has increased risk for peripheral neuropathy across aging), and actually worsened aged adipose tissue health.

[0006] Further, age-related peripheral neuropathy (PN) is a top cause of small fiber PN in humans, and it has been previously demonstrated that PN also impacts subcutaneous adipose tissue of aged mice and humans. There are numerous observations of less severe diabetic PN in female mice, with protection from age-related PN in females until reproductive senescence (ie: menopause), but it was recently found that PN in skin, muscle and adipose was not mitigated with rapamycin longevity treatment in aged HET3 mice of either sex.

[0007] There is currently no cure for PN, including age-related PN. Accordingly, new methods and compositions for the diagnosing, preventing, and / or treating of age-related disorders, metabolic perturbations, and / or peripheral neuropathic conditions are needed, as well as kits comprising tools to do so.

[0008] SUMMARY

[0009] Disclosed herein are methods and compositions for the treatment of metabolic disease, (such as age-related metabolic perturbations), as well as peripheral neuropathic conditions, Attorney Docket No.: 103362-074WO1

[0010] and / or improvement of overall health span and effects of aging or reproductive senescence, including with menopause or loss of reproductive hormones with aging in males or females. Additionally, metabolic diseases like obesity, diabetes or cardiometabolic disease, or any small fiber neuropathies (including but not limited to those caused by aging, chemotherapy, viruses, metabolic disease) can benefit from targeting the estrogen signaling axis at the level of the ligand or receptor.

[0011] Methods for the treatment of metabolic disease (such as age-related metabolic perturbations), as well as peripheral neuropathic conditions, and / or improvement of overall health span and effects of aging can comprise targeting estrogen receptors, such as the estrogen receptor p (also referred to herein as ERp or ERBeta), This can be done, for example, by administering a therapeutically effective amount of an estradiol, such as 17a estradiol (or a derivative thereof), carborane, or a carborane analog to the subject. In some embodiments, these methods can comprise administering a therapeutically effective amount of 17a estradiol or a carborane.

[0012] In some embodiments, the estradiol can be defined by Formula XV, or a pharmaceutically acceptable salt thereof

[0013]

[0014] Specifically, the estradiol can be defined by Formula XVI, which is 17a estradiol: Attorney Docket No.: 103362-074WO1

[0015]

[0016] In some embodiments, the carborane can be defined by Formula II, or a pharmaceutically acceptable salts thereof

[0017] X— Z Q-R1

[0018] / /

[0019] Formula II

[0020] wherein

[0021] Q is a substituted or unsubstituted dicarba-closo-dodecaborane cluster, and

[0022]

[0023] and R1are attached to Q in a para configuration;

[0024] X is OH, NHR2, SH, or S(O)(O)NHR2;

[0025] R1is substituted or unsubstituted C4-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C3-C20 alkylaryl, substituted or unsubstituted C3-C20 alkylheteroaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, substituted or un substituted C4-C20 alkylheterocycloalkyl, substituted or unsubstituted C1-C20 acyl, or NR3R4;

[0026] R2is H, OH, halogen, or substituted or unsubstituted C1-C1 alkyl;

[0027] R3and R4are independently selected from substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or un substituted C2-C20 alkylaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, or substituted or unsubstituted C1-C20 acyl;

[0028] with the proviso that when X is OH, R1is not (CH2)sCH(CH3)2 or NH2.

[0029] In some examples of Formula II, Q can be:

[0030]

[0031] Attorney Docket No.: 103362-074WO1

[0032] wherein

[0033] • is a carbon atom or a boron atom; and

[0034] o is C-H, C-halogen, C-alkyl, C-OH, C-NH2, B-H, B-halogen, B-alkyl, B-OH, or B-NH2. In some examples of Formula II, X is OH.

[0035] In some examples of Formula II, R1is a substituted or unsubstituted Ce-Cio alkyl. In some examples of Formula II, R1is a Ce-Cio hydroxyalkyl. In some examples of Formula II, R1is a C3-C16 hydroxyalkylaryl. In some examples of Formula II, R1is a substituted or unsubstituted branched C4-C10 alkyl. In some examples of Formula II, R1is a branched C1-C10 hydroxy alkyl.

[0036] In some examples, the carborane can defined by Formula III, or a pharmaceutically acceptable salt thereof:

[0037]

[0038] Formula III

[0039] wherein

[0040] • is a carbon atom;

[0041] o is B-H, B-halogen, B-alkyl, B-OH, or B-NH2;

[0042] X is OH, NHR2, SH, or S(O)(O)NHR2;

[0043] R1is substituted or un substituted C4-C20 alkyl, substituted or un substituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C3-C20 alkylaryl, substituted or unsubstituted C3-C20 alkylheteroaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, substituted or unsubstituted C4-C20 alkylheterocycloalkyl, substituted or unsubstituted C1-C20 acyl, or NR3R4;

[0044] R2is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl; and

[0045] R3and R4are independently selected from substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C2-C20 alkylaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, or substituted or unsubstituted C1-C20 acyl;

[0046] with the proviso that when X is OH, R1is not (CH2)sCH(CH3)2 or NH2.

[0047] In some examples of Formula III, X is OH. Attorney Docket No.: 103362-074WO1

[0048] In some examples, the carborane can be defined by Formula IV, or a pharmaceutically acceptable salt thereof

[0049]

[0050] Formula IV

[0051] wherein

[0052] • is a carbon atom;

[0053] o is B-H, B-halogen, B-alkyl, B-OH, or B-NH2;

[0054] the dotted line to Y indicates that the bond can be a single bond or a double bond, as valence permits;

[0055] X is OH, NHR2, SH, or S(O)(O)NHR2;

[0056] Y is O, OR2', NHR2, SH, or S(O)(O)NHR2;

[0057] R5is substituted or unsubstituted C2-C19 alkyl, substituted or unsubstituted C2-C19 alkenyl, substituted or unsubstituted C2-C19 alkynyl, substituted or unsubstituted C2-C19 alkylaryl, substituted or unsubstituted C2-C19 alkylheteroaryl, substituted or unsubstituted C3-C19 alkylcycloalkyl, substituted or un substituted C3-C19 alkylheterocycloalkyl, or NR3R4;

[0058] R2is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl;

[0059] R2is H or substituted or unsubstituted C1-C4 alkyl; and

[0060] R3and R4are independently selected from substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or un substituted C2-C20 alkylaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, or substituted or unsubstituted C1-C20 acyl.

[0061] In some examples of Formula IV, the carborane cluster can include a heteroatom. In some examples of Formula IV, the carborane cluster can include an isotopically labeled atom (i.e., a radiolabel ed atom). In some examples of Formul a IV, the carborane cluster can include an isotopically labeled Boron atom (e.g.,10B).

[0062] In some examples of Formula IV, X is OH.

[0063] In some examples of Formula IV, Y is OH. In some examples of Formula IV, Y is O. In some examples of Formula IV, R5is a substituted or unsubstituted C3-C9 alkyl. In some examples of Formula IV, R5is a substituted or unsubstituted C6-C9 alkyl. In some examples of Formula IV, R5is a substituted or unsubstituted C2-C15 alkylaryl. In some examples of Formula IV, R5is a substituted or unsubstituted branched C2-C9 alkyl.

[0064] In some embodiments, the carborane or carborane analog comprises an ERP agonist. For Attorney Docket No.: 103362-074WO1

[0065] example, in some cases, the carborane or carborane analog has an EC₅₀ of 800 nM or less, such as an EC₅₀ of 6 nM or less, against estrogen receptor beta (ERP).

[0066] In certain embodiments, the carborane or carborane analog comprises a selective ER agonist. For example, in some cases, the carborane or carborane analog can have an ERP-to-ERa agonist ratio of 8 or more, such as an ERP-to-ERa agonist ratio of 400 or more.

[0067] In certain embodiments, the carborane or carborane analog can comprise WT-IV-012, the structure of which is shown below

[0068] OH HO

[0069]

[0070] Also provided are pharmaceutical compositions comprising a therapeutically effective amount of a carborane or carborane analog described herein for the treatment of metabolic disease (such as age-related metabolic perturbations), as well as peripheral neuropathic conditions, and / or improvement of overall health span and effects of aging.

[0071] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

[0072] DESCRIPTION OF DRAWINGS

[0073] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate certain examples of the present disclosure and together with the description, serve to explain, without limitation, the principles of the disclosure. Like numbers represent the same elements throughout the figures.

[0074] Figure 1 A-1E shows the expression of Estrogen Receptors on Peripheral Nerves. Fig. 1 A shows ERa expression in dorsal root ganglia (DRG). Fig. IB shows ERa expression in support cells of the sciatic nerve, Navi.8 reporter labels sensory nerves. Fig. 1C-D shows that ERP is expressed in DRG of female and male mice at levels that innervate scWAT. Confocal imaging at 40X (2X digital zoom in inserts). Fig. IE shows schematic of study design and timeline of interventions.

[0075] Fig. 2 A-C shows that estrogen receptors a (ERa) (Fig. 2A) and ERP (Fig. 2B) are highly expressed in mouse inguinal scWAT including on nerve support cells of scWAT axons (labeled with pan-neuronal PGP9.5) in both female (left panels) and male (right panels). Confocal imaging Attorney Docket No.: 103362-074WO1

[0076] at 10X (top panels) and 40X (bottom panels). Fig. 2C shows validation of ERp antibody in liver of wild type (WT) versus whole body ERP knock-out (KO ) female mice.

[0077] Figure 3A-C show circulating estrogens in HET3 mice with anti-aging 17a-Estradiol (17aE2) diet and impacts on metabolism for both sexes. Figure 3A shows that 17a-estradiol (17aE2), 17p~estradiol (E2), and estrone (El), were measured by mass spec in male HET3 mice, following 19wks of 17aE2 treatment, confirming a specific increase in only 17aE2 after diet treatment. N=10-14 per group. Figure 3B show that body weight, and total fat mass were significantly decreased for both males and females in Early Intervention (El ) 17aE2 treatment, total fat mass was also decreased with Late Intervention (LI) 17aE2 treatment. Figure 3C shows glucose tolerance testing revealed improved glucose sensitivity for 17aE2 treated male mice compared to control at LI, while female glucose sensitivity was improved in El and LI 17aE2 treatment groups.

[0078] Figure 4A-D shows effects of 17oE2 treatment on adipose tissue by gross anatomy and histological assessments. Fig. 4A shows that subcutaneous (sc), visceral / peri gonadal (pg) white adipose tissue (WAT), and brown adipose tissue (BAT) decreased in size and appeared browner (gross anatomy images), with Early Intervention (El) and Late Intervention (LI) 17aE2 treatment, indicating an improved metabolic phenotype. Fig. 4B shows terminal body and tissue weight for male and female mice. Fig. 4C shows hemalum staining and cell size quantification of axillary (ax)- scWAT from male El 17aE2 treatment group. Fig. 4D shows hemalum staining of inguinal (ing)-scWAT from El 17ctE2 and LI 17aE2 treatments for male and female animals. (C-D) Brightfield imaging at 10X.

[0079] Figure 5 shows hemalum staining of perigonadal (pg)-scWAT from El 17aE2 and LI 17aE2 treatments for male and female animals. Brightfield imaging at 1 OX.

[0080] Figure 6A-B shows adipose fibrosis assessed by Piero Sirius Red staining of collagen in axillary (ax)-scWAT from male (Fig. 6A) and ing-scWAT from female (Fig. 6B) El and LI 17aE2 treatment groups. Polarized light imaging used to determine total birefringence and collagen fiber types. Brightfield and polarized light imaging at 10X.

[0081] Figure 7A-B shows energy expenditure is increased in male HET3 mice following El 17aE2 treatment. Fig. 7A shows oxygen consumption (VO2), carbon dioxide production (VCO2), energy expenditure (calculated from VO2 and VCO2), and respiratory exchange ratio (RER), measure in metabolic cages. All males, N=4 per group. Fig. 7B shows lipidomics analysis of ing-scWAT from El 17aE2 treated males, including significant changes in expression of signaling Attorney Docket No.: 103362-074WO1

[0082] lipids; (i) heat map of differenti lly expressed lipids, (ii) Volcano plot of differentially expressed lipids with top 15 labeled.

[0083] Figure 8A-E shows lipidomics analysis of ing-scWAT from El 17aE2 treated males. Fig.

[0084] 8A-B show Principle Component Analysis (PCA) plots for 17aE2 treated (pink) and control groups (green). Fig. 8C shows Partial Least Squares Discriminant Analysis (PLS-DA) plots for 17aE2 treated (pink) and control groups (green). Fig. 8D shows Variable Importance in Projection (VIP) scores from PLS-DA analysis, indicating the main discriminating features (lipids) between the two groups. Fig. 8E show a correlation plot for all differentially expressed lipids in the analysis.

[0085] Figure 9A-B shows that El and LI 17aE2 treatment improved peripheral nerve parameters in male and female HET3 mice. In Fig. 9A muscle strength and contractility was measured as hind limb (HL) grip strength and tetanic torque (max muscle contractility). The Early Intervention (El) 17aE2 treatment trended to increase grip and resulted in increased contractility, indicating overall improved neuromuscular junction (NMJ) function. Fig. 9B shows results from repetitive nerve stimulation (RNS) testing. RNS causes NMJ fatigue through ACh depletion. A decremental response on RNS is the electrical correlate of clinical muscle fatigue and weakness. El 17aE2 treatment showed improved NM J function in male HET3 mice (Fig. 9B).

[0086] Figures 10A-C show that 17aE2 longevity treatment improved small fiber nerve health peripheral nerve parameters in female and male HET3 mice. Figure 5A shows that early intervemion (El) 17oE2 treatment improved mechanical nociception only in female HE T3 mice, as determined by SUDO Von Frey analysis. Figure 5B-C shows that small fiber peripheral neuropathy (PN) in glabrous skin was assessed by intraepidermal nerve fiber density (IENFD) staining with PGP9.5. IENFD was significantly improved in female HET3 mice in the LI 17CLE2 treated group compared to controls.

[0087] Figure 11A-B shows whole-mount staining of innervation and vasculature in female inguinal scWAT tissues. Adipose was excised from female HET3 mice in Early Intervention (El) 17aE2 treatment. Late Intervention (LI) 17aE2 treatment, and respective control groups. Tissues were immunostained against the sensory nerve marker CGRP (magenta), vasculature (CD31, green), pan-neuronal marker (PGP9.5 yellow), and nuclear stain (D PI, blue). Micrographs of the entire tissues were generated by tiling 10X objective magnification images. (B) Quantification of whole mount staining for neurite density (left panels) and vascular density (right panels).

[0088] Figure 12A-B shows innervation of popliteal adipose, a white adipose depot located in the popliteal fossa, as assessed by Western Blot in El (Fig. 12A) and LI males (Fig. 12B). Attorney Docket No.: 103362-074WO1

[0089] Markers of innervation included: PGP9.5 (pan-neuronal), advillin (sensory), tyrosine hydroxylase (predominately sympathetic), and GAP43 (growth-cone, and Schwann cell marker).

[0090] Figure 13A-B shows food intake and body weight from diet-induced obese (DIO) mice on 17aE2 and ERP-agonist treatment (in diet). A diet induced obesity model of peripheral neuropathy (PN) was employed to evaluated effects of estrogenic treatment in (PN) with metabolic etiology. Adult male C57BL6 / CR mice were placed on a 58% high fat neuropathyinducing diet (HFND) for 10 wks. Animals were then placed on a 58% HFND with 14.4ppm 17aE2 (standard ITP dose), 58% HFND with 400ppm OSU-ERP-12 (a ERP selective agonist), or maintained on the 58% HFND. (Fig. 13 A) Daily food intake (FI) was measured for the first 7 days of dietary-drug intervention. Longitudinal data, (left panel), cumulative FI (right panel). (Fig. 13B) Percent change in body weight from start of drug-diet intervention shown longitudinally across 3 weeks (left panel) and cumulatively (right panel).

[0091] Figure 1 shows tactile sensitivity in standard chow versus DIO male mice with or without estrogenic treatment. Adult male C57BL6 / CR mice were placed on a 58% high fat neuropathy¬ inducing diet (HFND) for 10 wks. Animals were then placed on a 58% HFND with 14.4ppm 17aE2 (standard ITP dose), 58% HFND with 400ppm OSU-ERP-12 (a ERP selective agonist), or maintained on the 58% HFND. At 3 weeks of treatment SUDO Von Frey behavioral assay was performed on both hind paws. Results are shown for each individual paw (left and middle panels) as well as averaged across both paws (right panel).

[0092] Figure 15 shows study design to evaluate neuroprotective effects of 17a-E2 treatment in a mouse model (3xTg) of Alzheimer’s disease (AD). Female transgenic (3xTg) mice were placed on either a standard chow or 17a-E2 diet (14.4ppm) at 4-5 months old. Control groups included non-transgenic (Non-Tg) on standard chow (control for AD progression) and a Non-Tg group on 58% high fat neuropathy inducing diet (HFND) (control for peripheral neuropathy development).

[0093] Figure 16 shows, for the model described in Figure 15, glucose tolerance testing (GTT) and body weight (BW) at baseline, prior to 17a-E2 treatment intervention (left panel) and after 11 weeks of 17a-E2 treatment intervention (right panel). At baseline testing, when mice were 4-5 months old 3xTg animals exhibited mild metabolic impairment compared to non-Tg animals. Following 11 weeks of 17a-E2 treatment no difference in body weight or GTT was observed in 3xTg animals.

[0094] Figure 17 shows glucose tolerance testing (GTT) and body weight (BW) 17 weeks of 17a-E2 treatment for the model described in Figure 15. By 17 weeks of 17a-E2 treatment, no significant difference in GTT or BW is seen between 3xTg mice on 17a-E2 diet and 3xTg mice Attorney Docket No.: 103362-074WO1

[0095] on standard chow (control). However, 3xTg control and 17a-E2 treatment groups appear to be diverging.

[0096] Figure 18 shows tactile sensitivity testing for the model described in Figure 15. SUDO Von Frey assessments were performed at baseline in 4-5 month 3xTg and non-Tg female mice.

[0097] 3xTg mice showed reduced tactile sensitivity compared to non-Tg controls indicating impaired small fiber nerve function (left panel). / At 11- (middle panel) and 17 weeks (right panel) of 17a-E2 treatment no difference in tactile sensitivity is seen in 3xTg control versus of 17a-E2 treatment groups.

[0098] Figure 19 shows indirect calorimetry' for the model described in Figure 15. Compared to sex and age matched non-Tg animals and 3xTg on 11 weeks of 17a-E2 treatment, 3xTg on standard chow diet show increased oxygen consumption.

[0099] Figure 20 shows increased energy expenditure (Figure 20 top panel). 3xTg on 11 weeks of 17a-E2 treatment, show lower respiratory exchange ratio (RER) compared to 3xTg on standard chow and non-Tg mice indicative of preferential lipid metabolism over carbohydrates for fuel (Figure 20 bottom panel).

[0100] Figure 21 shows 3xTg 17a-E2 treated mice also exhibit decrease in food intake compared to 3xTg mice on standard chow (Figure 21 top panel). These results indicate that 17a-E2 treatment alters metabolic phenotype in 3xTg mice.

[0101] Figure 22 shows nerve conductance velocity (NCV) testing for the model described in Figure 15. NCV measures function of large fiber motor and sensory nerves. No difference is seen in sensory NCV (SNCV) or motor NCV (MNCV) between non-Tg and 3xTg at 4-5 months of age (baseline, top left panel). No difference in SNC V or MNCV is seen for any groups following 11 weeks of 17a-E2 treatment (top right panels) or 18 weeks of 17a-E2 treatment (bottom left and middle panels). At 18 weeks of 17a-E2 treatment and increase in amplitude of evoked action potentials is evident in 3xTg mice on 17a-E2 treatment compared to 3xTg mice on standand chow (control ) (bottom right panel).

[0102] Figure 23 Compared to age-matched non-Tg control mice, 35-38 week old female 3xTg mice show reduced strength in evoked action potentials in motor nerves. However, 35-38 week old female 3xTg mice that were on 18wks of 17aE2 treatment (14.4ppm in diet) do not exhibit reduced action potential strength and are comparable to age-matched non-Tg controls, implying protection against large fiber nerve regeneration in this model. Attorney Docket No.: 103362-074WO1

[0103] DETAILED DESCRIPTION

[0104] The compounds, compositions, and methods described herein may be understood more readily by reference to the following detailed description of specific aspects of the disclosed subject matter and the Examples included therein.

[0105] Before the present compounds, compositions, and methods are disclosed and described, it is to be understood that the aspects described below are not limited to specific synthetic methods or specific reagents, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting.

[0106] Also, throughout this specification, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which the disclosed matter pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon.

[0107] General Definitions

[0108] In this specification and in the claims that follow, reference will be made to a number of terms, which shall be defined to have the following meanings.

[0109] As used in the description and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a composition” includes mixtures of two or more such compositions, reference to “an agent” includes mixtures of two or more such agents, reference to “the component” includes mixtures of two or more such components, and the like.

[0110] Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that when a value is disclosed that “less than or equal to” the value, “greater than or equal to the value” and possible Attorney Docket No.: 103362-074WO1

[0111] ranges between values are also disclosed, as appropriately understood by the skilled artisan. For example, if the value “10” is disclosed the “less than or equal to 10” as well as “greater than or equal to 10” is also disclosed. It is also understood that throughout the application, data is provided in a number of different formats, and that this data represents endpoints and starting points, and ranges for any combination of the data points. For example, if a particular data point “10” and a particular data point 15 are disclosed, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as well as between 10 and 15. It is also understood that each unit between two particular units is also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0112] The term “administer,” “administering”, or derivatives thereof refer to delivering a composition, substance, inhibitor, or medication to a subject or object by one or more the following routes: oral, topical, intravenou, subcutaneous, transcutaneous, transdermal, intramuscular, intrajoint, parenteral, intra- arteriole, intradermal, intraventricular, intracranial, intraperitoneal, intralesional, intranasal, rectal, vaginal, by inhalation or via an implanted reservoir. The term “parenteral” includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injections or infusion techniques.

[0113] As used herein, the term “buffer” refers to a solution consisting of a mixture of acid and its conjugate base, or vice versa. The solution is used as a means of keeping the pH at a nearly constant range to be used in a wide variety of chemical and biological applications.

[0114] Throughout the description and claims of this specification the word “comprise” and other forms of the word, such as “comprising” and “comprises,” means including but not limited to, and is not intended to exclude, for example, other additives, components, integers, or steps.

[0115] " Comprising" is intended to mean that the compositions, methods, etc. include the recited elements, but do not exclude others. " Consisting essentially of' when used to define compositions and methods, shall mean including the recited elements, but excluding other elements of any essential significance to the combination. Thus, a composition consisting essentially of the elements as defined herein would not exclude trace contaminants from the isolation and purification method and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives, and the like. " Consisting of" shall mean excluding more than trace elements of other ingredients and substantial method steps for administering the compositions provided and / or claimed in this disclosure. Embodiments defined by each of these transition terms are within the scope of this disclosure. Attorney Docket No.: 103362-074WO1

[0116] As used herein, “diagnose,” “diagnosed,” “diagnosing,” and any grammatical variations thereof as used herein, refers to the act of process of identifying the nature of an illness, disease, disorder, or condition in a subject by examination or monitoring of symptoms.

[0117] The term “detect” or “detecting” refers to an output signal released for the purpose of sensing of physical phenomenon. An event or change in environment is sensed and signal output released in the form of light.

[0118] " Differentially expressed" as applied to a gene or protein, refers to the differential production of the mRNA transcribed from the gene, or the protein product. A differentially expressed gene (or its protein product) may be overexpressed or under expressed as compared to the expression level of a normal or control cell. In one aspect, it refers to a differential that is 2.5 times, preferably 5 times, or preferably 10 times higher or lower than the expression level detected in a control sample. The term "differentially expressed" also refers to nucleotide sequences or proteins in a cell or tissue which are expressed / present where silent in a control cell or not expressed / present were expressed in a control cell.

[0119] A "decrease" can refer to any change that results in a smaller amount of a symptom, disease, composition, condition, or activity. A substance is also understood to decrease the genetic output of a gene when the genetic output of the gene product with the substance is less relative to the output of the gene product without the substance. Also, for example, a decrease can be a change in the symptoms of a disorder such that the symptoms are less than previously observed. A decrease can be any individual, median, or average decrease in a condition, symptom, activity, composition in a statistically significant amount. Thus, the decrease can be a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% decrease so long as the decrease is statistically significant.

[0120] “Expression” as used herein refers to the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce a peptide / protein end product, and ultimately affect a phenotype, as the final effect.

[0121] It is understood that throughout this specification the identifiers “first” and “second” are used solely to aid in distinguishing the various components and steps of the disclosed subject matter. The identifiers “first” and “second” are not intended to imply any particular order, amount, preference, or importance to the components or steps modified by these terms.

[0122] A "gene" refers to a polynucleotide containing at least one open reading frame that is capable of encoding a particular polypeptide or protein after being transcribed and translated. Any Attorney Docket No.: 103362-074WO1

[0123] of the polynucleotide’s sequences described herein may be used to identify larger fragments or full-length coding sequences of the gene with which they are associated.

[0124] An "increase" can refer to any change that results in a greater amount of a symptom, disease, composition, condition, or activity. An increase can be any individual, median, or average increase in a condition, symptom, activity, composition in a statistically significant amount. Thus, the increase can be a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% increase so long as the increase is statistically significant.

[0125] " Inhibit," "inhibiting," and "inhibition" mean to decrease an activity, response, condition, disease, or other biological parameter. This can include but is not limited to the complete ablation of the activity, response, condition, or disease. This may also include, for example, a 10% reduction in the activity, response, condition, or disease as compared to the native or control level. Thus, the reduction can be a 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%, or any amount of reduction in between as compared to native or control levels.

[0126] The term “inhibit” refers to a decrease in an activity, response, condition, disease, or other biological parameter. This can include but is not limited to the complete ablation of the activity, response, condition, or disease. This can also include, for example, a 10% reduction in the activity, response, condition, or disease as compared to the native or control level. Thus, the reduction can be a 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%, or any amount of reduction in between as compared to native or control levels.

[0127] “Marker” in the context of the present invention refers to a polypeptide (of a particular apparent molecular weight) which is differentially present in a sample taken from patients having peripheral neuropathy as compared to a comparable sample taken from control subjects (e.g., a person with a negative diagnosis, normal or healthy subject).

[0128] A “nucleic acid” is a chemical compound that selves as the primary information-carrying molecules in cells and makes up the cellular genetic material. Nucleic acids comprise nucleotides, which are monomers made of a 5-carbon sugar (usually ribose or deoxyribose), a phosphate group, and a nitrogenous base. A nucleic acid can also be a deoxyribonucleic acid (DNA) or a ribonucleic acid (RNA). A chimeric nucleic acid comprises two or more of the same kind of nucleic acid fused together to form one compound comprising genetic material.

[0129] “Optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0130] By “prevent” or other forms of the word, such as “preventing” or “prevention,” is meant Attorney Docket No.: 103362-074WO1

[0131] to stop a particular event or characteristic, to stabilize or delay the development or progression of a particular event or characteristic, or to minimize the chances that a particular event or characteristic will occur. Prevent does not require comparison to a control as it is typically more absolute than, for example, reduce. As used herein, something could be reduced but not prevented, but something that is reduced could also be prevented. Likewise, something could be prevented but not reduced, but something that is prevented could also be reduced. It is understood that where reduce or prevent are used, unless specifically indicated otherwise, the use of the other word is also expressly disclosed. For example, the terms “prevent” or “suppress” can refer to a treatment that forestalls or slows the onset of a disease or condition or reduced the severity of the disease or condition. Thus, if a treatment can treat a disease in a subject having symptoms of the disease, it can also prevent or suppress that disease in a subject who has yet to suffer some or all of the symptoms.

[0132] As used herein, unless otherwise specified, the terms “prevent,” “preventing” and “prevention” refers to an action that occurs before the subject begins to suffer from the condition, or relapse of such condition. The prevention need not result in a complete prevention of the condition; partial prevention or reduction of age-related metabolic perturbations and / or peripheral neuropathic conditions (or a symptom thereof) in a subject is encompassed by this term.

[0133] A “protein,” "polypeptide", or “peptide” each refer to a polymer of amino acids and does not imply a specific length of a polymer of amino acids. Thus, for example, the terms peptide, oligopeptide, protein, antibody, and enzyme are included within the definition of polypeptide. This term also includes polypeptides with post-expression modification, such as glycosylation (e.g., the addition of a saccharide), acetylation, phosphorylation, and the like.

[0134] / As used herein, unless otherwise specified, a “prophylactically effective amount” of an ERP that, when administered alone or in combination, prevent the condition, or one or more symptoms associated with the condition, or prevent its recurrence. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. The prophylactic amount need not result in a complete prevention of the condition; partial prevention or reduction of age-related metabolic perturbations and / or peripheral neuropathic conditions (or a symptom thereof) in a subject is encompassed by this term. In other embodiments, a “prophylactically effective amount” can refer to an amount that prevents a flare of metabolic disorders and / or peripheral neuropathic conditions symptoms in a subject. Attorney Docket No.: 103362-074WO1

[0135] The term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0136] A “receptor” is a cellular protein whose activation causes a cell to modify its present functions or actions.

[0137] By “reduce” or other forms of the word, such as “reducing” or “reduction,” is meant lowering of an event or characteristic. It is understood that this is typically in relation to some standard or expected value, in other words it is relative, but that it is not always necessary for the standard or relative value to be referred to.

[0138] As used herein, by a “subject” is meant an individual. Thus, the “subject” can include domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), laboratory animals (e.g., mouse, rabbit, rat, guinea pig, etc.), and birds. “Subject” can also include a mammal, such as a primate or a human. Thus, the subject can be a human or veterinary patient. The term “patient” refers to a subject under the treatment of a clinician, e.g., physician.

[0139] The term “treatment” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. By way of example, in the context of age-related metabolic perturbations and / or peripheral neuropathic conditions, “treating,” “treat,” and “treatment” as used herein, refers to partially or completely inhibiting of peripheral neuropathic conditions from which the subject is suffering. In one embodiment, this term refers to an action that occurs while a patient is suffering from, or is diagnosed with, age- metabolic disorders, effects of aging, and / or peripheral neuropathic conditions, which reduces the severity of the condition, or retards or slows the progression of the condition. Treatment need not Attorney Docket No.: 103362-074WO1

[0140] result in a complete cure of the condition; partial inhibition or reduction of metabolic disorders, effects of aging, and / or peripheral neuropathic conditions is encompassed by this term.

[0141] “Therapeutically effective amount,” as used herein, refers to a minimal amount or concentration of an ERp agonist that, when administered alone or in combination, is sufficient to provide a therapeutic benefit in the treatment of the condition, or to delay or minimize one or more symptoms associated with the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent. The therapeutic amount need not result in a complete cure of the condition; partial inhibition or reduction of metabolic disorders, effects of aging, and / or peripheral neuropathic conditions (or a symptom thereof) is encompassed by this term.

[0142] A “test amount” of a marker refers to an amount of a marker present in a sample being tested. A test amount can be either in absolute amount (e.g., pg / ml) or a relative amount (e.g., relative intensity of signals).

[0143] A “control” is an alternative subject or sample used in an experiment for comparison purposes. A control can be "positive" or "negative."

[0144] A “control amount” of a marker can be any amount or a range of amount which is to be compared against a test amount of a marker. For example, a control amount of a marker can be the amount of a marker in a person without peripheral neuropathy. A control amount can be either in absolute amount (e.g., pg / ml) or a relative amount (e.g., relative intensity of signals).

[0145] “Peripheral neuropathy” is defined herein as aberrant nerve function, axonal loss, demyelination, or dysfunction / loss of nerve support cells. Generally, peripheral neuropathy refers to a group of disorders resulting from damage or dysfunction of the peripheral nervous system, which includes the sensoiy, motor, and autonomic nerves outside the brain and spinal cord. It is characterized by a wide range of clinical manifestations, including sensory disturbances (e g., pain, paresthesia, or numbness), motor deficits (e.g., weakness or atrophy), and autonomic dysfunction (e.g., orthostatic hypotension or gastrointestinal motility issues). The etiology of peripheral neuropathy is diverse and includes metabolic disorders (e.g., diabetes mellitus), infectious diseases, autoimmune conditions, toxic exposures, nutritional deficiencies, hereditary' factors, and idiopathic causes. Its clinical presentation may vary' from focal to diffuse involvement, and it can be acute, subacute, or chronic in onset. Diagnostic evaluation typically involves a combination of clinical assessment, electrophysiological studies, and, in some cases, laboratory testing or nerve biopsy. Attorney Docket No.: 103362-074WO1

[0146] “Adsorbent” refers to any material capable of adsorbing a marker. The term “adsorbent” is used herein to refer both to a single material (“monoplex adsorbent”) (e.g., a compound or functional group) to which the marker is exposed, and to a plurality of different materials (“multiplex adsorbent”) to which the marker is exposed. The adsorbent materials in a multiplex adsorbent are referred to as “adsorbent species.” For example, an addressable location on a probe substrate can comprise a multiplex adsorbent characterized by many different adsorbent species (e.g., anion exchange materials, metal chelators, or antibodies), having different binding characteristics. Substrate material itself can also contribute to adsorbing a marker and may be considered part of an “adsorbent.”

[0147] “Adsorption” or “retention” refers to the detectable binding between an absorbent and a marker either before or after washing with an eluant (selectivity threshold modifier) or a washing solution.

[0148] “Eluant” or “washing solution” refers to an agent that can be used to mediate adsorption of a marker to an adsorbent. Eluants and washing solutions are also referred to as “selectivity threshold modifiers.” Eluants and washing solutions can be used to wash and remove unbound materials from the probe substrate surface.

[0149] “Substrate” or “probe substrate” refers to a solid phase onto which an adsorbent can be provided (e.g., by attachment, deposition, etc.).

[0150] “Resolve,” “resolution,” or “resolution of marker” refers to the detection of at least one marker in a sample. Resolution includes the detection of a plurality of markers in a sample by separation and subsequent differential detection. Resolution does not require the complete separation of one or more markers from all other biomolecules in a mixture. Rather, any separation that allows the distinction between at least one marker and other biomolecules suffices.

[0151] “Detectable moiety” or a “label” refers to a composition detectable by spectroscopic, photochemical, biochemical, immunochemical, or chemical means. For example, useful labels include32P,35S, fluorescent dyes, electron-dense reagents, enzymes (e.g., as commonly used in an ELISA), biotin-streptavidin, digoxigenin, haptens and proteins for which antisera or monoclonal antibodies are available, or nucleic acid molecules with a sequence complementary to a target. The detectable moiety often generates a measurable signal, such as a radioactive, chromogenic, or fluorescent signal, that can be used to quantify the amount of bound detectable moiety in a sample. Quantitation of the signal is achieved by, e.g., scintillation counting, densitometry, or flow cytometry. Attorney Docket No.: 103362-074WO1

[0152] “Immunoassay” is an assay that uses an antibody to specifically bind an antigen (e.g., a marker). The immunoassay is characterized by the use of specific binding properties of a particular antibody to isolate, target, and / or quantify the antigen.

[0153] “Sample” is used herein in its broadest sense. A sample comprising polynucleotides, polypeptides, peptides, antibodies and the like may comprise a bodily fluid; a soluble fraction of a cell preparation, or media in which cells were grown; a chromosome, an organelle, or membrane isolated or extracted from a cell; genomic DNA, RNA, or cDNA, polypeptides, or peptides in solution or bound to a substrate; a cell; a tissue; a tissue print; a fingerprint, skin or hair; and the like.

[0154] “Substantially purified” refers to nucleic acid molecules or proteins that are removed from their natural environment and are isolated or separated, and are at least about 60% free, preferably about 75% free, and most preferably about 90% free, from other components with which they are naturally associated.

[0155] “Substrate” refers to any rigid or semi-rigid support to which nucleic acid molecules or proteins are bound and includes membranes, filters, chips, slides, wafers, fibers, magnetic or nonmagnetic beads, gels, capillaries or other tubing, plates, polymers, and microparticles with a variety of surface forms including wells, trenches, pins, channels, and pores.

[0156] “Neural cells” as defined herein, are cells that reside in the brain, central and peripheral nerve systems, including, but not limited to, nerve cells, glial cell, oligodendrocyte, microglia cells or neural stem cells.

[0157] “Neuronal specific or neuronally enriched proteins” are defined herein, as proteins that are present in neural cells and not in non-neuronal cells, such as, for example, cardiomyocytes, myocytes, in skeletal muscles, hepatocytes, kidney cells and cells in testis.

[0158] “Neural (neuronal) defects, disorders or diseases” as used herein refers to any neurological disorder, including but not limited to neurodegenerative disorders (Parkinson's; Alzheimer's) or autoimmune disorders (multiple sclerosis) of the central nervous system; memory loss; long term and short term memory disorders; learning disorders; autism, depression, benign forgetfulness, childhood learning disorders, close head injury, and attention deficit disorder; autoimmune disorders of the brain, neuronal reaction to viral infection; brain damage; depression; psychiatric disorders such as bi-polarism, schizophrenia and the like; narcolepsy / sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy); severance of nerves or nerve damage; severance of the cerebrospinal nerve cord (CNS) and any damage to brain or nerve cells; neurological deficits associated with AIDS; tics (e.g. Giles de la Tourette's syndrome); Attorney Docket No.: 103362-074WO1

[0159] Huntington's chorea, schizophrenia, traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, MS and motor neuron disease, ataxias, muscular rigidity (spasticity) and temporomandibular joint dysfunction; Reward Deficiency Syndrome (RDS) behaviors in a subject.

[0160] Chemical Definitions

[0161] Terms used herein will have their customary meaning in the art unless specified otherwise. The organic moieties mentioned when defining variable positions within the general formulae described herein (e.g., the term “halogen”) are collective terms for the individual substituents encompassed by the organic moiety. The prefix Cn-Cm preceding a group or moiety indicates, in each case, the possible number of carbon atoms in the group or moiety that follows.

[0162] / As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms present in a compound or moiety, such as nitrogen, can have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valency of the heteroatom. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. Also, the terms “substitution” or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound (e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.

[0163] “Z1,” “Z2,” “Z3,” and “Z4” are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents.

[0164] As used herein, the term “alkyl” refers to saturated, straight-chained or branched saturated hydrocarbon moieties. Unless otherwise specified, C1-C24 (e.g., C1-C22, C1-C20, C1-C18, C1-C16, C1-C14, C1-C12, C1-C10, C1-C8, C1-C6, or C1-C4) alkyl groups are intended. Examples of Attorney Docket No.: 103362-074WO1

[0165] alkyl groups include methyl, ethyl, propyl, 1 -methyl -ethyl, butyl, 1-methyl-propyl, 2 -methylpropyl, 1,1 -dimethyl -ethyl, pentyl, 1 -methyl -butyl, 2-methyl-butyl, 3 - ethyl -butyl, 2,2-dimethyl-propyl, 1-ethyl-propyl, hexyl, 1,1-dimethyl-propyl, 1,2-dimethyl-propyl, 1 -methyl¬ pentyl, 2-methyl-pentyl, 3-methyl-pentyl, 4-methyl-pentyl, 1,1-dimethyl-butyl, 1,2-dimethyl-butyl, 1,3-dimethyl-butyl, 2,2-dimethyl-butyl, 2,3-dimethyl-butyl, 3,3-dimethyl-butyl, 1 -ethyl¬ butyl, 2-ethyl-butyl, 1,1,2-trimethyl-propyl, 1,2,2-trimethyl-propyl, 1-ethyl-l-methyl-propyl, and l-ethyl-2-methyl-propyl. Alkyl substituents may be unsubstituted or substituted with one or more chemical moieties. The alkyl group can be substituted with one or more groups including, but not limited to, hydroxy, halogen, acyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, acyl, aldehyde, amino, carboxylic acid, ester, ether, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol, as described below, provided that the substituents are sterically compatible and the rules of chemical bonding and strain energy are satisfied. The alkyl group can also include one or more heteroatoms (e.g., from one to three heteroatoms) incorporated within the hydrocarbon moiety. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus.

[0166] Throughout the specification “alkyl” is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group. For example, the term “halogenated alkyl” specifically refers to an alkyl group that is substituted with one or more halides (halogens; e.g., fluorine, chlorine, bromine, or iodine). The term “alkoxyalkyl” specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below. The term “alkylamino” specifically refers to an alkyl group that is substituted with one or more amino groups, as described below, and the like. When “alkyl” is used in one instance and a specific term such as “alkylal cohol” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “alkylalcohol” and the like.

[0167] This practice is also used for other groups described herein. That is, while a term such as “cycloalkyl” refers to both unsubstituted and substituted cycloalkyl moieties, the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g, an “alkyl cycloalkyl.” Similarly, a substituted alkoxy can be specifically referred to as, e.g., a “halogenated alkoxy,” a particular substituted alkenyl can be, e.g, an “alkenylalcohol,” and the like. Again, the practice of using a general term, such as “cycloalkyl,” and a specific term, such as “alkylcycloalkyl,” is not meant to imply that the general term does not also include the specific term. Attorney Docket No.: 103362-074WO1 As used herein, the term “alkenyl” refers to unsaturated, straight-chained, or branched hydrocarbon moieties containing a double bond. Unless otherwise specified, C2-C24 (e.g., C2-C22, C2-C20, C2-C18, C2-C16, C2-C14, C2-C12, C2-C10, C2-C8, C2-C6, C2-C4) alkenyl groups are intended. Alkenyl groups may contain more than one unsaturated bond. Examples include ethenyl, 1-propenyl, 2 -propenyl, 1 -methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1 -methyl- 1 -propenyl, 2-methyl-1 -propenyl, 1 -methyl -2-propenyl, 2-methyl-2-propenyl, 1 -pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1 -methyl- 1-butenyl, 2-methyl- 1-butenyl, 3 -methyl- 1-butenyl, l-methyl-2- butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1 -methyl -3 -butenyl, 2-methyl-3 -butenyl, 3-methyl-3 -butenyl, 1, 1 -dimethyl-2-propenyl, 1,2-dimethyl- 1 -propenyl, 1,2-dimethyl-2-propenyl, 1 -ethyl -1 -propenyl, l-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1 -methyl- 1 -pent enyl, 2-methyl-1-pentenyl, 3 -methyl- 1 -pentenyl, 4-methyl-1-pentenyl, 1-methyl- 2 -pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, l-methyl-3- pentenyl, 2-methyl-3-pentenyl, 3 -methyl-3 -pentenyl, 4-methyl-3 -pentenyl, l-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, l,l-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl- 1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3 -dimethyl- 1-butenyl, 1, 3 -dimethyl-2 -butenyl, l,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl- 1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1 -butenyl, 3,3-dimethyl-2-butenyl, 1 -ethyl- 1-butenyl, l-ethyl-2-butenyl, l-ethyl-3 -butenyl, 2- ethyl- 1-butenyl, 2-ethyl -2-butenyl, 2-ethyl-3 -butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-l-methyl-2-propenyl, l-ethyl-2-methyl-1-propenyl, and l-ethyl-2-methyl-2-propenyl. The term “vinyl” refers to a group having the structure -CH=CH2; 1 -propenyl refers to a group with the structure--CH=CH-CH3; and 2- propenyl refers to a group with the structure - CH2-CH=CH2. Asymmetric structures such as (Z1Z2)C=C(Z3Z4) are intended to include both the E and Z isomers. This can be presumed in structural formulae herein wherein an asymmetric alkene is present, or it can be explicitly indicated by the bond symbol C=C. Alkenyl substituents may be unsubstituted or substituted with one or more chemical moieties. Examples of suitable substituents include, for example, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, acyl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol, as described below, provided that the substituents are sterically compatible and the rules of chemical bonding and strain energy are satisfied.

[0168] As used herein, the term “alkynyl” represents straight-chained or branched hydrocarbon moieties containing a triple bond. Unless otherwise specified, C2-C24 (e.g., C2-C22, C2-C20, C2- Attorney Docket No.: 103362-074WO1

[0169] Ci8, C2-C16, C2-C14, C2-C12, C2-C10, C2-C8, C2-C6, C2-C4) alkynyl groups are intended. Alkynyl groups may contain more than one unsaturated bond. Examples include C2-C6-alkynyl, such as ethynyl, 1-propynyl, 2-propynyl (or propargyl), 1-butynyl, 2-butynyl, 3-butynyl, 1 -methyl -2-propynyl, 1 -pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3 -methyl- 1-butynyl, l-methyl-2-butynyl, l-methyl-3-butynyl, 2-methyl-3-butynyl, l,l-dimethyl-2-propynyl, l-ethyl-2-propynyl, 1 -hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 3-methyl-l-pentynyl, 4-methyl-l-pentynyl, l-methyl-2-pentynyl, 4-methyl-2-pentynyl, l-methyl-3 -pentynyl, 2-methyl-3 -pentynyl, l-methyl-4-pentynyl, 2-methyl-4-pentynyl, 3 -methyl -4-pentynyl, 1, l-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, l,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 3, 3 -dimethyl- 1-butynyl, 1-ethyl -2-butynyl, l-ethyl-3-butynyl, 2-ethyl-3-butynyl, and l-ethyl-l-methyl-2-propynyl. Alkynyl substituents may be unsubstituted or substituted with one or more chemical moieties. Examples of suitable substituents include, for example, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, acyl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol, as described below.

[0170] / As used herein, the term “aryl,” as well as derivative terms such as aryloxy, refers to groups that include a monovalent aromatic carbocyclic group of from 3 to 20 carbon atoms. Aryl groups can include a single ring or multiple condensed rings. In some embodiments, aryl groups include C6-C10 aryl groups. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, tetrahydronaphthyl, phenylcyclopropyl, and indanyl. In some embodiments, the aryl group can be a phenyl, indanyl or naphthyl group. The term “heteroaryl” is defined as a group that contains an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus. The term “non-heteroaryl,” which is included in the term “aryl,” defines a group that contains an aromatic group that does not contain a heteroatom. The aryl or heteroaryl substituents may be unsubstituted or substituted with one or more chemical moieties. Examples of suitable substituents include, for example, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, acyl, aldehyde, amino, carboxylic acid, cycloalkyl, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol as described herein. The term “biaryl” is a specific type of aryl group and is included in the definition of aryl. Biaryl refers to two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.

[0171] The term “cycloalkyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, Attorney Docket No.: 103362-074WO1

[0172] cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. The term “heterocycloalkyl” is a cycloalkyl group as defined above where at least one of the carbon atoms of the ring is substituted with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted. The cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, acyl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol as described herein.

[0173] The term “cycloalkenyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one double bound, i.e., C C' Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like. The term “heterocycloalkenyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term "‘cycloalkenyl,” where at least one of the carbon atoms of the ring is substituted with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted. The cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, acyl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol as described herein.

[0174] The term “cyclic group” is used herein to refer to either aryl groups, non-aryl groups (i.e., cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl groups), or both. Cyclic groups have one or more ring systems that can be substituted or unsubstituted. A cyclic group can contain one or more aryl groups, one or more non-aryl groups, or one or more aiyl groups and one or more non-aryl groups.

[0175] As used herein, “heteroaryl” refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, any ring-forming N in a heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl has 5-10 ring atoms and 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the Attorney Docket No.: 103362-074WO1

[0176] heteroaryl is a five-membered or six-membered heteroaryl ring. A five-membered heteroaryl ring is a heteroaryl with a ring having five ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl. A six- menibered heteroaryl ring is a heteroaryl with a ring having six ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary sixmembered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.

[0177] As used herein, “heterocycloalky 1” refers to non-aromatic monocyclic or polycyclic heterocycles having one or more ring-forming heteroatoms selected from O, N, or S. Included in heterocycloalkyl are monocyclic 4-, 5-, 6-, and 7-membered heterocycloalkyl groups.

[0178] Heterocycloalkyl groups can also include spirocycles. Example heterocycloalkyl groups include pyrrolidin-2-one, l,3-isoxazolidin-2~one, pyranyl, tetrahydropuran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, and the like. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by oxo or sulfido (e.g., C(O), S(O), C(S), or S(O)2, etc.). The heterocycloalkyl group can be attached through a ringforming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (z.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. In some embodiments, the heterocycloalkyl has 4-10, 4-7 or 4-6 ring atoms with 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members.

[0179] At certain places, the definitions or embodiments refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded. For example, an azetidine ring may be attached at any position of the ring, whereas a pyridin-3-yl ring is attached at the 3-position. Attorney Docket No.: 103362-074WO1

[0180] The term “acyl” as used herein is represented by the formula -C(O)Z1where Z1can be a hydrogen, hydroxyl, alkoxy, alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above. As used herein, the term “acyl” can be used interchangeably with “carbonyl.” Throughout this specification “C(O)” or “CO” is a shorthand notation for C=O.

[0181] / As used herein, the term “alkoxy” refers to a group of the formula Z^O-, where Z1is unsubstituted or substituted alkyl as defined above. Unless otherwise specified, alkoxy groups wherein Z1is a C1-C24 (e.g., C1-C22, C1-C20, C1-C18, C1-C16, C1-C14, C1-C12, C1-C10, Ci-Cs, Ci-C6, C1-C4) alkyl group are intended. Examples include methoxy, ethoxy, propoxy, 1 -methylethoxy, butoxy, 1 -methyl-propoxy, 2-methyl-propoxy, 1,1-dimethyl-ethoxy, pentoxy, 1 -methylbutyloxy, 2-methyl-butoxy, 3-methyl-butoxy, 2,2-di-methyl-propoxy, 1-ethyl-propoxy, hexoxy, 1.1-dimethyl-propoxy, 1,2-dimethyl-propoxy, 1-methyl-pentoxy, 2-methyl-pentoxy, 3-methyl-pentoxy, 4-methyl-penoxy, 1,1-dimethyl-butoxy, 1,2-dimethyl-butoxy, 1,3-dimethyl-butoxy, 2.2-dimethyl-butoxy, 2,3-dimethyl-butoxy, 3,3-dimethyl-butoxy, 1-ethyl-butoxy, 2-ethylbutoxy, 1.1.2-trimethyl -propoxy, 1,2,2-trimethyl-propoxy, 1 -ethyl- 1 -methyl -propoxy, and l-ethyl-2-methyl-propoxy.

[0182] The term “aldehyde” as used herein is represented by the formula — C(O)H.

[0183] The terms “amine” or “amino” as used herein are represented by the formula — NZ!Z2, where Z1and Z2can each be substitution group as described herein, such as hydrogen, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above. “Amido” is — C(O)NZ1Z2.

[0184] The term “carboxylic acid” as used herein is represented by the formula C(O)OH. A “carboxylate” or “carboxyl” group as used herein is represented by the formula — C(O)O • The term “ester” as used herein is represented by the formula - OC(O)Z1or

[0185] — C(O)OZ!, where Z1can be an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.

[0186] The term “ether” as used herein is represented by the formula Z’OZ2, where Z1and Z2can be, independently, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.

[0187] The term “ketone” as used herein is represented by the formula Z1C(O)Z2, where Z1and Z2can be, independently, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.

[0188] The term “halide” or “halogen” or “halo” as used herein refers to fluorine, chlorine, Attorney Docket No.: 103362-074WO1

[0189] bromine, and iodine.

[0190] The term “hydroxyl” as used herein is represented by the formula OH

[0191] The term “nitro” as used herein is represented by the formula — NO

[0192] The term “silyl” as used herein is represented by the formula SiZ]Z2Z3, where Zl, Z2, and Z3can be, independently, hydrogen, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.

[0193] The term “sulfonyl” is used herein to refer to the sulfo-oxo group represented by the formula — S(O)2ZI, where Z1can be hydrogen, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.

[0194] The term “sulfonylamino” or “sulfonamide” as used herein is represented by the formula S(O)2NH

[0195] The term “thiol” as used herein is represented by the formula — SH.

[0196] The term “thio” as used herein is represented by the formula - S

[0197]

[0198] As used herein, Me refers to a methyl group; OMe refers to a methoxy group; and z-Pr refers to an isopropyl group.

[0199] “R1,” “R2,” “RJ,” “Rn,” etc., where n is some integer, as used herein can, independently, possess one or more of the groups listed above. For example, if R1is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an amine group, an alkyl group, a halide, and the like. Depending upon the groups that are selected, a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group. For example, with the phrase “an alkyl group comprising an amino group,” the amino group can be incorporated within the backbone of the alkyl group. Alternatively, the amino group can be attached to the backbone of the alkyl group. The nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.

[0200] 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 stereoisomer or mixture of stereoisomer (e.g., each enantiomer, each diastereomer, each meso compound, a racemic mixture, or scalemic mixture).

[0201] Reference will now be made in detail to specific aspects of the disclosed materials, compounds, compositions, articles, and methods, examples of which are illustrated in the Attorney Docket No.: 103362-074WO1

[0202] accompanying Examples and Figures.

[0203] Carboranes and Carborane Analogs

[0204] Dicarba-closo-dodecaborane (also referred to herein as “carborane”) is an icosahedrai cluster containing two carbon atoms and ten boron atoms in which both atoms are hexacoordinated. In carboranes, depending on the position of the carbon atoms in the cluster, 3 kinds of isomers exist, i.e., 1,2-dicarba-closo-dodecaborane (ortho-carborane), 1,7-dicarba-closo-dodecaborane (meta-carborane), and 1,12-dicarba-closo-dodecaborane (para-carborane). These structures are unique among boron compounds, as they can have high thermal stabilities and hydrophobi cities, for example, comparable to hydrocarbons.

[0205] Carboranes can be used, for example, in10B or on-Neutron Capture Therapy (BNCT). BNCT has been developed as a therapy for glioma and melanoma. When10B is irradiated with thermal neutron (slow neutron), and a ray with 2.4 MeV energy is emitted and the atom decomposed to 'Li and ’He. The range of a ray is about 10 pm, which corresponds to the diameter of cells Therefore, effects are expected that only cells in which10B atoms are uptaken are destroyed and other cells are not damaged. For the development of BNCT, it is important to have cancer cells selectively uptake10B atoms in a concentration capable of destroying cells with neutron radiation. For that purpose, other-carborane skeleton has been utilized which has been utilized which has low toxicity and a high10B content, and is easy to be synthesized. Moreover, nucleic acid precursors, amino acids, and porphyrins which contain ortho-carboranes have been synthesized and subjected to evaluation.

[0206] Carborane-based ER agonists and carborane analogs are described, for example, in U. S. Patent No. 6,838,574 to Endo, U. S. Patent Application Publication No. 2018 / 0264017 to Tjarks et al., and PCT / US2019 / 064228 to Coss et al., and PCT / US2021 / 021909 to Bansal et al., each of which is hereby incorporated by reference in its entirety.

[0207] In some embodiments, the carborane can be defined by Formula I below

[0208]

[0209] R2

[0210] Formula I

[0211] wherein

[0212] R1represents a dicarba-closo-dodecaboran-yl group which may have one or more substituents selected from the group consisting of an alkyl group, an alkenyl group, a carboxyl group, an alkoxycarbonyl group, an amino group, a hydroxyl group, a hydroxyalkyl group, a Attorney Docket No.: 103362-074WO1

[0213] mono or di-alkylcarbamoyl-substituted alkyl group, an alkanoyl group, an aryl group, and an aralkyl group, each of which may be substituted or unsubstituted;

[0214] R2represents a carboxyl group, an alkoxycarbonyl group, or a hydroxyl group;

[0215] X represents a single bond, or a linking group selected from the group consisting of groups represented by the following formulas:

[0216] o o

[0217] o

[0218]

[0219] R9

[0220] wherein Y1, Y2, Y3, Y4, Y5, Y6, and Y7independently represent an oxygen atom or — N(R3) — wherein R3represents hydrogen atom or an alkyl group; Y8represents an oxygen atom, — N(R4) - - wherein R4represents hydrogen atom or an alkyl group, - -CO -

[0221]

[0222] CHs -, or - -C(==CH2) —; R5, Rb, and R7independently represent hydrogen or one or more substituents on the phenyl group; R8represents an alkyl group or an aryl group which may be substituted;

[0223] R9represents an alkyl group; and R10represents a substituted or unsubstituted aryl group.

[0224] In some embodiments, the carborane can be defined by Formula II, or a pharmaceutically acceptable salts thereof:

[0225]

[0226] Formula II Attorney Docket No.: 103362-074WO1

[0227] wherein

[0228] Q is a substituted or unsubstituted dicarba-closo-dodecaborane cluster, and

[0229]

[0230] — U and R1are attached to Q in a para configuration;

[0231] X is OH, NHR2, SH, or S(O)(O)NHR2;

[0232] R1is substituted or un substituted C4-C20 alkyl, substituted or un substituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C3-C20 alkylaryl, substituted or unsubstituted C3-C20 alkylheteroaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, substituted or unsubstituted C4-C20 alkylheterocycloalkyl, substituted or unsubstituted C1-C20 acyl, or NR3R4;

[0233] R2is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl;

[0234] R3and R4are independently selected from substituted or unsubstituted C1-C20 alkyl, substituted or un substituted C2-C20 alkenyl, substituted or un substituted C2-C20 alkynyl, substituted or unsubstituted C2-C20 alkylaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, or substituted or unsubstituted C1-C20 acyl;

[0235] with the proviso that when X is OH, R1is not (CH2)sCH(CH3)2 or NH2.

[0236] In some examples of Formula I I, the carborane cluster can include a heteroatom. In some examples of Formula II, the carborane cluster can include an isotopically labeled atom (i.e., a radiol abeled atom). In some examples of Formula II, the carborane cluster can include an isotopically labeled Boron atom (e.g.,10B).

[0237] In some examples of Formula II, Q can be:

[0238]

[0239] wherein

[0240] • is a carbon atom or a boron atom; and

[0241] o is C-H, C-halogen, C-alkyl, C-OH, C-NH2, B-H, B-halogen, B-alkyl, B-OH, or B-NH2. In some examples of Formula II, X is OH.

[0242] In some examples of Formula II, R1is a substituted or unsubstituted Ce-Cio alkyl. In some examples of Formula II, R1is a Ce-Cio hydroxyalkyl. In some examples of Formula II, R1is a substituted or unsubstituted C3-C16 alkylaryl. In some examples of Formula II, R1is a C3-C16 hydroxyalkylaryl. In some examples of Formula II, R1is a substituted or unsubstituted C5-C10 acyl. In some examples of Formula II, R1is a substituted or unsubstituted branched C4-C10 alkyl. In some examples of Formula II, R1is a branched C4-C10 hydroxy alkyl. Attorney Docket No.: 103362-074WO1

[0243] In some examples of Formula II, the compounds can be of Formula III, or a pharmaceutically acceptable salt thereof

[0244]

[0245] Formula III

[0246] wherein

[0247] • is a carbon atom;

[0248] o is B-H, B-halogen, B-alkyl, B-OH, or B-NH2;

[0249] X is OH, NHR2, SH, or S(O)(O)NHR2;

[0250] R1is substituted or un substituted C4-C20 alkyl, substituted or un substituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C3-C20 alkylaryl, substituted or unsubstituted C3-C20 alkylheteroaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, substituted or unsubstituted C4-C20 alkylheterocycloalkyl, substituted or unsubstituted C1-C20 acyl, or NR3R4;

[0251] R2is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl; and

[0252] R3and R4are independently selected from substituted or unsubstituted C1-C20 alkyl, substituted or un substituted C2-C20 alkenyl, substituted or un substituted C2-C20 alkynyl, substituted or unsubstituted C2-C20 alkylaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, or substituted or unsubstituted C1-C20 acyl;

[0253] with the proviso that when X is OH, R1is not (CH2)sCH(CH3)2 or NH2.

[0254] In some examples of Formula III, the carborane cluster can include a heteroatom.

[0255] In some examples of Formula III, the carborane cluster can include an isotopically labeled atom (i.e., a radiolabeled atom). In some examples of Formula III, the carborane cluster can include an isotopically labeled Boron atom (e.g.,10B).

[0256] In some examples of Formula III, Xis OH.

[0257] In some examples of Formula III, R1is a substituted or unsubstituted C6-C10 alkyl. In some examples of Formula III, R1is a C6-C10 hydroxyalkyl. In some examples of Formula III, R1is a substituted or unsubstituted C3-C16 alkylaryl. In some examples of Formula III, R1is a C3-C16 hydroxyalkylaryl. In some examples of Formula III, R1is a substituted or unsubstituted C5- C10 acyl. In some examples of Formula III, R1is a substituted or unsubstituted branched C4-C10 alkyl. In some examples of Formula III, R1is a branched C4-C10 hydroxyalkyl. Attorney Docket No.: 103362-074WO1

[0258] In some examples of Formula III, the compounds can be of Formula IV, or a pharmaceutically acceptable salt thereof

[0259]

[0260] Formula IV

[0261] wherein

[0262] • is a carbon atom;

[0263] o is B-H, B-halogen, B-alkyl, B-OH, or B-NH2;

[0264] the dotted line to Y indicates that the bond can be a single bond or a double bond, as valence permits;

[0265] X is OH, NHR2, SH, or S(O)(O)NHR2;

[0266] Y is O, OR2', NHR2, SH, or S(O)(O)NHR2;

[0267] R5is substituted or unsubstituted C2-C19 alkyl, substituted or unsubstituted C2-C19 alkenyl, substituted or unsubstituted C2-C19 alkynyl, substituted or unsubstituted C2-C19 alkylaryl, substituted or unsubstituted C2-C19 alkylheteroaryl, substituted or unsubstituted C3-C19 alkylcycloalkyl, substituted or un substituted C3-C19 alkylheterocycloalkyl, or NR3R4;

[0268] R2is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl;

[0269] R2is H or substituted or unsubstituted C1-C4 alkyl; and

[0270] R3and R4are independently selected from substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or un substituted C2-C20 alkylaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, or substituted or unsubstituted C1-C20 acyl.

[0271] In some examples of Formula IV, the carborane cluster can include a heteroatom. In some examples of Formula IV, the carborane cluster can include an isotopically labeled atom (i.e., a radiolabel ed atom). In some examples of Formul a IV, the carborane cluster can include an isotopically labeled Boron atom (e.g.,10B).

[0272] In some examples of Formula IV, X is OH.

[0273] In some examples of Formula IV, Y is OH. In some examples of Formula IV, Y is O. In some examples of Formula IV, R5is a substituted or unsubstituted C3-C9 alkyl. In some examples of Formula IV, R5is a substituted or unsubstituted C6-C9 alkyl. In some examples of Formula IV, R5is a substituted or unsubstituted C2-C15 alkylaryl. In some examples of Formula IV, R5is a substituted or unsubstituted branched C2-C9 alkyl. Attorney Docket No.: 103362-074WO1

[0274] Also disclosed herein are compounds of Formula V, and pharmaceutically acceptable salts thereof

[0275]

[0276] Formula V

[0277] wherein

[0278] Q is a substituted or unsubstituted dicarba-closo-dodecaborane cluster, and

[0279] Y

[0280]

[0281] are attached to Q in a para configuration;

[0282] the dotted line to Y indicates that the bond can be a single bond or a double bond, as valence permits;

[0283] X is OH, NHR2, SH, or S(O)(O)NHR2;

[0284] Y is O, OR2’, NHR2, SH, or S(O)(O)NHR2;

[0285] R” is substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C2-C20 alkylaryl, substituted or unsubstituted C2-C20 alkylheteroaryl, substituted or unsubstituted C4-C20 alkyl cycloalkyl, substituted or un substituted C4-C20 alkylheterocycloalkyl, or NR3R4;

[0286] R2is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl;

[0287] R2is H or substituted or unsubstituted C1-C4 alkyl; and

[0288] R3and R4are independently selected from substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C2-C20 alkylaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, or substituted or unsubstituted C1-C20 acyl;

[0289] with the proviso that when X is OH, R6is not CH2OH, CH(CH3)0H, CH2CH2OH, CH2CH2CH2OH, (CH2)5CH(CH3)2, orNH2.

[0290] In some examples of Formula V, the carborane cluster can include a heteroatom. In some examples of Formula V, the carborane cluster can include an isotopically labeled atom (i.e., a radiolabeled atom). In some examples of Formula V, the carborane cluster can include an isotopically labeled Boron atom (e.g.,10B).

[0291] In some examples of Formula V, Q can be

[0292]

[0293] Attorney Docket No.: 103362-074WO1

[0294] wherein

[0295] • is a carbon atom or a boron atom; and

[0296] o is C-H, C-halogen, C-alkyl, C-OH, C-NH2, B-H, B-halogen, B-alkyl, B-OH, or B-NH2. In some examples of Formula V, X is OH.

[0297] In some examples of Formula V, Y is OH. In some examples of Formula V, Y is O. In some examples of Formula V, R6is a substituted or unsubstituted C6-C10 alkyl. In some examples of Formula V, R6is a substituted or unsubstituted C2-C15 alkylaryl. In some examples of Formula V, R6is a substituted or unsubstituted branched C3-C10 alkyl.

[0298] In some examples of Formula V, the compounds can be of Formula VI, or a pharmaceutically acceptable salt thereof:

[0299]

[0300] Formula VI

[0301] wherein

[0302] • is a carbon atom;

[0303] o is B-H, B-halogen, B-alkyl, B-OH, or B-NH2;

[0304] the dotted line to Y indicates that the bond can be a single bond or a double bond, as valence permits;

[0305] Xis OH, NHR2, SH, or S(O)(O)NHR2;

[0306] Y is O, OR2’, NHR2, SH, or S(O)(O)NHR2;

[0307] R” is substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C2-C20 alkylaryl, substituted or unsubstituted C2-C20 alkylheteroaryl, substituted or unsubstituted C4-C20 alkyl cycloalkyl, substituted or un substituted C4-C20 alkylheterocycloalkyl, or NR3R4;

[0308] R2is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl;

[0309] R2is H or substituted or unsubstituted C1-C4 alkyl; and

[0310] R3and R4are independently selected from substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C2-C20 alkylaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, or substituted or unsubstituted C1-C20 acyl;

[0311] with the proviso that when X is OH, R6is not CH2OH, CH(CH3)0H, CH2CH2OH, CH2CH2CH2OH, (CH2)5CH(CH3)2, orNH2. Attorney Docket No.: 103362-074WO1

[0312] In some examples of Formula VI, the carborane cluster can include a heteroatom. In some examples of Formula VI, the carborane cluster can include an isotopically labeled atom (i.e., a radiolabeled atom). In some examples of Formula VI, the carborane cluster can include an isotopically labeled Boron atom (e.g.,10B).

[0313] In some examples of Formula VI, X is OH.

[0314] In some examples of Formula VI, Y is OH. In some examples of Formula VI, Y is O. In some examples of Formula VI, R⁶ is a substituted or unsubstituted C6-C10 alkyl. In some examples of Formula VI, R6is a substituted or unsubstituted C2-C15 alkylaryl. In some examples of Formula VI, R6is a substituted or unsubstituted branched C3-C10 alkyl.

[0315] Also disclosed herein are compounds of Formula VII, and pharmaceutically acceptable salts thereof:

[0316] R8R9

[0317]

[0318] Formula VII

[0319] wherein

[0320] Q is a substituted or unsubstituted dicarba-closo-dodecaborane cluster, and

[0321]

[0322] and R7are attached to Q in a para configuration;

[0323] X is OH, NHR2, SH, or S(O)(O)NHR2;

[0324] R7is substituted or un substituted C1-C14 alkyl, substituted or un substituted C2-C14 alkenyl, substituted or unsubstituted C2-C14 alkynyl, substituted or unsubstituted C1-C14 acyl, or NR3R4;

[0325] R8, R9, R10, R11, and R12are independently H, OH, halogen, substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C2-C20 alkylaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, substituted or unsubstituted C1-C20 acyl, or NR3R4, or wherein, as valence permits, R8and R9, R9and R10, R10and R11, or R11and R12, together with the atoms to which they are attached, form a 3-10 membered substituted or unsubstituted cyclic moiety optionally including from 1 to 3 heteroatoms;

[0326] R2is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl; and Attorney Docket No.: 103362-074WO1

[0327] R3and R4are independently selected from substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C2-C20 alkylaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, or substituted or unsubstituted C1-C20 acyl.

[0328] In some examples of Formula VII, the carborane cluster can include a heteroatom. In some examples of Formula VII, the carborane cluster can include an isotopically labeled atom (i.e., a radio labeled atom). In some examples of Formula VII, the carborane cluster can include an isotopically labeled Boron atom (e.g.,10B).

[0329] In some examples of Formula VII, Q can be

[0330]

[0331] wherein

[0332] • is a carbon atom or a boron atom; and

[0333] o is C-H, C -halogen, C-alkyl, C-OH, C-NH2, B-H, B-halogen, B-alkyl, B-OH, or B-NH2. In some examples of Formula VII, X is OH.

[0334] In some examples of Formula VII, R7is a substituted or unsubstituted C1-C7 alkyl. In some examples of Formula VII, R7is a C1-C7 hydroxy alkyl.

[0335] In some examples of Formula VII, R8-R12are independently H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl, or wherein, as valence permits, R8and R9, R9and R10, R10and R11, or R11and R12, together with the atoms to which they are attached, form a 3-10 membered substituted or unsubstituted cyclic moiety optionally including from 1 to 3 heteroatoms. In some examples of Formula VII, R8-R12are each H. In some examples of Formula VII, R8, R10, and R12are each H, and R9and R10, together with the atoms to which they are attached, form a substituted or unsubstituted 5-7 membered cyclic moiety.

[0336] In some examples of Formula VII, the compounds can be of Formula VIII, or a pharmaceutically acceptable salt thereof:

[0337] R8R9

[0338] v _ / \ P 7 / \ _ p 10

[0339]

[0340] Formula VIII

[0341] wherein

[0342] • is a carbon atom; Attorney Docket No.: 103362-074WO1

[0343] o is B-H, B-halogen, B-alkyl, B-OH, or B-NH2;

[0344] X is OH, NHR2, SH, or S(O)(O)NHR2;

[0345] R7is substituted or unsubstituted C1-C14 alkyl, substituted or unsubstituted C2-C14 alkenyl, substituted or unsubstituted C2-C14 alkynyl, substituted or unsubstituted C1-C14 acyl, or NR3R4;

[0346] R8, R9, R10, R11, and R12are independently H, OH, halogen, substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C2-C20 alkylaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, substituted or unsubstituted C1-C20 acyl, or NR3R4, or wherein, as valence permits, R8and R9, R9and R10, R10and R11, or R11and R12, together with the atoms to which they are attached, form a 3-10 membered substituted or unsubstituted cyclic moiety optionally including from 1 to 3 heteroatoms;

[0347] R2is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl; and

[0348] R3and R4are independently selected from substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C2-C20 alkylaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, or substituted or unsubstituted C1-C20 acyl.

[0349] In some examples of Formula VIII, the carborane cluster can include a heteroatom. In some examples of Formula VIII, the carborane cluster can include an isotopically labeled atom (i.e., a radiolabeled atom). In some examples of Formula VIII, the carborane cluster can include an isotopically labeled Boron atom (e.g.,10B).

[0350] In some examples of Formula VIII, X is OH.

[0351] In some examples of Formula VIII, R7is a substituted or unsubstituted C1-C7 alkyl. In some examples of Formula VIII, R7is a C1-C7 hydroxyalkyl.

[0352] In some examples of Formula VIII, R8-R12are independently H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl, or wherein, as valence permits, R8and R9, R9and R10, R10and R11, or R11and R12, together with the atoms to which they are attached, form a 3-10 membered substituted or unsubstituted cyclic moiety optionally including from 1 to 3 heteroatoms. In some examples of Formula VIII, R8-R12are each H. In some examples of Formula VIII, R8, R10, and R12are each H, and R9and R10, together with the atoms to which they are attached, form a substituted or unsubstituted 5-7 membered cyclic moiety. Attorney Docket No.: 103362-074WO1

[0353] Also disclosed herein are compounds of Formula IX, and pharmaceutically acceptable salts thereof

[0354]

[0355] Formula IX

[0356] wherein

[0357] Q is a substituted or unsubstituted dicarba-closo-dodecaborane cluster, and

[0358]

[0359] " and R13are attached to Q in a para configuration;

[0360] Xis OH, NHR2, SH, or S(O)(O)NHR2;

[0361] R13is substituted or unsubstituted C1-C19 alkyl, substituted or unsubstituted C2-C19 alkenyl, substituted or unsubstituted C2-C19 alkynyl, or substituted or unsubstituted C1-C20 acyl; and

[0362] R14, R15, and R16are independently hydrogen, halogen, hydroxyl, substituted or unsubstituted C1-C18 alkyl, substituted or unsubstituted C2-C18 alkenyl, substituted or unsubstituted C1-C18 alkynyl, substituted or unsubstituted C2-C18 aryl, substituted or unsubstituted C3-C18 cycloalkyl, substituted or un substituted C1-C20 acyl, or NR3R4, or wherein, as valence permits, R14and R15, R14and R16, or R15and R16, together with the atoms to which they are attached, form a 3-10 membered substituted or unsubstituted cyclic moiety optionally including from 1 to 3 heteroatoms,

[0363] with the proviso that at least two of R14, R13and R16are not hydrogen, halogen, or hydroxyl; and

[0364] with the proviso that when X is OH and R13is a C5 alkyl, R14, R15, and R16are not H, methyl, and methyl.

[0365] In some examples of Formula IX, the carborane cluster can include a heteroatom. In some examples of Formula IX, the carborane cluster can include an isotopically labeled atom (i.e., a radio labeled atom). In some examples of Formula IX, the carborane cluster can include an isotopically labeled Boron atom (e.g.,10B). In some examples of Formula IX, Q is

[0366]

[0367] wherein

[0368] • is a carbon atom or a boron atom; and Attorney Docket No.: 103362-074WO1

[0369] o is C-H, C-halogen, C-alkyl, C-OH, C-NH2, B-H, B-halogen, B-alkyl, B-OH, or B-NH2. In some examples of Formula IX, X is OH.

[0370] In some examples of Formula IX, R13is a substituted or unsubstituted C4-C8 alkyl. In some examples of Formula IX, R13is a C4-C8 hydroxyalkyl.

[0371] In some examples of Formula IX, R14-R16are independently hydrogen, halogen, hydroxyl, substituted or unsubstituted C1-C4 alkyl, with the proviso that at least two of R14, R15and R16are not hydrogen, halogen, or hydroxyl; and with the proviso that when X is OH and R13is a C5 alkyl, R14R15, and R16are not H, methyl, and methyl.

[0372] In some examples of Formula IX, the compounds can be of Formula X, or a pharmaceutically acceptable salt thereof:

[0373]

[0374] Formula X

[0375] wherein

[0376] • is a carbon atom;

[0377] o is B-H, B-halogen, B-alkyl, B-OH, or B-NH2;

[0378] X is OH, NHR2, SH, or S(O)(O)NHR2;

[0379] R13is substituted or unsubstituted C1-C19 alkyl, substituted or unsubstituted C2-C19 alkenyl, substituted or unsubstituted C2-C19 alkynyl, or substituted or unsubstituted C1-C20 acyl; and

[0380] R14, R15, and R16are independently hydrogen, halogen, hydroxyl, substituted or unsubstituted C1-C18 alkyl, substituted or unsubstituted C2-C18 alkenyl, substituted or unsubstituted C1-C18 alkynyl, substituted or unsubstituted C2-C18 aryl, substituted or unsubstituted C3-C18 cycloalkyl, substituted or unsubstituted C1-C20 acyl, or NR3R4, or wherein, as valence permits, R14and R15, R14and R16, or R15and R16, together with the atoms to which they are attached, form a 3-10 membered substituted or unsubstituted cyclic moiety optionally including from 1 to 3 heteroatoms,

[0381] with the proviso that at least two of R14, R15and R16are not hydrogen, halogen, or hydroxyl; and

[0382] with the proviso that when X is OH and R13is a Cs alkyl, R14R15, and R16are not H, methyl, and methyl. Attorney Docket No.: 103362-074WO1

[0383] In some examples of Formula X, the carborane cluster can include a heteroatom. In some examples of Formula X, the carborane cluster can include an isotopically labeled atom (i.e., a radio labeled atom). In some examples of Formula X, the carborane cluster can include an isotopically labeled Boron atom (e.g.,10B).

[0384] In some examples of Formula X, X is OH.

[0385] In some examples of Formula X, R13is a substituted or unsubstituted C4-Cs alkyl. In some examples of Formula X, R13is a C4-C8 hydroxyalkyl.

[0386] In some examples of Formula X, R14-R16are independently hydrogen, halogen, hydroxyl, substituted or unsubstituted C1-C4 alkyl, with the proviso that at least two of R14, R15and R16are not hydrogen, halogen, or hydroxyl; and with the proviso that when X is OH and R13is a C5 alkyl, R14R15, and R16are not H, methyl, and methyl.

[0387] In some examples, the compounds can be selected from the group consisting of:

[0388]

[0389] Attorney Docket No.: 103362-074WO1

[0390] OH OH

[0391] OH OH OH OH

[0392] OH

[0393]

[0394] Attorney Docket No.: 103362-074WO1

[0395]

[0396] pharmaceutically acceptable salts thereof. In some examples, the carborane cluster can include a heteroatom.

[0397] Also disclosed herein are compounds of Formula XI, and pharmaceutically acceptable salts thereof:

[0398]

[0399] Formula XI

[0400] wherein

[0401] Q is a substituted or unsubstituted dicarba-closo-dodecaborane cluster;

[0402] D is -S-, -S(O)-, -S(O)(O)-, -S(O)(NH)-, -P(O)(OH)O-, -P(O)(OH)NH- or -O-; Xis OH, NHR2, SH, or S(O)(O)NHR2;

[0403] R6is substituted or un substituted C1-C20 alkyl, substituted or un substituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C2-C20 alkylaryl, substituted or unsubstituted C2-C20 alkylheteroaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, or substituted or unsubstituted C4-C20 alkylheterocycloalkyl; and

[0404] R2is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl.

[0405] X~~4XR6

[0406] In some examples of Formula XI,

[0407]

[0408] Jand are attached to Q in a para configuration.

[0409] In some examples of Formula XI, the carborane cluster can include a heteroatom. In some examples of Formula XI, the carborane cluster can include an isotopically labeled atom (i.e., a radiolabeled atom). In some examples of Formula XI, the carborane cluster can include an isotopically labeled Boron atom (e.g.,10B). Attorney Docket No.: 103362-074WO1

[0410] In some examples of Formula XI, Q can be

[0411]

[0412] wherein

[0413] • is a carbon atom or a boron atom; and

[0414] o is C-H, C-halogen, C-alkyl, C-OH, C-NH₂, B-H, B-halogen, B-alkyl, B-OH, or B-NH2. In some examples of Formula XI, X is OH.

[0415] In some examples of Formula XI, R⁶ is a substituted or unsubstituted C6-C10 alkyl. In some exampl es of Formula XI, R6is a substituted or unsubstituted C2-C15 alkylaryl. In some examples of Formula XI, R6is a substituted or unsubstituted branched C3-C10 alkyl.

[0416] In some examples, the compounds can be selected from the group consisting of:

[0417]

[0418] Attorney Docket No.: 103362-074WO1

[0419]

[0420] Attorney Docket No.: 103362-074WO1

[0421]

[0422] Attorney Docket No.: 103362-074WO1

[0423]

[0424] pharmaceutically acceptable salts thereof. In some examples, the carborane cluster can include a heteroatom. Attorney Docket No.: 103362-074WO1

[0425] In some embodiments, the carborane can be defined by Formula XII, or a pharmaceutically acceptable salt thereof

[0426] A-Q-R1

[0427] Formula XII

[0428] wherein Q is a substituted or unsubstituted dicarba-closo-dodecaborane cluster, and A and R1are attached to Q in a para configuration; A is a substituted or unsubstituted heteroaryl ring; R1is substituted or unsubstituted C2-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C3-C20 alkylaryl, substituted or unsubstituted C3-C20 alkyl heteroaryl, substituted or unsubstituted C1-C20 alkylcycloalkyl, substituted or unsubstituted C4-C20 alkylheterocycloalkyl, substituted or unsubstituted C1-C20 acyl, C1-C20 acyl, — C(O)N R3R4, — S(O)-R3, — S(O2)-R3, substituted or unsubstituted C2-C20 heteroalkyl, or NR3R4; and R3and R4are independently selected from substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C2-C20 alkylaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, and substituted or unsubstituted C2-C20 heteroalkyl.

[0429] In some embodiments, Q is

[0430]

[0431] wherein • is a carbon atom or a boron atom; and o is C-H, C-halogen, C-alkyl, C-OH, C-NH2, B-H, B-halogen, B-alkyl, B-OH, or B-NH2.

[0432] In some embodiments, A can be a five-membered substituted or unsubstituted heteroaryl ring. For example, A can comprise a thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3- oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, or 1,3,4-oxadiazolyl ring. In some embodiments, A can be a six-membered substituted or unsubstituted heteroaryl ring. For example, A can comprise a pyridyl, pyrazinyl, pyrimidinyl, triazinyl, or pyridazinyl ring.

[0433] In some cases, the compound can be defined by Formula XIIA, or a pharmaceutically acceptable salt thereof:

[0434]

[0435] Formula XII A Attorney Docket No.: 103362-074WO1

[0436] wherein • is a carbon atom; o is B-H, B-halogen, B-alkyl, B-OH, or B-NH2; X is OH, NHR2, SH, or S(O)(O)NHR2; Z is, individually for each occurrence, N or CH, with the proviso that at least one of Z is N; R1is substituted or unsubstituted C2-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or un substituted C3-C20 alkylaryl, substituted or unsubstituted C3-C20 alkylheteroaryl, substituted or unsubstituted C4-C20 alkyl cycloalkyl, substituted or un substituted C4-C20 alkylheterocycloalkyl, substituted or unsubstituted C1-C20 acyl, C1-C20 acyl, — C(O)N R3R4, — S(O)-R3, — S(O2)-R3, substituted or unsubstituted C2-C20 heteroalkyl, or NR3R4; R2is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl; and R3and R4are independently selected from substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C2-C20 alkylaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, and substituted or unsubstituted C2-C20 heteroalkyl.

[0437] In some cases, one of Z can be N. In some cases, two or more of Z can be N. In some cases, three of Z can be N.

[0438] In some embodiments, the compound can be defined by one of the formulae below, or a pharmaceutically acceptable salt thereof:

[0439]

[0440] wherein • is a carbon atom; o is B-H, B-halogen, B-alkyl, B-OH, or B-NH2; X is OH, NHR2, SH, or S(O)(O)NHR2; R1is substituted or unsubstituted C2-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C3-C20 alkylaryl, substituted or unsubstituted C3-C20 alkylheteroaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, substituted or unsubstituted C4-C20 alkylheterocycloalkyl, substituted or unsubstituted C1-C20 acyl, C1-C20 acyl, — C(O)NR3R4, — S(O)-R3, — S(O2)-R3, substituted or unsubstituted C2-C20 heteroalkyl, or NR3R4; R2is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl; and R3and R4are independently selected from substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or Attorney Docket No.: 103362-074WO1

[0441] unsubstituted C2-C20 alkynyl, substituted or unsubstituted C2-C20 alkylaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, and substituted or unsubstituted C2-C20 heteroalkyl.

[0442] In some embodiments, the compound can be defined by one of Formula XIIB-XIIF, or a pharmaceutically acceptable salt thereof

[0443] Formula XIIC

[0444]

[0445] Formula XI IF

[0446] wherein • is a carbon atom; o is B-H, B-halogen, B-alkyl, B-OH, or B-NH2; R1is substituted or unsubstituted C2-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C3-C20 alkylaryl, substituted or unsubstituted C3-C20 alkylheteroaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, substituted or unsubstituted C4-C20 alkylheterocycloalkyl, substituted or un substituted C1-C20 acyl, C1-C20 acyl, — C(O)N R3R4, — S(O)-R3, — S(O2)-R3, substituted or unsubstituted C2-C20 heteroalkyl, or NR3R4; R2is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl; and R3and R4are independently selected from substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or Attorney Docket No.: 103362-074WO1

[0447] unsubstituted C2-C20 alkylaryl, substituted or unsubstituted C4-C20 alkyl cycloalkyl, and substituted or unsubstituted C2-C20 heteroalkyl.

[0448] In some of the embodiments above, X can be OH.

[0449] In some of the embodiments above, R1can be a substituted or unsubstituted C6-C10 alkyl (e.g., a C6-C10 hydroxyalkyl).

[0450] In some of the embodiments above, R1can be a substituted or unsubstituted C3-C16 alkylaryl (e.g., a C3-C16 hydroxyalkylaryl).

[0451] In some of the embodiments above, R1can be a substituted or unsubstituted C8-C20 alkylaryl (e.g., a C8-C20 hydroxyalkylaryl).

[0452] In some of the embodiments above, R1can be a substituted or unsubstituted C5-C10 acyl. In some of the embodiments above, R1can be a substituted or unsubstituted branched C4-C10 alkyl (e.g., a branched C4-C10 hydroxyalkyl).

[0453] In some embodiments, the compound is defined by a formula below, or a pharmaceutically acceptable salt thereof:

[0454]

[0455] wherein • is a carbon atom; o is B-H, B-halogen, B-alkyl, B-OH, or B-NH2; the dotted line to Y indicates that the bond can be a single bond or a double bond, as valence permits; A is a substituted or unsubstituted heteroaryl ring; Y, when present, is O, halogen, OR2, NHR2, SH, or S(O)(O)NHR2; R'1is substituted or unsubstituted C1-C19 alkyl, substituted or unsubstituted C2- C19 alkenyl, substituted or un substituted C2-C19 alkynyl, substituted or unsubstituted C2-C19 alkylaryl, substituted or unsubstituted C2-C19 alkylheteroaryl, substituted or unsubstituted C4-C19 alkylcycloalkyl, substituted or un substituted C4-C19 alkylheterocycloalkyl, and substituted or unsubstituted C2-C20 heteroalkyl. or NR3R4; R2is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl; R2is H or substituted or unsubstituted C1-C4 alkyl; and R3and R4are Attorney Docket No.: 103362-074WO1

[0456] independently selected from substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C2-C20 alkylaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, and substituted or unsubstituted C2-C20 heteroalkyl.

[0457] In some embodiments, A can be a five-membered substituted or unsubstituted heteroaryl ring. For example, A can comprise a thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, or 1,3,4-oxadiazolyl ring. In some embodiments, A can be a six-membered substituted or unsubstituted heteroaryl ring. For example, A can comprise a pyridyl, pyrazinyl, pyrimidinyl, triazinyl, or pyridazinyl ring.

[0458] In some of these embodiments, Y is OH. In some of these embodiments, Y is F. In some of these embodiments, Y is O.

[0459] In some examples, R6can be a substituted or unsubstituted C3-C10 alkyl, such as a substituted or unsubstituted C6-C9 alkyl.

[0460] In some examples, R6can be a substituted or unsubstituted C2-C 5 alkylaryl.

[0461] In some examples, Rbcan be a substituted or unsubstituted branched C2-C9 alkyl.

[0462] In some examples, R6can be a substituted or unsubstituted C3-C10 heteroalkyl, such as a substituted or unsubstituted C6-C9 heteroalkyl.

[0463] Also provided are compounds defined by Formula XIII, or a pharmaceutically acceptable salt thereof:

[0464] A-Q-R1

[0465] Formula XIII

[0466] wherein Q is a substituted or unsubstituted dicarba-closo-dodecaborane cluster, and A and R1are attached to Q in a para configuration; A is a substituted or unsubstituted aryl ring or a substituted or unsubstituted heteroaryl ring; R1is substituted or unsubstituted C2-C20 heteroalkyl, — C(O)N R3R4, --- -S(O)-R3, -- -S(O2)-R3, or NR3R4; and R3and R4are independently selected from substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C2-C20 alkylaryl, substituted or unsubstituted C2-C20 alkylheteroaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, substituted or unsubstituted C4-C20 alkylheterocycloalkyl, and substituted or unsubstituted C2-C20 heteroalkyl, with the proviso that when present, at least one of R3and R4is C2-C20 heteroalkyl. Attorney Docket No.: 103362-074WO1

[0467] In some embodiments, A can comprise a substituted or unsubstituted aryl ring (e g., a substituted or unsubstituted phenyl ring). In some embodiments, A can be a five-membered substituted or unsubstituted heteroaryl ring. For example, A can comprise a thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, or 1,3,4-oxadiazolyl ring. In some embodiments, A can be a six-membered substituted or unsubstituted heteroaryl ring. For example, A can comprise a pyridyl, pyrazinyl, pyrimidinyl, triazinyl, or pyridazinyl ring.

[0468] In some embodiments, Q is

[0469]

[0470] wherein • is a carbon atom or a boron atom; and o is C-H, C-halogen, C-alkyl, C-OH, C-NH2, B-H, B-halogen, B-alkyl, B-OH, or B-NH2.

[0471] In some embodiments, the compound can be defined by Formula XIIIA, or a pharmaceutically acceptable salt thereof:

[0472]

[0473] Formula XIIIA

[0474] wherein • is a carbon atom; o is B-H, B-halogen, B-alkyl, B-OH, or B-NH2; X is OH, NHR2, SH, or S(O)(O)NHR2; Z is, individually for each occurrence, N or CH, with the proviso that at least one of Z is N; R1is substituted or unsubstituted C2-C20 heteroalkyl, C(O)N R3R4, --- S(O)-R3, — S(O2)-R3, or NR3R4; and R3and R4are independently selected from substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C2-C20 alkylaryl, substituted or unsubstituted C2-C20 alkyl heteroaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, substituted or unsubstituted C4-C20 alkylheterocycloalkyl, and substituted or unsubstituted C2-C20 heteroalkyl, with the proviso that when present, at least one of R3and R4is C2-C20 heteroalkyl.

[0475] In some of these embodiments, X can be OH.

[0476] Also provided are compounds defined by any of the formula below, or a pharmaceutically acceptable salt thereof:

[0477] 57 Attorney Docket No.: 103362-074WO1

[0478]

[0479] wherein • is a carbon atom; o is B-H, B-halogen, B-alkyl, B-OH, or B-NEfc; the dotted line to Y indicates that the bond can be a single bond or a double bond, as valence permits; A is a substituted or unsubstituted aryl ring a substituted or unsubstituted heteroaryl ring; Y, when present, is O, halogen, OR2, NUR2, SH, or S(O)(O)NHR2; R6is substituted or unsubstituted Ci-C19 alkyl, substituted or unsubstituted C2-C19 alkenyl, substituted or unsubstituted C2-C19 alkynyl, substituted or unsubstituted C2-C19 alkylaryl, substituted or unsubstituted C2-C19 alkylheteroaryl, substituted or un substituted C4-C19 alkylcycloalkyl, substituted or un substituted C4-C19 alkylheterocycloalkyl, and substituted or unsubstituted C2-C20 heteroalkyl, or NR3R4; R2is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl; R2is H or substituted or unsubstituted C1-C4 alkyl; and R3and R4are independently selected from substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C2-C20 alkylaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, and substituted or unsubstituted C2-C20 heteroalkyl.

[0480] In some embodiments, A can comprise a substituted or unsubstituted aryl ring (e.g., a substituted or unsubstituted phenyl ring). In some embodiments, A can be a five-membered substituted or unsubstituted heteroaryl ring. For example, A can comprise a thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, or 1,3,4-oxadiazolyl ring. In some embodiments, A can be a six-membered substituted or unsubstituted heteroaryl ring. For example, A can comprise a pyridyl, pyrazinyl, pyrimidinyl, triazinyl, or pyridazinyl ring. Attorney Docket No.: 103362-074WO1

[0481] In some of these embodiments, Y is OH, In some of these embodiments, Y is F. In some of these embodiments, Y is O.

[0482] In some examples, R6can be a substituted or unsubstituted Cs-Cio alkyl, such as a substituted or un substituted C6-C9 alkyl.

[0483] In some examples, R6can be a substituted or unsubstituted C2-C15 alkylaryl.

[0484] In some examples, R6can be a substituted or unsubstituted branched C2-C9 alkyl.

[0485] In some examples, R6can be a substituted or unsubstituted Cs-Cio heteroalkyl, such as a substituted or un substituted C6-C9 heteroalkyl.

[0486] In some examples, the carborane can be selected from the group consisting of:

[0487]

[0488] Attorney Docket No.: 103362-074WO1

[0489]

[0490] some examples, the carborane cluster can include a heteroatom.

[0491] In some embodiments, the compound can be a carborane analog, such as a dicarba-closo-dodecaborane analog of, for example, the compounds described in WO 2017 / 049307 to Tjarks et al. The compounds include a spacer group which replaces the carborane moiety in the compounds therein. The resulting compounds can exhibit similar biological activity to the compounds described in WO 2017 / 049307.

[0492] For example, provided herein are compounds defined by Formula XIV, or a pharmaceutically acceptable salt thereof:

[0493] A-Q-R1

[0494] Formula XIV

[0495] wherein A is a substituted or unsubstituted aryl ring or a substituted or unsubstituted heteroaryl ring; Q is a spacer group chosen from one of the following:

[0496]

[0497] Attorney Docket No.: 103362-074WO1

[0498]

[0499] where m and n are each individually 0, 1, 2, or 3; R1is substituted or unsubstituted O-C20 alkyl, substituted or un substituted C4-C20 heteroalkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C3-C20 alkylaryl, substituted or unsubstituted C3-C20 alkylheteroaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, substituted or unsubstituted C4-C20 alkylheterocycloalkyl, substituted or unsubstituted C1-C20 acyl, C1-C20 acyl, C(O)N R3R4, or NR3R4; and R3and R4are independently selected from substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C1-C20 heteroalkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C2-C20 alkylaryl, or substituted or unsubstituted C4-C20 alky ley cloalkyl.

[0500] In certain embodiments, Q can be chosen from one of the following:

[0501]

[0502] In some embodiments, A can comprise a substituted or unsubstituted aryl ring (e.g., a substituted or unsubstituted phenyl ring). In some embodiments, A can be a five-membered substituted or unsubstituted heteroaryl ring. For example, A can comprise a thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, or 1,3,4-oxadiazolyl ring. In some embodiments, A can be a six-membered substituted or unsubstituted heteroaryl ring. For example, A can comprise a pyridyl, pyrazinyl, pyrimidinyl, triazinyl, or pyridazinyl ring. Attorney Docket No.: 103362-074WO1

[0503] X-Z \ — |

[0504] In some embodiments, A is

[0505]

[0506] ”, wherein X is OH, NHR2, SH, or S(O)(O)NHR2and R2is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl. In some of these embodiments, X is OH.

[0507] In some embodiments, A is

[0508]

[0509] , wherein X is OH, NHR2, SH, or S(O)(O)NHR2and R2is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl. In some of these embodiments, X is OH.

[0510] Z=Z

[0511] x~4

[0512] In some embodiments, A is

[0513]

[0514] Z-Z, wherein Z is, individually for each occurrence, N or CH, with the proviso that at least one of Z is N; X is OH, NHR2, SH, or S(O)(O)NHR2;and R2is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl. In some of these embodiments, A can be one of the following:

[0515]

[0516] In some of these embodiments, X is OH.

[0517] In some embodiments, A is

[0518]

[0519] , wherein Y is S or O; X is OH, NHR2, SH, or S(O)(O)NHR2; and R2is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl. In some of these embodiments, X is OH.

[0520] In some embodiments, A is

[0521]

[0522] , wherein Y is S or O; X is OH, NHR2, SH, or S(O)(O)NHR2; and R2is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl. In some of these embodiments, X is OH.

[0523] In some embodiments,

[0524]

[0525] A is Attorney Docket No.: 103362-074WO1

[0526] In some of the embodiments above, R1can be a substituted or unsubstituted Ce-Cio alkyl (e.g., a C6-C10 hydroxyalkyl).

[0527] In some of the embodiments above, R1can be a substituted or unsubstituted C3-C16 alkylaryl (e.g., a C3-C16 hydroxyalkylaryl).

[0528] In some of the embodiments above, R1can be a substituted or unsubstituted C8-C20 alkylaryl (e.g., a C8-C20 hydroxyalkylaryl).

[0529] In some of the embodiments above, Rlcan be a substituted or unsubstituted C5-C10 acyl. In some of the embodiments above, R1can be a substituted or unsubstituted branched C4- C10 alkyl (e.g., a branched C4-C10 hydroxyalkyl).

[0530] In some embodiments, R1can comprise one of the following

[0531]

[0532] wherein the dotted line to Y indicates that the bond can be a single bond or a double bond, as valence permits; Y, when present, is O, halogen, OR2, NHR2, SH, or S(O)(O)NHR2; R6is substituted or unsubstituted C1-C19 alkyl, substituted or unsubstituted C2-C19 alkenyl, substituted or unsubstituted C2-C19 alkynyl, substituted or unsubstituted C2-C19 alkylaryl, substituted or unsubstituted C2-C19 alkylheteroaryl, substituted or unsubstituted C4-C19 alkylcycloalkyl, substituted or unsubstituted C4-C19 alkyl heterocycloalkyl, and substituted or unsubstituted C2-C20 heteroalkyl, or NR3R4; R2is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl; R2is H or substituted or unsubstituted C1-C4 alkyl; and R3and R4are independently selected from substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C2-C20 alkylaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, and substituted or unsubstituted C2-C20 heteroalkyl.

[0533] In some embodiments, A can comprise a substituted or unsubstituted aryl ring (e.g., a substituted or unsubstituted phenyl ring). In some embodiments, A can be a five-membered Attorney Docket No.: 103362-074WO1

[0534] substituted or unsubstituted heteroaryl ring. For example, A can comprise a thienyl, fund, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, or 1,3,4-oxadiazolyl ring. In some embodiments, A can be a six-membered substituted or unsubstituted heteroaryl ring. For example, A can comprise a pyridyl, pyrazinyl, pyrimidinyl, triazinyl, or pyridazinyl ring.

[0535] In some of these embodiments, Y is OH. In some of these embodiments, Y is F. In some of these embodiments, Y is O.

[0536] In some examples, R6can be a substituted or unsubstituted C3-C10 alkyl, such as a substituted or unsubstituted C6-C9 alkyl.

[0537] In some examples, R6can be a substituted or unsubstituted Cz-Cis alkylaryl.

[0538] In some examples, R6can be a substituted or unsubstituted branched C2-C9 alkyl.

[0539] In some examples, Rbcan be a substituted or unsubstituted C3-C10 heteroalkyl, such as a substituted or unsubstituted C6-C9 heteroalkyl.

[0540] In some embodiments, the compound can comprise one of the following:

[0541]

[0542] Attorney Docket No.: 103362-074WO1

[0543]

[0544] Also disclosed herein are pharmaceutically-acceptable salts and prodrugs of the carboranes and carborane analogs described herein. Pharmaceutically-acceptable salts include salts of the disclosed carboranes and carborane analogs that are prepared with acids or bases, depending on the particular substituents found on the compounds. Under conditions where the carboranes and carborane analogs disclosed herein are sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compounds as salts can be appropriate.

[0545] Examples of pharmaceutically-acceptable base addition salts include sodium, potassium, calcium, ammonium, or magnesium salt. Examples of physiologically-acceptable acid addition salts include hydrochloric, hydrobromic, nitric, phosphoric, carbonic, sulfuric, and organic acids like acetic, propionic, benzoic, succinic, fumaric, mandelic, oxalic, citric, tartaric, malonic, ascorbic, alpha-ketoglutaric, alpha-glycophosphoric, maleic, tosyl acid, methanesulfonic, and the like. Thus, disclosed herein are the hydrochloride, nitrate, phosphate, carbonate, bicarbonate, sulfate, acetate, propionate, benzoate, succinate, fumarate, mandelate, oxalate, citrate, tartarate, malonate, ascorbate, alpha-ketoglutarate, alpha-glycophosphate, maleate, tosylate, and mesylate salts. Pharmaceutically acceptable salts of a compound can be obtained using standard procedures well known in the art, for example, by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made. Attorney Docket No.: 103362-074WO1

[0546] In some examples, the carboranes and carborane analogs can have an EC₅₀ of 800 nM or less at estrogen receptor beta (ERP) (e.g., 700 nM or less, 600 nM or less, 500 nM or less, 400 nM or less, 300 nM or less, 200 nM or less, 100 nM or less, 90 nM or less, 80 nM or less, 70 nM or less, 60 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4.5 nM or less, 4 nM or less, 3.5 nM or less, 3 nM or less, 2.5 nM or less, 2 nM or less, 1.5 nM or less, 1 nM or less, 0.9 nM or less, 0.8 nM or less, 0.7 nM or less, 0.6 nM or less, 0.5 nM or less, 0.4 nM or less, 0.3 nM or less, 0.2 nM or less, or 0.1 nM or less).

[0547] In some examples, the carboranes and carborane analogs can have an EC₅₀ of 1 pM or more at ERP (e.g., 0.1 nM or more, 0.2 nM or more, 0,3 nM or more, 0.4 nM or more, 0.5 nM or more, 0.6 nM or more, 0.7 nM or more, 0.8 nM or more, 0.9 nM or more, 1 nM or more, 1.5 nM or more, 2 nM or more, 2.5 nM or more, 3 nM or more, 3.5 nM or more, 4 nM or more, 4.5 nM or more, 5 nM or more, 6 nM or more, 7 nM or more, 8 nM or more, 9 nM or more, 10 nM or more, 20 nM or more, 30 nM or more, 40 nM or more, 50 nM or more, 60 nM or more, 70 nM or more, 80 nM or more, 90 nM or more, 100 nM or more, 200 nM or more, 300 nM or more, 400 nM or more, 500 nM or more, 600 nM or more, or 700 nM or more).

[0548] The EC₅₀ of the carboranes and carborane analogs at ERp can range from any of the minimum values described above to any of the maximum values described above. For example, the carboranes and carborane analogs can have an EC₅₀ of from 1 pM to 800 nM at ERp (e.g,, from 1 pM to 400 nM, from 400 nM to 800 nM, from 1 pM to 300 nM, from 1 pM to 200 nM, from 1 pM to 100 nM, from 1 pM to 50 nM, from 1 pM to 20 nM, from 1 pM to 10 nM, from 1 pM to 6 nM, from 1 pM to 5 nM, from 1 pM to 2 nM, from 1 pM to 1 nM, from 1 pM to 0.7 nM, from 1 pM to 0.5 nM, from 1 pM to 0.2 pM, or from 1 pM to 0.1 nM).

[0549] In some examples, the carboranes and carborane analogs are selective ERp agonist. In some examples, a selective ERp agonist is a compound that has a lower EC₅₀ at ERp than at estrogen receptor a (ERa). The selectivity of the compounds can, in some examples, be expressed as an ERP-to-ERa agonist ratio, which is the EC₅₀ of the compound at ERa divided by the EC₅₀ of the compound at ERp. In some examples, the compounds can have an ERP-to-ERa agonist ratio of 8 or more (e.g., 10 or more, 20 or more, 30 or more, 40 or more, 50 or more, 60 or more, 70 or more, 80 or more, 90 or more, 100 or more, 150 or more, 200 or more, 250 or more, 300 or more, 350 or more, 400 or more, 450 or more, 500 or more, 600 or more, 700 or more, 800 or more, 900 or more, 1000 or more, 1100 or more, 1200 or more, 1300 or more, 1400 or more, 1500 or more, 2000 or more, 2500 or more). Attorney Docket No.: 103362-074WO1

[0550] In some examples, the carboranes and carborane analogs can have an ERP-to-ERa agonist ratio of 3000 or less (e.g., 2500 or less, 2000 or less, 1500 or less, 1400 or less, 1300 or less, 1200 or less, 1100 or less, 1000 or less, 900 or less, 800 or less, 700 or less, 600 or less, 500 or less, 450 or less, 400 or less, 350 or less, 300 or less, 250 or less, 200 or less, 150 or less, 100 or less, 90 or less, 80 or less, 70 or less, 60 or less, 50 or less, 40 or less, 30 or less, 20 or less, or 10 or less).

[0551] The ERP-to-ERa agonist ratio of the carboranes and carborane analogs at ERp can range from any of the minimum values described above to any of the maximum values described above. For example, the carboranes and carborane analogs can have an ERP-to-ERa agonist ratio of from 8 to 3000 (e.g., from 8 to 1500, from 1500 to 3000, from 400 to 3000, from 500 to 3000, from 600 to 3000, from 700 to 3000, from 800 to 3000, from 900 to 3000, from 1000 to 3000, or from 2000 to 3000).

[0552] Methods of Making

[0553] The compounds described herein can be prepared in a variety of ways known to one skilled in the art of organic synthesis or variations thereon as appreciated by those skilled in the art. The compounds described herein can be prepared from readily available starting materials. Optimum reaction conditions can vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art.

[0554] Variations on the compounds described herein include the addition, subtraction, or movement of the various constituents as described for each compound. Similarly, when one or more chiral centers are present in a molecule, the chirality of the molecule can be changed.

[0555] Additionally, compound synthesis can involve the protection and deprotection of various chemical groups. The use of protection and deprotection, and the selection of appropriate protecting groups can be determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 4th Ed., Wiley & Sons, 2006, which is incorporated herein by reference in its entirety.

[0556] The starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Katchem (Prague, Czech Republic), Aldrich Chemical Co., (Milwaukee, WI), Acros Organics (Morris Plains, NJ), Fisher Scientific (Pittsburgh, PA), Sigma (St. Louis, MO), Pfizer (New York, NY), GlaxoSmithKline (Raleigh, NC), Merck (Whitehouse Station, NJ), Johnson & Johnson (New Brunswick, NJ), Aventis (Bridgewater, NJ), AstraZeneca (Wilmington, DE), Novartis (Basel, Switzerland), Wyeth (Madison, NJ), Bristol-Myers-Squibb (New York, NY), Roche (Basel, Switzerland), Attorney Docket No.: 103362-074WO1

[0557] Lilly (Indianapolis, IN), Abbott (Abbott Park, IL), Schering Plough (Kenilworth, NJ), or Boehringer Ingelheim (Ingelheim, Germany), or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Suppiementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition); and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). Other materials, such as the pharmaceutical excipients disclosed herein can be obtained from commercial sources.

[0558] Reactions to produce the compounds described herein can be carried out in solvents, which can be selected by one of skill in the art of organic synthesis. Solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products under the conditions at which the reactions are carried out, i.e., temperature and pressure. Reactions can be carried out in one solvent or a mixture of more than one solvent. Product or intermediate formation can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g,1H or13C) infrared spectroscopy, spectrophotometry (e.g, UV-visible), or mass spectrometry, or by chromatography such as high-performance liquid chromatography (HPLC) or thin layer chromatography.

[0559] Example methods of preparing carboranes and carborane analogs are described, for example, in U. S. Patent No. 6,838,574 to Endo, U. S. Patent Application Publication No.

[0560] 2018 / 0264017 to Tjarks et al., and PCT / US2019 / 064228 to Coss et al., and

[0561] PCT / US2021 / 021909 to Bansal et al., each of which is hereby incorporated by reference in its entirety.

[0562] Methods of Use

[0563] Targeting estrogen receptors, such as ERp, can be done in order to treat a variety of conditions, disorders, and diseases disclosed herein. These estrogen receptors can be targeted by 17a estradiol and derivatives thereof, as well as other ERBeta agonists described herein (such as carboranes and analogs thereof). These compounds can be administered to a subject in need thereof to metabolic perturbati ons (for example: adipose dysfunction, increased adipose mass, increased adipose inflammation and / or fibrosis, decreased adipose innervation and / or vascularization, and age-related metabolic issues such as impaired glucose control, dyslipidemia, cardiovascular dysfunction) and peripheral nerve integrity (protecting against small fiber Attorney Docket No.: 103362-074WO1

[0564] neuropathy in skin or other organs, decreased motor nerve function, and loss of NMJ integrity, due to either axonal loss or demyelination including due to dysfunction / ! os s of nerve support cells such as Schwann cells, for example).

[0565] These diseases and disorders can be associated with overall health span, age span, or undesired effects of biological aging or reproductive senescence as a result of physiological / biological aging or induced by disease, environmental exposures, genetic predisposition, or surgical intervention. Surgical intervention can include, but is not limited to, loss of reproductive organ function or hysterectomy.

[0566] The diseases and disorders described herein can also include, but are not limited to, adipose dysfunction, increased adipose mass, increased adipose inflammation and / or fibrosis, decreased adipose innervation and / or vascularization, loss of metabolic control, small fiber neuropathy in skin or any other organs, decreased motor nerve function, or loss of NMJ integrity.

[0567] These diseases, disorders, and symptoms are generally referred to herein as “metabolic disease, peripheral neuropathy, and aging.” This phrase is meant to include any and all symptoms, diseases, and disorders that respond to an agonist of ERBeta, including 17a estradiol or a derivative thereof, or to carboranes and carborane analogs as disclosed herein. Thus, these compositions can be used in promoting health-span and / or age-span.

[0568] Accordingly, in one aspect, disclosed herein is a method of reducing metabolic perturbations and / or peripheral neuropathic conditions and associated symptoms in a subject. These methods can comprise administering 17a estradiol or a derivative thereof, or a carborane or carborane analog described herein (e.g., as a single agent or in combination with another agent or therapeutic modality) in an amount sufficient to reverse, decrease or inhibit age-related metabolic perturbations and / or peripheral neuropathic conditions (e.g., to decrease age-related metabolic perturbations and / or peripheral neuropathic conditions associated symptoms). In one embodiment, the method is carried out in vivo, for example, in a mammalian subject, e.g., an animal model or as part of therapeutic protocol.

[0569] / Also disclosed herein are methods of treating or preventing metabolic perturbations and / or peripheral neuropathic conditions in a subject. The methods include administering an ERBeta agonist, 17a estradiol or a derivative thereof, or a carborane or carborane analog (e.g., as a single agent or in combination with another agent or therapeutic modality), to a subject in need thereof, in an amount sufficient to decrease age-related metabolic perturbations and / or peripheral neuropathic conditions or an age-related metabolic perturbations and / or peripheral neuropathic Attorney Docket No.: 103362-074WO1

[0570] conditions associated symptom in the subject.

[0571] In some embodiments, one or more symptoms of metabolic disease, peripheral neuropathy, and / or aging is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% relative to a control level. The control level includes any appropriate control as known in the art. For example, the control level can be the pre-treatment level in the sample or subject treated, or it can be the level in a control population (e.g., the level in subjects who do not have age-related metabolic perturbations and / or peripheral neuropathic conditions or the level in samples derived from subjects who do not have age-related metabolic perturbations and / or peripheral neuropathic conditions). In some embodiments, the decrease is statistically significant, for example, as assessed using an appropriate parametric or non-parametric statistical comparison.

[0572] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In certain embodiments, the subject is an animal model of metabolic perturbations, aging, and / or peripheral neuropathic conditions, a human with metabolic perturbations, aging, and / or peripheral neuropathic conditions, or a subject (e.g., a human) at risk for

[0573] developing metabolic perturbations (such as those which are age-related), and / or peripheral neuropathic conditions. In some embodiments, the subject is a human who has a family history of metabolic perturbations and / or peripheral neuropathic conditions, who carries a gene associated with metabolic perturbations and / or peripheral neuropathic conditions, who is positive for a biomarker associated with metabolic perturbations and / or peripheral neuropathic conditions, or a combination thereof. In some embodiments, the subject has been diagnosed with metabolic perturbations and / or peripheral neuropathic conditions. In some embodiments, the subject has one or more signs or symptoms associated with metabolic perturbations and / or peripheral neuropathic conditions. In some embodiments, the subject is at risk for developing metabolic perturbations and / or peripheral neuropathic conditions (e.g., the subject carries a gene that, individually, or in combination with other genes or environmental factors, is associated with development of age-related metabolic perturbations and / or peripheral neuropathic conditions).

[0574] Also disclosed herein is a method of diagnosing the disease or disorder before it is treated. This can be done in a manner of ways described herein. Once the subject / patient has received a diagnosis of metabolic dysfunction or peripheral neuropathy or age-related disease or disorder as described herein, they can then be treated. Attorney Docket No.: 103362-074WO1

[0575] Compositions, Formulations and Methods of Administration

[0576] In vivo application of the disclosed compounds, and compositions containing them, can be accomplished by any suitable method and technique presently or prospectively known to those skilled in the art. For example, the disclosed compounds can be formulated in a physiologically- or pharmaceutically-acceptable form and administered by any suitable route known in the art including, for example, oral, nasal, rectal, topical (such as a patch), and parenteral routes of administration. As used herein, the term parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intraperitoneal, and intrastemal administration, such as by injection. Administration of the disclosed compounds or compositions can be a single administration, or at continuous or distinct intervals as can be readily determined by a person skilled in the art.

[0577] Also disclosed herein are half-life increasing compositions which can increase the amount of time the compounds disclosed herein, such as 17a-estradiol (17aE2)-related treatments or carborane-related treatments, retain efficacy or viability in a subject. For example, these compositions can increase ligand binding efficiency or increase how long the 17a-estradiol (17aE2)-related treatments or carborane-related treatment remain in the blood. This can therefore prevent or slow degradation, thereby increasing active efficacy. The compounds disclosed herein can also be specifically targeted to peripheral nerves through means known to those with skill in the art.

[0578] The compounds disclosed herein, and compositions comprising them, can be administered utilizing liposome technology, slow release capsules, implantable pumps, and biodegradable containers. These delivery methods can, advantageously, provide a uniform dosage over an extended period of time. The compound s can also be administered in their salt derivative forms or crystalline forms.

[0579] The compounds disclosed herein can be formulated according to known methods for preparing pharmaceutically acceptable compositions. Formulations are described in detail in a number of sources which are well known and readily available to those skilled in the art. For example, Remington 's Pharmaceutical Science by E. W. Martin (1995) describes formulations that can be used in connection with the disclosed methods. In general, the compounds disclosed herein can be formulated such that a therapeutically effective amount of the compound is combined with a suitable excipient in order to facilitate effective administration of the compound. The compositions used can also be in a variety of forms. These include, for example, solid, semi-solid, and liquid dosage forms, such as tablets, pills, powders, liquid solutions or Attorney Docket No.: 103362-074WO1

[0580] suspension, suppositories, injectable and infusible solutions, and sprays. The preferred form depends on the intended mode of administration and therapeutic application. The compositions also preferably include conventional pharmaceutically-acceptable carriers and diluents which are known to those skilled in the art. Examples of carriers or diluents for use with the compounds include ethanol, dimethyl sulfoxide, glycerol, alumina, starch, saline, and equivalent carriers and diluents. To provide for the administration of such dosages for the desired therapeutic treatment, compositions disclosed herein can advantageously comprise between about 0.1% and 100% by weight of the total of one or more of the subject compounds based on the weight of the total composition including carrier or diluent.

[0581] Formulations suitable for administration include, for example, aqueous sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and nonaqueous sterile suspensions, which can include suspending agents and thickening agents. The formulations can be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and can be stored in a freeze dried (lyophilized) condition requiring only the condition of the sterile liquid carrier, for example, water for injections, prior to use.

[0582] Extemporaneous injection solutions and suspensions can be prepared from sterile powder, granules, tablets, etc. It should be understood that in addition to the excipients particularly mentioned above, the compositions disclosed herein can include other agents conventional in the art having regard to the type of formulation in question.

[0583] Compounds disclosed herein, and compositions comprising them, can be delivered to a cell either through direct contact with the cell or via a carrier means. Carrier means for delivering compounds and compositions to cells are known in the art and include, for example, encapsulating the composition in a liposome moiety. Another means for delivery of compounds and compositions disclosed herein to a cell comprises attaching the compounds to a protein or nucleic acid that is targeted for delivery to the target cell. U. S. Patent No. 6,960,648 and U. S. Application Publication Nos. 20030032594 and 20020120100 disclose amino acid sequences that can be coupled to another composition and that allows the composition to be translocated across biological membranes. U. S. Application Publication No. 20020035243 also describes compositions for transporting biological moieties across cell membranes for intracellular delivery. Compounds can also be incorporated into polymers, examples of which include poly (D-L lactide-co-glycolide) polymer; poly[bis(p-carboxyphenoxy) propane: sebacic acid] in a 20:80 molar ratio (as used in GLIADEL); chondroitin; chitin; and chitosan. Attorney Docket No.: 103362-074WO1

[0584] For preventing and / or treating of age-related disorders, metabolic perturbations, and / or peripheral neuropathic conditions, the compounds disclosed herein can be administered to a patient in need of treatment in combination with one or more additional therapies, e g., additional therapies for the treatment of metabolic perturbations and / or peripheral neuropathic conditions or for the treatment of symptoms of age-related metabolic perturbations and / or peripheral neuropathic conditions. These other substances or treatments can be given at the same as or at different times from the compounds disclosed herein.

[0585] In certain examples, compounds and compositions disclosed herein can be locally administered at one or more anatomical sites, optionally in combination with a pharmaceutically acceptable carrier such as an inert diluent. Compounds and compositions disclosed herein can 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. They can be enclosed in hard or soft shell gelatin capsules, can be compressed into tablets, or can be incorporated directly with the food of the patient’s diet. For oral therapeutic administration, the active compound can be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, aerosol sprays, and the like.

[0586] The tablets, troches, pills, capsules, and the like can also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; diluents such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring can be added. When the unit dosage form is a capsule, it can contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials can be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules can be coated with gelatin, wax, shellac, or sugar and the like. A syrup or elixir can contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound can be incorporated into sustained-release preparations and devices.

[0587] Compounds and compositions disclosed herein, including pharmaceutically acceptable salts or prodrugs thereof, can be administered intravenously, intramuscularly, or intraperitoneally Attorney Docket No.: 103362-074WO1

[0588] by infusion or injection. Solutions of the active agent or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations can contain a preservative to prevent the growth of microorganisms.

[0589] The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient, which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. The ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. Optionally, the prevention of the action of microorganisms can be brought about by various other antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the inclusion of agents that delay absorption, for example, aluminum monostearate and gelatin.

[0590] Sterile injectable solutions are prepared by incorporating a compound and / or agent disclosed herein in the required amount in the appropriate solvent with various other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.

[0591] For topical administration, compounds and agents disclosed herein can be applied in as a liquid or solid. However, it will generally be desirable to administer them topically to the skin as compositions, in combination with a dermatologically acceptable carrier, which can be a solid or a liquid. Compounds and agents and compositions disclosed herein can be applied topically to a subject’s skin such as through a patch.

[0592] Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or Attorney Docket No.: 103362-074WO1

[0593] water-alcohol / glycol blends, in which the compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers, for example.

[0594] Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.

[0595] Useful dosages of the compounds and 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.

[0596] The dosage ranges for the administration of the compositions are those that are 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.

[0597] Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days.

[0598] Also disclosed are pharmaceutical compositions that comprise a compound disclosed herein in combination with a pharmaceutically acceptable excipient. Pharmaceutical compositions adapted for oral, topical or parenteral administration, comprising an amount of a compound constitute a preferred aspect. The dose administered to a patient, particularly a human, should be sufficient to achieve a therapeutic response in the patient over a reasonable time limit, without lethal toxicity, and preferably causing no more than an acceptable level of side effects or morbidity. One skilled in the art will recognize that dosage will depend upon a variety of factors including the condition (health) of the subject, the body weight of the subject, kind of concurrent treatment, if any, frequency of treatment, therapeutic ratio, as well as the severity and stage of the pathological condition. Attorney Docket No.: 103362-074WO1

[0599] The pharmaceutical compositions can comprise a therapeutically effective amount of 17a estradiol or a derivative thereof, or a carborane or carborane analog described herein for the treatment of metabolic perturbations, aging, and / or peripheral neuropathic conditions.

[0600] Optionally, these compositions can further include at least one additional therapeutic as part of the treatment regimen, such as a corticosteroid (e.g., prednisone, prednisolone, methylprednisolone, betamethasone, dexamethasone, triamcinolone, hydrocortisone, or any combination thereof), an NS AID, an antimalarial, an immunomodulating agent, an anticoagulant, or a combination thereof.

[0601] Also disclosed are kits that comprise a compound disclosed herein in one or more containers. The disclosed kits can optionally include pharmaceutically acceptable carriers and / or diluents. In one embodiment, a kit includes one or more other components, adjuncts, or adjuvants as described herein. In one embodiment, a kit includes instructions or packaging materials that describe how to administer a compound or composition of the kit. Containers of the kit can be of any suitable material, e.g., glass, plastic, metal, etc., and of any suitable size, shape, or configuration. In one embodiment, a compound and / or agent disclosed herein is provided in the kit as a solid, such as a tablet, pill, or powder form. In another embodiment, a compound and / or agent disclosed herein is provided in the kit as a liquid or solution. In one embodiment, the kit comprises an ampoule or syringe containing a compound and / or agent disclosed herein in liquid or solution form.

[0602] A number of embodiments of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. / Accordingly, other embodiments are within the scope of the following claims.

[0603] EXAMPLES

[0604] The following examples are set forth to illustrate the 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 exclude equivalents and variations which are apparent to one skilled in the art.

[0605] Example 1: 17a-estradiol, a longevity treatment in male HET3 mice, improves metabolic and peripheral nerve health span parameters in male and female aged mice Attorney Docket No.: 103362-074WO1

[0606] During this study, the striking observation was made that female mice are protected against peripheral neuropathy at middle-age compared to males who start to exhibit neuropathy symptoms, whereas later in life following reproductive senescence, or loss of reproductive hormones (‘mouse menopause’), female neuropathy became worse than males. The same was true for their adipose health at those ages. In both rodents and humans, females appear more resistant than males to neurodegeneration, until a significant decrease in circulating estrogen levels occurs. Therefore, it was hypothesized that female sex hormones, especially estrogen, conferred protection against age-rel ted neurodegeneration and peripheral neuropathy, and predicted that increasing / maintaining estrogen levels across aging could prevent the development or reduce that severity of peripheral neuropathy and thereby have beneficial effects on metabolic health. Previously, the ITP found that the less prominent estrogen form, 17a estradiol (17aE2), increased lifespan in male HEF3 mice only, but health span data were lacking. It is demonstrated herein that 17aE2 improves both measures of peripheral nerve health, and measures of adipose and metabolic health, in both male and female mice across either a mid-life or late-life intervention. Furthermore, since estrogen receptor expression on the peripheral nerves themselves was found herein, it is hypothesized that estrogen is acting directly on the nerves as part of its mechanism of action, and that improvements to nerve health may underlie some or all of the metabolic improvements. Finally, it was predicted that 17aE2 is acting via the estrogen receptor P (ERP), since similar to 17aE2, activation of this receptor is associated with more beneficial impacts versus the 17PE2~> ERa signaling axis that is more associated with cancer and other deleterious effects. It is proposed that targeting the milder 17aE2-> ERp axis across aging in males and females could serve as a health span-promoting intervention.

[0607] Thus, disclosed herein, given the observed sex differences in age-related PN, another validated longevity treatment, 17a-Estradiol (17a-E2), was tested. 17a-E2 is a non-feminizing sex hormone that extends lifespan in male but not female mice. Female and male HET3 mice 17a-E2 (14,4ppm) in diet for 19-22 weeks at early (-52 weeks of age) and late (-84 weeks of age) intervention time points. An increased grip and plantarflexion muscle contractility and improved NMJ function was observed in males at early intervention with 17a-E2. 17a-E2 treatment improved intraepidermal innervation (a histological measure of small fiber PN) only in the late intervention group of male mice. Reduced fat mass was seen in all 17a-E2 -treated mice regardless of age and sex. Glucose sensitivity was improved in male mice only in the late 17a-E2 intervention group; while in female mice glucose sensitivity was improved in early and late

[0608] 7? Attorney Docket No.: 103362-074WO1

[0609] 17a-E2 intervention groups. Increased energy expenditure was seen in early 17a-E2 intervention male mice. Overall, it was found that 17a-E2 treatment is a translationally relevant way to maintain metabolic and nerve health across aging.

[0610] Materials & Methods

[0611] Mice And Treatment Intervention: Female CByB6Fl / J (JAX® #100009) bred to male C3D2F 1 / J (JAX® #100004) at the Jackson Laboratory' to produce the male and female HET3 offspring used in this study. Mice were housed initially as 4 to a cage in a climate-controlled vivarium with 12 / 12 h light / dark cycle and ad libitum access to food and water. For some histology studies C57BL / 6J Strain # 000664 from The Jackson Laboratory were used. Mice were euthanized by CO2 asphyxiation with cervical dislocation as a secondary confirmation of death. All procedures and handling of animals were performed In accordance with The Ohio State University’s Institutional Animal Care and Use Committee (IACUC), to comply with the guidelines of the PHS Policy on Humane Care and Use of Laboratory Animals, and Guide for the Care and Use of Laboratory Animals. This study was approved by The Ohio State University’s IACUC under protocol 2020A00000096.

[0612] Physiological assessments

[0613] Body Composition: Body composition of adult male mice was measured using the EchoMRITM3-inl analyzer (EchoMRI, LLC.)

[0614] GTT: Mice were fasted overnight for 16 hours, then received an i.p. injection of 2g / kg glucose. A hand-held glucometer (OneTouch UltraMini, LifeScan, Milpitas, CA, Johnson & Johnson, New' Brunswick, NJ), was used to measure blood glucose levels (from tail vein blood) at time t=0 and at intervals of 15 min, 30 min, 60 min, and 120 min after glucose injection.

[0615] CLAMS: For physiological assessment, male mice from the early intervention group were placed individually in metabolic cages for respiratory analyses (Comprehensive Laboratory Animal Monitoring System (CLAMS); Columbus Instruments, Columbus, OH). Following 48hr acclimation period oxygen consumption (VO2) and carbon dioxide production (VCO2) were measured every 15 minutes, from which both respiratory exchange ratio (RER), and energy expenditure (Heat) were calculated using the following equations: RER = VCO2 / VO2; Energy expenditure (heat) = CV × kcal / hour, where CV is the “caloric value ” as given by

[0616] C’F= (3.815 + 1.232)ERER. Throughout assessment animals were single housed in a bedding free cage, at room temperature on a 12 h light / dark cycle Following a 48hr acclimation period, waveform analysis of CLAMS data was performed by matching every 15 min measurement Attorney Docket No.: 103362-074WO1

[0617] across two 24 h~cycles. Two-way analysis of variance (ANOVA) was performed for average VO2, VCO2, RER, and Heat per group. An uncorrected Fisher’s Least Significance Difference test was performed for each time point between dietary groups as a post-hoc test Interaction P values are reported, which represent differences in 48 h data between groups, as well as multiple comparison results for differences which were only day / night phase specific.

[0618] Motor strength and neuromuscular function: Motor function was assessed as previously described (Willows 2024). Briefly, Motor function and neuromuscular integrity in mice were assessed through grip strength testing, electrophysiological measurements, and in vivo muscle contractility analysis. For grip strength, both forelimbs and hindlimbs were tested using a grip meter, with the average of three trials recorded for each. Electrophysiological assessments were conducted under isoflurane anesthesia and included measurements of compound motor unit action potential (CMAP) to evaluate muscle excitation, single motor unit potential (SMUP) to determine motor unit size, and motor unit number estimation (MUNE), calculated as CMAP divided by SMUP. Repetitive nerve stimulation (RNS) w'as performed to assess neuromuscular junction function, with percentage decrement in CM AP amplitude recorded. For muscle contractility, the tibial nerve w'as stimulated to measure maximal twitch and tetanic torque using a torque-measuring motor, and the values were normalized to body weight. All tests adhered to established protocols (as previously published, Willows 2024) to ensure accuracy and reliability.

[0619] “Motor function was assessed using bilateral forelimb and hindlimb grip strength testing as previously described (BIO-GS3, Bioseb, Vitrolles, France). During grip testing, mice were scruffed by the rater in a manner that immobilized the mice but did not limit limb range of motion. For forelimb testing, mice were held vertically, allowed to grip the T-shaped bar attached on the grip meter with bilateral forelimbs. Then the mice were pulled in a steady manner away from the meter until grip was lost. Three trials were averaged to determine forelimb grip strength. Hindlimb grip strength was performed in the similar manner but allowing mice to grip using bilateral hindlimbs.

[0620] In addition to behavioral assessment of motor function, motor unit electrophysiology and in vivo pl antarfl exion muscle contractility were assessed to determine neuromuscular functional integrity. During in vivo measures, mice were anesthetized with isoflurane anesthesia (3-5% for induction, 1-2% for maintenance) low-flow anesthesia system (SomnoSuite, Kent Scientific, Torrington, CT). Motor unit electrophysiological measures were performed that included compound motor unit action potential amplitude (CMAP), average single motor unit potential Attorney Docket No.: 103362-074WO1

[0621] amplitude (SMUP), motor unit number estimation (MUNE), and repetitive nerve stimulation (RNS) similar to prior work. During electrophysiological measurements, a pair of electrodes were placed over the proximal portion of the gastrocnemius muscle (active electrode) and the mid metatarsal region of the foot (reference electrode) for recording (Alpine Biomed, Skovlunde, Denmark). A pair of 28 gauge monopolar needle electrodes were used for subcutaneous stimulation at the region of the proximal hindlimb near the sciatic nerve (Teca, Oxford Instruments Medical, NY, USA). To elicit CMAP, a measure of summated muscle sarcolemma excitation, a supramaximal stimulation was delivered and the peak-to-peak amplitude was used for analysis. To determine SMUP, a measure of motor unit size, the incremental method was used to obtain 10 all-or-none increments during a gradually increasing stimulations of the sciatic nerve. The SMUP was determined by averaging the 10 increments. Then MUNE, an estimate of the number of functional motor units innervating a muscle, was determined as follows: MUNE = Peak-to-peak CMAP Amplitude / SMUP. During RNS, a measure of neuromu scular junction transmission, CMAP responses were recorded while stimulating the sciatic nerve with supramaximal stimulations at 50 Hz. Then, RNS decrement was calculated as follows: % amplitude decrement = ((Amplitude of tenth response - Amplitude first response) / Amplitude of first response) multiplied by 100%. In vivo plantarflexion muscle contractile torque production was assessed similar to prior work (1300 A, Aurora Scientific, Aurora, ON, Canada). Briefly, mice were placed on the testing platform in supine, and the right hindlimb paw was taped into footplate linked to the torque measuring motor. The limb was then locked into the testing rig using a blunt clamp at the knee while orienting the tibia at 90 degrees relative to the footpl ate / foot. The tibial nerve was then supramaximally stimulated to elicit maximum twitch torque following a single stimulation and maximal tetanic torque following a train of supramaximal stimulations at 150 Hz for 1 s. The peak torque values normalized to body weight were used for analyses of twitch and tetanic measurements.”

[0622] Histology

[0623] Whole mount adipose nerve imaging: Intact inguinal scWAT depots were excised from male and female mice, fixed overnight in 2% PF A at 4°C, and processed following the Z-depth reduction method as described previously (CITE Willows 2021) with accompanying protocol (CITE Willows 2022).

[0624] DRG imaging: Dorsal root ganglia were excised bilaterally, immediately fixed in Zamboni Fixative (Newcomer Supply, Cat#l 459A) for 1 hour at room temperature after which tissues received 1 wash in IX PBS at room temperature. DRGs were moved into fresh IX PBS Attorney Docket No.: 103362-074WO1

[0625] overnight at 4°C. The following day DRGs were moved to 30% sucrose overnight at 4°C prior to embedding in OCT. DRGs were sectioned at 14 pm thick onto glass slides. Slides were submerged in ice-cold acetone for 15 minutes followed by two 5-minute washes in IX Millipore Rinse Buffer (Millipore, Cat#20845). Next, slides were submerged for 20 minutes in 0.5% Tween-20 in IX PBS followed by two 5-minute washes in rinse buffer. Slides were then submerged into Target Retrieval Solution followed by two more 5-minute washes in rinse buffer. A drop of IHC Select Blocking Reagent was added to each tissue and incubated at 37°C for 20 minutes. Primary antibodies were diluted into Dako Antibody Diluent, 100 pL of antibody solution was added to each tissue, incubated overnight at 4°C. The next day, slides were washed twice for 10-minutes in rinse buffer and incubated in secondary antibody solution for 10 minutes at room temperature. Slides were washed twice for 10-minutes in rinse buffer, and two more washes in deionized H2O for 5-minutes each. Slides were submerged in DAPI lOOng / ml in H2O for 5 minutes at room temperature followed by two more 5-minute washes in deionized H2O. Slides were cover slipped and sealed for imaging.

[0626] NMJ Imaging: Medial gastrocnemius muscles were excised from male and female HET3 mice and processed to assess neuromu scular junction occupancy as described previously (Willows Aging Cell).

[0627] IENFD: Glabrous hind paw skin was excised from male and female HET3 mice and processed for quantification of intraepidermal nerve fiber density as described previously (Willows Aging Cell).

[0628] Hemalum Staining: Intact ing-scWAT depots were excised from male HET3 mice and processed for general histological staining with hemalum as described previously (Willows Aging Cell).

[0629] Microscopy: Micrographs were captured with Leica Stellaris 5 confocal microscope using white light laser with excitation and emission spectra tuned specifically for each fluorophore or groups of fluorophores to eliminate crosstalk. Scanning speed was 600 Hz.

[0630] Multiple channels were scanned sequentially. Photons were detected with Power HyD S detectors. Objectives included: HC PL APO 10x / 0.40 CS2 and HC PL APO 40x / l.30 OIL CS2. PinholeAiry 1.00 AU. Confocal zoom was applied to further increase magnification when necessary. Entire tissues were visually scanned, and representative images were captured. Z-stacks were maximum intensity projected. Tiling of z-stacks was performed to display entire adipose depots. LUTs were adjusted to improve structure visualization. All imaging parameters Attorney Docket No.: 103362-074WO1

[0631] were kept consistent between groups when making direct comparisons. Image processing performed in Leica LASX software and Fiji (PMID: 22743772).

[0632] Statistical Analyses: All plots represent mean ± SEM. Statistical calculations were carried out in Excel or GraphPad Prism 9.0, utilizing the ANOVA or Student’s T-test as indications of significance. For all figures, *P<0.05, **P<0.01, ***P<0.005, ****P<0.001.

[0633] Results

[0634] 17 a-E2 signals through estrogen receptors, which are expressed in the peripheral nervous system: It is demonstrated herein for the first time that estrogen receptors (ERa and ERP) are expressed in peripheral nerves, including the fibers innervating adipose, and the sensory dorsal root ganglia (DRGs) innervating adipose and muscle (Fig, 1 -D, Fig. 2A-B). There is receptor expression in DRG cell bodies (Fig. 1 A, C, D), as well as support cells around the axons (Fig. IB, Fig. 2A-B). ERa and ERP are also expressed on adipocytes of scWAT in both female and male mice (Fig. 2A-B), providing us with a 17a-E2 target in both metabolic and nerve tissues. Considering this and previous findings that female mice exhibit protection again neurodegeneration until reproductive senescence, a study (Fig. IE) was designed to determine the effects of 17a-E2 longevity treatment on health span in both sexes. Male and female HET3 mice were fed 14.4 ppm 17a-E2 compounded in diet for up to 22 weeks, with metabolic and nerve assessments staring after 1 Owks of treatment intervention. Diet was started at two time points, early intervention (El), when animals were 50-56wks old, or late intervention (LI), when animals ranged 83-85wks of age. Chow fed aged littermates (Control ), and adult mice were used as controls. These two intervention time points allowed us to investigate whether or not 17a-E2 treatment needs to be started at middle age to be effective, an age when female sex hormones are still relatively high in mice.

[0635] Early and late intervention with 17 a-Estradiol longevity treatment improves metabolic parameters in both male and female agedHET3 mice: To ensure that a physiological increase in 17a-E2 was bring induced, estrogen levels were measured in plasma in male HET3 mice (Fig.

[0636] 3 A), and only saw an increase in 17a-E2 with no effect on other circulating estrogens. At 14 weeks of 17aE2 intervention, body mass composition was measured. Body weight, and total fat mass were significantly decreased for both males and females in El 17aE2 treatment, total fat mass was also decreased with LI 17aE2 treatment, but only significantly so in males (Fig. 3B middle panels). No difference in lean mass was seen for either sex in either intervention groups (Fig. 3B bottom panels). These data indicate that the body mass decrease in 17aE2 treated Attorney Docket No.: 103362-074WO1

[0637] animals was due to a decrease in fat mass and not lean mass. Considering lean mass loss with aging is associated with poorer health span, these data were encouraging as a viable translational treatment. Next considered were the effects of 17aE2 treatment on metabolism by assessing glucose homeostasis which becomes dysregulated with age. Glucose tolerance testing revealed improved glucose sensitivity for 17ctE2 treated male mice compared to control at LI, while female glucose sensitivity was improved in early and late 17cxE2 intervention groups, albeit more robustly in LI (Fig. 3C). To further assesses metabolic effects of 17aE2 treatment, males mice from the El time point were placed in metabolic cages. LI animals were not assessed due to the frailty of the animals at the age. El 17aE2 treated male mice showed increased energy expenditure (calculated from VO2 and VCO2) compared to control animals, and a respiratory exchange ratio (RER) more consistent with preferentially metabolizing carbohydrates over lipids (Fig. 7 A), possibly due their reduced fat mass. Upon study termination, gross anatomy examination of adipose depots also supported the in vivo metabolic assessments. Subcutaneous (sc) and visceral / perigon adal (pg) white adipose tissue (WAT), as well as brown adipose tissue (BAT) in male mice decreased in size and both scWAT and BAT appeared browner (Fig. 4A) with El and LI 17aE2 treatment, indicating an improved metabolic phenotype. Due to time constraints, photographic cataloguing of gross anatomy of female adipose depots was not performed, but the same observations were noted. These findings correlated to decreased body weight and adipose depot weights at study termination for both interventions and across both sexes, although the effect was more pronounced in males (Fig. 4B). Hemalum staining was performed on axillary (ax) scWAT to assess adipocyte size, degree of browning and presence of crown-like structures (marker of inflammation). Histological assessment of ax-scWAT revealed decreased adipocyte size and increased browning in male mice on the El 17aE2 treatment compared to controls (Fig. 4C). Histological assessment of ax-scWAT revealed decreased adipocyte size and increased browning in male mice on the El 17aE2 treatment compared to controls (Fig. 4C). By contrast, histological assessment of pg-scWAT revealed decreased adipocyte size in both female and male mice on El and LI 17aE2 treatment compared to controls (Fig. 5), but only female mice at El and LI 17aE2 treatment exhibited increased browning in pg-WAT (Fig. 5). Considering adipose fibrosis increases with aging and has detrimental effects on the tissue function including contributing to chronic inflammation we evaluated adipose fibrosis and changes to collagen fiber types using Pirco Sirius Red staining and polarized light imaging. We found that 17aE2 treatment had no effect on total adipose fibrosis or collagen fiber type in male or female mice at either El or LI (Fig. 6). Attorney Docket No.: 103362-074WO1

[0638] Early and late intervention with 17 a-Estradiol longevity treatment improves nerve parameters in aged, male and female HET3 mice: To determine the effects of 17aE2 longevity treatment on peripheral nerve parameters in middle aged and old age male HET3 mice, neurophysiological assessments that typically exhibit diminished performance in aging animals, were performed. Neuromuscular physiology was assessed in vivo at ~15 weeks of treatment, and while motor unit number estimation (MUNE) showed no difference at either El or LI, response to repetitive nerve stimulation (RNS) in the El group was improved (Fig. 6A). RNS causes neuromuscular junction (NMJ) fatigue through? ACh depletion. A decremental response in RN S is the electrical correlate of clinical muscle fatigue and weakness. The results of the RNS assessment indicate that early, but not late, intervention 17ctE2 treatment showed improved NMJ function in male HET3 mice (Fig. 9A). Muscle strength and contractility was measured as hind limb (HL) grip strength and tetanic torque (max muscle contractility). The El 17aE2 treatment trended to increase grip and resulted in increased contractility, indicating overall improved NMJ function. However, LI 17otE2 treatment reduced HL grip, and had no effect on contractility (Fig.

[0639] 9B.

[0640] Next the effect of 17a-E2 treatment on small fiber nerves specifically was evaluated, as these are the first to be targeted in age-induced PN. El, but not LI, improved mechanical nociception only in female HET3 mice, as determined by SUDO Von Frey analysis (Fig. 10A). Conversely, age-related small fiber peripheral neuropathy (PN) in glabrous skin (as assessed by intraepidermal nerve fiber density (IENFD) of paw skin) was improved female HET3 mice in the LI 17aE2 treated group compared to controls (Fig. 10B-C). Compared to female HET3 mice in either El or LI groups, male HET3 mice showed a wider range of IENFD in hind paw skin, this varied range of response to 17aE2 treatment in males may be due to lower estrogen receptor expression in males versus females.

[0641] Since it was previously reported that aging decreases adipose innervation and vascular denisity in scWAT, whole mount imaging of the inguinal scWAT depot was also performed. Subtle differences were observed in CGRP protein expression (nociceptive sensory nerve marker) across the inguinal scWAT depots in response to each treatment. Early 17aE2 intervention appeared to increase CGRP expression while the later intervention resulted in decreased CGRP across the tissue (Fig. 11 A-B). No difference in vascular density was seen with 17aE2 at either intervention timepoint (CD31 vascular marker imaging in Fig. 11 A and quantification Fig. 1 IB). Attorney Docket No.: 103362-074WO1

[0642] In summary, 17aE2 dietary supplementation at both mid-or late-age clearly demonstrated a health span improvement in both metabolism and peripheral nerve function in both sexes.

[0643] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of skill in the art to which the disclosed invention belongs. Publications cited herein and the materials for which they are cited are specifically incorporated by reference.

[0644] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

[0645] TABLES

[0646] Table 1: Summary of peripheral nerve and metabolic improvements across aging with 17aE2 intervention (HET3 mice, 14.4ppm 17aE2 compounded in diet)

[0647] Endpoint Early Intervention 17aE2 Late Intervention 17oE2

[0648] Treatment Treatment

[0649] Females Males Females Maks Smail Fiber Strong No effect Strong Slight Peripheral improvement improvement improvement Neuropathy (von

[0650] Frey, IENFD)

[0651] Large fiber Not assessed Strong Not assessed No effect peripheral improvement

[0652] neuropathy

[0653] (muscle

[0654] neurophysiology)

[0655] Large fiber

[0656] peripheral

[0657] neuropathy

[0658] (neuromuscular

[0659] junction)

[0660] Adipose Trend-increased Not assessed Trend- Not assessed intervention CGRP + nerves Decreased

[0661] CGRP + nerves

[0662] Glucose Slight No effect Strong Strong sensitivity improvement improvement improvement Body Strong Strong No effect Strong composition improvement improvement improvement Energy Not assessed Strong Not assessed Not assessed

[0663]

[0664] expenditure improvement Attorney Docket No.: 103362-074WO1

[0665] TA BLE 2: Detailed summary of metabolic improvements across aging with 17aE2 intervention (HET3 mice, 14.4 ppm 17aE2 compounded in diet)

[0666] 17aE2 Early Invention (started -50-56 Late Invention (started -83-85 weeks of age) weeks of age)

[0667] Endpoint Females Males Females Males

[0668] BW 14wks on Decreased Decreased No effect No effect diet

[0669] Fat mass 14 wks Decreased Decreased Trend down Decreased diet

[0670] GTT (14-17 wks Slight No effect Improved Improved diet) improvement

[0671] Energy No data Increased No data No data Expenditure

[0672] Terminal BW Decreased Decreased No effect No effect 19-22 wks on

[0673] diet

[0674] Terminal scWAT Decreased Decreased No effects No effect weight 19-22

[0675] wks on diet

[0676] Terminal Trend down Decreased No effect No effect pgWAT weight

[0677] 19-22 wks on

[0678] diet

[0679] Terminal BAT Decreased Decreased No effect Decreased weight 19-22

[0680] wks on diet

[0681] Adipose Increased Smaller cell Increased Smaller cell size Histology browning size / increased browning (qualitative (pgWAT only); browning (H& E (pgWAT only); assessment) no no difference in only); no no difference in difference in fibrosis; no difference in fibrosis; no fibrosis; no difference in fibrosis; no difference in difference in total vasculature difference in total vasculature total vasculature total vasculature

[0682] Adipose gross No data Smaller, No data Smaller, anatomy browner depots browner depots

[0683]

[0684] (B AT & scWAT) (BAT & scWAT)

Claims

Attorney Docket No.: 103362-074WO1 WHAT IS CLAIMED IS:

1. A method for treating or preventing metabolic disease and / or peripheral neuropathic conditions and / or improving overall health-span in aging in a subject in need thereof, the method comprising:administering a therapeutically effective amount of 17a estradiol or an estrogen receptor P-targeting composition to the subject in need thereof.

2. The method of claim 1, wherein the estrogen receptor P-targeting composition comprises estradiol or a derivative thereof, or a carborane or carborane analog.

3. The method of claim 2, wherein the estradiol is 17a estradiol.

4. The method of any one of claims 1-3, wherein the metabolic disease and / or peripheral neuropathy or aberrant peripheral nerve function is associated with overall health span, age span, or undesired effects of biological aging or reproductive senescence as a result of physiological / biological aging or induced by disease, environmental exposures, genetic predisposition, or surgical intervention.

5. The method of claim 4, wherein surgical intervention comprises loss of reproductive organ function or hysterectomy.

6. The method of any one of claims 1-5, wherein the disease or disorder comprises adipose dysfunction, increased adipose mass, increased adipose inflammation and / or fibrosis, decreased adipose innervation and / or vascularization, loss of metabolic control, small fiber neuropathy in skin or any other organs, decreased motor nerve function, or loss of NMJ integrity.

7. The method of claim 6, wherein loss of metabolic control comprises glucose sensitivity, dyslipidemia, or cardiometabolic risks.

8. The method of any one of claims 1-7, wherein the estradiol comprises Formula XV, or a pharmaceutically acceptable salt thereof:Attorney Docket No.: 103362-074WO19. The method of claim 8, wherein the estradiol comprises 17a estradiol, as defined by Formula XVI:

10. The method of any one of claims 1-7, wherein the carborane or carborane analog comprises a compound defined by Formula I, or a pharmaceutically acceptable salt thereof R1-X~~C^R2Formula IwhereinR1represents a dicarba-closo-dodecaboran-yl group which may have one or more substituents selected from the group consisting of an alkyl group, an alkenyl group, a carboxyl group, an alkoxycarbonyl group, an amino group, a hydroxyl group, a hydroxyalkyl group, aAttorney Docket No.: 103362-074WO1 mono or di-alkylcarbamoyl-substituted alkyl group, an aikanoyi group, an aryl group, and an aralkyl group, each of which m ay be substituted or unsubstituted;R2represents a carboxyl group, an alkoxycarbonyl group, or a hydroxyl group; and X represents a single bond, or a linking group selected from the group consisting of groups represented by the following formulas:owherein Y1, Y2, Y3, Y4Y5, Y6, and Y7independently represent an oxygen atom or — N(R3) — wherein R3represents hydrogen atom or an alkyl group; Ysrepresents an oxygen atom, ----- N(R4) — wherein R4represents hydrogen atom or an alkyl group, — CO —, — CH2 —, or — C(=CH2) ---; R5, R6, and R7independently represent hydrogen or one or more substituents on the phenyl group; R8represents an alkyl group or an aryl group which may be substituted;R9represents an alkyl group; and R10represents a substituted or unsubstituted aryl group.

11. The method of any of claims 1 -7, wherein the carborane or carborane analog comprises a compound defined by Formula II, or a pharmaceutically acceptable salt thereofQ-R1Attorney Docket No.: 103362-074WO1Formula IIwhereinX-- - Q is a substituted or unsubstituted dicarba-closo-dodecaborane cluster, and — and R1are attached to Q in a para configuration;X is OH, NHR2, SH, or S(O)(O)NHR2;R1is substituted or unsubstituted C4-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C3-C20 alkylaryl, substituted or un substituted C3-C20 alkylheteroaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, substituted or unsubstituted C4-C20 alkylheterocycloalkyl, substituted or unsubstituted C1-C20 acyl, or NR3R4;R2is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl; andR3and R4are independently selected from substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C2-C20 alkylaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, or substituted or unsubstituted C1-C20 acyl.

12. The method of any of claims 1-7, wherein the carborane or carborane analog comprises a compound defined by Formula III, or a pharmaceutically acceptable salt thereofFormula IIIwherein• is a carbon atom;o is B-H, B-halogen, B-alkyl, B-OH, or B-NH2;Xis OH, NHR2, SH, or S(O)(O)NHR2;R1is substituted or unsubstituted C4-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C3-C20 alkylaryl, substituted or unsubstituted C3-C20 alkylheteroaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, substituted or unsubstituted C4-C20 alkylheterocycloalkyl, substituted or un substituted C1-C20 acyl, or NR3R4;R2is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl; andAttorney Docket No.: 103362-074WO1 R3and R4are independently selected from substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C2-C20 alkylaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, or substituted or unsubstituted C1-C20 acyl.

13. The method of any of claims 1 -7, wherein the carborane or carborane analog comprises a compound defined by Formula IV, or a pharmaceutically acceptable salt thereofFormula IVwherein• is a carbon atom;o is B-H, B-halogen, B-alkyl, B-OH, or B-NH2;the dotted line to Y indicates that the bond can be a single bond or a double bond, as valence permits;X is OH, NHR2, SH, or S(O)(O)NHR2;Y is O, OR2, NHR2, SH, or S(O)(O)NHR2;R5is substituted or unsubstituted C2-C19 alkyl, substituted or unsubstituted C2-C19 alkenyl, substituted or unsubstituted C2-C19 alkynyl, substituted or unsubstituted C2-C19 alkylaryl, substituted or unsubstituted C2-C19 alkylheteroaryl, substituted or unsubstituted C3-C19 alkyl cycloalkyl, substituted or un substituted C3-C19 alkylheterocycloalkyl, or NR3R4;R2is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl;R2is H or substituted or unsubstituted C1-C4 alkyl; andR3and R4are independently selected from substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C2-C20 alkylaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, or substituted or unsubstituted C1-C20 acyl.

14. The method of any of claims 1-7, wherein the carborane or carborane analog comprises a compound defined by Formula VII, or a pharmaceutically acceptable salt thereofAttorney Docket No.: 103362-074WO1R8R9Formula VIIwhereinQ is a substituted or unsubstituted dicarba-closo-dodecaborane cluster, andand R7are attached to Q in a para configuration;X is OH, NHR2, SH, or S(O)(O)NHR2;R7is substituted or un substituted C1-C14 alkyl, substituted or un substituted C2-C14 alkenyl, substituted or unsubstituted C2-C14 alkynyl, substituted or unsubstituted C1-C14 acyl, or NR3R4;R8, R9, R10, R11, and R12are independently H, OH, halogen, substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C2-C20 alkylaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, substituted or unsubstituted C1-C20 acyl, orNRJR4, or wherein, as valence permits, R8and R9, R9and R10, R10and R11, or R11and R12, together with the atoms to which they are attached, form a 3-10 membered substituted or unsubstituted cyclic moiety optionally including from 1 to 3 heteroatoms;R2is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl; andR3and R4are independently selected from substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C2-C20 alkylaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, or substituted or unsubstituted C1-C20 acyl.

15. The method of any of claims 1 -7, wherein the carborane or carborane analog comprises a compound defined by Formula IX, or a pharmaceutically acceptable salt thereofX-Z \-Q— R13-4-R15Formula IXwhereinAttorney Docket No.: 103362-074WO1 Q is a substituted or unsubstituted dicarba-closo-dodecaborane cluster, andand R13are attached to Q in a para confi uration;X is OH, NHR2, SH, or S(O)(O)NHR2;R13is substituted or unsubstituted C1-C19 alkyl, substituted or unsubstituted C2-C19 alkenyl, substituted or unsubstituted C2-C19 alkynyl, or substituted or unsubstituted C1-C20 acyl; andR14, R15, and R16are independently hydrogen, halogen, hydroxyl, substituted or unsubstituted C1-C18 alkyl, substituted or unsubstituted C2-C18 alkenyl, substituted or unsubstituted C1-C18 alkynyl, substituted or un substituted C2-C18 aryl, substituted or unsubstituted C3-C18 cycloalkyl, substituted or unsubstituted C1-C20 acyl, or NR3R4, or wherein, as valence permits, R14and R15, R14and R16, or R15and R16, together with the atoms to which they are attached, form a 3-10 membered substituted or unsubstituted cyclic moiety optionally including from 1 to 3 heteroatoms,with the proviso that at least two of R14, R15and R16are not hydrogen, halogen, or hydroxyl; andwith the proviso that when X is OH and R13is a Cs alkyl, R14R15, and R16are not H, methyl, and methyl.

16. The method of any one of claims 1-7, wherein the carborane or carborane analog comprises a compound defined by Formula XI, or a pharmaceutically acceptable salt thereofFormula XIwhereinQ is a substituted or unsubstituted dicarba-closo-dodecaborane cluster;D is -S-, -S(O)- -S(O)(O)-, —S(O)(NH)—, -P(O)(OH)O- -P(O)(OH)NH-,or~O~ X is OH, NHR2, SH, or S(O)(O)NHR2;R6is substituted or un substituted C1-C20 alkyl, substituted or un substituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C2-C20 alkylaryl, substituted or unsubstituted C2-C20 alkylheteroaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, or substituted or unsubstituted C4-C20 alkylheterocycloalkyl; andAttorney Docket No.: 103362-074WO1 R2is H, OH, halogen, or substituted or unsub sti tilted C1-C4 alkyl.

17. The method of any one of claims 1-7, wherein the carborane or carborane analog comprises a compound defined by Formula XII, or a pharmaceutically acceptable salt thereof A-Q-R1Formula XIIwhereinQ is a substituted or unsubstituted dicarba-closo-dodecaborane cluster, and A and R1are attached to Q in a para configuration;A is a substituted or unsubstituted heteroaryl ring;R1is substituted or unsubstituted C2-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C3-C20 alkylaryl, substituted or unsubstituted C3-C20 alkylheteroaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, substituted or un substituted C4-C20 alkylheterocycloalkyl, substituted or unsubstituted C1-C20 acyl, C1-C20 acyl, — C(O)NR3R4, — S(O)-R3, — S(Ch)-R3, substituted or unsubstituted C2-C20 heteroalkyl, or NR3R4; andR3and R4are independently selected from substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or un substituted C2-C20 alkylaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, and substituted or unsubstituted C2-C20 heteroalkyl.

18. The method of claim 17, wherein the carborane or carborane analog comprises a compound defined by Formula XII A, or a pharmaceutically acceptable salt thereofFormula XII Awherein• is a carbon atom;o is B-H, B-halogen, B-alkyl, B-OH, or B-NH2;X is OH, NHR2, SH, or S(O)(O)NHR2;Z is, individually for each occurrence, N or CH, with the proviso that at least one of Z is N;Attorney Docket No.: 103362-074WO1 R1is substituted or unsubstituted C2-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C3-C20 alkylaryl, substituted or unsubstituted C3-C20 alkylheteroaryl, substituted or unsubstituted C4-C20 alkyl cycloalkyl, substituted or un substituted C4-C20 alkylheterocycloalkyl, substituted or unsubstituted C1-C20 acyl, C1-C20 acyl, — C(O)N R3R4, — S(O)-R3, — S(O2)-R3, substituted or unsubstituted C2-C20 heteroalkyl, or NR3R4;R2is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl; andR3and R4are independently selected from substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C2-C20 alkylaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, and substituted or unsubstituted C2-C20 heteroalkyl.19, The method of claim 18, wherein the carborane or carborane analog comprises a compound defined by one of the formulae below, or a pharmaceutically acceptable salt thereof:wherein• is a carbon atom;o is B-H, B-halogen, B-alkyl, B-OH, or B-NH2;X is OH, NHR2, SH, or S(O)(O)NHR2;R1is substituted or un substituted C2-C20 alkyl, substituted or un substituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C3-C20 alkylaryl, substituted or unsubstituted C3-C20 alkylheteroaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, substituted or unsubstituted C4-C20 alkylheterocycloalkyl, substituted or unsubstituted C1-C20 acyl, C1-C20 acyl, — C(O)NR3R4, — S(O)-R3, — S(O2)-R3, substituted or unsubstituted C2-C20 heteroalkyl, or NR3R4;R2is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl; andAttorney Docket No.: 103362-074WO1 R3and R4are independently selected from substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C2-C20 alkylaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, and substituted or un substituted C2-C20 heteroalkyl.

20. The method of claim 18, wherein the carborane or carborane analog comprises a compound defined by one of Formula XIIB-XIIF, or a pharmaceutically acceptable salt thereof:Formula XIIBFormula XIICFormula XIIDFormula XIIEFormula XIIFwherein• is a carbon atom;o is B-H, B-halogen, B-alkyl, B-OH, or B-NH2;R1is substituted or unsubstituted C2-C20 alkyl, substituted or un substituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C3-C20 alkylaryl, substituted or unsubstituted C3-C20 alkylheteroaryl, substituted or unsubstituted C4-C20Attorney Docket No.: 103362-074WO1 alkylcycloalkyl, substituted or unsubstituted C4-C20 alkylheterocycloalkyl, substituted or unsubstituted C1-C20 acyl, C1-C20 acyl, — C(O)N R3R4, — S(O)-R3, — S(O2)-R3, substituted or unsubstituted C2-C20 heteroalkyl, or NR3R4;R2is H, OH, halogen, or substituted or unsubstituted C1-C1 alkyl; andR3and R4are independently selected from substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or un sub stituted C2-C20 alkylaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, and substituted or unsubstituted C2-C20 heteroalkyl.

21. The method of any of claims 1-7 or 17-19, wherein the carborane or carborane analog comprises a compound defined by one of the formulae below, or a pharmaceutically acceptable salt thereof:wherein• is a carbon atom;o is B-H, B-halogen, B-alkyl, B-OH, or B-NH2;the dotted line to Y indicates that the bond can be a single bond or a double bond, as valence permits;Ais a substituted or unsubstituted heteroaryl ring;Y, when present, is O, halogen, OR2, NHR2, SH, or S(O)(O)NHR2;R6is substituted or unsubstituted C1-C19 alkyl, substituted or unsubstituted C2-C19 alkenyl, substituted or unsubstituted C2-C19 alkynyl, substituted or unsubstituted C2-C19 alkylaryl, substituted or un sub stituted C2-C19 alkylheteroaryl, substituted or unsubstituted C4-C19Attorney Docket No.: 103362-074WO1 alkylcycloalkyl, substituted or unsubstituted C4-C19 alkylheterocycloalkyl, and substituted or unsubstituted C2-C20 heteroalkyl, or NR3R4;R2is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl;R2is H or substituted or unsubstituted C1-C4 alkyl; andR3and R4are independently selected from substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or un sub stituted C2-C20 alkylaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, and substituted or unsubstituted C2-C20 heteroalkyl.

22. The method of claim 21, wherein A is a five-membered substituted or unsubstituted heteroaryl ring, such as a thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, or 1,3,4-oxadiazolyl ring.

23. The method of claim 21, wherein A is a six-membered substituted or unsubstituted heteroaryl ring, such as a pyridyl, pyrazinyl, pyriniidinyl, triazinyl, or pyridazinyl ring.

24. The method of any one of claims 1-7, wherein the carborane or carborane analog comprises a compound defined by Formula XIV, or a pharmaceutically acceptable salt thereofFormula XIVwhereinA is a substituted or unsubstituted aryl ring or a substituted or unsubstituted heteroaryl ring;Q is a spacer group chosen from one of the following:CHAttorney Docket No.: 103362-074WO1where m and n are each individually 0, 1, 2, or 3;R1is substituted or unsubstituted C4-C20 alkyl, substituted or unsubstituted C4-C20 heteroalkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, substituted or unsubstituted C3-C20 alkylaryl, substituted or unsubstituted C3-C20 alkylheteroaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, substituted or unsubstituted C4-C20 alkylheterocycloalkyl, substituted or unsubstituted C1-C20 acyl, C1-C20 acyl, — C(O)N R3R4, or NR3R4; andR3and R4are independently selected from substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted C1-C20 heteroalkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or un substituted C2-C20 alkynyl, substituted or unsubstituted C2-C20 alkylaryl, or substituted or unsubstituted C4-C20 alkylcycloalkyl.

25. The method of claim 24, wherein A is a five-membered substituted or unsubstituted heteroaryl ring, such as a thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4- triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triaz.olyl, 1,3,4-thiadiazolyl, or 1,3,4-oxadiazolyl ring.

26. The method of claim 24, wherein A is a six-membered substituted or un substituted heteroaryl ring, such as a pyridyl, pyrazinyl, pyriniidinyl, triazinyl, or pyridazinyl ring.X— / \ —27. The method of claim 24, wherein A is; X is OH, NHR2, SH, or S(O)(O)NHR2;and R2is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl.Attorney Docket No.: 103362-074WO1)>28. The method of claim 22, wherein A. is—j / ; X is OH, NHR2, SH, or S(O)(O)NHR2; and R2is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl.

29. The method of any of claims 24-28, wherein R1is one of the followingwhereinthe dotted line to Y indicates that the bond can be a single bond or a double bond, as valence permits;Y, when present, is O, halogen, OR2, NHR2, SH, or S(O)(O)NHR2;R6is substituted or unsubstituted Ci-Ci 9 alkyl, substituted or unsubstituted C2-C19 alkenyl, substituted or unsubstituted C2-C19 alkynyl, substituted or unsubstituted C2-C19 alkylaryl, substituted or unsubstituted C2-C19 alkylheteroaryl, substituted or unsubstituted C4-C19 alkylcycloalkyl, substituted or un substit ted C4-C19 alkylheterocycloalkyl, and substituted or unsubstituted C2-C20 heteroalkyl. or R3R4;R2is H, OH, halogen, or substituted or unsubstituted C1-C1 alkyl;R2is H or substituted or unsubstituted C1-C4 alkyl; andR3and R4are independently selected from substituted or unsubstituted C1-C20 alkyl, substituted or un substituted C2-C20 alkenyl, substituted or un substituted C2-C20 alkynyl, substituted or unsubstituted C2-C20 alkylaryl, substituted or unsubstituted C4-C20 alkylcycloalkyl, and substituted or unsubstituted C2-C20 heteroalkyl.

30. The method of any one of claims 1-7, wherein the carborane or carborane analog comprises WT-IV-012, the structure of which is shown belowAttorney Docket No.: 103362-074WO1OH31, The method of any of claims 1-30, wherein the composition comprises an ERP agonist.

32. The method of any of claims 1-31, wherein the composition comprises an EC₅₀ of 800 nM or less, such as an EC₅₀ of 6 nM or less, at estrogen receptor beta (ERP).

33. The method of claim 31, wherein the composition comprises a selective ERP agonist.

34. The method of any of claims 1 -33, wherein the composition has an ERP-to-ERa agonist ratio of 8 or more, such as an ERP-to-ERa agonist ratio of 400 or more.

35. The method of any of claims 1-34, wherein the method further comprises administration of at least one additional therapeutic as part of the treatment regimen.

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