WO2019018119A1 - Methods of treating epilepsy and kcnti related conditions - Google Patents

Abstract

The invention relates to a method for preventing, inhibiting or treating one or more symptoms associated with epilepsy, encephalopathies or cardiac dysfunction in a mammal. The method comprises administering to the mammal an effective amount of a composition comprising a compound of formula (I) (LXXXXIII), or a pharmaceutically acceptable salt thereof, or any combination thereof.

Description

METHODS OF TREATING EPILEPSY A D CNTI RELATED CONDITIONS

Cross Reference to Related Applications

This application ciairns the benefit of the filing date of U.S. application Serial No. 82/648,523, filed on March 27, 2018, and U.S. application Serial No. 62/533,866, filed on, July 18, 2017, the disclosures of which are incorporated by reference herein.

Background

In the United States (U.S.), rare diseases are defined by the FDA Orphan Drug Act of 1983 as those with less than 200,000 sufferers. Though for each disease this represents only a small fraction of the population, combined, miiiions of people in the U.S. live with a rare disease, with estimates of between 5-7% of the global population. The majority of these diseases are genetic, many caused by single gene changes, yet for 95% of these cases, there are no FDA approved drugs ( einikova, 2012). Personalized medicine provides a new research avenue to identify candidate therapies for these diseases (EpiPIVl Consortium, 2015). Epilepsy affects roughly 1 % of the U.S. population, typically characterized by unprovoked seizure episodes. In two-thirds of diagnoses, the cause is unknown. Epileptic

encephalopathies are a group of rare, severe neurological disorders manifesting in childhood often caused by de novo mutations ( cTague, Howell, Cross, Ku ian, & Scheffer, 2016).

Standard treatment of epilepsy consists of anti-epileptic drugs (AEDs). However, many patients with epilepsy are refractory to pharmacological treatment. 25-30% of those diagnosed with an epileptic condition are refractory to currently prescribed AEDs (Novy et ai., 2010; Mayer et al., 2002). Epileptic encephalopathies are particularly resistant to drug treatment, creating a critical unmet need for the development of new therapies

Summary

Genetic mutations, e.g., somatic or germline mutations, can impact protein function and those mutations may in turn be associated with neural and behavioral symptoms, e.g., symptoms associated with epilepsy, other seizure disorders and epileptic encephalopathies. The methods described herein are based, in part, on the identification of molecules that directly or indirectly modulate ion channel activity, e.g., potassium channel (KCN) activity, e.g., directly or indirectly modulate KCNT1 channel activity. In one embodiment, those molecules are useful in decreasing the activity of ion channels, including those for disorders characterized by seizures or other encephalopathies that have increased activity in those channels, e.g., increased activity associated with a mutation(s) in a gene encoding those channels (the mutation results in a variant channel protein). In another embodiment, molecules that are useful in decreasing the activity of ion channels that are not mutated (wild-type potassium ion channels such as wild-type KCNT1) may also be employed as a therapeutic, e.g., for disorders including but not limited to those characterized by seizures or other encephalopathies.

KCNT1 encodes a potassium channel commonly referred to as Slo2.2, KNa1 .1 or Slack (sequence like a calcium-activated K⁺ channel). Slack is an outwardly rectifying, voltage-gated potassium channel, that is activated by sodium, it is widely expressed in brain and contributes to slow after-hyperpoiarization of the neuron by outward flow of potassium sons following action potentials and thereby helps to regulate neuronal firing and activity. Slack is a homotetrameric protein comprised of subunits encoded by KCNT1 , which combine to form a central pore that allows the passage of potassium sons. Each subunit contains a large cytoplasmic sequence with two domains that act to regulate potassium ion flow. As described herein, a mutation of the KCNT1 gene leading to mutation of the expressed protein whereby proline is replaced by leucine at amino acid position 924 (designated P924L) was studied. This same mutation was described in a patient diagnosed with epilepsy of infancy with migrating focal seizures (EIMFS) (Milligan et. a!,, 2014). This is a form of early infantile epileptic encephalopathy (EiEE) with onset before 6 months of age accompanied by profound developmental delay. The P924L mutation described herein, as well as other missense mutations of the KCNT1 gene, typically give rise to gain-of-function mutations with greatly increased potassium ion conductance or flow compared to wild-type channels.

To identify compounds that may alter the activity of the protein encoded by the mutant KCNT1 gene, a cell line expressing the P924L mutation was screened with a drug library to identify compounds that reverse or inhibit the mutant phenotype of enhanced potassium ion conductance or flow. In particular, a cell line expressing Slack channels comprised of a KCNT1 subuniis with a P924L mutation was created by site-directed mutagenesis of a plasmid containing a wild-type KCNT1 gene, which was then transfected into CHO cells to create a mutant P924L cell line. For comparative purposes, a wild-type copy of the KCNT1 gene was transfected into Chinese Hamster Ovary (CHO) ceils to create a cell line expressing wild-type Slack channels. Patch clamp electrophysioiogy was conducted to characterize cells expressing mutant and wild-type KCNT1 . P924L mutant cells were observed to have a gain-of-function phenotype resulting in excess outward potassium ion flow or current compared to wild-type potassium channels. Specifically, the mutant ceils were observed to have a greatly enhanced basal potassium current (larger currents and increased current density) compared to wild-type ceils. Following

electrophysiological characterization of the mutant phenotype, a high-throughput drug screen was developed and a library of about 1 ,320 approved drugs (including drugs approved in the US and outside the US) was evaluated. A total of 41 compounds out of 1 ,290 (3.2%) that were screened demonstrated significant inhibitory activity on ion flow or conductance, defined as inhibition that was greater than two standard deviations from the overall mean inhibition of all compounds tested (see Figure 3 and Table 1A). A similar screen was performed on a wild-type KCNT1 cell line. A total of 56 compounds out of 1 ,320

(4.2%) that were screened demonstrated significant inhibitory activity on ion flow or conductance, defined as inhibition that was greater than two standard deviations from the overall mean inhibition of all compounds tested (see Table 5A). Those compounds included FDA-approved drugs that do not report clinical utility in epilepsy or seizure disorders, as well as other compounds that do not report clinical utility in epilepsy or seizure disorders. These compounds may be used prophylacticaily or therapeutically and for design of related compounds. Compounds that inhibit potassium ion flow through mutant channels may be of therapeutic value in treating epilepsy related to KCNT1 mutations including KCNT1 P924L mutations. Compounds that inhibit potassium ion flow through wild-type channels may be of therapeutic value in treating a wider range of epilepsies, other seizure-related disorders, and other nervous system diseases and disorders (described below) associated with excess potassium ion flow through KCNT1 - bearing channels.

The disclosure provides a method to prevent, inhibit or treat one or more symptoms associated with epilepsy or other encephalopathies, e.g., associated with seizures, in a mammal. The method includes, in one embodiment, administering to the mammal an effective amount of a composition comprising a compound that alters the activity of a KCNT1 channel with at least 80%, 85%, 90%, 92%, 94%, 95%, 98%, 97% 98%, or 99% amino acid sequence identity to one of SEQ ID Nos.1 -2 and which has at least one amino acid residue that differs from SEQ ID Nos.1 -2 (a "variant" KCNT1 ) that alters the activity of the variant potassium channel relative to SEQ ID NO:1 or 2. In one embodiment, the variant is a gain-of-fu notion variant relative to wild-type KCNT1 , in one embodiment, the variant has an amino acid residue at position 924 that is not proline (P), e.g., the variant has a leucine (L) at residue 924.

The disclosure further provides a method to prevent, inhibit or treat one or more symptoms associated with epilepsy or other encephalopathies, e.g., those associated with seizures, in a mammal. The method includes, in one embodiment, administering to the mammal an effective amount of a composition comprising a compound of formula (I), a compound of formula (II), a compound of formula (111), a compound of formula (IV), a compound of formula (V), a compound of formula (VI), a compound of formula (VII), a compound of formula (VIII), a compound of formula (IX), a compound of formula (X), a compound of formula (XI), a compound of formula (XII), a compound of formula (XIII), a compound of formula (XIV), a compound of formula (XV), a compound of formula (XVI), a compound of formula (XVII), a compound of formula (XVIII), a compound of formula (XIX), a compound of formula (XX), a compound of formula (XXI), a compound of formula (XXII), a compound of formula (XXIII), a compound of formula (XXIV), a compound of formula (XXV), a compound of formula (XXVI), a compound of formula (XXVII), a compound of formula (XXVIII), a compound of formula (XXIX), a compound in Table 1 , 2, 3, 4 or 5, a pharmaceutically acceptable salt thereof, or any combination thereof. In one embodiment, the mammal has a KCNT1 variant having an amino acid residue at position 924 that is not proline (P). in one embodiment, the mammal is heterozygous for the variant KCNT1 . In one embodiment, the mammal is a human. In one embodiment, the compound is not raititrexed. In one embodiment, the compound is not fenofibrate. in one embodiment, the compound is not nelfinavir mesylate. In one embodiment, the compound is not estradioi-17 beta. In one embodiment, the compound is not paclitaxei. In one embodiment, the compound is not diethyistiibestroi. In one embodiment, the compound is not racecadotril. in one embodiment, the compound is not mometason furoate. in one embodiment, the compound is not carvediiol. In one embodiment, the compound is not doxazosin mesylate. In one embodiment, the compound is not ritonavir, in one embodiment, the compound is not raloxifene hydrochloride. In one embodiment, the compound is not loperamide hydrochloride, in one embodiment, the mammal is identified as having a variant KCNT1 gene or channel, in one embodiment, the compound to be administered is selected based on in vitro screening of a plurality of compounds in cells with the variant KCNT1 versus ceils with wild-type KCNT1 . in one embodiment, the compound inhibits at least 5%, 10%, 15%, 20%, 50% or more of the activity of a variant KCNT1 . In one embodiment, the compound inhibits up to at least 90% or more of the activity of a variant KCNT1 . In one embodiment, the compound decreases KCNT1 activity in a mammal having a gain-of-function variant KCNT1 to an activity that is no greater or no less than 5%, 10% or 15% that of wild-type KCNT1 .

In one embodiment, the disclosure further provides a method to prevent, inhibit or treat cardiac dysfunction, e.g., prevent, inhibit or treat arrhythmias, Brugada syndrome or myocardial infarction. The method includes, in one embodiment, administering to the mammal an effective amount of a composition comprising a compound of formula (i), a compound of formula (ii), a compound of formula (ill), a compound of formula (IV), a compound of formula (V), a compound of formula (VI), a compound of formula (Vii), a compound of formula (VIII), a compound of formula (IX), a compound of formula (X), a compound of formula (XI), a compound of formula (Xii), a compound of formula (XIII), a compound of formula (XIV), a compound of formula (XV), a compound of formula (XVI), a compound of formula (XVII), a compound of formula (XVIII), a compound of formula (XIX), a compound of formula (XX), a compound of formula (XXI), a compound of formula (XXII), a compound of formula (XXIII), a compound of formula

(XXIV), a compound of formula (XXV), a compound of formula (XXVI), a compound of formula (XXVII), a compound of formula (XXVIII), a compound of formula (XXIX), a compound in Table 1 , 2, 3, 4 or 5, a pharmaceutically acceptable salt thereof, or any combination thereof. In one embodiment, the mammal is a human, in one embodiment, the compound is not raltitrexed. in one embodiment, the compound is not fenofibrafe. in one embodiment, the compound is not nelfinavir mesylate. In one embodiment, the compound is not estradioi-17 beta. In one embodiment, the compound is not paclitaxei, in one embodiment, the compound is not diethylstilbestrol. In one embodiment, the compound is not racecadotril. In one embodiment, the compound is not mometason furoate. in one embodiment, the compound is not carvedilol. In one embodiment, the compound is not doxazosin mesylate. In one embodiment, the compound is not ritonavir. In one embodiment, the compound is not raloxifene hydrochloride. In one embodiment, the compound is not loperamide hydrochloride. In one embodiment, the cardiac arrhythmia is tachycardia, including but not limited to atrial flutter/atrial fibrillation/atrial tachycardia, paroxysmal supraventricular tachycardia, accessory pathway tachycardia, V nodal reentrant tachycardia, ventricular tachycardia, ventricular fibrillation, or digitalis-induced arrhythmia.

Also provided is a method to prevent, inhibit or treat one or more symptoms associated with gain- of-function in a potassium channel in a mammal. The method includes, in one embodiment, administering to the mammai an effective amount of a composition comprising a compound of formula (1), a compound of formula (II), a compound of formula (111), a compound of formula (IV), a compound of formula (V), a compound of formula (VI), a compound of formula (VII), a compound of formula (VIII), a compound of formula (IX), a compound of formula (X), a compound of formula (XI), a compound of formula (XII), a compound of formula (XIII), a compound of formula (XIV), a compound of formula (XV), a compound of formula (XVI), a compound of formula (XVII), a compound of formula (XVIII), a compound of formula (XIX), a compound of formula (XX), a compound of formula (XXI), a compound of formula (XXII), a compound of formula (XXiil), a compound of formula (XXIV), a compound of formula (XXV), a compound of formula (XXVI), a compound of formula (XXVli), a compound of formula (XXVIII), a compound of formula (XXIX), a compound in Table 1 , 2, 3, 4 or 5, a pharmaceutically acceptable salt thereof, or any combination thereof, in one embodiment, the mammal is a human, in one embodiment, the compound is not raltitrexed. In one embodiment, the compound is not fenofibrafe. in one embodiment, the compound is not nelfinavir mesylate, in one embodiment, the compound is not estradiol-"! ? beta, in one embodiment, the compound is not paclitaxei. In one embodiment, the compound is not diethylstilbestrol. In one embodiment, the compound is not racecadotril. In one embodiment, the compound is not mometasone furoate. In one embodiment, the compound is not carvedilol. In one embodiment, the compound is not doxazosin mesylate. In one embodiment, the compound is not ritonavir. In one embodiment, the compound is not raloxifene hydrochloride. In one embodiment, the compound is not loperamide hydrochloride.

In one embodiment, the composition is administered to a mammal such as a human by routes including but not limited to oral, intravenous, intra-arteriai, subcutaneous, intranasal, intrathecal, intracerebroventricular, intraparenchymal, trans-retinal, intra-aural, intramuscular, transdermal, or rectal. in one embodiment, the administration of the composition prevents, inhibits or treats seizures, developmental delay or cardiac dysfunction, in one embodiment, the administration of the composition improves kinestics of slow after-hyperpolarization, decreases potassium ion flow, decreases current density, decreases current, decreases voltage-dependent activation, or improves kinetics of slow reactivation.

The disclosure further provides a method to prevent, inhibit or treat one or more symptoms associated with epilepsy or other encephalopathies, e.g., those associated with seizures, in a mammal. The method includes, in one embodiment, administering to the mammal an effective amount of a composition comprising a compound of any one of formulas (XXX)-(LXXXXIII), a compound in Table 5A, a pharmaceutically acceptable salt thereof, or any combination thereof. A composition comprising a compound of any one of formulas (XXX)-(LXXXXHi), a compound in Table 5A, a pharmaceutically acceptable salt thereof, or any combination thereof, may also be employed in a method to prevent, inhibit or treat cardiac dysfunction, e.g., prevent, inhibit or treat arrhythmias, Brugada syndrome or myocardial infarction, or to prevent, inhibit or treat symptoms associated with gain-of-function mutations in ion channels. In one embodiment, the compound is not hexestrol. In one embodiment, the compound is not diethylstilbestrol. In one embodiment, the compound is not mometasone furoate. In one embodiment, the compound is not loperamide. In one embodiment, the compound is not miconazole. In one embodiment, the compound is not racecadotril. In one embodiment, the compound is not doxazosin mesylate, in one embodiment, the compound is not fulvestrant. In one embodiment, the compound is not dienestrol. in one embodiment, the compound is not raloxifene. In one embodiment, the compound is not THiP

hydrochloride, in one embodiment, the compound is not fluspirilen. In one embodiment, the compound is not ezetimibe. In one embodiment, the compound is not triclosan. In one embodiment, the compound is not bromhexine. In one embodiment, the compound is not halcinonide. In one embodiment, the compound is not loratadine. In one embodiment, the compound is not darifenacin hydrobromide. in one embodiment, the compound is not econazole nitrate. In one embodiment, the compound is not dosulepin

hydrochloride. In one embodiment, the compound is not alprostadil. in one embodiment, the compound is not isosorbide dinitrate. In one embodiment, the compound is not fenofibrate. in one embodiment, the compound is not avermectin b1 , In one embodiment, the compound is not nicergoline. in one

embodiment, the compound is not niclosamide. In one embodiment, the compound is not fentiazac. In one embodiment, the compound is not triclabendazole. In one embodiment, the compound is not prenylamine lactate. In one embodiment, the compound is mometasone furoate. In one embodiment, the compound is doxazosin mesylate, in one embodiment, the compound is fulvestrant. in one embodiment, the compound is raloxifene, in one embodiment, the compound is fluspirilen. in one embodiment, the compound is ezetimibe. In one embodiment, the compound is triclosan. In one embodiment, the compound is bromhexine. in one embodiment, the compound is halcinonide. In one embodiment, the compound is econazole nitrate, in one embodiment, the compound is isosorbide dinitrate. In one embodiment, the compound is fenofibrate. In one embodiment, the cardiac arrhythmia is tachycardia, including but not limited to atrial flutter/atrial fibrillation/atrial tachycardia, paroxysmal supraventricular tachycardia, accessory pathway tachycardia, V nodal reentrant tachycardia, ventricular tachycardia, ventricular fibrillation, or digitalis-induced arrhythmia, in one embodiment, the composition is administered to a mammal such as a human by routes including but not limited to oral, intravenous, intra-arterial, subcutaneous, intranasal, intrathecal, intracerebroventricuiar, intraparenchymai, trans-retinal, intra-aurai, intramuscular, transdermal, or rectal.

The compounds disclosed herein may be employed with other therapeutic compounds. Brief Description of Figures

Figure 1 , Amino acid sequences of exemplary KCNT1 proteins (SEQ ID Nos, 1 -2),

Figure 2, Wild-type (green circles) and P924L mutant (blue squares) cell lines were tested in the ⁸⁶Rb efflux assay with increasing concentrations of ioxapine. Efflux from untreated cells was set to 0% inhibition. 100% activation was designated as the ⁸⁶Rb efflux after addition of 100 μΜ Ioxapine. Error bars represent standard deviations.

Figure 3. Inhibition of efflux by each of the about 1320 compounds (blue circles) are plotted by rank in order of activity from left to right. The orange and green lines cross the x-axis at 2 and 3 standard deviations, respectively. The top 5 inhibitors identified in the HTS are indicated with arrows.

Detailed Description

Definitions

In describing and claiming the invention, the following terminology will be used in accordance with the definitions set forth below.

The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one or more than one element.

The term "about," as used herein, means approximately, in the region of, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. For example, in one aspect, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of 20%. The term "about", when referring to a numerical value or range, allows for a degree of variability in the value or range, for example, within 10%, or within 5% of a stated value or of a stated limit of a range.

As used herein, "individual" (as in the subject of the treatment) means both mammals and non-mammals. Mammals include, for example, humans; non-human primates, e.g. apes and monkeys; and non-primates, e.g. dogs, cats, cattle, horses, sheep, goafs, and rodents including rabbits, mice, rats and ferrets. Non-mammals include, for example, fish and birds.

The term "disease" or "disorder" or "malcondition" are used interchangeably.

The expression "effective amount", when used to describe therapy to an individual suffering from a disorder, refers to the amount of a compound or composition that is effective to prevent or inhibit or otherwise treat one or more symptoms of a disease or disorder.

Phrases such as "under conditions suitable to provide" or "under conditions sufficient to yield" or the like, in the context of methods of synthesis, as used herein refers to reaction conditions, such as time, temperature, solvent, reactant concentrations, and the like, that are within ordinary skill for an experimenter to vary, that provide a useful quantity or yield of a reaction product. It is not necessary that the desired reaction product be the only reaction product or that the starting materials be entirely consumed, provided the desired reaction product can be isolated or otherwise further used.

"Substantially" as the term is used herein means completely or almost completely; for example, a composition that is "substantially free" of a component either has none of the component or contains such a trace amount that any relevant functional property of the composition is unaffected by the presence of the trace amount, or a compound is "substantially pure" is there are only negligible traces of impurities present. The administration of a composition may be for either a "prophylactic" or "therapeutic" purpose.

When provided prophylactically, the compositions are provided before any symptom or clinical sign of a disease becomes manifest. The prophylactic administration of the composition serves to prevent or attenuate any subsequent symptom or clinical sign. When provided therapeutically, the compositions are provided upon the detection of a symptom or clinical sign of disease.

Thus, a composition may be provided either before the onset of disease or a symptom (so as to prevent or attenuate a symptom) or after the initiation of symptoms or clinical signs of disease.

A composition is said to be "pharmacologically acceptable" if its administration can be tolerated by a recipient mammal. Such an agent is said to be administered in a "thera eutically effective amount" if the amount administered is physiologically significant.

The "protection" provided need not be absolute, i.e., need not be totally prevented or eradicated, if there is a statistically significant improvement compared with a control population or set of mammals. Protection may be limited to mitigating the severity or rapidity of onset of symptoms or clinical signs of the disease.

"Treating" or "treatment" within the meaning herein refers to an alleviation of symptoms associated with a disorder or disease, or inhibition of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder, or curing the disease or disorder. Similarly, as used herein, an "effective amount" or a "therapeutically effective amount" of a compound of the invention refers to an amount of the compound that alleviates, in whole or in part, symptoms associated with the disorder or condition, or halts or slows further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disorder or condition, in particular, a "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount is also one in which any toxic or detrimental effects of compounds of the invention are outweighed by the therapeutically beneficial effects.

By "chemically feasible" is meant a bonding arrangement or a compound where the generally understood rules of organic structure are not violated; for example, a structure within a definition of a claim that would contain in certain situations a pentavalent carbon atom that would not exist in nature would be understood to not be within the claim. The structures disclosed herein, in all of their embodiments are intended to include only "chemically feasible" structures, and any recited structures that are not chemically feasible, for example in a structure shown with variable atoms or groups, are not intended to be disclosed or claimed herein.

When a substituent is specified to be an atom or atoms of specified identity, "or a bond", a configuration is referred to when the substituent is "a bond" that the groups that are immediately adjacent to the specified substituent are directly connected to each other in a chemically feasible bonding configuration.

Ail chiral, diastereomeric, racemic forms of a structure are intended, unless a particular stereochemistry or isomeric form is specifically indicated. Compounds used in the present invention can include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions, at any degree of enrichment. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their

enantiomeric or diastereomeric partners, and these are all within the scope of the invention. The inclusion of an isotopic form of one or more atoms in a molecule that is different from the naturally occurring isotopic distribution of the atom in nature is referred to as an "isofopicaiiy labeled form" of the molecule. Ail isotopic forms of atoms are included as options in the composition of any molecule, unless a specific isotopic form of an atom is indicated. For example, any hydrogen atom or set thereof in a molecule can be any of the isotopic forms of hydrogen, i.e., protium OH), deuterium (²H), or tritium (³H) in any combination. Similarly, any carbon atom or set thereof in a molecule can be any of the isotopic form of carbons, such as ^{1 ,}C, ²C, ⁱ³C, or ¹ C, or any nitrogen atom or set thereof in a molecule can be any of the isotopic forms of nitrogen, such as ¹³N, ¹ N, or ¹⁵N. A molecule can include any combination of isotopic forms in the component atoms making up the molecule, the isotopic form of every atom forming the molecule being independently selected, in a multi-molecular sample of a compound, not every individual molecule necessarily has the same isotopic composition. For example, a sample of a compound can include molecules containing various different isotopic compositions, such as in a tritium or ¹⁴C radiolabeled sample where only some fraction of the set of molecules making up the macroscopic sample contains a radioactive atom. It is also understood that many elements that are not artificially isotopicaliy enriched themselves are mixtures of naturally occurring isotopic forms, such as and ¹⁵N, ³²S and ³⁴S, and so forth. A molecule as recited herein is defined as including isotopic forms of ail its constituent elements at each position in the molecule. As is well known in the art, isotopicaliy labeled compounds can be prepared by the usual methods of chemical synthesis, except substituting an isotopicaliy labeled precursor molecule. The isotopes, radiolabeled or stable, can be obtained by any method known in the art, such as generation by neutron absorption of a precursor nuclide in a nuclear reactor, by cyclotron reactions, or by isotopic separation such as by mass spectrometry. The isotopic forms are incorporated into precursors as required for use in any particular synthetic route. For example, ¹⁴C and ³H can be prepared using neutrons generated in a nuclear reactor. Following nuclear transformation, ¹⁴C and ³H are incorporated into precursor molecules, followed by further elaboration as needed.

The term "amino protecting group" or "N~protected" as used herein refers to those groups intended to protect an amino group against undesirable reactions during synthetic procedures and v/hich can later be removed to reveal the amine. Commonly used amino protecting groups are disclosed in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999). Amino protecting groups include acyi groups such as formyl, acetyl, propionyl, pivaloyi, t-butyiacetyl, 2-chloroacetyi, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chiorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesuifonyl and the like; aikoxy- or aryloxy-carbonyl groups (which form urethanes with the protected amine) such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyi, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl,

p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4- dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyi, 3,4,5-trimethoxybenzyloxycarbonyl, 1 -(p-biphenylyl)-1 -methylethoxycarbonyl, a,a-dimethyl-3,5- dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyi, t-buty!oxycarbonyi (Boc),

diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, aiiyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethyloxycarbonyl (Teoc), phenoxycarbonyi, 4- nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl, adamantyloxycarbonyi, cyclohexyloxycarbonyi, phenylthiocarbonyl and the iike; araikyi groups such as benzyl, triphenyirnethy!, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Amine protecting groups also include cyclic amino protecting groups such as phthaioyi and

dithiosuccinimidyl, which incorporate the amino nitrogen into a heterocycle. Typically, amino protecting groups include formy!, acetyl, benzoyl, pivaioyl, t-butylacetyl, phenyisu!fony!, Alloc, Teoc, benzyl, Fmoc, Boc and Cbz, It is well within the skill of the ordinary artisan to select and use the appropriate amino protecting group for the synthetic task at hand.

The term "hydroxyl protecting group" or "O-protected" as used herein refers to those groups intended to protect an OH group against undesirable reactions during synthetic procedures and which can later be removed to reveal the amine. Commonly used hydroxyl protecting groups are disclosed in

Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999). Hydroxyl protecting groups include acyi groups such as formyl, acetyl, propionyi, pivaioyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; acyloxy groups (which form urethanes with the protected amine) such as benzyioxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl,

p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl,

p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4- dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1 -(p-biphenylyl)-1 -methylethoxycarbonyl, a,a-dimethy!-3,5- dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl (Boc),

diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, ai!yloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilyiethyioxycarbony! (Teoc), phenoxycarbonyi, 4- nitrophenoxycarbonyl, fluoreny!-9-methoxycarbonyl (Fmoc), cyclopentyioxycarbony!,

adamantyloxycarbonyi, cyclohexyloxycarbonyi, phenylthiocarbonyl and the like; araikyi groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and siiy! groups such as trimethylsilyl and the like, it is well within the skill of the ordinary artisan to select and use the appropriate hydroxy! protecting group for the synthetic task at hand.

In genera!, "substituted" refers to an organic group as defined herein in which one or more bonds to a hydrogen atom contained therein are replaced by one or more bonds to a non-hydrogen atom such as, but not limited to, a halogen (i.e., F, CI, Br, and I); an oxygen atom in groups such as hydroxyl groups, a!koxy groups, aryloxy groups, araikyloxy groups, oxo(carbony!) groups, carboxyi groups including carboxyiic acids, carboxy!ates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alky! and ary! sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxylamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups. Non-limiting examples of substituents that can be bonded to a substituted carbon (or other) atom include F, CI, Br, i, OR',

OC(0)N(R')₂, CN, NO, NQ₂, ON0₂, azido, CF₃, OCF₃, R', O (oxo), S (thiono), methylenedioxy, ethylenedsoxy, N(R')₂, SR^*, SOR^*, S0₂R^*, S0₂N(R')₂, SO3R', C(0)R', C(0)C(0)R\ C(0)CH₂C(0)R^*, C(S)R', C(0)OR', 0C(0)R', C(0)N(R')₂, 0C(0)N(R')₂, C(S)N(R')₂, (CH₂)o-₂N(R')C(Q)R\ (CH₂)o-₂N(R')N(R')₂,

N(R')N(R')C(0)R', N(R')N(R')C(0)0R^*, N(R')N(R')CON(R*)2, N(R')S0₂R', N(R')S0₂N(R')₂, N(R')C(0)0R', N(R')C(0)R', N(R')C(S)R', N(R')C(0)N(R')₂, N(R')C(S)N(R')₂, N(COR')COR', N(OR')R', C(=NH)N(R')₂, C(G)N(OR')R', or C(=NOR')R' wherein R' can be hydrogen or a carbon-based moiety, and wherein the carbon-based moiety can itseii be further substituted.

When a substituent is monovalent, such as, for example, F or CI, it is bonded to the atom it is substituting by a single bond. When a substituent is more than monovalent, such as O, which is divalent, it can be bonded to the atom it is substituting by more than one bond, i.e., a divalent substituent is bonded by a double bond; for example, a C substituted with O forms a carbonyi group, C=0, which can also be written as "CO", "C(O)", or "C(=0)", wherein the C and the O are double bonded. When a carbon atom is substituted with a double-bonded oxygen (=0) group, the oxygen substituent is termed an "oxo" group. When a divalent substituent such as NR is double-bonded to a carbon atom, the resulting C(=NR) group is termed an "imino" group. When a divalent substituent such as S is double-bonded to a carbon atom, the results C(=S) group is termed a "thiocarbonyl" group.

Alternatively, a divalent substituent such as O or S can be connected by two single bonds to two different carbon atoms. For example, O, a divalent substituent, can be bonded to each of two adjacent carbon atoms to provide an epoxide group, or the O can form a bridging ether group, termed an "oxy" group, between adjacent or non-adjacent carbon atoms, for example bridging the 1 ,4-carbons of a cyclohexyl group to form a [2.2.1 j-oxabicycio system. Further, any substituent can be bonded to a carbon or other atom by a linker, such as (CH2)n or (C '2)_ri wherein n is 1 , 2, 3, or more, and each R' is independently selected. Similarly, a methyienedioxy group can be a substituent when bonded to two adjacent carbon atoms, such as in a phenyl ring.

C(0) and S(0)2 groups can be bound to one or two heteroatoms, such as nitrogen, rather than to a carbon atom. For example, when a C(O) group is bound to one carbon and one nitrogen atom, the resulting group is called an "amide" or "carboxamide." When a C(O) group is bound to two nitrogen atoms, the functional group is termed a urea. When a S(0)2 group is bound to one carbon and one nitrogen atom, the resulting unit is termed a "sulfonamide." When a S(0)2 group is bound to two nitrogen atoms, the resulting unit is termed a "suifamate."

Substituted aikyl, alkenyi, alkynyl, cycioaikyl, and cycloalkenyi groups as well as other substituted groups also include groups in which one or more bonds to a hydrogen atom are replaced by one or more bonds, including double or triple bonds, to a carbon atom, or to a heteroatom such as, but not limited to, oxygen in carbonyi (oxo), carboxyi, ester, amide, imide, urethane, and urea groups; and nitrogen in imines, hydroxyzines, oximes, hydrazones, amidines, guanidines, and nitriles.

Substituted ring groups such as substituted cycioaikyl, aryi, heterocyclyl and heteroaryi groups also include rings and fused ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycioaikyl, aryl, heterocyclyl and heteroaryi groups can also be substituted with aikyl, alkenyi, and alkynyl groups as defined herein.

By a "ring sysiem" as the term is used herein is meant a moiety comprising one, two, three or more rings, which can be substituted with non-ring groups or with other ring systems, or both, which can be fully saturated, partially unsaturated, fully unsaturated, or aromatic, and when the ring system includes more than a single ring, the rings can be fused, bridging, or spirocyclic. By "spirocyciic" is meant the class of structures wherein two rings are fused at a single tetrahedral carbon atom, as is well known in the art.

As to any of the groups described herein, which contain one or more substituents, it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterica!ly impractical and/or synthetically non-feasible. In addition, the compounds of this disclosed subject matter include ail stereochemical isomers arising from the substitution of these compounds.

Selected substiiuents within the compounds described herein are present to a recursive degree, in this context, "recursive substituent" means that a substituent may recite another instance of itself. Because of the recursive nature of such substiiuents, theoretically, a large number may be present in any given claim. One of ordinary skill in the art of medicinal chemistry and organic chemistry understands that the total number of such substituents is reasonably limited by the desired properties of the compound intended. Such properties include, by of example and not limitation, physical properties such as molecular weight, solubility or log P, application properties such as activity against the intended target, and practical properties such as ease of synthesis.

Recursive substiiuents are an intended aspect of the disclosed subject matter. One of ordinary skill in the art of medicinal and organic chemistry understands the versatility of such substituents. To the degree thai recursive substiiuents are present in a claim of the disclosed subject matter, the total number should be determined as set forth above.

Alkyl groups include straight chain and branched alkyl groups and cycioaikyi groups having from 1 to about 20 carbon atoms, and typically from 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms. Examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyi, n-butyl, n-pentyl, n-hexyi, n-heptyi, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyi, sec-butyl, t-butyl, neopentyl, isopentyi, and 2,2-dimethyipropyl groups. Representative substituted alkyl groups can be substituted one or more times with any of the groups listed above, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

Cycioaikyi groups are cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyi, cyclohexyl, cycloheptyi, and cyciooctyi groups, in some embodiments, the cycioaikyi group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 4, 5, 6, or 7. Cycioaikyi groups further include polycyclic cycioaikyi groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyi, and carenyl groups, and fused rings such as, but not limited to, decalinyi, and the like. Cycioaikyi groups also include rings that are substituted with straight or branched chain alkyl groups as defined above. Representative substituted cycioaikyi groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substituted norbornyl or cycloheptyi groups, which can be substituted wiih, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term "cycioaikenyi" alone or in combination denotes a cyclic alkenyl group.

The terms "carbocyciic," "carbocyclyl," and "carbocycle" denote a ring structure wherein the atoms of ihe ring are carbon, such as a cycioaikyi group or an aryl group, in some embodiments, the carbocycle has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms is 4, 5, 6, or 7. Unless specifically indicated to the contrary, the carbocyciic ring can be substituted with as many as N-1 substituents wherein N is the size of the carbocyciic ring with, for example, alkyl, alkenyl, alkynyl, amino, aryl, hydroxy, cyano, carboxy, heteroaryi, heterocyclyl, nitro, thio, alkoxy, and halogen groups, or other groups as are listed above. A carbocyclyl ring can be a cycioaikyi ring, a cycioaikenyi ring, or an aryi ring. A carbocyclyi can be monocyciic or poiycyclic, and if poiycyclic each ring can be independently be a cye!oa!kyl ring, a cycioalkenyi ring, or an aryl ring.

(Cycloaikyl)alkyi groups, also denoted cyc!oalkyialkyl, are aiky! groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycioaikyi group as defined above.

Alkenyi groups include straight and branched chain and cyciic alkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Thus, aikenyi groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to vinyl,

cyclohexenyi, cyclopentenyi, cyciohexadienyl, butadienyl, pentadienyl, and hexadienyl among others.

Cycioalkenyi groups include cycioaikyi groups having at least one double bond between 2 carbons. Thus, for example, cycioalkenyi groups include but are not limited to cyclohexenyi,

cyclopentenyi, and cyciohexadienyl groups. Cycioalkenyi groups can have from 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 6, or 7. Cycioaikyi groups further include poiycyclic cycioaikyi groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyi, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like, provided they include at least one double bond within a ring. Cycioalkenyi groups also include rings that are substituted with straight or branched chain alkyl groups as defined above.

(Cycloalkenyl)alkyi groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycioalkenyi group as defined above.

Aikynyi groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, aikynyi groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to -C CH. -C C(CI~b) -C C(CH₂CH₃). -CH₂C CH, -CH₂C≡C(CH₃),

and ~CH2C≡C(CH₂CH₃) among others.

The term "heteroalkyl" by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized.

The heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group. Examples

include: -O-CH2-CH2-CH3, -CH₂-CH₂CH₂-OH, -CH₂-CH₂-NH-CH3, -CH2-S-CH2-CH3,

and ~CH2CH₂-0-CH₂CH₂-0-CH3. Up to two heteroatoms may be consecutive, such as, for

example, -CH₂-NH-OCH₃, or ---CH2-CH2-S-S-CH3,

A "cycioheteroalkyl" ring is a cycioaikyi ring containing at least one heteroatom. A

cycloheteroalkyl ring can also be termed a "heterocyciy!," described below.

The term "heteroalkenyl" by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain monounsaturated o di-unsaturated hydrocarbon group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heieroatom may optionally be quaternized. Up to two heteroatoms may be placed consecutively. Examples

include -CH=CH-0-CH₃, -CH=CH-CH₂-OH, -CH₂-CH=N-GCH₃, -CH=CH-N(CH₃)-CH₃, -CH₂-CH=CH-CH₂- SH, and -CH=CH-0-CH₂CH₂-0-CH₃.

Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms in the ring. Thus aryi groups include, but are not limited to, phenyl, azuienyl, heptalenyl, biphenyi, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyi, naphthacenyl, chrysenyl, biphenyienyl, anthracenyl, and naphthyi groups. In some embodiments, aryi groups contain about 6 to about 14 carbons in the ring portions of the groups. Aryl groups can be unsubstituted or substituted, as defined above. Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or 2-8 substituted naphthyi groups, which can be substituted with carbon or non-carbon groups such as those listed above.

Aralkyi groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryi group as defined above. Representative aralkyi groups include benzyl and phenyiethyi groups and fused (cycioalkylaryi)aikyl groups such as 4-ethyl-indanyl. Aralkenyl group are aikenyi groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryi group as defined above.

Heterocyclyl groups or the term "heterocyclyl" includes aromatic and non-aromatic ring compounds containing 3 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S. Thus a heterocyclyl can be a cycloheteroaikyl, or a heteroaryl, or if polycyclic, any combination thereof, in some embodiments, heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members. A heterocyclyl group designated as a C₂- heterocyciyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise, a C4-heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. A heterocyclyl ring can also include one or more double bonds. A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase

"heterocyclyl group" includes fused ring species including those comprising fused aromatic and non- aromatic groups. For example, a dioxoianyi ring and a benzdioxoianyi ring system (methylenedioxyphenyl ring system) are both heterocyclyl groups within the meaning herein. The phrase also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuciidyl. Heterocyclyl groups can be unsubstituted, or can be substituted as discussed above. Heterocyclyl groups include, but are not limited to, pyrroiidinyl, piperidinyi, piperazinyl, morpholinyl, pyrrolyi, pyrazolyl, triazolyi, tetrazolyl, oxazolyl, isoxazolyl, ihiazolyi, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyi, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazoiyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyi, imidazopyridinyi, isoxazolopyridinyl, thianaphthaienyi, purinyl, xanthinyl, adeninyi, guansnyi, quinolinyl, isoquinoiinyl, tetrahydroquinolinyl, quinoxalinyi, and quinazoiinyl groups.

Representative substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as, but not limited to, piperidinyi or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with groups such as those listed above. Heteroaryi groups are aromaiic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S; for instance, heteroaryi rings can have 5 to about 8-12 ring members. A heteroaryi group is a variety of a heterocyciyi group that possesses an aromatic electronic structure, A heteroaryi group designated as a C2-heteroaryl can be a 5- ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise, a C4-heteroaryl can be a 5-ring with one heteroatom, a 8-ring with two

heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. Heteroaryi groups include, but are not limited to, groups such as pyrrolyi, pyrazolyl, triazolyi, tetrazolyl, oxazolyl, isoxazoiyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyi, indolyl, azaindoiyl, indazoiyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl,

benzothiazolyl, benzoihiadiazolyi, imidazopyridinyl, isoxazolopyridinyl, thianaphthaienyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinoiinyl, quinoxaiinyl, and quinazolinyl groups. Heteroaryi groups can be unsubstituted, or can be substituted with groups as is discussed above.

Representative substituted heteroaryi groups can be substituted one or more times with groups such as those listed above.

Additional examples of aryl and heteroaryi groups include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1 -naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1 -anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophenyl (2-thienyl, 3-thienyi), fury! (2-furyl, 3- furyi) , indolyl, oxadiazolyi, isoxazoiyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyi (2-pyrroiyl), pyrazolyl (3-pyrazoiyl), imidazoiyl (1 -imidazolyl, 2-imidazoiyl, 4-imidazolyl, 5- imidazolyi), triazolyi (1 ,2,3-triazol-1 -yl, 1 ,2,3-triazoi-2-yi 1 ,2,3-triazol-4-yl, 1 ,2,4-triazol-3-yi), oxazolyl (2- oxazolyi, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazoiyl, 4-thiazolyi, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyi (2-pyrimidinyi, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyi (3- pyridazinyl, 4-pyridazinyl, 5-pyridazinyi), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyi, 5-quinolyi, 6-quinolyl, 7-quinolyi, 8-quinolyl), isoquinolyi (1 -isoquinolyl, 3-isoquinolyi, 4-isoquinoiyi, 5-isoquinolyi, 6-isoquino!yi, 7- isoquinolyi, 8-isoquiriolyl), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5- benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2- (2, 3-d i hydro- benzo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro- benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl (2- benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyi, 6~

benzo[b]thiophenyl, 7-benzo[b]t iophenyl), 2,3-di ydro-benzo[b]thiop enyl, (2-(2,3-dih dro- benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[bjihiophenyl), 4-(2,3-dihydro-benzo[b]thiophenyl), 5-(2,3- dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro-benzo[b]t iophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1 -indolyl, 2-indolyl, 3-indolyl, 4-indoiyl, 5-indolyi, 6-indolyl, 7-indolyl), indazole (1 -indazoiyl, 3-indazolyl, 4-indazolyl, 5-indazolyi, 6-indazoiyl, 7-indazolyl), benzimidazolyl (1 -benzimidazolyl,

2-benzimidazolyl, 4-benzimidazolyi, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyi,

8-benzimidazolyi), benzoxazolyl (1 -benzoxazolyl, 2-benzoxazoiyi), benzothiazolyl (1 -benzothiazolyl, 2- benzothiazoiyi, 4-benzothiazoiyi, 5-benzothiazolyi, 6-benzothiazoiyl, 7-benzothiazoiyl), carbazoiyl (1 - carbazolyi, 2-carbazolyi, 3-carbazolyi, 4-carbazolyi), 5H-dibenz[b,f]azepsne (5H-dibenz[b,f]azepin-1 -yl, 5H- dibenz[b,f|azepine-2-yi, 5H-dibenz[b,f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5- yi), 10,1 1 -dihydro-5H-dibenz[b,f]azepsne (10,1 1 -dihydro-5H-dibenz[b,f]azepine-1 -yl, 10,1 1 -dshydro-5H- dibenz[b,f]azepine-2-yi, 10,1 1 -dihydro-5H-dibenz[b,f]azepine-3-yl, 10,1 1 -dihydro-5H-dibenz[b,f]azepine-4- yl, 10,1 1 -dihydro-5H-dibenz[b,f]azepine-5-yl), and the like.

Heterocyclylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyi group as defined above is replaced with a bond to a heierocyc!yi group as defined above.

Representative heterocyclyl a!kyi groups include, but are not limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indoi-2-yi propyl.

Heteroaryiaikyi groups are alkyi groups as defined above in which a hydrogen or carbon bond of an alkyi group is replaced with a bond to a heteroaryi group as defined above.

The term "aikoxy" refers to an oxygen atom connected to an alkyi group, including a cycioalkyi group, as are defined above. Examples of linear aikoxy groups include but are not limited to methoxy, eihoxy, propoxy, butoxy, pentyloxy, hexyioxy, and the like. Examples of branched aikoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyioxy, and the like. Examples of cyclic aikoxy include but are not limited to cyciopropyioxy, cyciobutyioxy, cyclopentyloxy, cyc!ohexyioxy, and the like. An aikoxy group can include one to about 12-20 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms. For example, an allyioxy group is an aikoxy group within the meaning herein. A methoxyethoxy group is also an aikoxy group within the meaning herein, as is a methyienedioxy group in a context where two adjacent atoms of a structures are substituted therewith.

The terms "halo" or "halogen" or "halide" by themselves or as part of another substituent mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, e.g., fluorine, chlorine, or bromine.

A "haloalkyi" group includes mono-halo alkyi groups, poly-halo alkyl groups wherein all halo atoms can be the same or different, and per-haio alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro. Examples of haloalkyi include trifluoromethyl, 1 ,1 -dichloroethyl, 1 ,2- dichloroethyl, 1 ,3-dibromo-3,3-difluoropropyl, perfluorobutyi, and the like.

A "haioaikoxy" group includes mono-halo aikoxy groups, poly-halo aikoxy groups wherein all halo atoms can be the same or different, and per-haio aikoxy groups, wherein ail hydrogen atoms are replaced by halogen atoms, such as fluoro. Examples of haioaikoxy include trifluoromethoxy, 1 ,1 -dichloroethoxy, 1 ,2-dichloroethoxy, 1 ,3-dibromo-3,3-difluoropropoxy, perfluorobutoxy, and the like.

The term "(Cx-Cy)perfluoroalkyl," wherein x < y, means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein all hydrogen atoms are replaced by fluorine atoms. In one embodiment, (C_x-C_y)perfluoroaikyl is -(Ci-C6)perfluoroalkyl. In one embodiment, (Cx-C_y)perfluoroalkyl is -(Ci-C3)perfluoroalkyl. In one embodiment, (Cx-C_y)perfluoroalkyl is -CPs.

The term "(Cx-C_y)perfluoroalkylene," wherein x < y, means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein ail hydrogen atoms are replaced by fluorine atoms. In one embodiment, (Cx-C_y)perfluoroalkylene is -(Ci-C6)perfluoroalkylene. In one embodiment, (Cx-C_y)perfluoroalkylene is -(Ci-C3)perfluoroalkylene. in one embodiment, (Cx-C_y)perfluoroalkylene is -

The terms "aryioxy" and "arylalkoxy" refer to, respectively, an ary! group bonded to an oxygen atom and an aralkyl group bonded to the oxygen atom at the alkyl moiety. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy.

An "acyl" group as the term is used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is also bonded to another carbon atom, which can be part of an aiky!, aryi, araikyi cycioaikyi, eycioaikylalkyl, heterocyclyi, heterocyciyiaikyi, heteroaryi, heteroaryialkyl group or the like. In the special case wherein the carbonyi carbon atom is bonded to a hydrogen, the group is a "forrnyl" group, an acyl group as the term is defined herein. An acyl group can include 0 to about 12-20 additional carbon atoms bonded to the carbonyi group. An acyl group can include double or triple bonds within the meaning herein. An acryloyi group is an example of an acyl group. An acyl group can also include heteroatoms within the meaning here. A nicotinoyl group (pyridyl~3-carbonyl) group is an example of an acyl group within the meaning herein. Other examples include acetyl, benzoyl, phenyiacetyl, pyridylacetyi, cinnamoyl, and acryloyi groups and the like. When the group containing the carbon atom that is bonded to the carbonyi carbon atom contains a halogen, the group is termed a "haloacyl" group. An example is a trifluoroacetyl group.

The term "amine" includes primary, secondary, and tertiary amines having, e.g., the formula N(group)s wherein each group can independently be H or non-H, such as aikyl, aryl, and the like. Amines include but are not limited to R-NH2, for example, alkylamines, aryiamines, alkyiarylamines; R2NH wherein each R is independently selected, such as diaikylamines, diarylamines, aralkyiamines, heterocyciylamines and the like; and R3N wherein each R is independently selected, such as triaikylamines,

dialkylaryiamines, alky!diaryiamines, triaryiamines, and the like. The term "amine" also includes ammonium sons as used herein.

An "amino" group is a substituent of the form -NH2, -NHR, -NR2, -NRa⁺, wherein each R is independently selected, and protonated forms of each, except for -NR3⁺, which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine. An "amino group" within the meaning herein can be a primary, secondary, tertiary or quaternary amino group. An "a!kyiamino" group includes a monoalkyiamino, dialkylamino, and triaikyiamino group.

An "ammonium" ion includes the unsubstituted ammonium ion

but unless otherwise specified, it also includes any protonated or quaternarized forms of amines. Thus, trimethylammonium hydrochloride and tetramethylammonium chloride are both ammonium ions, and amines, within the meaning herein.

The term "amide" (or "amido") includes C- and N-amide groups, i.e., -C(0)NR2, and ~-NRC(0)R groups, respectively. Amide groups therefore include but are not limited to primary carboxamide groups (~ C(0)NH2) and formamide groups (~NHC(0)H). A "carboxamido" group is a group of the formula C(0)NR2, wherein R can be H, alkyl, aryi, etc.

The term "azido" refers to an 3 group. An "azide" can be an organic azide or can be a salt of the azide (N3^") anion. The term "nitro" refers to an NO2 group bonded to an organic moiety. The term "nitroso" refers to an NO group bonded to an organic moiety. The term nitrate refers to an ONO2 group bonded to an organic moiety or to a salt of the nitrate (NO3^") anion.

The term "ureihane" ("carbamoyl" or "carbamyl") includes N- and O-urethane groups, i.e., -NRC(0)QR and -OC(0)NR₂ groups, respectively.

The term "sulfonamide" (or "sulfonamide") includes S- and N-su!fonamide groups, i.e., -SO2NR2 and -NRSO2R groups, respectiveiy. Sulfonamide groups therefore include but are not limited to sulfamoyl groups (-SO2NH2). An organosuifur structure represented by the formula -S(0)(NR)- is understood to refer to a sulfoximine, wherein both the oxygen and the nitrogen atoms are bonded to the sulfur atom, which is also bonded to two carbon atoms. The term "amidine" or "amidino" includes groups of the formula -C(NR)N!¾. Typically, an amidino group is ~C(NH)NH₂.

The term "guanidine" or "guanidino" includes groups of the formula ~NRC(NR)NR2. Typically, a guanidino group is ~-NHC(NH)NH2.

A "salt" as is well known in the art includes an organic compound such as a carboxyiic acid, a sulfonic acid, or an amine, in ionic form, in combination with a counferion. For example, acids in their anionic form can form salts with cations such as metal cations, for example sodium, potassium, and the like; with ammonium salts such as NhV or the cations of various amines, including tetraalkyl ammonium salts such as tetramethylammonium, or other cations such as trimethylsulfonium, and the like. A

"pharmaceutically acceptable" or "pharmacologically acceptable" salt is a salt formed from an ion that has been approved for human consumption and is generally non-toxic, such as a chloride salt or a sodium salt. A "zwitterion" is an internal salt such as can be formed in a molecule that has at least two ionizable groups, one forming an anion and the other a cation, which serve to balance each other. For example, amino acids such as glycine can exist in a zwitterionic form. A "zwitterion" is a salt within the meaning herein. The compounds of the present invention may take the form of salts. The term "salts" embraces addition salts of free acids or free bases which are compounds of the invention. Salts can be

"pharmaceutically-acceptable salts." The term "pharmaceutically-acceptable salt" refers to salts which possess toxicity profiles within a range that affords utility in pharmaceutical applications.

Pharmaceutically unacceptable salts may nonetheless possess properties such as high crystaiiinity, which have utility in the practice of the present invention, such as for example utility in process of synthesis, purification or formulation of compounds of the invention.

Suitable pharmaceutically-acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids. Appropriate organic acids may be selected from aliphatic, cycloaiiphafic, aromatic, araiiphatic, heterocyclic, carboxyiic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, giycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maieic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenyiacefic, mandeiic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, sulfaniiic,

cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric, salicylic, galactaric and galacturoriic acid. Examples of pharmaceutically unacceptable acid addition salts include, for example, perchiorates and tetrafluoroborates.

Suitable pharmaceutically acceptable base addition salts of compounds include, for example, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, /V,/V-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyigiucamine) and procaine. Examples of pharmaceutically unacceptable base addition salts include lithium salts and cyanate salts. Although pharmaceutically unacceptable salts are not generally useful as medicaments, such salts may be useful, for example as intermediates in the synthesis of compounds, for example in their purification by recrystaliization. Ail of these salts may be prepared by conventional means from the corresponding compound by reacting, for example, the appropriate acid or base with the compound. The term "pharmaceutically acceptable salts" refers to nontoxic inorganic or organic acid and/or base addition salts, see, for example, Lit et a!., Salt Selection for Basic Drugs (1986), int J. Pharm., 33, 201 -217, incorporated by reference herein,

A "hydrate" is a compound that exists in a composition with water molecules. The composition can include water in stoichiometic quantities, such as a monohydrate or a dihydrate, or can include water in random amounts. As the term is used herein a "hydrate" refers to a solid form, i.e., a compound in water solution, while it may be hydrated, is not a hydrate as the term is used herein.

A "solvate" is a similar composition except that a solvent other that water replaces the water. For example, methanol or ethanol can form an "aicoholate", which can again be stoichiometic or non- stoichiometric. As the term is used herein a "solvate" refers to a solid form, i.e., a compound in solution in a solvent, while it may be solvated, is not a solvate as the term is used herein.

A "prodrug" as is well known in the art is a substance that can be administered to a patient where the substance is converted in vivo by the action of biochemicals within the patient's body, such as enzymes, to the active pharmaceutical ingredient. Examples of prodrugs include esters of carboxyiic acid groups, which can be hydroiyzed by endogenous esterases as are found in the bloodstream of humans and other mammals. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group. For example, if a group X is described as selected from the set consisting of bromine, chlorine, and iodine, claims for X being bromine and claims for X being bromine and chlorine are fully described. Moreover, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any combination of individual members or subgroups of members of Markush groups. Thus, for example, if X is described as selected from the group consisting of bromine, chlorine, and iodine, and Y is described as selected from the group consisting of methyl, ethyl, and propyl, claims fo being bromine and Y being methyl are fully described.

If a value of a variable that is necessarily an integer, e.g., the number of carbon atoms in an alkyl group or the number of substituents on a ring, is described as a range, e.g., 0-4, what is meant is that the value can be any integer between 0 and 4 inclusive, i.e., 0, 1 , 2, 3, or 4.

In various embodiments, the compound or set of compounds, such as are used in the inventive methods, can be any one of any of the combinations and/or sub-combinations of the above-listed embodiments.

In various embodiments, a compound as shown in any of the Examples, or among the exemplary compounds, is provided.

Provisos may apply to any of the disclosed categories or embodiments wherein any one or more of the other above disclosed embodiments or species may be excluded from such categories or embodiments.

Epilepsy

Epilepsy is a group of neurological disorders characterized by abnormal electrical discharges in the brain that result in loss of consciousness, convulsions, spasms, sensory confusion, and disturbances in the autonomic nervous system. There are many different types of epilepsy and seizures and the exact cause is frequently unknown. (For more information on this disorder, choose "epiiepsy" as your search term in the Rare Disease Database.) Epiiepsy can also occur as part of larger genetic syndromes. Types of epilepsy or disorders associated with epiiepsy include Rett syndrome, Autism Spectrum Disorders, Angleman syndrome, Dravet syndrome, and West syndrome.

Exemplary Methods and Compounds

The present disclosure provides methods to prevent or mitigate, e.g., inhibit or treat, in a mammal one or more symptoms associated with conditions such as epiiepsy, epileptic encephalopathies,

Angelman Syndrome, Benign Roinadic Epilepsy, CDKL5 disorder, Childhood Absence Epilepsy, Doose Syndrome, Dravet Syndrome, Epilepsy with Generalized Tonic-Clonic Seizures Alone, Epilepsy with Myoclonic-Absences, Frontal Lobe Epilepsy, Glutl Deficiency Syndrome, Hypothalamic Hamartoma, Infantile Spasms/West's Syndrome, Juvenile Myoclonic Epilepsy, Lafora Progressive Myoclonus Epilepsy, Landau-Kleffner Syndrome, Lennox-Gastaut Syndrome, Ohtahara Syndrome, Panayuotopoulos

Syndrome, PCDH19 Epilepsy, Progressive Myoclonic Epilepsies, Rasmussen's Syndrome, Ring

Chromosome 20 Syndrome, Reflex Epilepsies, TBCK-reiated ID Syndrome, Temporal Lobe Epilepsy, epilepsy associated with neurodeveiopment disorders such as autistic spectrum disorder, and epiiepsy associated with traumatic brain injury, including symptoms such as seizures, developmental and cognitive disabilities and movement disorders (e.g., hypotonia, dystonia, hyperrefiexia, and ataxia), in one embodiment, the compound(s) directly or indirectly inhibit activity of a potassium channel, e.g., KCNT1 .

In some embodiments, methods are provided for inhibiting or treating symptoms associated with a disease or condition characterized by seizures or abnormal neural activity or delaying or preventing the onset of symptoms of the disease or condition. Methods are also provided for reducing the risk, progression or onset of a pathological condition characterized by seizures, developmental delay or cognitive impairment. Methods are also provided for reducing the risk, progression or onset of a pathological condition characterized by arrhythmias.

Methods are also provided for reducing the risk, lessening the severity, or delaying the progression or onset of a pathological condition characterized by aberrant voitage-gated potassium channel activity, e.g., aberrant KCNT1 activity, including but not limited to potassium channel activity in a mammal having epiiepsy, epileptic encephalopathy, cardiac arrhythmias and the like. In certain embodiments, compositions and methods are provided for altering or modulating aberrant potassium voltage-gated channel activity in a mammal, in certain embodiments, methods are provided for altering or modulating voltage-gated potassium channel activity in a mammal. In various embodiments, the methods comprise administering to the mammal a composition having one or more compounds of formulas (l)~ (LXXXXIil), a compound in one of Tables 1 -5, or a pharmaceutically acceptable salt (or other

pharmaceutically acceptable form) thereof, in an amount effective to prevent, inhibit or treat a symptom of a condition, e.g., epilepsy or arrhythmias. In certain embodiments of these methods, the compounds are administered in a therapeutically effective or prophylactically effective amount.

In one embodiment, the method employs a compound of formula (I):

(I)

In one embodiment, each R¹ independently = Aryl or heteroaryl. in one embodiment, R² = CON ez, C02Ci-*alkyl, or OCi-ssatu rated, unsaturated aikyl, cydoaikyi, or heterocycioaikyi. In one embodiment, R³ = OH, CN, NH2, OCi-esatu rated or unsaturated a!kyl, NHC-i-esaturated or unsaturated alkyl, or N(Ci-8saturated or unsaturated alky)2. In one embodiment, R⁴ = Aryl, heteroaryl, o 4-Ci-C6H4. In one embodiment, A = C, N. In one embodiment, each R^¾ independently = Aryl or heteroaryl; R² =

CON 62, C02C i-4aikyi, or OCi-ssatu rated, unsaturated alkyl, cydoaikyi, or heterocycioaikyi; R³ = OH, CN, NH2, OCi-esatu rated or unsaturated alkyl, NHCi-ssaturated or unsaturated aikyl, or N(Ci-8saturated or unsaturated aiky)2; R⁴ = Aryl, heteroaryl, or 4-CI-CeH4; and A = CH, N. In one embodiment, n=1 -10.

In one embodiment, a compo formula (la):

In one embodiment of formula (la), R¹ = CI, Br, F, I, OH, NH2, CN, CO2H, CO2C1-8 saturated or unsaturated aikyl, NHC1 ^saturated, unsaturated alkyl, or cydoaikyi, or N(Ci-esaturated, unsaturated aikyl, or cycloalkyi)2. In one embodiment of formula (la), R² = CON e2, C02Ci-4alkyl, OCi-esatu rated, unsaturated aikyl, cydoaikyi, or heterocycioaikyi. In one embodiment of formula (la), R³ = OH, CN, NH2, OCi-esatu rated or unsaturated aikyl, NHCi-esaturated or unsaiuraied alkyl, N(Ci-esaturated or unsaturated alky)2. In one embodiment of formula (la), R⁴ = Aryl, heteroaryl, or 4-CI-C8H4. In one embodiment of formula (ia), A = C, N. In one embodiment of formula (la), n = 0-8. In one embodiment of formula (la), R = Ci, Br, F, I, OH, NH2, CN, CO2H, CO2C1 -8 saturated or unsaturated alkyl, NHd ssaturaied, unsaturated alkyl, or cydoaikyi, or N(Ci-8saturated, unsaturated aikyl, or cycloalkyi)2 ;R² = CONMe2,

OCi-esatu rated, unsaturated aikyl, cydoaikyi, or heterocycioaikyi; R³ = OH, CN, NH2, OCi-ssaturated or unsaturated aikyi, NHCi-ssaturated or unsaturated alkyl, N(Ci-asaturated or unsaturated alky)2; R⁴ = Aryl, heteroaryl, or 4-CI-C8H4; A = C, N; and n = 0-6. In one embodiment, the compound is loperamide.

In one embodiment, the method employs a compound of formula (II):

In one embodiment, each R independently = Ci, Br, F, I, OH, NH2, CN, CO2H, CO2C1 saturated or unsaturated alkyl, NHCi-esaturated, unsaturated alkyl, or cydoaikyi, or N(Ci-esaturated, unsaturated alkyl, or cycioaikyl)2. in one embodiment, R² = Aryl or heteroaryl, or GC ^satu ated, unsaturated alkyl, cydoaikyi, or cycloheteroalkyi. in one embodiment, R³ = CH2, O, NH, or NCi-ssaturated, unsaturated aikyi, or cydoaikyi. In one embodiment, R⁴ = Aryl or heteroaryl, or OCi-ssaturated or unsaturated aikyl. in one embodiment, A = CH2, N, O, or S. In one embodiment, each R¹ independently = Ci, Br, F, I, OH, NH2, CN, C02H, CO2C1-8 saturated or unsaturated aikyl, NHCi-esaturated, unsaturated aikyl, or cydoaikyi, or N(Ci- ssaturated, unsaturated alkyi, or cycioalkyl)2; R² = Aryl or heteroaryi, or OCi-esaturated, unsaturated alkyl, cycloalkyi, or cycloheteroalkyl; R³ = CH2, O, NH, or NC i-ssaturated, unsaturated alkyi, or cycloalkyi; R⁴ = Aryl or heteroaryi, OCi-esatu rated or unsaturated alkyi; and A = CH2, N, O, or S,

In one embodiment, a compound has formula (iia):

In one embodiment of formula (iia), R¹ = Ci, Br, F, i, OH, NH2, CN, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHd-esaturated, unsaturated alkyi, or cycloalkyi, or N(Ci-ssaturated, unsaturated alkyl, or cycloalkyi)2. In one embodiment of formula (iia), R² = Aryl or heteroaryi, OCi-esatu rated, unsaturated alkyl, cycloalkyi, or cycloheteroalkyl. In one embodiment, of formula (Iia), R³ = CH2, O, NH, NCi- ssaturated, unsaturated alkyi, or cycloalkyi. In one embodiment of formula (Ha), R⁴ = Aryl or heteroaryi, OC1-6 saturated or unsaturated alkyl. in one embodiment of formula (lla), A = CH2, N, O, or S

In one embodiment of formula (iia), R¹ = CI, Br, F, i, OH, NH₂, CN, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHd-esaturated, unsaturated alkyi, or cycloalkyi, N(Ci -ssaturated, unsaturated alkyl, or cycloalkyi^; R² = Aryl or heteroaryi, OC1 -ssaturated, unsaturated alkyl, cycloalkyi, or cycloheteroalkyl; R³ = CH2, O, NH, NCi ssaturated, unsaturated alkyl, or cycloalkyi; R⁴ = Aryl or heteroaryi, OC1 -5 saturated or unsaturated alkyi; and A = CH2, N, O, or S. in one embodiment, the compound is raloxifene.

In one embodiment, the method employs a compound of formula (III):

(HI)

In one embodiment each R^! independents CI, Br, F, I, OH, NH₂, CN, CO2H, CO2C1-8 saturated or unsaturated alkyl, NHCi-ssaturaied, unsaturated alkyl, or cycloalkyi, or N(Ci-8saturated, unsaturated alkyl, or cycloalkyl)2. In one embodiment, each R² independents Aryl, heteroaryi, OC-i-ssaturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, or Ci-ssaturated alkyl, unsaturated alkyi, cycloalkyi, or cycloheteroalkyl. In one embodiment, each R independents CI, Br, F, I, OH, NH2, CN, CO2H, CO2C1 -8 saturated or unsaturated alkyl, NHCi-ssaturated, unsaturated alkyl, or cycloalkyi, or N(Ci-ssaturated, unsaturated alkyi, or cycloalkyi^; and each R² independents Aryl, heteroaryi, OCi-ssaturated, unsaturated alkyi, cycloalkyi, cycloheteroalkyl, or Ci-asaturated alkyl, unsaturated alkyi, cycloalkyi, or cycloheteroalkyl.

In one embodiment, a compou has formula (ilia):

In one embodiment of formula (I lia), R¹ = Ci, Br, F, I , OH, NH₂, CN, CO2H, CO2C 1-8 saturated or unsaturated aikyi, NHC1-6 saturated , unsaturated aikyi, or cycioaikyi, or N(Ci-e saturated , unsaturated alkyi, or cycioaikyi; and R² = OC1 -6 saturated , unsaturated alkyi, cycioaikyi, cye!oheteroalkyl, Ci -e saturated alkyi, unsaturated aikyi, cycioaikyi, or cycioheteroalkyl. In one embodiment, the compound is diethylstiibestrol, hexestrol or dienestrol.

In one embodiment, the method employs a compound of formula (IV):

(IV)

In one embodiment, R^¾ = CI, Br, F, I, OH, NH2, CN, CO2H, CO2C1-8 saturated or unsaturated alkyi, NHCi-esaiuraied, unsaturated alkyi, or cycioaikyi, or N(Ci-8saturated, unsaturated alkyi, or cycioaikyi^. in one embodiment, R² = Aryl, heteroaryi, OCi-esaturated, OC5-8 ary! or heteroaryi, unsaturated alky!, cycioaikyi, cycioheteroalkyl, or Ci-ssatu rated alkyi, unsaturated aikyi, cycioaikyi, or cycioheteroalkyl. In one embodiment, each A independents CH, CH2, N, NH , or NHCi-esaiuraied, unsaturated alkyi, or cycioaikyi. in one embodiment, n = 0-10. In one embodiment, R¹ = CI, Br, F, I, OH, NH2, CN, CO2H , CO2G1-8 saturated or unsaturated alkyi, NHCi-ssaturated, unsaturated alkyi, or cycioaikyi, or N(Ci- ssaturated , unsaturated aikyi, or cycioaikyi^; R² = Aryl, heteroaryi, OCi-oSatu rated, OCs-s aryl or heteroaryi, unsaturated alkyi, cycioaikyi, cycioheteroalkyl, or Ci-ssaturated aikyi, unsaturated alkyi, cycioaikyi, or cycioheteroalkyl; each A independently^ CH, CH2, O, N, or NHCi-asaturated, unsaturated alkyi, or cycioaikyi; and n = 0-10.

In one embodiment, a co ):

In one embodiment of formula (iVa), R¹ = OH, NH2, CN, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHCi-s saturated, unsaturated alkyi, or cycioaikyi, or N(Ci-esatu rated, unsaturated aikyi, or cycloaikyi)2.

in one embodiment of formula (IVa), R² = Aryi, heteroaryi, OC1-6 saturated, OC5-6 aryl or heteroaryi, unsaturated aikyi, cycioaikyi, cycioheteroalkyl, Ci-asaturated alkyi, unsaturated alkyi, cycioaikyi, or cycioheteroalkyl. in one embodiment of formula (IVa), A = CH, CH2, O, N, NHC1-6 saturated, unsaturated alkyi, or cycioaikyi. in one embodiment of formula (IVa), n = 0-6. in one embodiment of formula (IVa), R¹ = OH , NH2, CN, CO2H, CO2C1 -8 saturated or unsaturated alkyi, NHCi-e saturated, unsaturated alkyi, or cycioaikyi, or N(Ci-esaturated, unsaturated aikyi, or cycioalkyl)_s; R² = Aryl, heteroaryi, OC1 -6 saturated , OC5-6 aryl or heteroaryi, unsaturated alkyi, cycioaikyi, cycioheteroalkyl, Ci -ssaturated aikyi, unsaturated alkyi, cycioaikyi, or cycioheteroalkyl; A O, NH, NC1-6 saturated, unsaturated alkyi, or cycioaikyi; and n = 0-6. In one embodiment, the compound is carvediol.

In one embodiment, the method employs a compound of formula (V):

In one embodiment, each R independently^ CI, Br, F, i, OH, NH2, CN, OC1-8 saturated or unsaturated alkyl, CO2H , CO2C1-S saturated or unsaturated alkyl, NHCi-ssaturated, unsaturated alkyl, or cycloaikyi, or N(Ci-8saturated, unsaturated alkyi, or cycioalkyl)2. in one embodiment, R² = CH2, O, NH , or NCi-esaturated , unsaturated alkyi, or cycloaikyi, S. In one embodiment, each A independently = CH, CH2, O, N , or NHCi-esaturated, unsaturated alkyi, or cycloaikyi, S, SO, SO2. In one emboiudment, each R¹ independentiy= CI, Br, F, I, OH, NH2, CN, OC1-8 saturated or unsaturated alkyi, CO2H , CO2C1-8 saturated or unsaturated alkyi, NHCi-ssaturated, unsaturated alkyl, or cycloaikyi, or N(Ci-ssaturated, unsaturated alkyl, or cycloaikyi^; R² = CH2, O, NH, or NC i-ssaturated, unsaturated alkyi, or cycloaikyi, S; and each A independently = CH, CH2, O, N, NH, or NHCi-esaturated, unsaturated alkyi, or cycloaikyi, S, SO, SO2.

In one embodiment, a compound of formula (V) has formula (Va):

In one embodiment of formula (Va), R¹ = CH2, O, NH, NCi-ssaturated, unsaturated alkyl, cycloalky, or cycloheterocyloalkyl. In one embodiment of formula (Va), R² = CH2, O, NH, or NCi- ssaturated , unsaturated alkyi, or cycloaikyi. In one embodiment of formula (Va), A = CH2, O, NH , or NCi- esaturated , unsaturated alkyi, or cycloaikyi, S, SO, or S02.

In one embodiment of formula (Va), R¹ = CI, Br, F, I , OH, NH2, CN, OCi-s saturated or unsaturated alkyl, CO2H, CO2C1-8 saturated or unsaturated alkyl, NHCi-ssaturated, unsaturated alkyl, or cycloaikyi, or N(Ci-esaturated , unsaturated alkyl, or cycloaikyi; R² = CH2, O, NH, NCi -ssaturated, unsaturated alkyi, cycloalky, or cycloheterocyloalkyl, S; and A = CH2, O, NH, or NCi-esaturated, unsaturated alkyl, or cycloaikyi, S, SO, SO2 , In one embodiment, the compound is doxazosin .

In one embodiment, the method employs a compound of formula (VI):

(VI)

In one embodiment, each R independents CH2, O, NH, NCi -ssaturated, unsaturated alkyl, cycloalky, or cycloheterocyloalkyl. In one embodiment, each R² independently^ CI, Br, F, I , OH, NH2, CN, OC1-8 saturated or unsaturated alkyl, CO2H, CO2C1-8 saturated or unsaturated alkyi, NHCi-esaturated, unsaturated alkyi, or cycloaikyi, or N(Ci-esaturated, unsaturated alkyl, or cycloalkyl)2. In one embodiment, R³ = Aryl, heteroaryl, OCi-ssaturated, OC5-8 aryi or heteroaryi, unsaturated alkyl, cycloaikyi, cycloheteroalkyl, or Ci-3saturated alkyi, unsaturated alkyi, cycioaikyl, or cycloheteroalkyl. in one embodiment, A = CH2, O, NH or NCi-ssatu rated, unsaturated aikyl, or cycioaikyl. In one embodiment, each R¹ independents CH2, O, NH, NCi-esaturated, unsaturated alkyi, cycloalky, or cycloheterocyloalkyl; each R² independents CI, Br, F, I , OH, NH2, CN, OCi-s saturated or unsaturated aikyl, CO2H, CQ2C1-8 saturated or unsaturated alkyi, NHCi-ssatu rated, unsaturated aikyl, or cycioaikyl, or N(Ci-esaturated, unsaturated alkyi, or cycioalkyl)2; R³ = Aryl, heteroaryl, OCi-esatu rated, OC5-8 aryi or heteroaryl, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, or Ci-esaturated aikyl, unsaturated aikyl, cycioaikyl, or cycloheteroalkyl; and A = CH2, O, NH or NCi-esaturated, unsaturated aikyl, or cycioaikyl. In one embodiment, a compound of formula

In one embodiment of formula (Via), R¹ = CH2, O, NH, NCi-esaturated, unsaturated aikyl, cycloalky, or cycloheterocyloalkyl. In one embodiment of formula (Via), R² = OH, NH2, CN, OCi-e

saturated or unsaturated aikyl, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated aikyl, or cycioaikyl, or N(Ci-e saturated , unsaturated aikyl, or cycloaikyi)2. In one embodiment of formula (Via), A = CH2, O, NH or NCi-esaturated, unsaturated alkyi, or cycioaikyl. In one embodiment of formula (Via), R¹ = CH2, O, NH, NCi-asaturated, unsaturated aikyl, cycloalky, or cycioheterocyioaikyi; R² = OH, NH2, CN, OCi-e saturated or unsaturated aikyl, CO2H , CO2C1-6 saturated or unsaturated aikyl, NHC1-6 saturated , unsaturated alkyi, or cycioaikyl, or N(Ci-e saturated , unsaturated aikyl, or cycioaikyl^; and A = CH2, O, NH or NCi-esaturated, unsaturated aikyl, or cycioaikyl. In one embodiment, the compound is mometasone furoate, loieprednoletabonate, mifepristone, halconide, clobetasoi propionate or beciomethasone dipropionate.

In one embodiment, the method employs a compound of formula (VI I):

2 Me

(VI I)

In one embodiment, each R independents CI, Br, F, I, OH, NH2, CN, OC1-8 saturated or unsaturated alkyi, CO2H , CO2C1-8 saturated or unsaturated alkyi, NHCi-ssaturated, unsaturated alkyi, or cycioaikyl, or N(Gi-ssaturated, unsaturated alkyi, or cycioalkyl)2.

In one embodiment, each R² = CH2, O, NH, NCi-asaturated, unsaturated aikyl, cycloalky, or cycloheterocyloalkyl.

In one embodiment, each A independents CH2, O, NH or Nd-ssaturated, unsaturated aikyl, or cycioaikyl, S, SO, SO2; and n = 0-10. in one embodiment, each R independents CI, Br, F, I, OH, NH2, CN, OCi-s saturated or unsaturated aikyl, CO2H, CO2C1-8 saturated or unsaturated aikyl, NHCi-esaturated, unsaturated alkyi, or cycioaikyl, or N(Ci-3saturated, unsaturated aikyl, or cycloalky^; each R² = CH2, O, NH, NC i-ssaturated, unsaturated aikyl, cycloalky, or cycloheterocyloalkyl; each A independents CH2, O, NH or NCi-esaturated, unsaturated aikyl, or cycioaikyl, S, SO, SO2 ; and n = 0-10. In one embodiment, a co formula (Vi la):

In one embodiment of formula (Vi la), R¹ = OH, NH2, CN, Ci-esaturaied aikyl, unsaturated alkyl, cycloalkyl, or cycloheteroalkyl, OCi-e saturated or unsaturated alkyl, NHd-e saturated , unsaturated alkyl, or cycloalkyl, or N(Ci-e saturated, unsaturated alkyl, or cycioaikyl)2 In one embodiment of formula (Vila), R² = CH2, O, NH, NC1-6 saturated, unsaturated alkyl, cycloaiky, or cycloheterocyloalkyi. In one embodiment of formula (Vila), A = CH2, NH, NCi-esaturated, unsaturated alkyl, or cycloalkyl, O, S, SO or SO2. In one embodiment of formula (Vila), n = 0-8. In one embodiment of formula (Vi la), R¹ = OH, NH2, CN, OCi-e saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated aikyl, or cycloalkyl, or N(Ci-e saturated , unsaturated alkyl, or cycloalkyl^; R² = CH2, O, NH, NC1-6 saturated, unsaturated aikyl, cycloaiky, or cycloheterocyloalkyi; A = CH2, NHCi-asaturated , unsaturated alkyl, or cycloalkyl, O, S, SO, or SO2; and n = 0-8. in one embodiment, the compound is racecadotril.

In one embodiment, the method employs a compound of formula (VI II):

(VIII)

In one embodiment, each R independentiy= CI, Br, F, I, OH, NH2, CN, OC1-8 saturated or unsaturated alkyl, CO2H , CO2C1-8 saturated or unsaturated alkyl, NHCi-ssaturated, unsaturated alkyl, or cycloalkyl, or N(Ci-esaturated, unsaturated alkyl, or cycioalkyl)2. in one embodiment, each R² independentiy= CH2, O, NH, NCi-ssatu rated, unsaturated alkyl, cycloaiky, or cycloheterocyloalkyi. in one embodiment, each A independents CH2 O, or NHCi-ssatu rated , unsaturated alkyl, or cycloalkyl, S, SO, SO2. In one embodiment, each R¹ independently^ CI, Br, F, I , OH, NH2, CN, OCi-s saturated or unsaturated aikyl, CO2H , CO2C1-8 saturated or unsaturated alkyl, NHCi-ssatu rated, unsaturated alkyl, or cycloalkyl, or N(Ci ^saturated, unsaturated aikyl, or cycloalkyl^; each R² independently= CH2, O, NH, NCi ssat.urat.ed , unsaturated alkyl, cycloaiky, or cycloheterocyloalkyi; and each A independently^ CH2, O, or NHCi-ssaturated, unsaturated aikyl, or cycloalkyl, , S, SO, SO2.

In one embodiment, a compound of formula (VII I) has formula (Vil la):

In one embodiment, of formula (Vi lla), R¹ = OH, NH2, CN, OC1 -6 saturated or unsaturated aikyl, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated aikyl, or cycloalkyl, or N(Ci saturated , unsaturated alkyl, or cycloalkyl^; R² = CH2, O, NH, NC1-6 saturated, unsaturated aikyl, cycloaiky, or cycloaiky, or heterocyioalkyl; and A = CH2, O, or NHCi-ssaturated, unsaturated alkyl, or cycloalkyl, S, SO, SO2. In one embodiment, the compound is ritonavir.

In one embodiment, the method employs a compound of formula (IX):

( x)

In one embodiment., each R¹ independents H, F, Ci, Br, OH, CF3, C i-e Aryloxy, C1-6 saturated aikyl, CO2H, CO2C1-4 aikyl, SO2NH2, S0₂NHCi -₅ saturated aikyl, aryi or heteroaryl, S0₂N(Ci-s saturated aikyl, aryl or heteroaryl)2, or Cs-e aryl/heteroaryl. In one embodiment, each A independently = CH2, NH, O, or S. In one embodiment, each R independents H, F, Ci, Br, OH , CF3, C1-6 Aryloxy, Ci-e saturated aikyl, CO2H, CO2C1-4 aikyl, SO2NH2, SO2NHC1-6 saturated aikyl, aryl orheteroaryl, S02N(Ci-e saturated aikyl, aryl orheteroaryl)2, or C5-5 aryl/heteroaryl; and each A independently = CH2, NH, O, S, SO, SO2.

In one embodiment, a compound of formula (IX) has formula (iXa):

In one embodiment of formula (IXa), R¹ = H, F, CI, Br, OH, CFs, C1-6 Aryloxy, C1-6 saturated aikyi, CO2H, CO2C1-4 aikyl, SO2NH2, SO2NHC1-6 saturated aikyl, aryl or heteroaryl,S02N(Ci-6 saturated aikyl, aryi oOr heteroaryl^, or C5-6 aryl or heteroaryl; and A = CH2, NH , 0,S, SO, SO2. In one embodiment, the compound is econazole, sulconazole, sertaconazole, or miconazole.

In one embodiment, the method employs a compound of formula (X):

(X)

In one embodiment, each R¹ independents Ci, Br, F, I, OH, NH2, CN, OC1-8 saturated or unsaturated aikyi, CO2H, CQ2C1-8 saturated or unsaturated alkyi, NHCi-ssaturated, unsaturated alkyi, or cydoaikyi, or N(C i-ssaturated, unsaturated aikyi, or cycioalkyl)2. in one embodiment, each R²

independently³ CH2, O, NH, NCi-ssaturated, unsaturated alkyi, cycioaiky, or cycioheterocyioaikyl. in one embodiment, each A independently = CH, CH2, O, N, NH , NCi-ssaturated, unsaturated aikyl, or cydoaikyi, S, SO, SO2. in one embodiment, n = 0-10, in one embodiment, each R¹ independents CI, Br, F, I , OH, NH2, CN, OC i-8 saturated or unsaturated aikyl, CO2H, CO2C1-8 saturated or unsaturated alkyi, NHC1- ssaturated, unsaturated alkyi, or cydoaikyi, or N(Ci-8saturated, unsaturated aikyl, or cydoaikyi^; each R² independents CH2, O, NH, NCi -esaturated , unsaturated alkyi, cycioaiky, or cycioheterocyioaikyl; each A independently = CH, CH2, O, N.NCi-esaturated, unsaturated aikyl, or cydoaikyi, S, SO, SO2; and n = 0- 10.

In one embodiment, a compound of formula (X) has formula (Xa):

In one embodiment, of formula (Xa), R¹ = Br, CI, F, CN, OCi-s saturated or unsaturated alkyl, CO2H, CO2C1-8 saturated or unsaturated alky!, NHCi-esaturated , unsaturated alky!, or cycloalky!, or N(Ci- esaturated , unsaturated a!ky!, or cyc!oa!ky!)2; A = CH, CH2, O, N, NH, NCi-ssaturated, unsaturated a!ky!, or cycloalkyi, S, SO, SO?; and n = 0-6. In one embodiment, the compound is !omer!zine, prenylamirie, fluspirilen, or GBR 12909,

In one embodiment, the method employs a compound of formula (XI):

(XI)

In one embodiment, each R¹ independently = Aryi, heteroaryi, OCi-esaturated, OC5-8 aryi or heteroaryl, unsaturated alkyi, cycloalkyi, cycloheteroalkyl, Ci-ssaturated alkyl, unsaturated alkyl, cycloalkyi, or cycloheteroalkyl. in one embodiment, R² = CI, Br, F, I , OH, NH2, CN, OC1-8 saturated or unsaturated alkyi, CO2H , CO2C1-8 saturated or unsaturated alkyl, NHCi-ssaturated, unsaturated alkyl, or cycloalkyi, or N(Ci-8saturated, unsaturated alkyi, or cycloalkyl)2. in one embodiment, R³ = CH2, O, NH, NCi-esaturated , unsaturated alkyi, cycloalky, or cycioheterocyioaikyl. In one embodiment, A = CH, N or NCi-ssaturated , unsaturated alkyi, or cycloalkyi. In one embodiment, n = 0-10. in one embodiment, each R¹ independently = Aryi, heteroaryi, OCi-ssaturated, OCs-e aryl or heteroaryi, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, Ci-ssaturated alkyi, unsaturated alkyi, cycloalkyi, or cycloheteroalkyl; R² = CI, Br, F, I, OH, NH2, CN, OCi-s saturated or unsaturated alkyl, CO2H , CO2C1-8 saturated or unsaturated alkyl, NHC1- ssaturated, unsaturated alkyi, or cycloalkyi, or N(Ci-ssaturated, unsaturated alkyl, or cydoalkyl; R³ = CH2, O, NH, NCi-ssaturated, unsaturated alkyi, cycloalky, or cycioheterocyioaikyl; A = CH, N or NCi- ssaturated, unsaturated alkyi, or cycloalkyi; and wherein n = 0-10.

In one embodiment, a compound of formula (XI) has formula (Xla):

In one embodiment of formula (Xla), R¹ = CI, Br, F, i, OH, NH2, CN, OCi-ssaturated, OCs s aryi or heteroaryi, unsaturated alkyi, cycloalkyi, cycloheteroalkyl, or Ci-ssaturated alkyl, unsaturated alkyl, cycloalkyi, or cycloheteroalkyl; R² = OH, OC1-8 saturated or unsaturated alkyl, CO2H , CO2C1-8 saturated or unsaturated alkyi, NHCi-esaturated, unsaturated alkyi, or cycioaikyi, or N(Ci-3saturated, unsaturated aikyl, or cycioaikyi^; A = CH, or N; and n = 0-6, In one embodiment, the compound is ezetimbe.

In one embodiment, the method employs a compound of formula (XI I):

(XI I)

In one embodiment, each R¹ independently = Aryi, heteroaryl, GCi-esaturated, OCs-e aryl or heteroaryl, unsaturated alkyi, cycioaikyi, cycloheteroalkyl, or Ci-ssaturated aikyl, unsaturated alkyi, cycioaikyi, or cycloheteroalkyl. In one embodiment, each R² independently = CH2, O, NH, or NC1-8 saturated , unsaturated alkyi, cycloalky, or cycioheterocyioaikyl. In one embodiment, each R³

independently = CI, Br, F, I, OH, NH2, CN, OC1-8 saturated or unsaturated alkyi, CO2H, CO2C 1-8 saturated or unsaturated alkyi, NHCi-esaturated, unsaturated alkyi, or cycioaikyi, or N(Ci-8saturated, unsaturated alkyi, or cycioaikyl)2. In one embodiment, each A independently = CH2, CH, O, NH, NHCi-esaturated, unsaturated alkyi, or cycioaikyi.

in one embodiment, each n = 0-10. In one embodiment, each R¹ independently = Aryl, heteroaryl, OC1- esaturated , OCs-e aryl or heteroaryl, unsaturated aikyl, cycioaikyi, cycloheteroalkyl, or Ci-ssatu rated aikyl, unsaturated alkyi, cycioaikyi, or cycloheteroalkyl: each R² independently = CH2, O, NH, or NCi-esaturated, unsaturated alkyi, cycloalky, or cycioheterocyioaikyl; each R³ independently = CI, Br, F, I, OH, NH2, CN, OC1-8 saturated or unsaturated aikyl, CO2H, CO2C1-8 saturated or unsaturated alkyi, NHCi-esaturated, unsaturated alkyi, or cycioaikyi, or N(Ci-8saturated, unsaturated aikyl, or cycioaikyi^; each A

independently = CH2, CH, O, ΝΗ,Ν, or NHCi-esaturated, unsaturated alkyi, or cycioaikyi; and each n = 0- 10.

In one embodiment, a compound of formula (XII) has formula (Xi la):

In one embodiment of formula (Xi la), R^! = OC1-6 saturated, OC5-8 aryi or heteroaryl, unsaturated alkyi, cycioaikyi, cycloheteroalkyl, or Ci-e saturated aikyl, unsaturated alkyi, cycioaikyi, or cycloheteroalkyl. in one embodiment of formula (Xi la), R² = CH2, O, NH, or NC1 -5 saturated, unsaturated alkyi, cycloalky, or cycioheterocyioaikyl. In one embodiment of formula (Xila), R³ = OH, NH2, CN, OC1 -6 saturated or unsaturated alkyi, NHCi-e saturated , unsaturated alkyi, or cycioaikyi, or N(Ci-e saturated , unsaturated alkyi, or eycioaikyl)2. In one embodiment of formula (Xila), A = CH2, CH, O, NH, or NHCi-e saturated, unsaturated alkyi, or cycioaikyl. In one embodiment of formula (Xila), n = 0-6.

In one embodiment of formula (Xila), R¹ = OC1-6 saturated, OC5-8 aryi or heteroaryl, unsaturated alkyi, cycioaikyl, cycloheteroalkyi, or Cre saturated alkyi, unsaturated alkyi, cycioaikyl, cycloheteroalkyi; R² = CH2, O, NH, or NC1-6 saturated, unsaturated alkyi, cycioaiky, or cyeloheteroeyloalkyi; R³ = OH, NH2, CN, OC1-6 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated alkyi, or cycloalkyi, or N(Ci-e saturated, unsaturated alkyi, or cycloalkyi)?; A = CH2, CH, O, NH, NHC1-6 saturated, unsaturated aikyl, or cycloalkyi; and n = 0-6. In one embodiment, the compound is raltitrexed.

In one embodiment, the method employs a compound of formula (XIII):

(XI I i)

In one embodiment, each R¹ independently = Aryi, heteroaryl, OCi-esaturated, OC5-8 aryi or heteroaryl, unsaturated alkyi, cycloalkyi, cycloheteroalkyi, or Ci-ssaturated aikyl, unsaturated aikyl, cycloalkyi, or cycloheteroalkyi, in one embodiment, R² = CH2, O, NH, NCi-ssaturated, unsaturated aikyl, cycioaiky, or cyeloheteroeyloalkyi. In one embodiment, each R³ independently = Ci, Br, F, I, OH, NH2, CN, OC1-8 saturated or unsaturated aikyl, CO2H, CO2C1-8 saturated or unsaturated alkyi, NHC i-ssatu ated, unsaturated alkyi, or cycloalkyi, or N(Ci-8saturated, unsaturated aikyl, or cycloalkyi)2. In one embodiment, each A independently = CH2, CH, O, NH, N, NCi-ssaturated, unsaturated aikyl, or cycloalkyi.

In one embodiment, each R¹ independently = Aryi, heteroaryl, OCi-esaturated, OC5-8 aryi or heteroaryl, unsaturated alkyi, cycloalkyi, cycloheteroalkyi, or Ci-esaturated aikyl, unsaturated aikyl, cycloalkyi, or cycloheteroalkyi; R² = CH2, O, NH, NCi-ssaturated, unsaturated aikyl, cycioaiky, or cyeloheteroeyloalkyi; each R³ independently = CI, Br, F, I, OH, NH2, CN, OC1-8 saturated or unsaturated alkyi, CO2H, CO2C1-8 saturated or unsaturated aikyl, NHCi-ssaturated, unsaturated aikyl, or cycloalkyi, or N(Ci-esatu rated, unsaturated aikyl, or cycloalkyi^; and each A independently = CH2, CH, O, NH, NCi- ssaturated, unsaturated alkyi, or cycioaikyl.

In one embodiment, a compound of formula (Xlii) has formula (XII la):

In one embodiment of formula (Xiila), R¹ = OCi-e saturated, GC5-6 ary! or heteroaryl, unsaturated alkyi, cydoaikyi, cydoheteroalkyl, orCi-e saturated aikyl, unsaturated alkyi, cydoaikyi, or eycloheteroaikyi. in one embodiment of formula (Xllia), R² = CH2, O, NH, or NC1-6 saturated, unsaturated aikyl, cycloalky, or eycloheteroeyloalkyi. In one embodiment of formula (Xiila), R³ = Ci, Br, F, I, OH, NH2, CN, OC1-6 saturated or unsaturated aikyl, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated alkyi, or cydoaikyi, or N(C1 -6 saturated, unsaturated aikyl, or eycloaiky!)2. In one embodiment of formula (Xllia), A = CH2, CH, O, NH, or NCi-ssaturated, unsaturated aikyl, or cydoaikyi, in one embodiment of formula (Xllia), n = 0-8. In one embodiment of formula (Xllia), R^¾ = OCi-e saturated, OCS-B aryl or heteroaryl, unsaturated aikyl, cydoaikyi, cydoheteroalkyl, or C i-s saturated alkyi, unsaturated aikyl, cydoaikyi, or cydoheteroalkyl; R² = CH2, O, NH, or NCi-e saturated, unsaturated aikyl, cycloalky, or eycloheteroeyloalkyi; R³ = CI, Br, F, I, OH, NH₂, CN, OCi-e saturated or unsaturated aikyl, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated alkyi, or cydoaikyi, or N(C1 -6 saturated, unsaturated aikyl, or cycloalkyl)2; A = CH2, CH, O, NH, N, or NCi-ssaturated, unsaturated aikyl, or cydoaikyi; and n = 0-6. in one embodiment, the compound is nscergoiine.

In one embodiment, the method employs a compound of formula (XIV):

(XIV)

In one embodiment, each R¹ independently = Aryi, heteroaryl, QCi ^saturated, OCs-s aryl or heteroaryl, unsaturated alkyi, cydoaikyi, cydoheteroalkyl, or Ci ^saturated aikyl, unsaturated alkyi, or cydoaikyi, cydoheteroalkyl. in one embodiment, R² = CH2, O, NH, NCi-ssatu rated, unsaturated aikyl, cycloalky, or eycloheteroeyloalkyi. In one embdiment, each R³ independently = CI, Br, F, I, OH , NH2, CN, OC1-8 saturated or unsaturated aikyl, CO2H, CO2C1-8 saturated or unsaturated alkyi, NHC-i-esatu rated, unsaturated alkyi, or cydoaikyi, or N(Ci-esaturated, unsaturated aikyl, or cycloalkyl)2. In one embodiment, each A independently = CH or N; and in one embodiment, each n independently = 0-10. In one embodiment, each R¹ independently = Aryl, heteroaryl, OCi-esaturated, OC5-8 aryl or heteroaryl, unsaturated alkyi, cydoaikyi, cydoheteroalkyl, or Ci-ssaturated aikyl, unsaturated alkyi, cydoaikyi, or cydoheteroalkyl; R² = CH2, O, NH, NCi-asaturated, unsaturated alkyi, cycloalky, or eycloheteroeyloalkyi; each R³ independently = CI, Br, F, I, OH, NH2, CN, OCi-e saturated or unsaturated aikyl, CO2H , CO2C1-8 saturated or unsaturated alkyi, NHCi-esaturated, unsaturated aikyl, or cydoaikyi, or N(Ci-ssaturated, unsaturated aikyl, or cycioalkyl)2; each A independently = CH or N; and each n independently = 0-10.

In one embodiment, a compoun has formula (XVia):

In one embodiment of formula (XI Va), R¹ = OCi-e saturated, OCs-s aryl or heieroaryi, unsaturated alkyi, cycioaikyi, cycloheteroaikyi, o Ci-e saturated alkyi, unsaturated alkyi, cycloaikyi, or cycloheteroaikyi, in one embodiment of formula (XI Va), R² = CH2, O, NH, or NC1-6 saturated, unsaturated aikyi, cycloalky, or cycloheterocyloalkyi. In one embodiment of formula (XiVa), R³ = CN, C1-6 saturated or unsaturated alkyi, OC1-6 saturated or unsaturated alkyi, NHCi-e saturated, unsaturated alkyi, or cycloaikyi, or N(Ci-e saturated, unsaturated alkyi, or cycloaikyi)?. in one embodiment of formula (XiVa), A = CH or N, in one embodiment of formula (XiVa), n = 0-3, in one embodiment of formula (XiVa), R¹ = OC1-6 saturated, OCs-e aryl or heieroaryi, unsaturated aikyi, cycloaikyi, cycloheteroaikyi, Ci-e saturated alkyi, unsaturated alkyi, cycloaikyi, cycloheteroaikyi; R² = CH2, O, NH, or NC1-6 saturated, unsaturated aikyi, cycloaiky, or cycioheterocyioaikyl; R³ = CN, C1-6 saturated or unsaturated alkyi, OC1 -5 saturated or unsaturated alkyi, NHCi-e saturated, unsaturated alkyi, or cycloaikyi, or N(Ci-e saturated, unsaturated aikyi, or cycloalkyl)2; A = CH or N; and n = 0-3. in one embodiment, the compound is vinpocetine.

In one embodiment, the method employs a compound of formula (XV):

(XV)

In one embodiment, each R independently = Aryi, heteroaryi, OCi-ssaiuraied, QC5-8 aryl or heieroaryi, unsaturated alkyi, cycloaikyi, cycloheteroaikyi, or Ci-ssaturated aikyi, unsaturated alkyi, cycloaikyi, or cycloheteroaikyi. in one embodiment, n = 0-10. In one embodiment, each R¹ independently = Aryi, heteroaryi, OCi-ssatu rated, QCs-s aryl or heteroaryi, unsaturated aikyi, cycloaikyi, cycloheteroaikyi, or Ci-esatu rated alkyi, unsaturated alkyi, cycioaikyi, or cycloheteroaikyi; and

n = 0-10.

In one embodiment, a compoun has formula (XVa):

In one embodiment of formula (XVa), R¹ = H, OH, OCi-esatu rated, OC5-8 aryl or heteroaryi, unsaturated aikyi, cycloaikyi, or cycloheteroaikyi, or Ci-issaturated alkyi, unsaturated aikyi, heteroalkyi, cycloaikyi, or cycloheteroaikyi; A = CH or N; and n = 0-4. in one embodiment, the compound is estradiol or fluvestrant.

In one embodiment, the method employs a compound of formula (XVI):

(XVI)

In one embodiment, each R independently = Aryi, heteroaryi, OCi-ssaturated, QC5-8 ary! or heteroaryl, unsaturated alkyi, cycioaikyl, cycloheteroaikyl, Ci-ssaturated alkyl, unsaturated alkyi, cydoalkyl, cycloheteroaikyl, CI, Br, F, I, OH, NH2, CN, OC1-8 saturated or unsaturated alkyl, CO2H, CG2C1- 8 saturated or unsaturated alkyl, NHCi-ssaturated, unsaturated alkyl, or cycioaikyl, or N(Ci-ssaturated, unsaturated alkyi, or cycioalkyl)2. in one embodiment, R² = CH2, O, NH, NCi-ssaturated, unsaturated aikyl, cycloalky, or cycloheterocyloalkyl. In one embodiment, each A independently = CH2, CH, NH,C, N,or NCi- ssaturated, unsaturated alkyi or cycioaikyl, O, or S. In one embodiment, each n independently = 0-10. in one embodiment, each R¹ independently = Aryi, heteroaryi, QCi ^saturated, OC5-8 aryi or heteroaryl, unsaturated alkyi, cydoalkyl, cycioheieroaikyl, Ci-ssaturated alkyl, unsaturated alkyi, cycioaikyl, cycloheteroaikyl, Ci, Br, F, I, OH, NH2, CN, OC1-8 saturated or unsaturated alkyi, CO2H , CO2C1-8 saturated or unsaturated alkyi, NHCi-esaturated, unsaturated alkyl, or cycioaikyl, or N(Ci-esaturated, unsaturated alkyl, or cycioaikyl; R² = CH2, O, NH, NCi-esaturated, unsaturated aikyl, cycloalky, or

cycloheterocyloalkyl; each A independently = CH2, CH, NH, NCi-ssaturated, unsaturated aikyl or cydoalkyl, O, or S; andeach n independently = 0-10.

In one embodiment, a compo formula (XVia):

In one embodiment of formula (XVia), R¹ = OC1-6 saturated, OC5-6 aryi or heteroaryl, unsaturated alkyi, cycioaikyl, cycloheteroaikyl, C1-6 saturated alkyl, unsaturated alkyi, cydoalkyl, cycioheieroaikyl, CI, Br, F, i, OH, NH2, CN, OCi-e saturated or unsaturated aikyl, CO2H, CQ2C1 6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycioaikyl, or N(Ci-esaturated , unsaturated alkyi, or cycioaikyl^. in one embodiment of formula (XVia), R² = CH2, O, NH, or NCi-ssaturated, unsaturated aikyl, cycloalky, or cycloheterocyloalkyl. In one embodiment of formula (XVia), A = CH2, CH, C, N, NH, NCi-e saturated, unsaturated alkyl, or cycioaikyl, O, or S. In one embodiment of formula (XVia), n = 0-6. In one

embodiment of formula (XVia), R¹ = OC1 -6 saturated, OCs e aryi or heteroaryl, unsaturated alkyl, cydoalkyi, cycloheieroaikyl, Ci-e saturated aikyl, unsaturated aikyl, cydoalkyi, cydoheteroalkyl, CI, Br, F, I, OH, NH2, CN, OC1-6 saturated or unsaturated aikyl, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated alkyi, or cydoalkyi, or N(Ci-8saturated, unsaturated aikyl, or cydoalkyi; R² = CH2, O, NH, or NCi-esaturated, unsaturated aikyl, cycioaiky, or cycloheterocyloalkyl; A = CH2, CH, NH, or NC1-6 saturated, unsaturated alkyi, or cydoalkyi, O, S; and n = 0-6, In one embodiment, the compound is neifinavir or squanavir.

In one embodiment, the method employs a compound of formula (XVII):

(XVii)

In one embodiment, each R independently = Aryi, heteroaryi, Od-ssaturated, QC5-8 ary! or heteroaryi, unsaturated alkyi, cydoalkyi, cydoheteroalkyl, Ci-ssaturated aikyl, unsaturated aikyl, cydoalkyi, cydoheteroalkyl, CI, Br, F, i, OH, NH2, CN, OCi-a saturated or unsaturated aikyl, CO2H, CQ2C1- 8 saturated or unsaturated alkyi, NHCi-ssaturated, unsaturated alkyi, or cydoalkyi, or N(Ci-esaturated, unsaturated aikyl, or cycioalkyl)2.

In one embodiment, each R² independently = CH2, O, NH, NCi-esaturated, unsaturated alkyi, cycioaiky, or cycloheterocyloalkyl. In one embodiment, each A independently = CH2, CH, NH, NCi- esaturated, unsaturated aikyl, or cydoalkyi, O, or S. In one embodiment, each R¹ independently = Aryl, heteroaryi, OCi-esatu rated, OC5-8 aryi or heteroaryi, unsaturated aikyl, cydoalkyi, cydoheteroalkyl, Ci- ssaturated alkyi, unsaturated aikyl, cydoalkyi, cycioheteroaikyi, CI, Br, F, I, OH, NH2, CN, OC1-8 saturated or unsaturated alkyi, CO2H, CO2C1-8 saturated or unsaturated aikyl, NHCi-ssaturated, unsaturated aikyl, or cydoalkyi, or N(Ci ^saturated, unsaturated alkyi, or cycioaiky!^; each R² independently = CH2, O, NH, NCi-esaturated, unsaturated alkyi, cycioaiky, or cydoheierocyioaikyi; and each A independently = CH2, CH,C, N, NH, NCi-esaturated, unsaturated alkyi, or cydoalkyi, O, or S.

In one embodiment, a com formula (XVI la):

In one embodiment of formula (XVila), R = OCi-e saturated, OC5-6 aryl or heteroaryi, unsaturated alkyi, cydoalkyi, cydoheteroalkyl, C1-8 saturated aikyl, unsaturated aikyl, cydoalkyi, cydoheteroalkyl, CI, Br, F, I, OH, NH2, CN, OCi-e saturated or unsaturated aikyl, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHCi-6 saturated, unsaturated alkyl, or cydoalkyi, or N(Ci-e saturated, unsaturated alkyi, or cycloalkyl)2. in one embodiment of formula (XVila), R² = CH2, O, NH, or NCi-e saturated, unsaturated alkyl, cycioaiky, or cycloheterocyloalkyl. In one embodiment of formula (XVila), A = CH2, CH, C, N, NH, NC1-6 saturated, unsaturated aikyl, or cydoalkyi, O, or S.ln one embodiment of formula (XVila), R¹ = OC1-6 saturated, OC5-6 aryl or heteroaryi, unsaturated aikyl, cydoalkyi, cydoheteroalkyl, C1-6 saturated alkyi, unsaturated aikyl, cydoalkyi, cydoheteroalkyl, Ci, Br, F, I, OH, NH2, CN, OC1-6 saturated or unsaturated alkyl, CO2H, CO2C1- 6 saturated or unsaturated alkyi, NHCi-s saturated, unsaturated alkyi, or cydoalkyi, or N(Ci-e saturated, unsaturated alkyi, or cycloaikyi^; R² = CH2, Q, NH, or NC1-6 saturated, unsaturated alkyl, cycloalky, or cycloheterocyloalkyl; and A = CH2, CH, NH , NC1-6 saturated, unsaturated alkyl, or cycloaikyi, O, or S. in one embodiment, the compound is fenofibrate.

In one embodiment, the method employs a compound of formula (XVII I):

(XVI II)

In one embodiment, each R independently = Aryi, heteroaryl, OCi-esaturated, OC5-8 aryl or heteroaryl, unsaturated alkyi, cycloaikyi, cycioheteroalkyi, Ci-ssaturated alkyl, unsaturated alkyl, cycloaikyi, cycioheteroalkyi, CI, Br, F, i , OH, NH2, CN, OCi-a saturated or unsaturated alkyl, CO2H, C02Ci- s saturated or unsaturated alkyi, NHCi-ssaturated, unsaturated alkyi, or cycloaikyi, or N(Ci-esaturated, unsaturated alkyi, or cycioalkyl)2. in one embodiment, each A independently = CH2, CH, C, N, NH, NCi- ssaturated , unsaturated alkyi, or cycloaikyi, O, or S. In one embodiment, each n independently = 0-10. in one embodiment, each R¹ independently = Aryi, heteroaryl, Od-ssaturated, OC5-8 aryl or heteroaryl, unsaturated alkyi, cycloaikyi, cycioheteroalkyi, Ci-ssaturated alkyl, unsaturated alkyi, cycloaikyi, cycioheteroalkyi, CI, Br, F, I, OH, NH2, CN, OC1-8 saturated or unsaturated alkyi, CO2H , C02C i-s saturated or unsaturated alkyi, HCi-asatu rated, unsaturated alkyi, or cycloaikyi, orN(Ci-ssaturated, unsaturated alkyi, or cycloaikyi; each A independently = CH2, CH, NH, NCi-asaturated, unsaturated alkyl, or cycloaikyi, O, or S; and each n independently = 0-10.

in one embodiment, a compound of formula (XVi il) has formula (XVII la):

In one embodiment of formula (XVII la), R¹ = OCi-e saturated, OC5-6 aryl or heteroaryl, unsaturated alkyi, cycloaikyi, cycioheteroalkyi, C1 -6 saturated alkyl, unsaturated alkyi, cycloaikyi, cycioheteroalkyi, CI, Br, F, i , OH, NH2, CN, OCi-e saturated or unsaturated alkyl, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycloaikyi, or N(Ci-e saturated, unsaturated alkyi, or cycloalkyl)2. In one embodiment of formula (XVII la), R² = CI, Br, or I . In one embodiment of formula (XVI I la), A = CH2, CH, C, N , NH, NHC1-6 saturated , unsaturated alkyl, or cycloaikyi, O, or S. in one embodiment of formula (XVI ila), n = 0-8. In one embodiment of formula (XVI ila), R¹ = OCi-e saturated, OCs-e aryl or heteroaryl, unsaturated alkyi, cycloaikyi, cycioheteroalkyi, C1-6 saturated alkyl, unsaturated aikyl, cycloaikyi, cycioheteroalkyi, Ci, Br, F, I, OH, NH2, CN, OCi-e saturated or unsaturated alkyi, CO2H , CO2C1-B saturated or unsaturated alkyi, NHC1-8 saturated, unsaturated alkyi, or cycloaikyi, N(Ci-e saturated , unsaturated alkyi, or cycloaikyi^; A = CH2, CH , NH, NHC1-6 saturated, unsaturated aikyl, or cycloaikyi, O, S; and n = 0-6. In one embodiment, the compound is thonzonium bromide.

In one embodiment, the method employs a compound of formula (XIX):

(XIX)

In one embodiment., each R¹ independently = Aryl, heteroaryi, GCi ^saturated, OCs-s aryl or heteroaryi, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, Ci-ssaturated alkyl, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, CI, Br, F, i , OH, NH₂, CN, OC i-s saturated or unsaturated alkyl, CO2H, CO2C1 - 8 saturated or unsaturated alkyl, NHCi-ssaturated, unsaturated alkyl, or cycloalkyi, or N(Ci-8saturated, unsaturated alkyl, or cycioalkyl)2. in one embodiment, each A independently = CH2, CH, C, N, NH, NCi- esaiuraied , unsaturated alkyl, or cycloalkyi, O, S, SO, or SO2. in one embodiment, n = 0-10. In one embodiment, each R¹ independently = Aryl, heteroaryi, OCi-esaturated, OC5-8 aryl or heteroaryi, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, Ci-ssaturated alkyl, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, CI, Br, F, I, OH, NH2, CN, OC1-8 saturated or unsaturated alkyl, CO2H , CO2C1-8 saturated or unsaturated alkyl, NHCi-gsaturated, unsaturated alkyl, or cycloalkyi, or N(Ci-oSatu rated, unsaturated alkyl, or cycioaikyl)2;each A independently = CH2, CH, NH, NCi-esaturated, unsaturated alkyl, or cycloalkyi, O, S, SO, or S0₂; and n = 0-10.

In one embodiment, a compound of formula (XIX) has formula (XiXa):

In one embodiment of formula (XiXa), R¹ = OC5-6 aryl or heteroaryi, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, Ci-e saturated alkyl, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, CI, Br, F, OH, NH2, CN, OC1-6 saturated or unsaturated alkyl, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHC1-6 saturated , unsaturated alkyl, or cycloalkyi, or N(Ci-6satu rated, unsaturated alkyl, or cycloalkyl)₂; A = CH2, NH, NCi-eaturated, unsaturated alkyl, or cycloalkyi, O, S, SO, or S02; and n = 0-8. In one embodiment, the compound is mafenide.

In one embodiment, the method employs a compound of formula (XX):

R¹

(XX)

In one embodiment, each R independently = Aryl, heteroaryi, OCi-ssaturated, OC5-8 aryl or heteroaryi, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, Ci-ssaturated alkyl, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, CI, Br, F, I , OH, NH_2> CN, OC1-8 saturated or unsaturated alkyl, CO2H, CO2C1 8 saturated or unsaturated alkyl, NHCi-ssaturated, unsaturated alkyl, or cycloalkyi, or N(Ci-ssaturated, unsaturated alkyl, or cycioalkyl)2. in one embodiment, each A independently = CH₂, CH, C,N, NH, NC i- ssaturated , unsaturated alkyl, or cycloalkyi, O, S, SO, or S02. in one embodiment, n = 0-10. In one embodiment, each R¹ independently = Aryl, heteroaryl, GCi-ssaturated, OC5-8 aryi or heteroaryl, unsaturated alkyl, cycioaikyi, cydoheteroaikyi, Ci-ssaturated alkyl, unsaturated alkyl, cycioaikyi, cydoheteroaikyi, CI, Br, F, I, OH, NH2, CN, OC1-8 saturated or unsaturated aikyi, CO2H , CO2C1-8 saturated or unsaturated aikyi, NHCi -esaturated, unsaturated alkyl, or cycioaikyi, or N(Ci-₈safurafed, unsaturated alkyl, or cycioaikyi^; each A independently = CH2, CH, NH, NCi-ssaturated, unsaturated aikyi, or cycioaikyi, O, S, SO, or S0₂; and n = 0-10,

In one embodiment, a compou formula (XXa):

In one embodiment of formula (XXa), R¹ = OC1-6 saturated, unsaturated alkyl, cycioaikyi, cydoheteroaikyi, C1-6 saturated alkyl, unsaturated aikyi, cycioaikyi, cydoheteroaikyi, CI, Br, F, I , OH, NH2, CN, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHCi-e saturated , unsaturated alkyl, or cycioaikyi, or N(Ci-6 saturated, unsaturated alkyl, or cycloalky^; A = CH2, C, N, NH, NCi-ssaturated , unsaturated alkyl, or cycioaikyi, O, S, SO, or SO2; and n = 0-6, In one embodiment, the compound is bromhexine.

In one embodiment, the met ula (XXI):

(XXI)

In one embodiment, each R¹ independently = Aryi, heteroaryl, QCi ^saturated, OCs-s aryl or heteroaryl, unsaturated aikyi, cycioaikyi, cydoheteroaikyi, Ci -ssaturated alkyl, unsaturated aikyi, cycioaikyi, cydoheteroaikyi, CI, Br, F, I , OH, NH₂, CN, OC1-8 saturated or unsaturated alkyl, CO2H, CO2C1 - 8 saturated or unsaturated alkyl, NHCi -esaturated, unsaturated alkyl, or cycioaikyi, or N(Ci-esaturated, unsaturated alkyl, or cycloalkyl)2. in one embodiment, each A independently = CH2, CH, NH, NCi- ssaturated , unsaturated alkyl, or cycioaikyi, O, S, SO, or SO2. in one embodiment, n = 0-10. In one embodiment, each R¹ independently = Aryl, heteroaryl, OCi-esaturated, OC5-8 aryl or heteroaryl, unsaturated alkyl, cycioaikyi, cydoheteroaikyi, Ci -ssaturated alkyl, unsaturated alkyl, cycioaikyi, cydoheteroaikyi, CI, Br, F, I, OH, NH₂, CN, OC1-8 saturated or unsaturated aikyi, CO2H , CO2C1-8 saturated or unsaturated alkyl, NHCi-esatu ated, unsaturated alkyl, or cycioaikyi, or N (Ci-ssaturated, unsaturated alkyl, or cycioaikyi; each A independently = CH2, CH, N , NH, NCi-ssaturated, unsaturated aikyi, or cycioaikyi, O, S, SO, o SOa; and

n = 0-10.

In one embodiment, a co formula (XXia):

In one embodiment of formula (XXia), R¹ = OCi-e saturated, unsaturated aikyl, cycloalkyi, cycloheteroalkyl, Ci-e saturated alkyl, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, CI, Br, F, I, OH, NH2, CN, CO2H, C02Ci-6 saturated or unsaturated alkyl, NHCi-e saturated, unsaturated alkyl, or cycloalkyi, or N(Ci-6 saturated, unsaturated alkyl, or cycloalkyi; A = CH2, CH, NH, NCi-esaturated, unsaturated alkyl, or cycloalkyi, O, or S; and n = 0-6. In one embodiment, the compound is tegaserod.

In one embodiment, the method employs a compound of formula (XXII):

(XXII)

In one embodiment, each R¹ independently = Aryi, heteroaryi, OC1 -ssaiuraied, OC5-8 aryl or heteroaryi, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, Ci-ssaturated alkyl, unsaturated aikyl, cycloalkyi, cycloheteroalkyl, CI, Br, F, i, OH, NH₂, CN, OC i-s saturated or unsaturated alkyl, CO2H, CO2C1- 8 saturated or unsaturated alkyl, NHCi-ssaturated, unsaturated alkyl, or cycloalkyi, or N(Ci-esaturated, unsaturated aikyl, or cycioalkyl)2. in one embodiment, R² = CH2, O, NH, NCi-ssaturated, unsaturated aikyl, cycloaiky, or cycloheterocyloalkyi. In one embodiment, each A independently = CH2, CH, C, Ν,ΝΗ, NCi- ssaturated, unsaturated aikyl, or cycloalkyi, O, S, SO, or SO2. in one embodiment, each n independently = 0-1 Q. In one embodiment, each R¹ independently = Aryl, heteroaryi, OCi-asaturated, OC5-8 aryl or heteroaryi, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, Ci-ssaturated alkyl, unsaturated aikyl, cycloalkyi, cycloheteroalkyl, CI, Br, F, I, OH, NH_2> CN, OC1-8 saturated or unsaturated alkyl, CO2H, CG2C1- s saturated or unsaturated alkyl, NHCi-ssaturated, unsaturated alkyl, or cycloalkyi, or N(Ci-ssaturated, unsaturated alkyl, or cycloalkyi; R^{2 =} CH2, O, NH, NCi-ssaturated, unsaturated aikyl, cycloaiky, or cycloheterocyloalkyi; each A independently = CH2, CH, NH, NCi-ssaturated, unsaturated aikyl, or cycloalkyi, O, S, SO, or S02_; and each n independently = 0-10.

In one embodiment, a compo formula (XXI la):

In one embodiment of formula (XXila), R = OC1-6 saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, CI, Br, F, I, OH, NH2, CN, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated aikyl, or cycloalkyi, or N(Ci-6 saturated, unsaturated alkyl, or cycloalkyi; ⁼ CH2, O, NH, NCi-esaturated, unsaturated alkyl, cycloaiky, or cycloheterocyloalkyi; A = CH_2> NH, NCi-e saturated, unsaturated aikyl, or cycloalkyi, O, S, SO, or SO2; and n = 0-6, in one embodiment, the compound is zafirlukast.

In one embodiment, the method employs a compound of formula (XXIII):

(XX II I)

In one embodiment, each R¹ independently = Aryi, heteroaryl, Od-ssaturated, OC5-8 aryi or heteroaryl, Lfnsaturated alkyl, cycloalkyi, cycloheteroalkyl, Ci-asaturated alkyl, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, CI, Br, F, i, OH, NH2, CN, OC1-8 saturated or unsaturated alkyl, CO2H, CO2C1- 8 saturated or unsaturated alkyl, NHCi-asaturated, unsaturated alkyl, or cycioaikyl, or N(Ci-ssatu rated, unsaturated alkyl, or cycioalkyl)2. in one embodiment, each R² independently = CH2, O, NH, NCi- esaturated, unsaturated alkyi, cycloalky, or cycioheterocyioaikyl. in one embodiment, each n

independently = 0-10.

In one embodiment, each R¹ independently = Aryi, heteroaryl, GCi-esaturated, OC5-8 aryi or heteroaryl, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, Ci-ssaturated alkyl, unsaturated alkyi, cycloalkyi, cycloheteroalkyl, Ci, Br, F, i, OH, NH2, CN, OC1-8 saturated or unsaturated alkyl, CO2H, CO2C1- 8 saturated or unsaturated alkyi, NHCi-asaturated, unsaturated alkyi, or cycioaikyl, or N(Ci-ssaturated, unsaturated alkyi, or cycloalkyi^; each R² independently = CH2, O, NH, NCi-esaturated, unsaturated alkyi, cycloalky, or cycioheterocyioaikyl; and each n independently = 0-10,

In one embodiment, a compoun has formula (XXIIIa):

In one embodiment of formula (XXIIIa), R¹ = OC1-6 saturated, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, C1 -6 saturated alkyl, unsaturated alkyi, cycloalkyi, cycloheteroalkyl, CI, Br, F, I, OH, NH2, CN, OC1-6 saturated or unsaturated alkyl, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHC1-6 saturated, unsaturated alkyi, or cycioaikyl, N(Ci-6 saturated, unsaturated alkyl, or cycloalkyi^; R² = CH2, O, NH, or NCi-esaturated, unsaturated alkyi, cycloalky, or cycioheterocyioaikyl; and n = 0-8. In one embodiment, the compound is aiprostadii.

In one embodiment, the method employs a compound of formula (XXIV):

IV)

In one embodiment, each R¹ independently = Aryi, heteroaryl, QCi ^saturated, OCs-s aryl or heteroaryl, unsaturated alkyi, cycloalkyi, cycloheteroalkyl, Ci-ssaturated alkyl, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, CI, Br, F, I, OH, NH₂, CN, OC1-8 saiuraied or unsaturated alkyl, CO2H, CO2C1 - 8 saturated or unsaturated alkyl, NHCi-ssaturated, unsaturated alkyl, or cycloalkyi, or N(Ci-8saturated, unsaturated alkyi, or cycioalkyi)2. in one embodiment, each R² independently = CH2, O, NH, NCi- ssaturated , unsaturated alkyi, cycloalky, or cycioheterocyioaikyl. in one embodiment, each A

independently = CH2, CH , N , C, NH, NCi-ssaturated, unsaturated alkyi, or cycioaikyl, O, S, SO, or SO2. In one embodiment, each R¹ independently = Aryi, heteroaryi, QCi ^saturated, OC5-8 aryl or heteroaryl, unsaturated alkyi, cycioaikyl, cycioheteroaikyl, Ci-ssaturated alkyi, unsaturated aikyi, cycioaikyl, cycioheteroaikyl, CI, Br, F, I, OH, NH2, CN, OC1-8 saturated or unsaturated alkyi, CO2H , CO2C1-8 saturated or unsaturated alkyi, NHCi-esaturated, unsaturated alkyi, or cycioaikyl, or N(Ci-esaturated, unsaturated alkyi, or cycioaikyl^; each R² independently = CH2, O, NH, NCi-esaturated, unsaturated alkyi, cycloalky, or cycioheterocyioaikyl; and each A independently = CH2, CH, N, NH , NCi-ssaturated, unsaturated alkyi, or cycioaikyl, O, S, SO, or SO2.

In one embodiment, a compoun has formula (XXIVa):

In one embodiment of formula (XXIVa), R^! = OCi-e saturated, unsaturated aikyl, cycioaikyl, cycioheteroaikyl, C1 -6 saturated alkyi, unsaturated alkyi, cycioaikyl, cycioheteroaikyl, CI, Br, F, I, OH, NH2, CN, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHCi-6satu rated, unsaturated aikyl, or cycioaikyl, or N(Ci-6 saturated, unsaturated aikyl, or cycloalky^; R² = CH2, O, NH, or NCi-s saturated, unsaturated aikyl, cycloalky, or cycioheterocyioaikyl; A = CH2, CH, C, NH, NCi-esaturated, unsaturated alkyi, or cycioaikyl, N, O, S, SO, or S02; and n = 0-6. in one embodiment, the compound is sarafloxacin .

In one embodiment, the method employs a compound of formula (XXV):

(XXV)

In one embodiment, each R independently = Aryi, heteroaryi, OCi-ssaturated, GCs-s aryl or heteroaryl, unsaturated alkyi, cycioaikyl, cycioheteroaikyl, Ci-ssaturated aikyl, unsaturated alkyi, cycioaikyl, cycioheteroaikyl, CI, Br, F, i , OH, NH2, CN, OC1-8 saturated or unsaturated aikyl, CO2H, CG2C1- s saturated or unsaturated aikyl, NHCi-ssaturated , unsaturated aikyl, or cycioaikyl, or N(Ci-ssaturated, unsaturated alkyi, or cycioalkyl)2. in one embodiment, each A independently = CH2, CH, C, N, NH, NCi- ssaturated , unsaturated aikyi, or cycioaikyl, O, S, SO, or S02. in one embodiment, each n independently = 0-10. In one embodiment, each R¹ independently = Aryi, heteroaryi, OCi-ssaturated, OC5-8 aryl or heteroaryl, unsaturated alkyi, cycioaikyl, cycioheteroaikyl, Ci-ssaturated aikyl, unsaturated alkyi, cycioaikyl, cycioheteroaikyl, CI, Br, F, i , OH, NH₂, CN, OC1 -8 saturated or unsaturated aikyl, CO2H, CO2C1- 8 saturated or unsaturated alkyi, NHCi-esaturated, unsaturated alkyi, or cycioaikyl, or N(Ci-esaturated, unsaturated alkyi, or cycloalkyl)2; each A independently = CH2, CH, C, N, NH, NCi-esaturated, unsaturated aikyl, or cycioaikyl, O, S, SO, or S0₂; and each n independently = 0-10,

In one embodiment, a comp formula (XXVa):

In one embodiment of formula (XXVa), R^! = OCi-e saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, C i-s saturated alkyl, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, CI, Br, F, I, OH, NH2, CN , CO2H , CO2C 1 -6 saturated or unsaturated alkyl, NHC1 -6 saturated, unsaturated alkyl, or cycloalkyi, or N(Ci-e saturated, unsaturated alkyl, or cycloalkyi; R² = CI, Br, or I; A = C H₂, C, N , N H , NC1 -6 saturated, unsaturated alkyl, or cycloalkyi, O, S, SO, or SOz; and n = 0-10.

In one embodiment, the compound is pinaverium bromide.

In one embodiment, the method employs a compound of formula (XXVI):

R¹

(XXVI)

In one embodiment, each R¹ independently = Aryi, heteroaryi, OCi-esaturated, OCs-e aryl or heteroaryi, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, Ci-ssaturated alkyl, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, CI, Br, F, I, OH , NH₂, CN , OC i-s saturated or unsaturated alkyl, CO2H , CO2C1 - 8 saturated or unsaturated alkyl, NHCi-ssaturated, unsaturated alkyl, or cycloalkyi, or N(Ci-8saturated, unsaturated alkyl, or cycloalkyl)2. in one embodiment, each A independently = CH , CH2, N , NH , NCi- esaiuraied, unsaturated alkyl, or cycloalkyi, O, or S. In one embodiment, each R¹ independently = Aryi, heteroaryi, OC i-oSatu rated, OCs-s aryi or heteroaryi, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, Ci- ssaturated alkyl, unsaturated alkyl, cycioaikyi, cycloheteroalkyl, CI, Br, F, I, OH , NH2, CN , OC1-8 saturated or unsaturated alkyl, C0₂H , CO2C1-8 saturated or unsaturated alkyl, NHCi-ssaturated, unsaturated alkyl, or cycioaikyi, or N(Ci-ssaturated, unsaturated alkyl, or cycloalkyi; and each A independently = CH , NH , NCi-ssaturated, unsaturated alkyl, or cycloalkyi, O, o S.

In one embodiment, a comp formula (XXVia):

In one embodiment of formula (XXVIa), R¹ = OC1-6 saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, Ci-e saturated aikyi, unsaturated a!kyi, cycloalkyi, cycloheteroalkyl, CI, Br, F, I , OH, NH2, CN, CO2H, CO2C1-6 saturated or unsaturated aikyi, NHCi-e saturated , unsaturated alkyl, or cycloalkyi, or N(Ci-6 saturated, unsaturated alkyl, or cycloalkyi; and A = CH, N, O, or S. In one embodiment, the compound is bifonazoie.

In one embodiment, the method employs a compound of formula (XXVII):

(XXVI I)

In one embodiment, each R¹ independently = Aryl, eteroaryl, Od-esaturated, OCs s ary! or heteroaryl, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, Ci-esaturated alkyl, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, CI, Br, F, I, OH , NH₂, CN, OC1 -8 saturated or unsaturated alkyl, CO2H, CO2C1- 8 saturated or unsaturated alkyl, NHC-i-esaturated , unsaiuraied alkyl, or cycloalkyi, N(Ci-8saturated, unsaturated aikyi, or cycloalkyi. In one embodiment, each A independently = CH2, CH, C, N.NH, NCi- ssaturated , unsaturated aikyi, or cycloalkyi, O, or S. In one embodiment, each R¹ independently = Aryl, heteroaryl, OCi-esatu rated , OC5-8 aryl or heteroaryl, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, Ci- ssaturated alkyl, unsaturated aikyi, cycloalkyi, cycloheteroalkyl, CI, Br, F, I, OH, NH2, CN, OCi-a saturated or unsaturated alkyl, CO2H, CO2C1-8 saturated or unsaturated alkyl, NHCi-esaturated, unsaturated alkyl, or cycloalkyi, or N(Ci-ssaturated, unsaturated aikyi, or cycloalkyi; and each A independently = CH2, CH, NH, NCi-ssaturated, unsaturated aikyi, or cycloalkyi, O, or S.

In one embodiment, a compound of formula (XXVi i) has formula (XXVI la):

In one embodiment of formula (XXVila), R = OC1-6 saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, CI, Br, F, I, OH, NH₂, CN, CO2H, CO2C1-6 saturated or unsaturated aikyi, NHCi-e saturated , unsaturated alkyl, or cycloalkyi, or N(Ci-6 saturated, unsaturated alkyl, or cycloalkyi; ^ano" A = CH₂, N, CH, NH, NCi-ssaturated , unsaturated alkyl, or cycloalkyi, O, or S. In one embodiment, the compound is vatalanib.

In one embodiment, the method employs a compound of formula (XXVII I):

(XXVIII)

In one embodiment, each R¹ independently = Aryl, heteroaryl, OCi-esaturated, OC5-8 aryl or heteroaryl, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, Ci-ssaturated alkyl, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, Ci, Br, F, I, OH, NH2, CN, OC1-8 saturated or unsaturated alkyl, CO2H, CO2C1- 8 saturated or unsaturated alkyi, NHC-i-esaturated, unsaturated alkyl, or cycloalkyi, or N(Ci-8saturated, unsaturated alkyi, or cycioalkyl)2. in one embodiment, each R² independently = CH2, O, NH, NCi- esaturated, unsaturated alkyi, cycloalky, or cydoheterocyloalkyl. in one embodiment, each A

independently = CH2, C, N, CH, NH, NCi-esaturated, unsaturated alkyl, or cycloalkyi, O, S, SO, or S02. In one embodiment, n = 0-1 Q. In one embodiment, each R¹ independently = Aryl, heteroaryl, OCi-esaturated, OC5-8 aryl or heieroaryi, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, C-i-esaturated alkyl, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, CI, Br, F, I, OH, NH2, CN, OC1-8 saturated or unsaturated alkyi, CO2H, CO2C1-8 saturated or unsaturated alkyl, NHC1 -ssaturated, unsaturated alkyl, or cycloalkyi, or N(Ci- esaturated, unsaturated alkyi, or cycloalkyi^; each R² independently = CH2, O, NH, NCi-esaturated, unsaturated alkyi, cycloalky, or cydoheterocyloalkyl; each A independently = CH2, CH, NH, NCi- ssaturated, unsaturated alkyi, or cycloalkyi, O, S, SO, o SOa; and n = 0-10.

In one embodiment, a compoun has formula (XXVI I la):

In one embodiment of formula (XXVII la), R¹ = OC1-6 saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, C1-6 saturated alkyl, unsaturated alkyi, cycloalkyi, cycloheteroalkyl, CI, Br, F, I, OH, NH2, CN, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHCi-e saturated, unsaturated alkyl, or cycloalkyi, or N(Ci-6 saturated, unsaturated alkyl, or cycloalkyi^; R² = CH2, O, NH, or NC1-6 saturated, unsaturated alkyl, cycloalky, or cydoheterocyloalkyl; A = CH2, CH, N, NH, NC1-6 saturated, unsaturated alkyl, or cycloalkyi, O, S, SO, or SO2; and n = 0-6. in one embodiment, the compound is eticiopride.

In one embodiment, the method employs a compound of formula (XXIX):

(XXIX)

In one embodiment, each R¹ independently = Aryi, heteroaryl, OCi-ssaturated, OC5-8 aryl or heteroaryl, unsaturated alkyi, cycloalkyi, cycloheteroalkyl, Ci-asaturated alkyl, unsaturated alkyi, cycloalkyi, cycloheteroalkyl, CI, Br, F, i, OH, NH2, CN, OC1-8 saturated or unsaturated alkyl, CO2H, CO2C1- 8 saturated or unsaturated alkyl, NHCi-asaturated, unsaturated alkyl, or cycloalkyi, or N(Ci-oSaiu rated, unsaturated alkyi, or cycioalkyl)2. in one embodiment, R² = CH2, O, NH, NCi-ssaturated, unsaturated aikyl, cycloalky, or cydoheterocyloalkyl. In one embodiment, each A independently = CH2, CH3, C, NH2, N, CH, NH, NHCi-ssaturated, unsaturated alkyl, or cycloalkyi, O, OH, SH, S, SO, SO2. In one embodiment, each n independently = 0-10. in one embodiment, each R¹ independently = Aryl, heteroaryl, OCi-esatu rated, OC5-8 aryl or heteroaryl, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, Ci-ssaturated aikyl, unsaturated alkyi, cycioaikyl, eycioheteroaikyl, Ci, Br, F, I, OH, N H2, CN, OC-i-s saturated or unsaturated aikyl, CO2H , CO2C1-8 saturated or unsaturated aikyl, NHC1 ^saturated, unsaturated alkyi, or cycioaikyl, or N(Ci- ssaturated , unsaturated aikyl, or cycioaikyl; R² = CH2, O, NH, NCi-ssaturated, unsaturated aikyl, cycloaiky, or cycloheteroeyloalky!; each A independently = CH2, CH, NH, NHCi -esaturated, unsaturated alkyi, or cycioaikyl, O, S, SO, SO2; and each n independently = 0-10.

In one embodiment, a compound of formula (XXIX) has formula (XXiXa):

In one embodiment of formula (XXiXa), R ¹ = OC1-6 saturated, unsaturated aikyl, cycioaikyl, eycioheteroaikyl, Ci-e saturated alkyi, unsaturated alkyi, cycioaikyl, eycioheteroaikyl, CI, Br, F, I , OH, NH2, CN, CO2H , CO2C 1 -6 saturated or unsaturated aikyl, NHCi -e saturated , unsaturated alkyi, or cycioaikyl, or N(Ci-6 saturated, unsaturated alkyi, or cycioaikyl^; R² = CH2, O, NH, or NCi -e saturated, unsaturated alkyi cycloaiky, or cycloheterocyloalkyi; A = CH2, CH, N, NH, NHC i-e saturated, unsaturated alkyi, or cycioaikyl, O, S, SO, or SO2; and n = 0-8. In one embodiment, the compound is oxethazaine.

Certain compounds were found to inhibit wild-type KCNT1 , e.g. , compounds having formulas (XXX)-(LXXXXil i).

In one embodiment, the method employs a compound of formula (XXX):

in one embodiment, each R¹ independently = H , CI, Br, F, i , OH , NH2, CN, OCi-e saturated, unsaturated alkyi, cycioaikyl, eycioheteroaikyl, o aryi, SC 1-6 saturated, unsaturated alkyi, cycioaikyl, eycioheteroaikyl, or aryi, C1-6 saturated alkyi, unsaturated aikyl, cycioaikyl, eycioheteroaikyl, CO2H , CO2C1-6 saturated or unsaturated alkyi, NHC1-6 saturated , unsaturated aikyl, or cycioaikyl, N(Ci-6 saturated , unsaturated alkyi, or cycloalkyi)2, or Cs-yaryi or heteroaryl. In one embodiment, R² = OCi-e saturated, unsaturated aikyl, cycioaikyl, eycioheteroaikyl, SC 1 -6 saturated, unsaturated alkyi, cycioaikyl, eycioheteroaikyl, or aryi, C1-6 saturated aikyl, unsaturated aikyl, cycioaikyl, eycioheteroaikyl, or Canary! or heteroaryl. in one embodiment, each X independently = C, CH , or N. In one embodiment, each R¹ independently = H, CI, Br, F, I , OH, N H2, CN, OC 1 -6 saturated, unsaturated alkyi, cycioaikyl, eycioheteroaikyl, or aryi, SC1-5 saturated , unsaturated alkyi, cycioaikyl, eycioheteroaikyl, or aryi, Ci-e saturated alkyi, unsaturated aikyl, cycioaikyl, eycioheteroaikyl, CO2H , CO2C1-6 saturated or unsaturated alkyi, NHC1-6 saturated, unsaturated alkyi, or cycioaikyl, N(Ci-e saturated , unsaturated aikyl, or cycioaikyl^, or C aryl or heteroaryl; R² = OC1- saturated , unsaturated alkyi, cycioaikyl, eycioheteroaikyl, SC 1-6 saturated, unsaturated alkyi, cycioaikyl, eycioheteroaikyl, or aryi, Ci-e saturated alkyi, unsaturated aikyl, cycioaikyl, eycioheteroaikyl, or Cs-raryi or heteroaryl; and each X independently = C, CH , or N. In one embodiment, formula (XXX) is

diethylstilbestrol, hexestrol, or dienestrol.

In one embodiment, the method employs a compound of formula (XXXI):

In one embodiment, each R¹ independently = H, OC1-6 saturated, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, o aryi, SC1-6 saturated, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, or aryi, C1 -6 saturated alkyl, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CFs, NH2, CN, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycioaikyl, N(Ci-e saturated, unsaturated alkyl, or cycioaikyl, or C aryl or heteroaryi. In one embodimeni, each X independently = C, CH2, N, NH, NCi-esaturated, unsaturated alkyl, or cycioaikyl, O, or S. In one embodiment, each n independently = 0-8. In one embodiment, each R¹ independently = H, OC1-6 saturated, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, or ary!, SCi-e saturated, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, or aryi, C1 -6 saturated alkyl, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CFs, NH₂, CN, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHC1-6

saturated, unsaturated alkyl, or cycioaikyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl)2, o Cs-v-aryl or heteroaryi; each X independently = C, CH2, N, NH, NCi-asaturated, unsaturated alkyl, or cycioaikyl, O, or S; and each n independently = 0-6. In one embodiment, formula (XXXI) is etrinate.

In one embodiment, the method employs a compound of formula (XXXII):

in one embodiment, each R¹ independently = CH2, O, NH, NCi-esaturated, unsaturated alkyl, cye!oa!ky, or cycloheterocyioaikyi. In one embodiment, each R² independently = H, Ci, Br, F, I, OAc, NO2, CF3, OH, NH2, CN, C1-6 saturated alkyl, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, OCi-e saturated or unsaturated alkyl, SC1-6 saturated or unsaturated alkyl, CO2H , CO2C1-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycioaikyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl)2, or C5-7aryl or heteroaryi. in one embodiment, each R³ independently = any C5-7 ary! or heteroaryi. in one embodiment, each X independently = CH2, NHd-esaturated, unsaturated alkyl, or cycioaikyl, or O. In one embodiment, each R¹ independently = CH2, O, NH, NCi-esaturated, unsaturated alkyl, cycloalky, or cycloheterocyioaikyi. In one embodiment, each R² independently = H, Ci, Br, F, I, OAc, NO2, CF3, OH, NH2, CN, C1-6 saturated alkyl, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, OC1-6 saturated or unsaturated alkyl, SC1 -5 saturated or unsaturated alkyl, CO2H , CO2C1-6 saturated or unsaturated alkyl, NHCi-6 saturated, unsaturated alkyl, or cycioaikyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl)2, or Cs-7aryl or heteroaryi; and each X independently = CH2, NCi-ssaturated, unsaturated alkyl, or cycioaikyl, or O. In one embodiment, formula (XXXII) is mometasone furoate.

In one embodiment, the method employs a compound of formula (XXXIII):

In one embodiment, each R¹ independently = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated alkyi, cycioaikyi, cycloheteroalkyl, or aryi, SC1-6 saturated, unsaturated aikyi, cycioaikyi, cycloheteroalkyl, or aryl, C1 -5 saturated alkyl, unsaturated alkyl, cycioaikyi, cycloheteroalkyl, CO2H, CO2C1- 5 saturated or unsaturated alkyl, NHC1 -8 saturated, unsaturated alkyi, or cycioaikyi, N(C i-e saturated, unsaturated alkyi, .or cycloalky!^, or Cs-yaryl or heteroaryl In one embodiment, each X independently = C, CH2, N, NH, O, S, SO, or SO2. In one embodiment, each n independently = 0-6. in one embodiment, each R¹ independently = H, CI, Br, F, i, OH, OAc, CF₃, NH₂, CN, OC1-6 saturated, unsaturated alkyl, cycioaikyi, cycloheteroalkyl, o aryl, SCi-e saturated, unsaturated aikyi, cycioaikyi, cycloheteroalkyl, or aryl, C1-6 saturated alkyl, unsaturated aikyi, cycioaikyi, cycloheteroalkyl, CO2H, CO2G1-8 saturated or unsaturated alkyl, NHC1-8 saturated, unsaturated alkyi, or cycioaikyi, N(Ci-e saturated, unsaturated alkyl, .or cycioaikyi, or Cs-jaryl or heteroaryl; each X independently = C, CH2, N, NH, O, S, SO, or SO2; and each n independently = 0-6. in one embodiment, formula (XXXIII) is econazole or miconazole.

In one embodiment, the method employs a compound of formula (XXXIV): '

in one embodiment, each R¹ = H, Ci, Br, F, I, OH, OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated alkyl, cycioaikyi, cycloheteroalkyl, or aryi, SC1-6 saturated, unsaturated alkyi, cycioaikyi, cycloheteroalkyl, or aryl, C1-6 saturated aikyi, unsaturated alkyl, cycioaikyi, cycloheteroalkyl, CO2H, C02Ci-e saturated or unsaturated aikyi, NHC1-6 saturated, unsaturated alkyi, or cycioaikyi, N(Ci-e saturated, unsaturated alkyl, or cycioaikyi, orC5-7aryl or heteroaryl. in one embodiment, each R² = CH2, S, O, NH, NC1-6 saturated, unsaturated aikyi, cycloalky, or cycioheterocyioalkyl. in one embodiment, each X = C, CH, CH2, N, NCi- esaturated, unsaturated alkyi, or cycioaikyi, O, S, SO, or SO2. in one embodiment, each n = 0-6. In one embodiment, each R¹ = H, Ci, Br, F, I, OH, OAc, CF3, NH2, CN, OCi-e saturated, unsaturated alkyl, cycioaikyi, cycloheteroaikyi, or aryl, SC1-6 saturated, unsaturated alkyi, cycioaikyi, cycloheteroalkyl, o aryl, C1-6 saturated alkyl, unsaturated alkyl, cycioaikyi, cycloheteroalkyl, CO2H, C02Ci-e saturated or unsaturated alkyi, NHC1-6 saturated, unsaturated aikyi, or cycioaikyi, N(Ci-e saturated, unsaturated alkyi, or cycloalkyl)2, orCs-7aiyl or heteroaryl; each R² = CH2, S, O, NH, NC1-6 saturated, unsaturated aikyi, cycloalky, or cycioheterocyioalkyl; each X = C, CH, CH2, N, NCi-esaturated, unsaturated aikyi, or cycioaikyi, O, S, SO, or SO2; and each n = 0-6. In one embodiment, formula (XXXIV) is racecadotril.

In one embodiment, the method employs a compound of formula (XXXV):

In one embodiment, each R¹ Independently = H , CI, Br, F, I , OH, OAc, CF₃, NH₂, CN, OC1 -6 saturated , unsaturated alkyl, cycioaikyl, cycloheteroaikyi, or aryl, SC1-6 saturated, unsaturated alkyl, cycioaikyl, cycloheteroaikyi, or aryl, C1 -6 saturated alkyl, unsaturated alkyl, cycioaikyl, cycloheteroaikyi, CO2H, CO2C 1-6 saturated or unsaturated alkyl, NHC 1-6 saturated, unsaturated alkyl, or cycioaikyl, N (Ci-e saturated , unsaturated alkyl, or cycioaikyl^, or C aryl or heteroaryl. In one embodiment, R² = CH2, S, O, NH, NCi-esaturated, unsaturated alkyl, cycloalky, or cycloheterocyloalkyl. In one embodiment, each X independently = C, CH, CH2, N, NH, NCi-esaturated, unsaturated alkyl, or cycioaikyl, O, SO, or SO2. In one embodiment, each n independently = 0-6. In one embodiment, each R¹ independently = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OC1-6 saturated , unsaturated alkyl, cycioaikyl, cycloheteroaikyi, or aryl, SC1-6 saturated , unsaturated alkyl, cycioaikyl, cycloheteroaikyi, or aryl, C1-6 saturated alkyl, unsaturated alkyl, cycioaikyl, cycloheteroaikyi, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHC1-6 saturated, unsaturated alkyi, or cycioaikyl, N(Ci-e saturated , unsaturated alkyl, or cycloaikyfb, or Cs-jaryi or heteroaryl; R² = CH2, S, O, NH , NCi-ssaturated , unsaturated alkyl, cycloalky, or cycloheterocyloalkyl; each X independently = C, CH, CH2, N , NH, NCi-ssaturated, unsaturated alkyl, or cycioaikyl, O, SO, or SO2; and each n

independently = 0-6. In one embodiment, formula (XXXV) is doxazosin.

In one embodiment, the method employs a compound of formula (XXXVI):

in one embodiment, each R¹ = H, Ci, Br, F, I, OH, OAc, CF3, NH2, CN, OCi -e saturated, unsaturated alkyi, cycioaikyl, cycloheteroaikyi, or aryl, SCi -e saturated, unsaturated alkyi, cycioaikyl, cycloheteroaikyi, or aryl, C1-6 saturated alkyl, unsaturated alkyi, cycioaikyl, cycloheteroaikyi, C02H, C02C 1 -6 saturated or unsaturated alkyl, NHC1 -5 saturated , unsaturated alkyi, or cycioaikyl, N(C i-e saturated , unsaturated alkyl, or cycloalkyl)₂, Cs-7aryl or heteroaryl In one embodiment, each X = C , CH, CH₂, N , NH, NCi -esaturated, unsaturated alkyl, or cycioaikyl, O, S, SO, or SO2. In one embodiment, each n = 0-1 0. In one embodiment, each R¹ = H , Ci, Br, F, I, OH , OAc, CF3, NH₂, CN, GCi-s saturated, unsaturated alkyl, cycioaikyl, cycloheteroaikyi, or aryl, SC1 -5 saturated, unsaturated alkyi, cycioaikyl, cycloheteroaikyi, or aryl, C1-6 saturated alkyl, unsaturated alkyi, cycioaikyl, cycloheteroaikyi, C02H, C02C1 -6 saturated or unsaturated alkyi, NHC1-6 saturated, unsaturated alkyi, or cycioaikyl, N (Ci-e saturated, unsaturated alkyl, or cycioaikyl, Cs-yaryi or heteroaryl; each X = C, CH, CH2, N , NH, NCi-ssaturated, unsaturated alkyi, or cycioaikyl, O, S, SO, or SO2, and each n = 0-10. In one embodiment, formula (XXXVI) is fulvestrant.

In one embodiment, the method employs a compound of formula (XXXVI I):

in one embodiment, each R¹ independentiy = H , Ci, Br, F, I , OH , OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryi, SC1-6 saturated , unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroaikyi, CO2H , CO2C1- 6 saturated or unsaturated alkyl, NHCi-s saturated, unsaturated alkyi, or cycloalkyl, N(Ci-6 saturated, unsaturated aikyi, or cycloalkyl, or Cs-7aryl or heteroaryl. In one embodiment, each X independently = C, CH, CH2, N , NH, NCi-esaturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or S02. In one embodiment, n = 0-10.

in one embodiment, each R¹ independently = H , CI, Br, F, I , OH , OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated aikyi, cycloalkyl, cycloheteroalkyl, or aryi, SC1-6 saturated, unsaturated aikyl, cycloalkyl, cycloheteroalkyl, o aryl, C1-6 saturated alkyi, unsaturated aikyl, cycloalkyl, cycloheteroaikyi, CO2H, CO2C1- 5 saturated or unsaturated alkyl, NHC1 -8 saturated, unsaturated alkyi, or cycloalkyl, N(C i-e saturated, unsaturated alkyi, or cycloalkyl, or Cs yaryl or heteroaryl; each X independently = C, CH, CH2, N, NH, NCi-esaturated , unsaturated alkyi, or cycloalkyl, O, S, SO, or S02_; and n = 0-10. In one embodiment, formula (XXXVI I) is ethinylestradiol.

In one embodiment, the method employs a compound of formula (XXXVI II):

in one embodiment, each R¹ independently = H , CI, Br, F, i , OH , OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated aikyi, cycloalkyl, cycloheteroaikyi, or aryi, SCi-e saturated , unsaturated aikyl, cycloalkyl, cycloheteroalkyl, or aryi, C1-6 saturated alkyi, unsaturated aikyl, cycloalkyl, cycloheteroaikyi, CO2H, CO2C1- e saturated or unsaturated alkyi, NHC i-s saturated, unsaturated alkyl, or cycloalkyl, N(Ci-e saturated, unsaturated aikyl, or cycloalkyl)2, or Cs- aryl or heteroaryl. In one embodiment, each R² independently = CH2, S, O, NH, NCi-esaturated, unsaturated alkyl, cycloalky, or cycloheterocyloalkyi. in one embodiment, each X independently

S, SO, SO2, NH, NCi-esaturated, unsaturated alkyl, or cycloalkyl, or O. In one embodiment, each R independently = H , CI, Br, F, I , OH, OAc, CF₃, NH₂, CN, OCi-e saturated, unsaturated aikyi, cycloalkyl, cycloheteroalkyl, or aryi, SC1-6 saturated, unsaturated aikyl, cycloalkyl, cycloheteroalkyl, or aryl, Ci-e saturated alkyi, unsaturated aikyl, cycloalkyl, cycloheteroaikyi, CO2H , CO2C1- 6 saturated or unsaturated alkyi, NHC1-8 saturated, unsaturated alkyi, or cycloalkyl, N(Ci-e saturated, unsaturated aikyi, or cycloalkyl)2, or Cs-^aryl or heteroaryl; each R² independently = CH2, S, O, NH, NCi- ssaturated , unsaturated aikyi, cycloalky, or cycloheterocyloalkyi; and each X independently =CH2, S, SO, SO2, NH, NCi-esaturated , unsaturated alkyl, or cycloalkyl, or O. in one embodiment, formula (XXXVi il) is algestone, acetophenide or halcinonide.

In one embodiment, the method employs a compound of formula (XXXIX):

In one embodiment, each R¹ independently = H, QCt-s saturated, unsaturated alkyi, cycloalkyi, cycloheteroalkyl, or aryl, SC1-6 saturated, unsaturated aikyi, cycloalkyi, cycloheteroalkyl, or aryi, C1-6 saturated alkyl, unsaturated aikyi, cycloalkyi, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CFs, NH2, CN, CO2H, CO2C1-6 saturated or unsaturated aikyi, NHC1-6 saturated, unsaturated alkyl, or cycloalkyi, N(Ci-e saturated, unsaturated alkyl, or cycloalkyi, or Ci,-?aryl or heteroaryl. In one embodiment, each X independently = C, CH2, N, NH, O, S, SO, or S02. In one embodiment, each R¹ independently = H, OC1 -5 saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, or ary!, SCi-e saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, or ary!, C1 -6 saturated alkyl, unsaturated alkyi, cycloalkyi, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF₃, NH₂, CN, CO2H , CO2C1-B saturated or unsaturated alkyi, NHC1-6 saturated, unsaturated alkyi, or cycloalkyi, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl)2, or C^aryi or heteroaryl; and each X independently = C, CH2, N, NH, O, S, SO, or SO2 In one embodiment, formula (XXXIX) is diciazuril.

In one embodiment, the method employs a compound of formula (XXXX):

in one embodiment, each R¹ independently = CI, Br, F, I, OH, NH2, CN, CO2H, CO2C1-8 saturated or unsaturated alkyi, NHC1 ^saturated, unsaturated alkyi, or cycloalkyi, N(Ci-ssatu rated, unsaturated alkyl, or cycloalkyi)2, Cs-7aryi or heteroaryl, o 4~C!-C6H4. In one embodiment, each R² independently = Ci, Br, F, I, OH, CO2H, CN, NH₂, CON e₂, C0₂Ci-4alkyl, OCi-₈saturated, unsaturated alkyl, cycloalkyi,

heterocycioalkyl, NHCi-ssaturated or unsaturated alkyl, N(Ci-esaturated or unsaturated alky)₂, or Cs-7aryl or heteroaryl. in one embodiment, each R³ independently = C5-7 aryl or heteroaryl, 4-CI-C6H4, CO2H, CN, NH2, CON e2, C0₂Ci-4aikyl, OCi-esaturated, unsaturated alkyl, cycloalkyi, heterocycioalkyl, NHC1- esaturated or unsaturated alkyl, N(Ci-8satu ated or unsaturated alky)2, Ci-s saturated alkyl, unsaturated alkyl, cycloalkyi, cycloheteroalkyl. In one embodiment, each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-ssaturated, unsaturated alkyl, or cycloalkyi, or O. in one embodiment, n = 0-6. In one embodiment, each R¹ independently = CI, Br, F, i, OH, NH2, CN, CO2H, CO2C1-8 saturated or unsaturated alkyl, NHCi-ssaturated, unsaturated alkyl, or cycloalkyi, N(Ci-esatu rated, unsaturated alkyl, or cycloalkyi)2, Cs-yaryl or heteroaryl, or 4-CI-C_eH4: each R² independently = CI, Br, F, I, OH, CO2H, CN, NH₂, CONMe2, C02Ci- aikyi, OCi-ssatu rated, unsaturated aikyi, cycloalkyi, heterocycioalkyl, NHCi-ssaturated or unsaturated aikyi, N(Ci-ssaturated or unsaturated alky)₂, or Cs-yaryi or heteroaryl: In one embodiment, each R³ independently = C5-7 aryl or heteroaiyi, 4-CI-C₆H4, CO2H, CN, NH₂, CON e₂, C0₂Ci-4alkyl, OC ssaturated, unsaturated aikyi, cycloalkyi, heterocycioalkyl, NHCi-asaturated or unsaturated alkyl, N(Ci- ssaturated or unsaturated alky)₂, C1-6 saturated alkyi, unsaturated aikyi, cycloalkyi, cycloheteroalkyl; and each X independently = C, CH, CH2, S, SO, SG2, N, NH, NC i-ssaturated, unsaturated alkyi, or cycioaikyi, or O. In one embodiment, formula (XXXX) is loperamide.

In one embodiment, the method employs a compound of formula (XXXXI):

in one embodiment, each R¹ independently = H, CI, Br, F, I, OH, NH2, CN, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHCi-esaturated, unsaturated alkyi, or cycioaikyi, N(Ci-asatu rated, unsaturated alkyi, or cycloalkyi)2, OC1-6 saturated, unsaturated alkyi, cycioaikyi, cycioheteroalkyi, or aryi, SC1-6 saturated, unsaturated alkyi, cycioaikyi, cycioheteroalkyi, or aryi, C1-6 saturated alkyi, unsaturated alkyi, cycioaikyi, or cycioheteroalkyi, C5-7 aryi or heteroaryl. in one embodiment, each X independently = C, CH, CH2, S, SO, SO2, NH, NCi-ssaturated, unsaturated alkyi, or cycioaikyi, or O. in one embodiment, n = 0-6. In one embodiment, each R¹ independently = H, Ci, Br, F, I , OH, NH2, CN, CO2H, CQ2C1-6 saturated or unsaturated alkyi, NHC1 ^saturated, unsaturated alkyi, or cycioaikyi, N(Ci ^saturated, unsaturated alkyi, or cycioaikyi, OC1 -6 saturated, unsaturated alkyi, cycioaikyi, cycioheteroalkyi, or aryi, SCi-e saturated, unsaturated alkyi, cycioaikyi, cycioheteroalkyi, or aryi, Ci e saturated alkyi, unsaturated alkyi, cycioaikyi, or cycioheteroalkyi, C5-7 aryi or heteroaryl; each X independently = C, CH, CH₂, S, SO, SO2, ΝΗ,Ν, NCi- ssaturated , unsaturated alkyi, or cycioaikyi, o O; and n = 0-6. In one embodiment, formula (XXXXI) is raloxifene.

In one embodiment, the method employs a compound of formula (XXXXI I):

R R

in one embodiment, each R¹ independently = H, CI, Br, F, i, OH, OAc, CF₃, NH₂, CN, OCi-e saturated, unsaturated alkyi, cycioaikyi, cycioheteroalkyi, or aryi, SC1-6 saturated, unsaturated alkyi, cycioaikyi, cycioheteroalkyi, o aryi, C1 -5 saturated alkyi, unsaturated alkyi, cycioaikyi, cycioheteroalkyi, CO2H, CO2C1- 5 saturated or unsaturated alkyi, NHC1 -8 saturated, unsaturated alkyi, or cycioaikyi, N(Ci-e saturated, unsaturated alkyi, or cycioaikyi, or Cs yaryl or heteroaryl. In one embodiment, each X independently = C or N. In one embodiment, each R independently = H, Ci, Br, F, i, OH, OAc, CF₃, NH₂, CN, OC1-6 saturated, unsaturated alkyi, cycioaikyi, cycioheteroalkyi, or aryi, SCi-e saturated, unsaturated alkyi, cycioaikyi, cycioheteroalkyi, or aryi, C1-6 saturated alkyi, unsaturated alkyi, cycioaikyi, cycioheteroalkyi, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated aikyl, or cycioaikyi, N(Ci-e saturated, unsaturated alkyi, or cycioaikyi, or Cs-raryi or heteroaryl; and each X independently = C or N. in one embodiment, formula (XXXX II) is mitotane.

In one embodiment, the method employs a compound of formula (XXXXI 11):

In one embodiment, each R¹ independently = H , CI, Br, F, i , OH , OAc, CFa, Nh½, GN, OC1-6 saturated, unsaturated alkyi, cycioaikyi, cycloheteroaikyi, or aryl, SC1-6 saturated , unsaturated alkyl, cycioaikyi, cycloheteroaikyi, or aryl, Ci-e saturated alkyi, unsaturated alkyl, cycioaikyi, cycloheteroaikyi, CO2H, CO2C1- e saturated or unsaturated alkyi, NHC1-6 saturated, unsaturated alkyi, or cycioaikyi, N(Ci-e saturated, unsaturated alkyi, or cycioalkyl)2, or Cs-yaryl or heteroaryi. In one embodiment, each X independently = CH, CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated alkyl, or cycioaikyi, or O. In one embodiment, each R¹ independently = H, Ci, Br, F, I, OH , OAc, CF3, H2, CN, OC1-6 saturated, unsaturated alkyl, cycioaikyi, cycloheteroaikyi, or aryl, SC1-6 saturated, unsaturated alkyi, cycioaikyi, cycloheteroaikyi, or aryl, Ci-e saturated aikyl, unsaturated alkyi, cycioaikyi, cycloheteroaikyi, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHC1 -6 saturated, unsaturated alkyi, or cycioaikyi, N(Ci-6 saturated, unsaturated alkyi, or cycioaikyi, or Cs-yary! or heteroaryi; and each X independently = CH, CH2, S, S(O), S(02), NH, NCi- esaturated , unsaturated aikyi, or cycioaikyi, o O. in one embodiment, formula (XXXXI Ii) is nitrofural, nifurtomix, or furazolidone.

In one embodiment, the method emplo compound of formula (XXXXIV):

in one embodiment, each R¹ independently = H , OC1-6 saturated, unsaturated alkyi, cycioaikyi, cycloheteroaikyi, C1-6 saturated alkyl, unsaturated aikyi, cycioaikyi, cycloheteroaikyi, CI, Br, F, I, OH, OAc, Ac, CF₃, NH₂, CN, NO2, C(0)CH₂OAc, CO2H , CO2C1-6 saturated or unsaturated alkyi, NHC1-6 saturated, unsaturated alkyi, or cycioaikyi, N(Ci-e saturated, unsaturated alkyl, or cycioaikyi, or Cs-yaryi or heteroaryi. in one embodiment, each X independently =CH, CH2, NH, NCi-asaturated, unsaturated alkyl, or cycioaikyi, O, S, SO, or SO2 In one embodiment, n = 0-6. in one embodiment, each R¹ independently = H, OC1-6 saturated, unsaturated aikyi, cycioaikyi, cycloheteroaikyi, C1-6 saturated alkyi, unsaturated aikyl, cycioaikyi, cycloheteroaikyi, Ci, Br, F, i , OH, OAc, Ac, CF₃, NH₂, CN , NO2, C(0)CH₂OAc, CO2H , CO2C1 saturated or unsaturated alkyl, NHCi-e saturated , unsaturated alkyl, or cycioaikyi, N(Ci-6 saturated, unsaturated aikyi, or cycioalkyl)2, or Cs-yaryl or heteroaryi; each X independently =CH, CH2, NH, NCi- esaturated , unsaturated aikyi, or cycioaikyi, O, S, SO, or S02_; and n = 0-6. In one embodiment, formula (XXXXiV) is THIP (gaboxadol).

In one embodiment, the method emplo compound of formula (XXXXV):

in one embodiment, each R¹ independently = H , CI, Br, F, i , OH , OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated aikyi, cycioaikyi, cycloheteroaikyi, or aryl, SC1-6 saturated , unsaturated aikyl, cycioaikyi, cycloheteroaikyi, o aryi, Ct-s saturated alkyi, unsaturated aikyl, cycioaikyi, cycloheteroaikyi, CO2H, CO2C1- 6 saturated or unsaturated alkyi, NHC1 -8 saturated, unsaturated alkyi, or cycioaikyi, N(Ci-e saturated, unsaturated alkyi, or cycioaikyi, or Cs ?aryl or heteroaryi. In one embodiment, each X independently = CH, CH2, S, SO, SO2, N, NH, NCi-ssaiuraied, unsaiuraied alkyi, or cycioaikyi, or O. In one embodiment, n = 0-6. In one embodiment, each R¹ independently = H, CI, Br, F, i, OH, OAc, CF₃, NH₂, CN, OC1-6 saturated, unsaturated alkyi, cycioaikyi, cycioheteroalkyl, or aryi, SC1-6 saturated, unsaturated alkyi, cycioaikyi, cycioheteroalkyl, or aryl, C1-6 saturated alkyi, unsaturated alkyi, cycioaikyi, cycioheteroalkyl, CO2H, CO2C1 -6 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated alkyi, or cycioaikyi, N(Ci-e saturated, unsaturated alkyi, or cycioaikyi, or Cs-yaryi or heteroaryi; each X independently = CH, CH2, S, S(O), S(02), N, NH, NCi-ssaturated, unsaturated alkyi, or cycioaikyi, or O; and n = 0-6, in one

embodiment, formula (XXXXV) is D,L-mevalonic acid lactone.

In one embodiment, the method employs a compound of formula (XXXXVI):

In one embodiment, each R¹ independently = H, CI, Br, F, I, OH, OAc, CF3, NH2, GN, OC1-6 saturated, unsaturated alkyi, cycioaikyi, cycioheteroalkyl, or aryi, SC1-6 saturated, unsaturated aikyl, cycioaikyi, cycioheteroalkyl, or aryi, Ci-e saturated alkyi, unsaturated aikyl, cycioaikyi, cycioheteroalkyl, CO2H, CO2C1- 6 saturated or unsaturated alkyi, NHC1-8 saturated, unsaturated alkyi, or cycioaikyi, N(Ci-e saturated, unsaturated alkyi, or cycloalkyl)2, or Cs-7aryl or heteroaryi. In one embodiment, R² = CI, Br, F, I, OH, CO2H, CN, NH2, CON e2, C02Ci-4alkyl, OCi-asatu rated, unsaturated alkyi, cycioaikyi, heterocycloalkyl, NHCi-3saturated or unsaiuraied alkyi, N(Ci-ssaturated or unsaturated alky)2, or Cs-yaryi or heteroaryi. In one embodiment, each X independently = C, CH, CH2, S, S(O), S(02), N, NH, NCi-ssaturated, unsaturated aikyl, or cycioaikyi, orO. in one embodiment, each n independently = 0-6. In one

embodiment, each R¹ independently = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated alkyi, cycioaikyi, cycioheteroalkyl, or aryi, SC1-6 saturated, unsaturated aikyl, cycioaikyi, cycioheteroalkyl, o aryl, C1-6 saturated alkyi, unsaturated aikyl, cycioaikyi, cycioheteroalkyl, CO2H, CO2C1- 6 saturated or unsaturated alkyi, NHC1-8 saturated, unsaturated alkyi, or cycioaikyi, N(Ci-e saturated, unsaturated alkyi, or cycloalkyl)₂, or C₅-7aryl or heteroaryi; R² = Ci, Br, F, I, OH, CO2H, CN, NH₂, CON e₂, C02C i-4aik i, OC i-ssatu ated, unsaturated alkyi, cycioaikyi, heterocycloalkyl, NHC-i-esaturated or unsaturated alkyi, N(Ci-esaturated or unsaturated alky)2, or C5-7ar i or heteroaryi; each X independently = C, CH, CH₂, S, SiO), S(0₂), NH, NCi-ssaturated, unsaturated aikyl, or cycioaikyi, or O; and each n independently = 0-6. In one embodiment, formula (XXXXVI) is fluspirilen.

In one embodiment, the method employs a compound of formula (XXXXVI I):

In one embodiment, each R¹ independently = H, CI, Br, F, i, OH, OAc, CF3, NH2, CN, OCi-e saturated, unsaturated aikyl, cycioaikyi, cycioheteroalkyl, or aryi, SC1-6 saturated, unsaturated aikyl, cycioaikyi, cycloheteroalkyl, or aryi, Ci-e saturated a!kyl, unsaturated aikyi, cycloalkyi, cycioheteroalkyi, CO2H, CO2C1- 6 saturated or unsaturated a!kyl, NHC1-6 saturated, unsaturated aikyi, or cycloalkyi, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl)2, or Cs-yaryl or heteroaryl. In one embodiment, R² = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, or aryi, SC1-6 saturated , unsaturated alkyl, cycloalkyi, cycloheteroalkyl, or aryi, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, CO2H, CO2C1-6 saturated or unsaturated aikyi, NHC1-6 saturated, unsaturated alkyl, or cycloalkyi, N(Ci-e saturated , unsaturated alkyl, or cycloalkyi, or Canary! or heteroaryl. In one embodiment, each X independently = C, CH , CH2, S, NH, N , NCi-esaturated , unsaturated alkyl, or cycloalkyi, or O. In one embodiment, each n independently = 0-6. in one embodiment, each R^¾ independently = H, CI, Br, F, I, OH, OAc, CF3, NH₂, CN, OCi-e saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, o aryi, SC1 -5 saturated, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, or aryi, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, CO2H, CQ2C1 -8 saturated or unsaturated alkyl, NHC1 -8 saturated, unsaturated alkyl, or cycloalkyi, N(Ci-e saturated, unsaturated alkyl, or cycloalkyi, or C^aryi or heteroaryl: R² = H, CI, Br, F, L OH, OAc, CF₃, NH₂, CN, OCi-₆ saturated, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, or aryi, SC1-6 saturated , unsaturated aikyi, cycloalkyi, cycloheteroalkyl, o aryi, Ci-e saturated alkyl, unsaturated aikyi, cycloalkyi, cycioheteroalkyi, CO2H, CO2C1- 6 saturated or unsaturated alkyl, NHC1-8 saturated, unsaturated aikyi, or cycloalkyi, N(Ci-e saturated, unsaturated aikyi, or cycloalkyi:, or Cs-yaryl or heteroaryl; each X independently = C, CH, CH2, S, NH, NCi-ssaturated , unsaturated aikyi, or cycloalkyi, or O; and each n independently = 0-6. In one

embodiment, formula (XXXXVH) is ezetimibe.

In one embodiment, the method employs a compound of formula (XXXXVI II):

in one embodiment, each R¹ independently = H, CI, Br, F, i , OH , OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated aikyi, cycloalkyi, cycioheteroalkyi, or aryi, SCi-e saturated , unsaturated aikyi, cycloalkyi, cycloheteroalkyl, or aryi, C1-6 saturated aikyi, unsaturated aikyi, cycloalkyi, cycioheteroalkyi, CO2H, CO2C1- 6 saturated or unsaturated aikyi, NHC1-6 saturated, unsaturated aikyi, or cycloalkyi, N(Ci-e saturated, unsaturated aikyi, In one embodiment, or cycloalkyi, ^Qj" Cs yaryl or heteroaryl. In one embodiment, each X independently = C, CH, CH2, S, SO, S02,N, NH, NCi-esaturated , unsaturated aikyi, or cycloalkyi, or O. In one embodiment, each R¹ independently = H, CI, Br, F, i , OH , OAc, CF3, NH2, CN, OCi-e saturated, unsaturated aikyi, cycloalkyi, cycloheteroalkyl, or aryi, SC1-6 saturated, unsaturated aikyi, cycloalkyi, cycloheteroalkyl, o aryi, Ci-e saturated aikyi, unsaturated aikyi, cycloalkyi, cycloheteroalkyl, CO2H , CO2C1- e saturated or unsaturated aikyi, NHC i-s saturated, unsaturated alkyl, or cycloalkyi, N(Ci-e saturated, unsaturated aikyi, In one embodiment, or cycloalkyi, ^or Cs ?aryl or heteroaryl; and ach X independently = C, CH, CH2, S, SO, SO2, NH, NCi-esaturated, unsaturated alkyl, or cycloalkyi, o O. In one embodiment, formula (XXXXVII I) is triclosan.

In one embodiment, the method employs a compound of formula (XXXXIX):

In one embodiment, each R¹ independently = H, CI, Br, F, I, OH, OAc, CFs, NH2, CN, OC1-6 saturated, unsaturated aikyl, cydoalkyi, cycioheteroalkyi, or aryi, SC1-6 saturated, unsaturated aikyl, cydoalkyi, cycloheteroalkyl, or aryi, C1-6 saturated aikyl, unsaturated aikyl, cydoalkyi, cycioheteroalkyi, CO2H, CO2C1- δ saturated or unsaturated aikyl, NHC1 -8 saturated, unsaturated alkyi, or cydoalkyi, N(Ci-e saturated, unsaturated alkyi, or cycloalkyl)2, or Cs yaryl or heteroaryl. In one embodiment, each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated alkyi, or cydoalkyi, or O. In one embodiment, n = 0-6.

In one embodiment, each R independently = H, Ci, Br, F, I, OH, OAc, CF3, NH₂, CN, OCi-e saturated, unsaturated aikyl, cydoalkyi, cycloheteroalkyl, or aryi, SCi-e saturated, unsaturated aikyl, cydoalkyi, cycloheteroalkyl, or aryi, C1 -6 saturated alkyi, unsaturated alkyi, cydoalkyi, cycioheteroalkyi, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated aikyl, or cydoalkyi, N(Ci-e saturated, unsaturated aikyl, or cycioaikyl)2, or Gs-raryi or heteroaryl; each X independently = C, CH, CH2, S, SO, SO2, NH, NCi-ssaturated, unsaturated alkyi, or cydoalkyi, or O; and n = 0-8. In one embodiment, formula (XXXXIX) is suloctidil.

In one embodiment, the method employs a compound of formula (L):

in one embodiment, each R¹ independently = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated alkyi, cydoalkyi, cycloheteroalkyl, or aryi, SCi-e saturated, unsaturated aikyl, cydoalkyi, cycloheteroalkyl, or aryi, C1-6 saturated aikyl, unsaturated aikyl, cydoalkyi, cycloheteroalkyl, CO2H , CO2C1- 6 saturated or unsaturated aikyl, NHC1 -8 saturated, unsaturated alkyi, or cydoalkyi, N(Ci-e saturated, unsaturated alkyi, or cycioalkyl)2, or Cs yaryl or heteroaryl. In one embodiment, each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated aikyl, or cydoalkyi, or O. In one embodiment, each n independently = 0-8. In one embodiment, each R¹ independently = H, CI, Br, F, i, OH, OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated aikyl, cydoalkyi, cycloheteroalkyl, or aryi, SC1-6 saturated, unsaturated alkyi, cydoalkyi, cycioheteroalkyi, or aryi, C1-6 saturated alkyi, unsaturated alkyi, cydoalkyi, cycloheteroalkyl, CO2H, CO2C 1-6 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated aikyl, or cydoalkyi, N(Ci-e saturated, unsaturated aikyl, or cycloalkyl)2, or Cs-yaryl or heteroaryl; each X

independently = C, CH, CH2, S, SO, SO2, NH, NCi-esaturated, unsaturated alkyi, or cydoalkyi, or O; and each n independently = 0-8. In one embodiment, formula (L) is bromhexine.

In one embodiment, the method employs a compound of formula (LI):

in one embodiment, each R¹ independently = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, GC1-6 saturated, unsaturated aikyi, cycioaikyl, cycloheteroalkyl, or aryi, SC1-6 saturated, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, or aryi, C1-6 saturated alkyi, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, CO2H, CO2C1- 6 saturated or unsaturated alkyl, NHCi-s saturated, unsaturated alkyi, or cycioaikyl, N(Ci-6 saturated, unsaturated aikyi, or cycioaikyl, or Cs-yaryl or heteroaryi. In one embodiment, each X independently = C, CH, CH2, S, SO, SO2, NH2, N, NH, NCi-8saturated, unsaturated alkyl, or cycioaikyl, o O. in one embodiment, each n independently = 0-6, In one embodiment, each R¹ independently = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated alkyl, cycioaikyl, cycloheteroaikyl, or aryi, SCi-e saturated, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, or aryi, C1-6 saturated alkyi, unsaturated alkyl, cycioaikyl, cycloheteroaikyl, CO2H, CO2C1-6 saturated or unsaturated aikyi, NHC1-6 saturated, unsaturated alkyl, or cycioaikyl, N(Ci-e saturated, unsaturated alkyl, or cycioaikyl, or Cs-yaryl or heteroaryi; each X independently = C, CH, CH2, S, SO, SO2, NH2, NH, NCi-esaturated, unsaturated alkyl, or cycioaikyl, or O; and each n independently = 0-6. In one embodiment, formula (LI) is ceftazidime.

In one embodiment, the method employs a compound of formula (Lll):

in one embodiment, each R¹ = H, Ci, Br, F, I, OH, OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated alkyl, cycioaikyl, cycloheteroaikyl, or aryi, SC1-6 saturated, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, or aryi, C1-6 saturated alkyl, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, CO2H, CO2C1-6 saturated or unsaturated aikyi, NHC1-6 saturated, unsaturated alkyi, or cycioaikyl, N(Ci-e saturated, unsaturated alkyl, or cycioaikyl, or Cs-yaryi or heteroaryi. in one embodiment, each X independently = C, CH, CH2, S, SO, SO2, NH, N, NCi-ssaturated, unsaturated alkyl, or cycioaikyl, or O. In one embodiment, each n independently = 0-6. In one embodiment, each R¹ = H, CI, Br, F, i, OH, OAc, CF₃, NH₂, CN, OCi_-6 saturated, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, or aryi, SC1-6 saturated, unsaturated alkyl, cycioaikyl, cycloheteroaikyl, or aryi, Ci-e saturated alkyl, unsaturated aikyi, cycioaikyl, cycloheteroalkyl, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycioaikyl, N(Ci-e saturated, unsaturated alkyi, or cycioaikyl, or Cs-7aryi or heteroaryi; each X independently = C, CH, CH2, S, SO, SO2, NH, NCt-ssaturated, unsaturated alkyi, or cycioaikyl, or O; and each n independently = 0-6. in one embodiment, formula (Lll) is loratadine,

In one embodiment, the method employs a compound of formula (LIH):

in one embodiment each R¹ independently = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OC1 -5 saturated, unsaturated alkyi, cycioalkyi, cycioheteroalkyi, or aryi, SC1-6 saturated, unsaturated aikyl, cycioalkyi, cycioheteroalkyi, or aryi, C1 -5 saturated alkyl, unsaturated aikyl, cycioalkyi, cycioheteroalkyi, CO2H, CO2C1- 5 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated alkyi, or cycioalkyi, N(Ci-e saturated, unsaturated alkyi, or cycioalkyl)2, or Cs-yaryl or heteroaryi. in one embodiment, each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated aikyl, or cycioalkyi, or O. In one embodiment, each n independently = 0-6. In one embodiment, each R¹ independently = H, CI, Br, F, 1, OH, OAc, CFs, NH2, CN, OC1-6 saturated, unsaturated alkyi, cycioalkyi, cycioheteroalkyi, or aryi, SC1-6 saturated, unsaturated alkyi, cycioalkyi, cycioheteroalkyi, or aryi, C1-6 saturated alkyi, unsaturated alkyl, cycioalkyi, cycioheteroalkyi, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated alkyl, or cycioalkyi, N(Ci-e saturated, unsaturated aikyl, or cycloalkyl)2, or Cs-jaryi or heteroaryi; each X

independently = C, CH, CH2, S, SO, SO2, NH, NCi-esaturated , unsaturated alkyl, or cycioalkyi, or O; and each n independently = 0-6. In one embodiment, formula (LIU) is oxandrolone.

In one embodiment, the method employs a compound of formula (LIV):

in one embodiment, each R¹ independently = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated alkyi, cycioalkyi, cycioheteroalkyi, or aryi, SC1-6 saturated, unsaturated aikyl, cycioalkyi, cycioheteroalkyi, or aryi, C1 -5 saturated alkyl, unsaturated alkyl, cycioalkyi, cycioheteroalkyi, CO2H, CO2C1- 5 saturated, unsaturated alkyi, or aryi, CONH2, CO2NHC1-6 saturated, unsaturated alkyl or aryi, C02N(Ci-e saturated, unsaturated alkyl or aryl)2, NHCi-s saturated, unsaturated alkyl, or cycioalkyi, N(Ci-e saturated, unsaturated alkyi, or cycioalkyi, or Cs yaryl or heteroaryi. In one embodiment, each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated alkyl, or cycioalkyi, or O. In one embodiment, each n independently = 0-6. In one embodiment, each R¹ independently = H, CI, Br, F, I, OH, OAc, CFs, NH2, CN, OC1-6 saturated, unsaturated alkyi, cycioalkyi, cycioheteroalkyi, or aryi, SC1-6 saturated, unsaturated alkyi, cycioalkyi, cycioheteroalkyi, or aryi, C1-6 saturated aikyl, unsaturated alkyl, cycioalkyi, cycioheteroalkyi, CO2H, CO2C1-6 saturated, unsaturated alkyl, or aryi, CONH2, CO2NHC1-6 saturated, unsaturated alkyi or aryi, C02 (Ci-6 saturated, unsaturated alkyi or aryi)2, NHCI-B saturated, unsaturated alkyi, or cycioalkyi, N(Ci-e saturated, unsaturated alkyl, or cycloaikyi)2, or Cs-jaryi or heteroaryi; each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-ssaturated, unsaturated aikyl, or cycioalkyi, or O; and each n independently = 0-6. In one embodiment, formula (LIV) is darifenacin.

In one embodiment, the method employs a compound of formula (LV):

in one embodiment each, R¹ independently = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OCi-e saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryi, SC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, Ci-e saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CO2H, COC1-8 alkyl unsaturated alkyl, or aryl, CO2C1-6 saturated, unsaturated alkyl, or aryi, CONH2, CO2NHC1-B saturated, unsaturated alkyl or aryi, C02N(Ci-s saturated, unsaturated alkyl or aryi)2, NHCi-s saturated, unsaturated alkyl, or cycloalkyl, N(Ci-6 saturated, unsaturated alkyl, or cycloalkyl, or Cs-7aryi or heteroaryl. in one embodiment, each X independently = C, CH, CH2, S, SO, SO2, N, NH, NC i-ssaturated, unsaturated alkyl, or cycloalkyl, or O. In one embodiment, each n independently = 0-6. In one

embodiment each, R¹ independently = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryi, SCi-e saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, o aryl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CO2H, COC1-8 alkyl unsaturated aikyi, or aryl, CO2C1-6 saturated, unsaturated alkyl, or aryl, CONH2, CO2NHC1-6

saturated, unsaturated alkyl o aryl, C02N(Ci-e saturated, unsaturated alkyl or aryl)2, NHC1-6 saturated, unsaturated aikyi, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl, or C5-7ar i or heteroaryl; each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi ^saturated, unsaturated alkyl, or cycloalkyl, or O; and each n independently = 0-6. In one embodiment, formula (LV) is ganaxolone.

In one embodiment, the method employs a compound of formula (LVI):

in one embodiment, each R¹ independently = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OCi-e saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryi, SC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, o aryl, Ci-e saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CO2H, COC1-8 alkyl unsaturated alkyl, or aryl, CO2C1-6 saturated, unsaturated alkyl, or aryl, CONH2, CO2NHC1-B saturated, unsaturated alkyl or aryi, C02N(Ci-6 saturated, unsaturated alkyl or aryi)2, NHC1-6 saturated, unsaturated aikyi, or cycloalkyl, N(Ci-6 saturated, unsaturated alkyl, or cycloalkyl, or Cs-7aryi or heteroaryl. in one embodiment, each X independently = C, CH, CH2, S, SO, SO2, N, NH, NC i-ssaturated, unsaturated aikyi, or cycloalkyl, or O. In one embodiment, each n independently = 0-6. In one

embodiment, each R¹ independently = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated aikyi, cycloalkyl, cycloheteroalkyl, or aryi, SCi-e saturated, unsaturated aikyi, cycloalkyl, cycloheteroalkyl, or aryl, C1-6 saturated alkyl, unsaturated aikyi, cycloalkyl, cycloheteroalkyl, CO2H, COC1-8 alkyl unsaturated aikyi, or aryl, CO2C1-6 saturated, unsaturated alkyl, or aryl, CONH2, CO2NHC1-6

saturated, unsaturated alkyl o aryl, C02N(Ci-e saturated, unsaturated alkyl or aryl)2, NHC1-6 saturated, unsaturated aikyi, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl, or Cs-7aryl or heteroaryl; each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi ^saturated, unsaturated alkyl, or cycloalkyl, or O; and each n independently = 0-6, In one embodiment, formula (LVi) is toiperisone. In one embodiment, the method employs a compound of formula (LVi l):

in one embodiment, each R¹ independently = H, CI, Br, F, I, OH , OAc, CF?,, NH2, GN, OC1-6 saturated, unsaturated alkyi, cycloalkyl, cycioheteroalkyi, or aryi, SC1-6 saturated, unsaturated aikyl, cycloalkyl, cycloheteroalkyl, or aryi, C1-6 saturated alkyi, unsaturated aikyl, cycloalkyl, cycloheieroalkyl, CO2H , COC1-8 alkyi unsaturated aikyl, or aryi, CO2C1-6 saturated , unsaturated aikyl, or aryi, CONH2, CO2NHC1-6 saturated , unsaturated alkyi or aryi, CQ2N(Ci-8 saturated , unsaturated alkyi or aryi)2, NHCi-s saturated , unsaturated alkyi, or cycloalkyl, N(Ci-e saturated, unsaturated alkyi, or cycloalkyl, or Cs-yaryi or heteroaryl. in one embodiment, each X = C, CH, CH2, S, SO, SO2, N , NH, NCi-asaturated, unsaturated aikyl, or cycloalkyl, or O. in one embodiment, each n independently = 0-6. In one embodiment, each R¹ independently = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated aikyl, cycloalkyl, cycloheteroalkyl, or aryi, SC1-6 saturated, unsaturated alkyi, cycloalkyl, cycioheteroalkyi, or aryi, C1-6 saturated aikyl, unsaturated alkyi, cycloalkyl, cycloheteroalkyl, CO2H, COC1-8 aikyl unsaturated aikyl, or aryi, CO2C1-6 saturated, unsaturated alkyi, or aryi, CONH2, CO2NHC1-6 saturated, unsaturated aikyl or aryi, C02lM(Ci-e saturated, unsaturated aikyl or aryl)2, NHC1-6 saturated, unsaturated aikyl, or cycloalkyl, N(Ci -e saturated , unsaturated aikyl, or cycloalkyl, or Cs-yaryi or heteroaryl; each X = C, CH, CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated aikyi, or cycloalkyl, or O; and each n independently = 0-6. In one embodiment, formula (LVH) is dosulepin.

In one embodiment, the method employs a compound of formula (LVIII):

In one embodiment, each R¹ independently = H, CI, Br, F, I , OH , OAc, CF3, NH2, CN, OCi-e saturated, unsaturated aikyl, cycloalkyl, cycloheteroalkyl, or aryi, SC1-6 saturated , unsaturated aikyl, cycloalkyl, cycloheteroalkyl, or aryi, Ci-e saturated alkyi, unsaturated aikyl, cycloalkyl, cycloheieroalkyl, CO2H, COC1-8 aikyl unsaiuraied aikyl, or aryi, CO2C1-6 saturated, unsaiuraied alkyi, or aryi, CONH2, CO2NHC1-5 saturated , unsaiuraied alkyi or aryi, C02N(Ci-8 saturated , unsaiuraied alkyi or aryi)2, NHC1 -8 saturated , unsaiuraied alkyi, or cycloalkyl, N(Ci-e saturated, unsaiuraied aikyl, or cycloalkyl, or Cs-yaryi or heteroaryl. in one embodiment, each R² independently = CI, Br, I , or F. In one embodiment, each X independently = C, CH, or N. In one embodiment, n = 0-6. In one embodiment, each R¹ independently = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN , OC1-6 saturated, unsaiuraied aikyl, cycloalkyl, cycioheteroalkyi, or aryi, SC1-6 saiuraied , unsaturated alkyi, cycloalkyl, cycioheteroalkyi, or aryi, C1-6 saturated aikyl, unsaturated alkyi, cycloalkyl, cycioheteroalkyi, CO2H, COC1-8 aikyl unsaturated alkyi, or aryi, CO2C1-6 saturated , unsaiuraied aikyl, or aryi, CONH2, CO2NHC1-6 saturated, unsaturated alkyi or aryi, C02N(Ci-6 saturated, unsaturated a!kyl or aryl)2, NHCi-s saturated, unsaturated a!kyl, or cycioalkyi, N(Ci-6 saturated, unsaturated alkyi, or cycioalkyi)2, or Cs-yaryl or heteroaryl; each X independently = C, CH, or N; and n = 0- 6, In one embodiment, formula (LViii) is amprolium chloride.

In one embodiment, the method employs a compound of formula (LIX):

in one embodiment, each R¹ = H, Ci, Br, F, I, OH, OAc, CFs, Nh , CN, OCi-e saturated, unsaturated alkyi, cycioalkyi, cycloheferoaikyl, or aryl, SCi-e saturated, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, o aryl, Ci-6 saturated alkyl, unsaturated alkyl, cycioalkyi, cycloheteroalkyl, CO2H, COC 1-8 alkyl unsaturated alkyi, or aryl, CO2C1-6 saturated, unsaturated alkyl, o aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyl or ary!, C02 (Ci-6 saturated, unsaturated alkyl or aryi)2, NHC1-8 saturated, unsaturated alkyi, or cycioaikyl, N(Ci-6 saturated, unsaturated alkyl, or cycioaikyl, or Cs-7aryl or heteroaryl. In one embodiment, each X = CH, CH2, S, N, NH, NCi-esaturated, unsaturated alkyi, or cycioaikyl, or O. In one embodiment, each R = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated alkyl, cycioalkyi, cycloheteroalkyl, or aryi, SCi-e saturated, unsaturated aikyi, cycioaikyl, cycloheteroalkyl, or aryl, C1-6 saturated alkyl, unsaturated aikyi, cycioalkyi, cycloheteroalkyl, CO2H, COCi-s alkyi unsaturated alkyi, or aryl, CO2C1-6 saturated, unsaturated alkyl, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyl or aryl, C02 (Ci-e saturated, unsaturated alkyi or aryi)2, NHCi-s saturated, unsaturated alkyl, or cycioaikyl, N(Ci-e saturated, unsaturated aikyi, or cycioalkyi, or Cs-yaryl or heteroaryl; and each X =CH, CH2, S,N, NH, NCi- ssaturated, unsaturated alkyi, or cycioalkyi, or O. in one embodiment, formula (LIX) is butabarbitai.

In one embodiment, the method empl nd of formula (LX):

in one embodiment, each R¹ independently = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OC1 -5 saturated, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, or aryi, SC1-6 saturated, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, o aryl, C1 -5 saturated alkyl, unsaturated alkyl, cycioalkyi, cycloheteroalkyl, CO2H, COC1-8 alkyi unsaturated alkyi, or aryl, CO2C1-6 saturated, unsaturated alkyl, o aryl, CONH2, CO2NHC1-B saturated, unsaturated alkyi or aryi, CQ2N(Ci-8 saturated, unsaturated alkyl or aryl)2, NHCi-s saturated, unsaturated alkyi, or cycioaikyl, N(Ci-e saturated, unsaturated alkyi, or cycloalkyl)2, or Cs-raryi or heteroaryl. in one embodiment, each X independently = CH, CH2, S, SO, SO2, N, NH, NCi-oSaturated, unsaturated aikyi, or cycioaikyl, or O. In one embodiment, each R independently = H, CI, Br, F, i, OH, OAc, CF3, NH2, CN, OCi-e saturated, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, or aryi, SC1-3 saturated, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, or aryi, C1-6 saturated alkyl, unsaturated alkyl, cycioalkyi, cycloheteroalkyl, CO2H, COC i-s aikyi unsaturated alkyl, or aryi, CO2C1-6 saturated, unsaturated alkyi, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyl o aryl, C02N(Ci-6 saturated, unsaturated alkyi or aryi)2, NHCi-s saturated, unsaturated alkyi, or cycioaikyl, N(Ci-e saturated, unsaturated alkyl, or cycioalkyi, or Cs-7aryl or heteroaryl; and each X independently = CH, CH2, S, SO, SO2, N, NH, NCi- esaturated, unsaturated alkyi, or cycioaikyl, or O. in one embodiment, formula (LX) is amantadine.

In one embodiment, the method employs a compound of formula (LXI): X

X

in one embodiment each R¹ independently = H, CI, Br, F, I , OH, OAc, CF3, NH2, CN, OC1 -5 saturated, unsaturated alkyi, cycioalkyi, cycioheteroalkyi, or aryi, SC1-6 saturated , unsaturated aikyl, cycioalkyi, cycioheteroalkyi, or aryi, C1 -5 saturated alkyl, unsaturated aikyl, cycioalkyi, cycioheteroalkyi, CO2H, COC1-8 alkyi unsaturated alkyi, or aryi, CO2C1 6 saturated, unsaturated alkyl, or aryi, CONH2, CO2NHC1-6

saturated , unsaturated alkyl or aryi, C02N(Ci-6 saturated, unsaturated alkyl o aryi)2, NHC1-6 saturated, unsaturated alkyi, or cycioalkyi, N(Ci-e saturated, unsaturated alkyi, or cycloalkyl)2, or C^aryi or heteroaryl. in one embodiment, each R² independently = CI, Br, I, or F. In one embodiment, each X independently = CH, CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated alkyl, or cycioalkyi, or O. In one embodiment, each n independently = 0-6. in one embodiment, each R¹ independently = H , CI, Br, F, i, OH, OAc, CF3, NH2, CN, OC1-6 saturated , unsaturated alkyl, cycioalkyi, cycioheteroalkyi, or aryi, SC1-6 saturated , unsaturated alkyl, cycioalkyi, cycioheteroalkyi, or aryi, C1-6 saturated alkyl, unsaturated aikyl, cycioalkyi, cycioheteroalkyi, ΟΟΣΗ, COCi-s aikyl unsaturated alkyl, or aryi, CO2C1-6 saturated, unsaturated alkyl, or aryi, CONH2, CO2NHC1-6 saturated, unsaturated alkyl or aryi, C02N(Ci-e saturated , unsaturated alkyl or aryi)2, NHCi-s saturated, unsaturated alkyl, or cycioalkyi, N(Ci-e saturated, unsaturated alkyl, or cycioalkyi, or Cs-7aryl or heteroaryl; and each X independently = CH, CH2, S, SO, SO2, N, NH, NCi- ssaturated , unsaturated alkyi, or cycioalkyi, or O. In one embodiment, each n independently = 0-6, In one embodiment, formula (LXI) is decamethonium bromide.

In one embodiment, the method employs a compound of formula (LXI I):

in one embodiment, each R¹ independently = H, CI, Br, F, I , OH , OAc, CF3, NH2, CN, OC1 -5 saturated, unsaturated alkyi, cycioalkyi, cycioheteroalkyi, or aryi, SC1-6 saturated , unsaturated alkyl, cycioalkyi, cycioheteroalkyi, or aryi, C1 -5 saturated alkyl, unsaturated alkyl, cycioalkyi, cycioheteroalkyi, CO2H, COC1-8 alkyl unsaturated alkyi, or aryi, CO2C1-6 saturated, unsaturated alkyl, or aryi, CONH2, CO2NHC1-6

saturated , unsaturated alkyl or aryi, C02 (Ci-s saturated , unsaturated alkyl or aryl)2, NHCi-s saturated , unsaturated alkyi, or cycioalkyi, N(Ci-e saturated, unsaturated alkyi, or cycloalkyl)2, or C^aryi or heteroaryl. in one embodiment, each X independently = C, CH, CH2, S, SO, SO2, N, NH , NCi-ssaturated , unsaturated alkyi, or cycioalkyi, or O. In one embodiment, each n independently = 0-6. In one

embodiment, each R¹ independently = H, CI, Br, F, I, OH, OAc, CF3, NH2, GN, OC1-6 saturated , unsaturated alkyi, cycioalkyi, cycioheteroalkyi, or aryi, SC1-6 saturated, unsaturated aikyl, cycioalkyi, cycioheteroalkyi, or aryi, C1-6 saturated alkyi, unsaturated aikyl, cycioalkyi, cycioheteroalkyi, CO2H , COC1-8 alkyl unsaturated alkyi, or aryi, CO2C1-6 saturated , unsaturated alkyl, or aryi, CONH2, CO2NHC1-6 saturated , unsaturated alkyl or aryi, C02 (Ci-s saturated , unsaturated alkyl or aryi)2, NHCi-s saturated , unsaturated alkyi, or cycloalkyi, N(Ci-e saturated, unsaturated alkyl, or cycloalkyi, or Cs-yaryi or heteroaryl; and each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-ssaturated, unsaturated alkyl, or cycloalkyi, or O, in one embodiment, formula (LXi i) is terfenadine.

In one embodiment, the method employs a compound of formula (LXI 11):

in one embodiment, each R¹ independently = H, CI, Br, F, I , OH, OAc, CF3, NH2, CN, OC1 -5 saturated, unsaturated alkyi, cycloalkyi, cydoheteroalkyi, or aryl, SC1-6 saturated, unsaturated alkyl, cycloalkyi, cydoheteroalkyi, or aryl, C1 -5 saturated alkyl, unsaturated alkyl, cycloalkyi, cydoheteroalkyi, C02H, COC1 -8 alkyl unsaturated alkyl, or aryl, CO2C1-6 saturated, unsaturated alkyl, or aryl, CONH₂, CO2NHC1 -5 saturated, unsaturated alkyi or aryl, CQ2N(Ci-8 saturated, unsaturated alkyi or aryl)2, NHC1-8 saturated, unsaturated alkyi, or cycloalkyi, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl)2, or C^aryi or heteroaryl. in one embodiment, each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-ssaturated, unsaturated alkyi, or cycloalkyi, or O. In one embodiment, n = 0-6. In one embodiment, each R¹ independently = H, Ci, Br, F, I, OH, OAc, CF3, NH2, CN, OCi-e saturated, unsaturated alkyl, cycloalkyi, cydoheteroalkyi, or aryl, SCi-e saturated, unsaturated alkyi, cycloalkyi, cydoheteroalkyi, or aryl, C1-6 saturated alkyl, unsaturated alkyi, cycloalkyi, cydoheteroalkyi, C02H, CQC1 -8 alkyl unsaturated alkyl, or aryl, CO2C1-6 saturated, unsaturated alkyl, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated aikyl or aryl, C02 (Ci-6 saturated, unsaturated alkyl or aryl)2, NHC1-6 saturated, unsaturated aikyl, or cycloalkyi, N(Ci-e saturated, unsaturated alkyl, or cycloalkyi, or Cs-yaryi or heteroaryl; each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-asaturated, unsaturated alkyl, or cycloalkyi, or O; and n = 0-6. in one

embodiment, formula (LXI II) is adiphenine.

In one embodiment, the method employs a compound of formula (LXIV):

in one embodiment, each R¹ independently = H, CI, Br, F, I , OH, OAc, CF3, NH2, CN, OC1 -5 saturated, unsaturated alkyi, cycloalkyi, cydoheteroalkyi, or aryl, SC1-6 saturated, unsaturated alkyl, cycloalkyi, cydoheteroalkyi, or aryl, C1 -5 saturated alkyl, unsaturated alkyl, cycloalkyi, cydoheteroalkyi, CO2H, COC1-8 alkyl unsaturated alkyi, or aryl, CO2C1-6 saturated, unsaturated aikyl, or aryl, CONH2, CO2NHC1-5 saturated, unsaturated alkyl or aryl, C02N(Ci-s saturated, unsaturated alkyl or aryl)2, NHCi-s saturated, unsaturated alkyi, or cycloalkyi, N(Ci-e saturated, unsaturated alkyl, or cycioalkyl)2, or C^aryi or heteroaryl.

in one embodiment, each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-ssaturated, unsaturated alkyl, or cycloalkyi, or O. in one embodiment, n = 0-6. In one embodiment, each R¹ independently = H, CI, Br, F, I , OH, OAc, CFs, NH2, CN, OC1-6 saturated, unsaturated alky!, cycioaikyl, cycloheteroalkyl, or aryi, SC1-6 saturated , unsaturated aikyi, cycioaikyl, cycloheteroalkyl, or aryl, C1-6 saturated alkyl, unsaturated aikyi, cycioaikyl, cycloheteroalkyl, CO2H, COCi-s aikyi unsaturated aikyi, or aryl, CO2C1-6 saturated , unsaturated aikyi, o aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyl or aryl, C02N(Ci-e saturated , unsaturated aikyi or aryl)2, NHC1 -8 saturated, unsaturated aikyi, or cycioaikyl, N(Ci-e saturated, unsaturated aikyi, or cycioalkyl)2, or Cs-7aryl or heteroaryi; each X independently = C, CH, CH2, S, SO, SO2, N, NH , NCi-esaturated, unsaturated aikyi, or cycioaikyl, or O; and n = 0-8. in one embodiment, formula (LXIV) is azacyclonol.

In one embodiment, the method employs a compound of formula (LXV):

in one embodiment, each R¹ = H , Ci, Br, F, I, OH , OAc, CF3, NH2, CN, OCi-e saturated, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, or aryl, SC1-6 saturated, unsaturated aikyi, cycioaikyl, cycloheteroalkyl, o aryl, C1-6 saturated aikyi, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, CO2H, COCi-s alkyl unsaturated aikyi, or aryl, CO2C1-6 saturated, unsaturated alkyl, o aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyl or aryi, C02 (Ci-6 saturated, unsaturated alkyl or aryl)2, NHCi-s saturated, unsaturated alkyl, or cycioaikyl, N(Ci-6 saturated, unsaturated alkyl, or cycioaikyl^, or Cs-7aryl or heteroaryi. In one embodiment, each X independently S, SO, SO2, NH, NCi-esaturated, unsaturated alkyl, or cycioaikyl, or O. in one embodiment, each n independently = 0-8. In one embodiment, each R¹ = H, CI, Br, F, i , OH , OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated aikyi, cycioaikyl, cycloheteroalkyl, or aryl, SC1-6 saturated, unsaturated aikyi, cycioaikyl, cycloheteroalkyl, or aryi, C1-6 saturated aikyi, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, CO2H, COC1 alkyl unsaturated alkyl, or aryl, CO2C 1-6 saturated , unsaturated aikyi, or aryi, CONH2, CO2NHC1-6 saturated, unsaturated alkyl or aryl, C02 (Ci-e saturated, unsaturated aikyi or aryi)2, NHC1-6 saturated, unsaturated aikyi, or cycioaikyl, N(Ci-e saturated, unsaturated aikyi, or cycioaikyl, or Cs-ja yi or heteroaryi; each X independently =CH2, S, SO, SO2, NH, NCi-esaturated, unsaturated alkyl, or cycioaikyl, o O; and each n independently = 0-6. In one embodiment, formula (LXV) is aiprostadil.

in one embodiment, the method employs a compound of formula (LXVI):

in one embodiment, each R¹ independently = H, CI, Br, F, i , OH , OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated aikyi, cycioaikyl, cycloheteroalkyl, or aryi, SCi-e saturated , unsaturated alkyl, cycioaikyl, cycloheteroalkyl, or aryl, C1-6 saturated aikyi, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, CO2H, COC1-8 alkyl unsaturated aikyi, or aryi, CO2C1-6 saturated, unsaturated aikyi, or aryi, CONH2, CO2NHC1-6 saturated , unsaturated alkyl o aryl, C02N(Ci-e saturated , unsaturated alkyl o aryi)2, NHC1-6 saturated , unsaturated aikyi, or cycioaikyl, N(Ci-e saturated, unsaturated alkyl, or cycioaikyl, or C5-7aryl or heteroaryi. in one embodiment, each X independently = C, CH2, S, SO, SO2, N , NH, NCi-ssaturated, unsaturated aikyi, or cycioaikyl, or O. In one embodiment, n = 0-8. in one embodiment, each R ¹ independently = H, Ci, Br, F, I, OH, OAc, CFs, NH2, CN, OC1-6 saturated, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, or aryi, SC1-6 saturated, unsaturated alkyi, cydoalkyl, cycloheteroalkyl, or aryi, C1-6 saturated alkyl, unsaturated alkyl, cydoalkyl, cycloheteroalkyl, CO2H, COC1-8 alkyl unsaturated aikyl, or aryl, CO2C1-6 saturated, unsaturated alkyl, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyl or aryl, C02N(Ci-6 saturated, unsaturated aikyl or aryl)2, NHC1-6 saturated, unsaturated aikyl, or cydoalkyl, N(Ci-e saturated, unsaturated alkyi, or cycioaikyl)2, or Cs-yaryi or heteroaryl; each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-8saturated, unsaturated alkyi, or cydoalkyl, or O; and n = 0-6. in one

embodiment, formula (LXVI) is betazole.

In one embodiment, the method employs a compound of formula (LXVI I):

in one embodiment, each R¹ independently^ H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated alkyi, cydoalkyl, cycloheteroalkyl, or aryl, SCi-e saturated, unsaturated aikyl, cydoalkyl, cycloheteroalkyl, or aryi, C1-6 saturated alkyi, unsaturated aikyl, cydoalkyl, cycloheteroalkyl, CO2H, COC i-s alkyi unsaturated alkyi, or aryl, CO2C1-6 saturated, unsaturated aikyl, or aryl, CONH2, C02NHCi-e saturated, unsaturated alkyi or aryl, C02N(Ci-8 saturated, unsaturated alkyi or aryi)2, NHC1-8 saturated, unsaturated alkyi, or cydoalkyl, N(CI-B saturated, unsaturated alkyi, or cycioaikyfk, or Cs-Taryi or heteroaryl. In one embodiment, each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated aikyl, or cydoalkyl, or O. In one embodiment, n = 0-8. In one embodiment, each R¹ independently^ H, Ci, Br, F, I, OH, OAc, CF₃, NH₂, CN, OCi-e saturated, unsaturated alkyl, cydoalkyl, cycloheteroalkyl, o aryi, SC1 -5 saturated, unsaturated alkyi, cydoalkyl, cycloheteroalkyl, or aryi, C1-6 saturated alkyl, unsaturated alkyi, cydoalkyl, cycloheteroalkyl, CO2H, COC1-8 alkyl unsaturated aikyl, or aryl, CO2C1-6 saturated, unsaturated alkyl, or aryi, CONH2, C02NHCi-e saturated, unsaturated alkyl or aryl, C02N(Ci-e saturated, unsaturated alkyl or aryl)2, NHC1-8 saturated, unsaturated alkyl, or cydoalkyl, N(Ci-6 saturated, unsaturated alkyl, or cycloalkyi)2, or Cs-jaryi or heteroaryl; each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated aikyl, or cydoalkyl, o O: and n = 0-6. in one embodiment, formula (LXVI I) is R(-) apomorphine.

In one embodiment, the method employs a compound of formula (LXVI 11):

in one embodiment, R each ¹ = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OC1-5 saturated, unsaturated alkyi, cydoalkyl, cycloheteroalkyl, o aryi, SC1 -5 saturated, unsaturated alkyi, cydoalkyl, cycloheteroalkyl, or aryl, C1-6 saturated alkyl, unsaturated aikyl, cydoalkyl, cycloheteroalkyl, CO2H, COC1-8 alkyi unsaturated alkyi, or aryi, CO2C1-B saturated, unsaturated alkyi, or aryi, CONH2, CO2NHC1-S saturated, unsaturated alkyi or aryl, C02 (Ci-6 saturated, unsaturated alkyi or aryfb, NHCI-B saturated, unsaturated alkyi, or cydoalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloaikyfb, or Cs-jaryi or heteroaryl. In one embodiment, each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-ssaturated, unsaturated alkyi, or cycloalkyl, or O. in one embodiment, n = 0-6. In one embodiment, R each ¹ = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated alky!, cycloalkyl, cycloheteroalkyl, or aryi, SC1-6 saturated, unsaturated aikyi, cycloalkyl, cycloheteroalkyl, or aryi, C1-6 saturated aikyi, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CO2H, COC1-8 alkyl unsaturated aikyi, or aryi, CO2C1-6 saturated, unsaturated alkyl, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated aikyl or aryl, C02N(Ci-6 saturated, unsaturated alkyl or aryl)2, NHC1-6 saturated, unsaturated alkyl, or cycloalkyl, N(Ci-e saturated, unsaturated aikyl, or cycloalkyl, or C5-7aryl or heteroaryl; each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi- esaturated , unsaturated alkyi, or cycloalkyl, o O; and n = 0-6. In one embodiment, formula (LXVli i) is serotonin.

In one embodiment, the method employs a compound of formula (LXIX):

in one embodiment, each R¹ independently = H, CI, Br, F, I, OH , OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated aikyi, cycloalkyl, cycloheteroalkyl, or aryi, SCi-e saturated, unsaturated aikyl, cycloalkyl, cycloheteroalkyl, o aryi, C1-6 saturated alkyl, unsaturated aikyl, cycloalkyl, cycloheteroalkyl, CO2H , COC i-s alkyl unsaturated alkyi, or aryl, CO2C1-6 saturated , unsaturated alkyl, or aryl, CONH2, CO2NHC1-6 saturated , unsaturated alkyl o aryi, C02N(Ci-e saturated, unsaturated alkyl o aryi)2, NHC1-6 saturated, unsaturated alkyi, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl^, or Cs-yaryi or heteroaryl. in one embodiment, each X independently = C, CH, CH2, S, N, NH , NCi-esaturated, unsaturated alkyi, or cycloalkyl, or O. In one embodiment, each n independently = 0-8. In one

embodiment, each R¹ independently = H, CI, Br, F, I, OH, OAc, CF₃, NH₂, CN, OC i-s saiuraied , unsaturated alkyi, cycloalkyl, cycloheteroalkyl, or aryi, SC1-6 saturated , unsaturated aikyl, cycloalkyl, cycloheteroalkyl, o aryi, Ci-e saturated alkyl, unsaturated aikyl, cycloalkyl, cycloheteroalkyl, CO2H, COC1-8 alkyl unsaturated alkyi, or aryl, CO2C1-6 saturated, unsaturated alkyl, or aryl, CONH2, CO2NHC1-6 saturated , unsaturated alkyl or aryi, C02N(Ci-6 saturated, unsaturated alkyl o aryi)2, NHC1-8 saturated, unsaturated alkyl, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl, or Cs-yaryi or heteroaryl; each X independently = C, CH, CH2, S, N, NH, NCi-oSaiuraied, unsaturated aikyl, or cycloalkyl, or O; and each n independently = 0-6. in one embodiment, formula (LXIX) is famprofazone.

In one embodiment, the method employs a compound of formula (LXX):

in one embodiment, each R¹ independently = H, CI, Br, F, I, OH , OAc, CF₃, NH₂, CN, ONO2, OCi_-6 saturated , unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, SC1-6 saturated, unsaturated alkyi, cycloalkyl, cycloheteroalkyl, or aryl, C1-6 saturated alkyl, unsaturated alkyi, cycloalkyl, cycloheteroalkyl, CO2H, COC1-8 aikyl unsaturated alkyl, or aryi, CQ2d-s saturated, unsaturated alkyl, or aryi, CONH2, CO2NHC1-6 saturated, unsaturated alkyi or aryi, C02lM(Ci-6 saturated, unsaturated alkyi or aryl)2, NHC-i saturated, unsaturated a!kyl, or cycloaikyi, N(Ci -6 saturated, unsaturated aikyl, or cycloalkyfh, or Cs-7aryl or heteroaryl. In one embodiment, each X independently = CH2, S, SO, SO2, NH, NCi-ssaturated, unsaturated alkyi, or cycioalkyi, or O, In one embodiment, each n independently = 0-6, In one

embodiment, each R¹ independently = H, CI, Br, F, I, OH, OAc, CF₃, NH₂, CN, ONO2, OC1-6 saturated, unsaturated alkyi, cycioalkyi, cycioheteroalkyi, or aryi, SC1-6 saturated, unsaturated aikyl, cycioalkyi, cycloheteroalkyl, or aryi, C1-6 saturated alkyi, unsaturated aikyl, cycloaikyi, cycioheteroalkyi, CO2H, COCi-s alkyi unsaturated alkyi, or aryi, CO2C1-6 saturated, unsaturated aikyl, or aryi, CONH₂, CO2NHC1-6 saturated, unsaturated alkyi or aryi, C0₂N(Ci-8 saturated, unsaturated alkyi or aryi)₂, NHC1-8 saturated, unsaturated aikyl, or cycioalkyi, N(Ci-e saturated, unsaturated aikyl, or cycloalkyl)₂, or C aryl or heteroaryl; each X independently = CH₂, S, SO, S0₂, NH, NCi-esaturated, unsaturated aikyl, or cycioalkyi, or O; and each n independently = 0-6. In one embodiment, formula (LXX) is isosorbide dinitrate.

In one embodiment, the method employs a compound of formula (LXXI):

in one embodiment, each R¹ independently = H, CI, Br, F, I, OH, OAc, CF?,, NH₂, CN, NO2, OCi-e saturated, unsaturated aikyl, cycioalkyi, cycioheteroalkyi, or aryi, SCi-e saturated, unsaturated aikyl, cycioalkyi, cycioheteroalkyi, or aryi, C1-6 saturated aikyl, unsaturated aikyl, cycioalkyi, cycioheteroalkyi, CO2H, COC1-0 aikyl unsaturated alkyi, or aryi, CO2C1-6 saturated, unsaturated alkyi, or aryi, CONH2, CO2NHC1-6 saturated, unsaturated alkyi or aryi, C02N(Ci-e saturated, unsaturated alkyi or aryl)2, NHC1-6 saturated, unsaturated aikyl, or cycioalkyi, N(Ci-e saturated, unsaturated aikyl, or cycloaikyi)₂, or Cs-yary! or heteroaryl In one embodiment, each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi- esaturated, unsaturated aikyl, or cycioalkyi, or O. in one embodiment, each R¹ independently = H, CI, Br, F, i, OH, OAc, CF3, NH₂, CN, NO2, OC1-6 saturated, unsaturated aikyl, cycioalkyi, cycioheteroalkyi, or aryi, SC1-6 saturated, unsaturated aikyl, cycioalkyi, cycioheteroalkyi, or aryi, Ci-e saturated aikyl, unsaturated alkyi, cycioalkyi, cycioheteroalkyi, CO2H, COC1-8 aikyl unsaturated aikyl, or aryi, CO2C1-6 saturated, unsaturated alkyi, or aryi, CONH2, CO2NHC1-8 saturated, unsaturated alkyi or aryi, C02N(Ci-8 saturated, unsaturated alkyi or aryi)2, NHC1-6 saturated, unsaturated alkyi, or cycioalkyi, N(Ci-s saturated, unsaturated alkyi, or cycioalkyl)2, or Cs-yaryl or heteroaryl; and each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated aikyl, or cycioalkyi, or O. In one embodiment, formula (LXXI) is fenofibrate.

In one embodiment, method employs a compound of formula (LXXIi):

in one embodiment, each Ri independently = H, CI, Br, F, I, OH, OAc, CF₃, NH₂, CN, NO2, OCi-e saturated, unsaturated aikyl, cycioalkyi, cycloheteroalkyl, or aryi, SCi-e saturated, unsaturated aikyl, cycioalkyi, cycloheteroalkyl, or aryi, C1-6 saturated aikyl, unsaturated alkyi, cycioalkyi, cycioheteroalkyi, CO2H, COC1-8 aikyl unsaturated alkyi, or aryi, CO2C1-8 saturated, unsaturated alkyi, or aryi, CONH₂,

CO2NHC1-8 saturated, unsaturated alkyi or aryi, C02 (CI-B saturated, unsaturated alkyi or aryl)2, NHC1-8 saturated, unsaturated alkyi, or cycioalkyi, N(Ci-e saturated, unsaturated aikyl, or cycloaikyi)2, o Cs-varyi or heteroaryi. in one embodiment, each X independentiy = C, CH, CH2, S, SO, SO2, N, NH, NCi- ssaturated, unsaturated aikyl, or cydoaikyi, OR O. in one embodiment, each n independently = 0-6. In one embodiment, each Ri independently = H, CI, Br, F, I, OH, OAc, CF₃, NH₂, CN, NO2, OCi-_S saturated, unsaturated aikyi, cydoaikyi, cycloheteroaikyi, or aryi, SCi-e saturated, unsaturated aikyl, cydoaikyi, cycloheteroaikyi, or aryi, C1-6 saturated alkyi, unsaturated aikyl, cydoaikyi, cycloheteroaikyi, CO2H, COC i-s aikyi unsaturated aikyl, or aryi, CO2C1-6 saturated, unsaturated aikyl, or aryi, CONH2, CO2NHC1-6

saturated, unsaturated alkyi or aryi, C02N(Ci-8 saturated, unsaturated alkyi or aryi)2, NHC1-8 saturated, unsaturated aikyl, or cydoaikyi, N(Ci-e saturated, unsaiuraied alkyi, or cycioaikyl)2, OR Cs-yaryl or heteroaryi; each X independently = C, CH, CH2, S, SO, SO2, N, NH, Nd-esaturated, unsaturated alkyi, or cydoaikyi, or O; and each n independently = 0-6. In one embodiment, formula (LXXII) is molindone.

In one embodiment, the method employs a compound of formula (LXXII I).

in one embodiment, each R¹ independently = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, NO2, OC1-6 saturated, unsaturated alkyi, cydoaikyi, cycloheteroaikyi, or aryi, SC1-6 saturated, unsaturated aikyi, cydoaikyi, cycloheteroaikyi, or aryi, C1-6 saturated alkyi, unsaturated aikyi, cydoaikyi, cycloheteroaikyi, CO2H, CQC1-8 aikyl unsaturated alkyi, or aryi, CO2C1-6 saturated, unsaturated alkyi, or aryi, CONH2, CO2NHC1-6 saturated, unsaturated aikyi or aryi, C02lM(Ci-6 saturated, unsaturated aikyi or aryl)2, NHC1-6 saturated, unsaturated alkyi, or cydoaikyi, N(Ci-6 saturated, unsaturated aikyl, or cycloaikyi)2, OR Cs yaryl or heteroaryi. in one embodiment, each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi- esaturated, unsaturated alkyi, or cydoaikyi, o O. In one embodiment, n = 0-6. in one embodiment, each R¹ independently = H, CI, Br, F, i, OH, OAc, CF₃, NH₂, CN, NO2, OC1-6 saturated, unsaturated aikyl, cydoaikyi, cycloheteroaikyi, or aryi, SC1-6 saturated, unsaiuraied alkyi, cydoaikyi, cycloheteroaikyi, or aryi, C1-6 saturated aikyl, unsaturated alkyi, cydoaikyi, cycloheteroaikyi, CO2H, COCi-e aikyl unsaturated aikyl, or aryi, CO2C1-6 saturated, unsaturated alkyi, or aryi, CONH2, CO2NHC1-6 saturated, unsaturated aikyl or aryi, C02N(Ci-e saturated, unsaturated alkyi or aryl)2, NHCi-s saturated, unsaturated aikyl, or cydoaikyi, N(Ci-6 saturated, unsaturated alkyi, or cycloalkyi)2, OR Cs-yaryl or heteroaryi; each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-oSaiuraied, unsaturated aikyl, or cydoaikyi, o O; and n = 0-6. in one embodiment, formula (LXXIII) is antimycin A.

In one embodiment, the method employs a compound of formula (LXXIV):

in one embodiment, each R¹ independently = H, CI, Br, F, i, OH, OAc, CF₃, NH₂, CN, NO2, OC1-6 saturated, unsaturated alkyi, cydoaikyi, cycloheteroaikyi, or aryi, SC1-6 saturated, unsaturated aikyi, cydoaikyi, cycloheteroaikyi, or aryi, C1-6 saturated aikyl, unsaturated alkyi, cydoaikyi, cycloheteroaikyi, CO2H, COC1-8 aikyl unsaiuraied alkyi, or aryi, CQ2C1-8 saturated, unsaiuraied alkyi, or aryi, CONH2, CO2NHC1-6 saturated, unsaturated alkyi or aryi, C02N(Ci-e saturated, unsaturated alkyi or aryl]2, NHC1-5 saturated, unsaturated aikyl, or cydoaikyi, N(Ci-e saturated, unsaturated aikyl, or cydoaikyi, Cs-yaryl or heteroaryi. In one embodiment, each X independentiy = C, CH, CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated alkyi, or cycioaikyl, o O. in one embodiment, each R¹ independently = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, NO2, OC1-6 saturated, unsaturated alkyl, cycioaikyl, cycloheteroaikyl, or aryl, SCi -e saturated, unsaturated alkyi, cycioaikyl, cycloheteroaikyl, or aryl, C1-6 saturated alkyi, unsaturated aikyl, cycioaikyl, cycloheteroaikyl, CO2H, COC i-s aikyl unsaturated alkyl, or aryl, CO2C1-6 saturated, unsaturated alkyi, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyl or aryl, C02 (Ci-e saturated, unsaturated alkyl or aryi)2, NHC1-6 saturated, unsaturated alkyl, or cycioaikyl, N(Ci-e saturated, unsaturated alkyl, or cycioaikyl, Cs-yaryi or heteroaryl; and each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi- esaturated, unsaturated alkyi, or cycioaikyl, o O. In one embodiment, formula (LXXIV) is acetazolamide.

In one embodiment, the method employs a compound of formula (LXXV):

in one embodiment, each R¹ independently = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, NO2, OC1-6 saturated, unsaturated alkyi, cycioaikyl, cycloheteroaikyl, or aryl, SC1-6 saturated, unsaturated alkyi, cycioaikyl, cycloheteroaikyl, or aryl, C1-6 saturated alkyl, unsaturated aikyi, cycloalkyl, cycloheteroaikyl, CO2H, COC1-8 aikyl unsaturated alkyi, or aryl, CO2C1-8 saturated, unsaturated alkyl, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated aikyi or aryl, C02N(Ci-e saturated, unsaturated aikyi or aryl)2, NHC1-6 saturated, unsaturated alkyi, or cycioaikyl, N(Ci-e saturated, unsaturated aikyl, or cycloalkyl^, or Cs-7aryl or heteroaryl ;each R2 = Mono, di, or trigiycoside, OC(O) C3-5 alkenyl in one embodiment, each X independently = CH, CH2, S, SO, SO2, NH, NCi-asaturated, unsaturated alkyi, or cycioaikyl, or O, in one embodiment, n = 0-6. In one embodiment, each R¹ independently = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, NO2, OC1-6 saturated, unsaturated alkyl, cycioaikyl, cycloheteroaikyl, or aryl, SC1-6 saturated, unsaturated alkyi, cycloalkyl, cycloheteroaikyl, or aryl, Ci-e saturated alkyi, unsaturated alkyl, cycioaikyl, cycloheteroaikyl, CO2H, COC1-8 alkyl unsaturated alkyi, or aryl, CQ2C1-8 saturated, unsaturated alkyi, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated aikyl or aryl, C02N(Ci-e saturated, unsaturated aikyl or aryi)2, NHC1-8 saturated, unsaturated alkyi, or cycioaikyl, N(Ci-6 saturated, unsaturated aikyl, or cycloalkyl, or Cs-yaryl or heteroaryl; and each X independently = CH, CH2, S, SO, SO2, NH, NCi- esaturated, unsaturated aikyi, or cycioaikyl, o O. In one embodiment, formula (LXXV) is ivermectin or avermectin B1 .

In one embodiment, the method employs a compound of formula (LXXVI):

In one embodiment, each R¹ = H, Ci, Br, F, I, OH, ONa, OAc, CF₃, NH₂, CN, NO2, OCi-e saturated, unsaturated aikyl, cycloalkyl, cycloheieroalkyl, or aryl, SC1-6 saturated, unsaturated aikyl, cycloalkyl, cycloheteroaikyl, or aryl, Ci-e saturated alkyi, unsaturated aikyl, cycloalkyl, cycloheieroalkyl, CO2H, COC1-8 alkyl unsaturated aikyl, or aryl, CO2C1-6 saturated, unsaturated aikyl, or aryl, CONH2, CO2NHC1-5 saturated, unsaturated a!kyl or aryl, CG2 (Ci-s saturated, unsaturated a!kyl or aryl)2, NHCi-s saturated, unsaturated alkyl, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl)2, Cs-yaryl or heteroaryl In one embodiment, each X independently = CH, CH2, S, SO, SO2, N, NH, NC i-ssat.urat.ed, unsaturated alkyl, or cycloalkyl, or O, In one embodiment, each n independently = 0-6. In one embodiment, each R¹ = H, CI, Br, F, I, OH, ONa, OAc, CF₃, NH2, CN, NO2, OC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, SC1-6 saturated, unsaturated alkyl, cycloalkyl, cycioheteroalkyi, or aryl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycioheteroalkyi, CO2H, COC1 -8 alkyl unsaturated alkyl, or aryl, CO2C1-6 saturated, unsaiuraied alkyl, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyl or aryl, C02 (Ci-6 saturated, unsaturated alkyl or aryl)2, NHC1-6 saturated, unsaturated alkyl, or cycloalkyl, N(Ci-6 saturated, unsaiuraied alkyl, or cycloalkyl^, Cs yaryl or heteroaryl; each X independently = CH, CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated alkyl, or cycloalkyl, or O; and each n independently = 0-8. In one embodiment, formula (LXXVi) is cromolyn disodium.

In one embodiment, the method employs a compound of formula (LXXVIi):

x x

in one embodiment, each R¹ independently = H, CI, Br, F, I, OH, ONa, OAc, CF₃, NH₂, CN, NO2, OC1 -6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, SCi-e saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1 -6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycioheteroalkyi, CO2H, COC1-8 alkyl unsaiuraied alkyl, or aryl, CQ2C1 -8 saturated, unsaiuraied alkyl, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyl or aryl, C02N(Ci-e saturated, unsaturated alkyl or aryl]2, NHC1-5 saturated, unsaturated alkyl, or cycloalkyl, N(Ci-e saturated, unsaiuraied alkyl, or cycloaikyi)2, or Cs-v-ary! or heteroaryl. in one embodiment, each X independently = CH, CH2, S, N, NH, NCi-esaturated, unsaturated alkyl, or cycloalkyl, or O. In one embodiment, each R independently = H, CI, Br, F, i, OH, ONa, OAc, CFs, NH2, CN, NO2, OC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, SCi-e saturated, unsaiuraied alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycioheteroalkyi, CO2H, COC1-8 alkyl unsaturated alkyl, or aryl, CO2G1-6 saturated, unsaturated alkyl, or aryl, CONH2, C02 HCi-s saturated, unsaturated alkyl or aryl, C02 (Ci-s saturated, unsaturated alkyl or aryfh, NHC1-6 saturated, unsaturated alkyl, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl, or Cs-yaryl or heteroaryl; and each X independently = CH, CH2, S, N, NH, NCi-esaturated, unsaturated alkyl, or cycloalkyl, or O. In one embodiment, formula (LXXVil) isDiacerein.

In one embodiment, the method employs a compound of formula (LXXVI 11):

in one embodiment, each R¹ independently = H, CI, Br, F, I, OH, ONa, OAc, CF₃, NH₂, CN, NO2, OC1. saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, SCi-e saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1 -6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycioheteroalkyi, CO2H, COC1-8 alkyl unsaiuraied alkyl, or aryl, CQ2C1 -8 saturated, unsaiuraied alkyl, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyi or aryl, C02N(Ci-e saturated, unsaturated alkyi or aryl)2, NHC1-6 saturated, unsaturated a!kyl, or cycloaikyi, N(Ci-6 saturated, unsaturated aiky!, or cycloalkyl)2, or Cs-yary! or heteroaryi. In one embodiment, each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi- ssaturated, unsaturated alkyi, or cycloaikyi, or O. in one embodiment, each R independently = H, Ci, Br, F, i, OH, ONa, OAc, CF3, NH2, CN, NO2, OC1-6 saturated, unsaturated alkyi, cycloaikyi, cycioheteroa!kyi, or aryl, SCi-e saturated, unsaturated aikyi, cycloaikyi, cycloheteroalkyi, or aryi, C1-6 saturated alkyi, unsaturated alkyi, cycloaikyi, cycloheteroalkyi, CO2H, COCi-s alkyi unsaturated alkyi, or aryl, CO2C1-6 saturated, unsaiuraied alkyi, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyi or aryl, C0₂N(Ci-6 saturated, unsaiuraied alkyi or aryi)2, NHC1 -8 saturated, unsaiuraied alkyi, or cycloaikyi, N(Ci-e saturated, unsaturated alkyi, or cycloaikyi^, or Cs-yaryl or heteroaryi; and each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated aikyl, or cycloaikyi, or O. In one embodiment, formula (LXXVIil) is Dichlorphenamide.

In one embodimeni, the method employs a compound of formula (LXXIX):

in one embodiment, each R¹ independently = H, CI, Br, F, I, OH, ONa, OAc, CF₃, NH₂, CN, NO2, OCi_-6 saturated, unsaturated alkyi, cycloaikyi, cycloheteroalkyi, or aryl, SCi-e saturated, unsaturated alkyi, cycloaikyi, cycloheteroalkyi, or aryl, C1-6 saturated alkyi, unsaturated alkyi, cycloaikyi, cycloheteroalkyi, CO2H, COC1 aikyl unsaturated alkyi, o aryl, CO2C1-6 saturated, unsaturated alkyi, or aryl, CONH₂, CO2NHC1-6 saturated, unsaturated alkyi or aryl, C02N(Ci-e saturated, unsaturated alkyi or aryl)2, NHC1-6 saturated, unsaturated alkyi, or cycloaikyi, N(Ci-e saturated, unsaturated aikyl, or cycloalkyi)₂, or Cs-7aryl or heteroaryi. In one embodiment, each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi- esaturated , unsaturated alkyi, or cycloaikyi, or O. in one embodiment, each n independently = 0-6. In one embodiment, each R¹ independently = H, CI, Br, F, I, OH, ONa, OAc, CF₃, NH₂, CN, NO2, OC1-6 saturated, unsaturated alkyi, cycloaikyi, cycloheteroalkyi, or aryl, SC1-6 saturated, unsaturated alkyi, cycloaikyi, cycloheteroalkyi, or aryl, C1-6 saturated alkyi, unsaturated alkyi, cycloaikyi, cycloheteroalkyi, CO2H, COC1-8 aikyl unsaturated aikyl, o aryl, CO2C1-6 saturated , unsaturated alkyi, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyi or aryl, C02N(Ci-e saturated, unsaturated alkyi or aryl)2, NHC1-6 saturated, unsaturated alkyi, or cycloaikyi, N(C i e saturated, unsaturated aikyl, or cycloaikyi, or Cs-7aryl or heteroaryi; each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated alkyi, or cycloaikyi, or O; and each n independently = 0-8. In one embodiment, formula (LXXIX) is Nicergoline.

In one embodimeni, the method employs a compound of formula (LXXX):

in one embodiment, each R¹ independently = H, CI, Br, F, I, OH, ONa, OAc, CF₃, NH₂, CN, NO2, OCi-₆ saturated, unsaturated aikyl, cycioaikyl, cycloheteroalkyl, or aryl, SCt-s saturated, unsaturated alkyi, cycioaikyi, cycloheteroalkyl, or ary!, Ci-e saturated alkyi, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, CO2H, CGC1-8 aikyl unsaturated alkyi, or aryl, CO2C1-6 saturated, unsaturated alkyi, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyi or aryl, C02N(Ci-e saturated, unsaturated alkyi or aryl)2, NHC1-6 saturated, unsaturated alkyi, or cycioaikyl, N(Ci-6 saturated, unsaturated aikyl, or cycloalkyi)₂, o Cs-yaryl or heteroaryl. In one embodiment, each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi- esaturated , unsaturated alkyi, or cycioaikyl, or O. In one embodiment, each R independently = H, CI, Br, F, I, OH, ONa, OAc, CF3, NH₂, CN, NO2, OC1 -5 saturated, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, or aryl, SC1 -6 saturated, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, or aryl, C1-6 saturated alkyi, unsaturated aikyl, cycioaikyl, cycloheteroalkyl, CO2H, COC 1-8 alkyi unsaturated alkyi, or aryl, CO2C1-6 saturated, unsaturated alkyi, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated aikyl or aryl, C0₂N(Ci-6 saturated, unsaturated alkyi or aryi)₂, NHC1 -8 saturated, unsaturated alkyi, or cycioaikyl, N(Ci-e saturated, unsaturated aikyl, or cycioalkyl)₂, or Cs-7aryl or heteroaryl; and each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-asaturated, unsaturated aikyl, or cycioaikyl, or O. In one embodiment, formula (LXXX) is nevirapine.

In one embodiment, the method employs a compound of formula (LXXXI):

R¹

in one embodiment, each R¹ independently = H, CI, Br, F, I, OH, ONa, OAc, CF₃, NH₂, CN, NO2, OC1-6 saturated, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, or aryl, SC1-6 saturated, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, or aryl, C1-6 saturated aikyl, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, CO2H, COC1-8 aikyl unsaturated alkyi, or aryl, CQ2C1 -8 saturated, unsaturated alkyi, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyi or aryl, C02N(Ci-e saturated, unsaturated alkyi or aryl)2, NHC1-6 saturated, unsaturated alkyi, or cycioaikyl, N(Ci-e saturated, unsaturated aikyl, or cycioaikyl, or C5-7aryl or heteroaryl. In one embodiment, each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi- esaturated , unsaturated alkyi, or cycioaikyl, or O. in one embodiment, each R^¾ independently = H, CI, Br, F, i, OH, ONa, OAc, CF₃, NH₂, CN, NO2, OCi-e saturated, unsaturated aikyl, cycioaikyl, cycloheteroalkyl, or aryl, SC i-s saturated, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, or aryl, C1-6 saturated aikyl, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, CO2H, COCi-e alkyi unsaturated alkyi, or aryl, CO2C1-6 saturated, unsaturated alkyi, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated aikyl or aryl, C0₂N(Ci-6 saturated, unsaturated alkyi o aryl)₂, NHCi-s saturated, unsaturated alkyi, or cycioaikyl, N(Ci-e saturated, unsaturated alkyi, or cycioaikyl, or Cs yaryl or heteroaryl; and each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-ssaturated, unsaturated aikyl, or cycioaikyl, or O. In one embodiment, formula (LXXXI) is niclosamide.

In one embodiment, the method employs a compound of formula (LXXXH):

in one embodiment, each R¹ independently = H, CI, Br, F, i , OH , ONa, OAc, CFa, Nh½, CN, NO2, OC1-6 saturated, unsaturated alkyi, cycioaikyl, cycioheteroalkyl, or aryl, SC1-6 saturated, unsaturated alkyi, cycloalkyi, cycioheteroalkyl, or aryl, C1-6 saturated alkyl, unsaturated alkyi, cycloalkyi, cycioheteroalkyl, CO2H, COC1-S alkyl unsaturated alkyl, or aryl, C02Ci-s saturated , unsaturated alkyl, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyi or aryl, C02 (Ci-e saturated, unsaturated alkyi or aryl)2, NHC1-6 saturated , unsaturated alkyl, or cycioaikyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyi, or Cs-7aryl or heteroaryl. In one embodiment, each X independently = C, CH, CH2, S, SO, SO2, N, NH , NCi- esaturated , unsaturated alkyi, or cycioaikyl, or O. in one embodiment, each R¹ independently = H, CI, Br, F, i , OH, ONa, OAc, CF3, NH2, CN, NO2, OC1-6 saturated, unsaturated alkyi, cycloalkyi, cycioheteroalkyl, or aryl, SC1-6 saturated, unsaturated alkyi, cycloalkyi, cycioheteroalkyl, or aryl, C1-6 saturated alkyi, unsaturated alkyi, cycloalkyi, cycioheteroalkyl, CO2H, COCi-s alkyl unsaturated alkyi, or aryl, CO2C1-6 saturated , unsaturated alkyl, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyl or aryl, C02 (Ci-e saturated , unsaturated alkyl or aryi, NHC1-6 saturated, unsaturated alkyl, or cycioaikyl, N(Ci-e saturated, unsaturated alkyi, or cycloalkyi, or Cs yaryl or heteroaryl; and each X independently = C, CH , CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated alkyl, or cycloalkyi, or O. In one embodiment, n = 0-6. in one embodiment, formula (LXXXII) is fentiazac.

In one embodiment, the method employs a compound of formula (LXXXIl l):

in one embodiment, each R¹ independently = H, CI, Br, F, I, OH , ONa, OAc, CF₃, NH₂, CN, NO2, OCi-_S saturated , unsaturated alkyl, cycioaikyl, cycioheteroalkyl, or aryl, SC1-6 saturated, unsaturated alkyi, cycloalkyi, cycioheteroalkyl, or aryl, Ci-e saturated alkyl, unsaturated alkyi, cycloalkyi, cycioheteroalkyl, CO2H, COC1-8 alkyl unsaturated alkyi, or aryl, CQ2C1 -8 saturated , unsaturated alkyi, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyi or aryl, C02N(Ci-e saturated, unsaturated alkyi or aryl)2, NHC1-6 saturated , unsaturated alkyl, or cycioaikyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyi, or Canary! or heteroaryl. In one embodiment, each X independently = C, CH , CH2, S, SO, SO2, N , NH, NCi- esaturated, unsaturated alkyl, or cycloalkyi, or O. in one embodiment, each R^¾ independently = H, CI, Br, F, i , OH, ONa, OAc, CF₃, NH₂, CN, NO2, OCi-e saturated, unsaturated alkyl, cycloalkyi, cycioheteroalkyl, or aryl, SC i-s saturated, unsaturated alkyl, cycloalkyi, cycioheteroalkyl, or aryl, C1-6 saturated alkyl, unsaturated alkyi, cycloalkyi, cycioheteroalkyl, CO2H, COCi-e alkyl unsaturated alkyl, or aryl, CO2C1-6 saturated , unsaturated alkyi, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyl or aryl, C02 (Ci-e saturated , unsaturated alkyi or aryi, NHC1-8 saturated, unsaturated alkyi, or cycioaikyl, N(Ci-e saturated, unsaturated alkyi, or cycloalkyi, or Cs-yaryl or heteroaryl; and each X independently = C, CH , CH2, S, SO, SO2, N, NH, NCi-ssaturated, unsaturated aikyl, or cycloalkyi, or O. In one embodiment, formula (LXXXI ll) is triciabendazoie In one embodiment, the method employs a compound of formula (LXXX!V):

In one embodiment, each R¹ independently = H, CI, Br, F, I, OH, ONa, OAc, CFa, Nh½, CN, NO2, OC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyi, or aryl, SC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyi, or aryl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyi, CO2H, COC1-8 alkyl unsaturated alkyl, or aryl, CO2C1-8 saturated, unsaturated alkyl, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyl or aryl, C02 (Ci-e saturated, unsaturated alkyl or aryl)2, NHd-e saturated, unsaturated alkyl, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl, or Cs-jaryi or heteroaryl. In one embodiment, each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi- esaturated, unsaturated alkyl, or cycloalkyl, or O. in one embodiment, each R independently = H, CI, Br, F, I, OH, ONa, OAc, CF3, NH2, CN, NO2, OC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyi, or aryl, SC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyi, or aryl, Ci-e saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyi, CO2H, COC1-8 alkyl unsaturated alkyl, or aryl, CO2C1-6 saturated, unsaturated alkyl, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyl or aryl, C02 (Ci-e saturated, unsaturated alkyl or aryi)2, NHC1-6 saturated, unsaturated alkyl, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl, or Cs yaryl or heteroaryl; and each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated alkyl, or cycloalkyl, or O. In one embodiment, each n independently = 0-8. In one embodiment, form formula (LXXXIV) is prenylamine.

In one embodiment, the method employs a compound of formula (LXXXV):

in one embodiment, each R¹ independently = H, CI, Br, F, I, OH, OAc, CF3, NH2, GN, OC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyi, or aryl, SC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyi, or aryl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyi, CO2H, COC i-s alkyl unsaturated alkyl, or aryl, CO2C1-6 saturated, unsaturated alkyl, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyl or aryl, C02 (Ci-s saturated, unsaturated alkyl or aryi)2, NHCi-s saturated, unsaturated alkyl, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl, or Cs-yaryi or heteroaryl; each X independently = C, CH, CH2, S, SO, S02, N, NH, NC i-ssaturated, unsaturated alkyl, or cycloalkyl, or O; and each n = 0-6. In one embodiment, formula (LXXXV) is ganaxolone.

In one embodiment, the method employs a compound of formula (LXXXVi):

in one embodiment each R¹ independently = H, CI, Br, F, I, OH , ONa, OAc, CF₃, NH₂, CN, ONO2, OC1-6 saturated , unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, SCi-e saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, Ci-e saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CO2H, COC1-S alkyl unsaturated alkyl, or aryl, CQ2C1 -6 saturated, unsaturated alkyl, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyl or aryl, C02N(Ci-e saturated , unsaturated alkyl or aryl)2, NHC1-6 saturated , unsaturated alkyl, or cycioaikyi, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl, or Cs-7aryl or heteroaryl; and each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-asaturated, unsaturated alkyl, or cycioaikyi, or O. In one embodiment, formula (LXXXVI) is diacerein.

In one embodiment, the method employs a compound of formula (LXXXVl l):

In one embodiment, each R¹ independently = H, CI, Br, F, I, OH , ONa, OAc, CF3, NH₂, CN, ON0₂, GCi-s saturated , unsaturated alkyl, cycioaikyi, cycloheteroalkyl, or aryl, SC1 -5 saturated, unsaturated alkyi, cycloalkyl, cycloheteroalkyl, or aryl, Ci-s saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CO2H, COC1 -8 alkyl unsaturated alkyl, or aryl, CO2C1-6 saturated , unsaturated alkyl, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyl or aryl, C02N(Ci-e saturated, unsaturated alkyl or aryl)2, NHC-i-e saturated , unsaturated alkyl, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyi)₂, o Cs-jaryi or heteroaryl; each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-asaturated, unsaturated alkyl, or cycloalkyl, or O. In one embodiment, formula (LXXXVI) is dichlorphenamide.

In one embodiment, the method employs a compound of formula (LXXXVI 11):

in one embodiment, each R¹ independently = H, CI, Br, F, i , OH , ONa, OAc, CF₃, NH₂, CN, ONO2, OC1- saturated , unsaturated alkyl, cycioaikyi, cycloheteroalkyl, or aryl, SC1-6 saturated, unsaturated alkyl, cycioaikyi, cycloheteroalkyl, or aryl, Ci -e saturated alkyl, unsaturated alkyi, cycloalkyl, cycloheteroalkyl, CO2H, COC1-8 alkyl unsaturated alkyi, or aryl, CQ2C1-8 saturated , unsaturated alkyl, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyi or aryl, C0₂N(Ci-5 saturated, unsaturated alkyi or aryl)₂, NHC1-5 saturated , unsaturated alkyl, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl)₂, or Cs-7aryl or heteroaryl; and each X independently = C, CH, CH₂, S, SO, SO2, N, NH, NCi-esaturated, unsaturated alkyl, or cycioaikyi, or O. in one embodiment, formula (LXXXVI 11) is triclabendazole.

In one embodiment, the method employs a compound of formula (LXXXIX):

in one embodiment, each R¹ independently = H, CI, Br, F, I, OH , ONa, OAc, CF₃, NH₂, CN, N0₂, OCi -_S saturated , unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, SC1-6 saturated, unsaturated aikyl, cycloalkyl, cycloheteroalkyl, or aryl, C1 -6 saturated alkyl, unsaturated alkyi, cycloalkyl, cycloheteroalkyl, CO2H, COC1-8 aikyl unsaturated alkyl, or aryl, CQ2C1 -8 saturated , unsaturated alkyl, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyi or aryl, C02N(Ci-e saturated, unsaturated alkyi or aryl)2, NHC1 -5 saturated , unsaturated alkyl, or cycloalkyl, N(Ci-e saturated, unsaturated aikyl, or cycloalkyl, or Cs-7aryl or heteroaryl; and each X independently = CH, CH2, S, SO, SO2, N, NH, NC i-ssaturated, unsaturated alkyl, or cycloalkyl, or O. In one embodiment, formula (LXXXIX) is flubendazole.

In one embodiment, the method employs a compound of formula (LXXXX):

in one embodiment, each R¹ independently = H, CI, Br, F, I, OH , ONa, OAc, CF₃, NH₂, CN, N0₂, OC1-6 saturated , unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, SC1-6 saturated, unsaturated alkyi, cycloalkyl, cycloheteroalkyl, or aryl, C1-6 saturated alkyl, unsaturated alkyi, cycloalkyl, cycloheteroalkyl, CO2H, COC1-8 aikyl unsaturated alkyl, or aryl, CQ2C1 -8 saturated , unsaturated alkyl, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyi or aryl, C02N(Ci-e saturated, unsaturated alkyi or aryl)2, NHC1-6 saturated , unsaturated alkyi, or cycloalkyl, N(Ci-e saturated, unsaturated aikyl, or cycloalkyi)₂, o C5-7aryl or heteroaryl; each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi -ssaturated, unsaturated alkyi, or cycloalkyl, or O; and n = 0-6. in one embodiment, formula (LXXXX) is nisoldipine.

In one embodiment, the method employs a compound of formula (LXXXXI):

In one embodiment, each R¹ independently = H, CI, Br, F, I, OH , ONa, OAc, CF₃, NH₂, CN, NO2, OC i-s saturated , unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, SC1 -5 saturated, unsaturated alkyi, cycloalkyl, cycloheteroalkyl, or aryl, C1-6 saturated alkyl, unsaturated alkyi, cycloalkyl, cycloheteroalkyl, CO2H, COC1-8 alkyl unsaturated alkyl, or aryl, CO2C1-8 saturated , unsaturated alkyi, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyl or aryl, C02 (Ci-e saturated, unsaturated alkyi or aryl)2, NHC1-6 saturated , unsaturated alkyl, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl^, o C5- a i or heteroaryl; and each X independently = CH, CH₂, S, SO, SO2, N, NH, NCi-ssaturated, unsaturated alkyi, or cycloalkyl, or O. In one embodiment, formula (LXXXXI) is trioxsalen .

In one embodiment, the method employs a compound of formula (LXXXXIi):

in one embodiment each R¹ independently = H, CI, Br, F, I, OH, ONa, OAc, CF₃, NH₂, CN, N0₂, OCi-₅ saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or ary!, SCi-e saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, or ary!, Ci-e saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, COzH, COC1-0 alkyl unsaturated alkyl, or aryl, CO2C1-6 saturated, unsaturated alkyl, or aryl, CONH2, CO2NHC1-B saturated, unsaturated alkyl or aryl, C02 (CI-B saturated, unsaturated alkyl or aryl)2, NHCI-B saturated, unsaturated alkyl, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl, or Cs-v-aryi or heteroaryl; X = C, CH, CH², S, N, NH, NC ⁸saturated, unsaturated alkyl, or cycloalkyl, or O; and each n independently = 0-6. in one embodiment, formula (LXXXXil) is teimisartan.

In one embodiment, the method employs a compound of formula (LXXXXil I):

in one embodiment, each R¹ independently = H, CI, Br, F, i, OH, ONa, OAc, CF₃, NH₂, CN, NO2, OC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, SC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, Ci-s saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CO2H, COC1-8 alkyl unsaturated alkyl, or aryl, CO2C1-6 saturated, unsaturated alkyl, or aryl, CONH2,

CO2NHC1-6 saturated, unsaturated alkyl or aryl, C02N(Ci-e saturated, unsaturated alkyl or aryl)₂, NHCi-e saturated, unsaturated alkyl, or cycloalkyl, N(Ci-6 saturated, unsaturated alkyl, or cycloalkyl, o Cs-raryl or heteroaryl; each X independently = C, CH, CH2, S, N, NH, NCi-esaturated, unsaturated alkyl, or cycloalkyl, or O; and n = 0-6. In one embodiment, formula (LXXXXil I) is stanozolol.

The compounds described above may thus be employed in one embodiment to prevent, inhibit or treat one or more symptoms associated with epileptic encephalopathies. Epileptic encephalopathies are a group of rare, severe neurological disorders manifesting in childhood that may be strongly associated with de novo mutations. As described below, a simple rapidly generated, cellular assay was developed to model an individual's rare-genetic disorder and this model was applied to high throughput screening methods to identify patient specific indications for approved drugs, in various embodiments, compositions and methods are provided for mitigating in a mammal one or more symptoms associated with a disease characterized by seizures, or delaying or preventing the onset of symptoms thereof. Methods are also provided for reducing the risk, lessening the severity, or delaying the progression or onset of a disease characterized by dysfunction of a potassium channel in a mammal, in certain embodiments, methods are provided for preventing or delaying the onset of a seizure activity in a mammal. In certain embodiments, compositions and methods are provided for modulating, e.g., voltage-gated, potassium channel activity in a mammal, in certain embodiments, compositions and methods are provided for altering function of voltage-gated potassium channels in a mammal.

The methods described herein are based, in part, on the discovery that certain compounds, including those with other different activities/targets, were effective to decrease the activity of a potassium channel, e.g., by decreasing potassium ion flow through the channel. Thus, one or more of the compounds described herein or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, ester, amide, solvate, hydrate, or prodrug thereof or derivatives thereof, as well as one or more compounds of formulas (l)-(LXXXXill), a compound in Table 1 , 2, 3, 4, or 5, or a combination thereof, may be useful to modulate, in one embodiment, the activity of potassium channels.

Accordingly, in various embodiments, a compound of formula (l)-(LXXXXIil), a compound in Table 1 , 2, 3, 4 or 5, or formulations thereof and/or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, ester, amide, solvate, hydrate, or prodrug thereof, or a derivative, inhibits or treats epilepsy or cardiac dysfunction. In certain embodiments, the compounds or formulations thereof are used to prevent or delay the onset of one or more symptoms and/or to ameliorate one or more symptoms, and/or to prevent or delay the progression of the disease. In certain embodiments, the compound or formulations thereof are used in a method of mitigating in a mammal, one or more symptoms associated with a by seizures, developmental delay or cognitive impairment, or slow after hyperpo!arizing activity pathological condition characterized of a mammal are also provided. In certain embodiments, methods of directly or indirectly impacting potassium channels, in a mammal are provided.

Typically, each of these methods involve administering one or more compounds or formulations thereof and/or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, ester, amide, solvate, hydrate, or prodrug thereof, or a derivative thereof, in an amount sufficient to produce the desired activity, e.g., mitigating one or more symptoms associated with epilepsy or epileptic encephalopathies, or cardiac arrhythmias or delaying or preventing the onset of said symptoms, and/or reducing the risk, lessening the severity, or delaying the progression or onset of a disease characterized by altered potassium channel activity.

Pharmaceutical Compositions

Pharmaceutical compositions having one or more of the compounds described herein, suitable for administration, e.g., nasal, parenteral or oral administration, such as by intravenous, intramuscular, topical or subcutaneous routes, or by any other route of administration that allows drug to be delivered to the body or specific organs and tissues of the body, such as intrathecal, intracerebroventricular or intraparenchymal delivery to the central nervous system, optionally further comprising sterile aqueous or non-aqueous solutions, suspensions, and emulsions. The compositions can further comprise auxiliary agents or excipients, as known in the art. The composition having one or more of the compounds described herein is generally presented in the form of individual doses (unit doses).

Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and/or emulsions, which may contain auxiliary agents or excipients known in the art.

Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Carriers or occlusive dressings can be used to increase skin permeability and enhance antigen absorption. Liquid dosage forms for oral administration may generally comprise a liposome solution containing the liquid dosage form. Suitable forms for suspending liposomes include emulsions, suspensions, solutions, syrups, and elixirs containing inert diluents commonly used in the art, such as purified water. Besides the inert diluents, such compositions can also include adjuvants, wetting agents, emulsifying and suspending agents, or sweetening , flavoring , or perfuming agents.

When a composition having one or more of the compounds described herein is used for administration to an individual, it can further comprise salts, buffers, adjuvants, or other substances which are desirable for improving the efficacy of the composition .

In one embodiment, the pharmaceutical composition is part of a controlled release system, e.g., one having a pump, or formed of polymeric materials (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres. , Boca Raton , Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Bali (eds.), Wiley, New York (1984); Ranger & Peppas, J,.

Macromol. Sci. Rev. Macromol. Chem. , 23:81 (1983); see also Levy et a!., Science, 228: 190 (1985); During et al., Ann . Neurol. , 25:351 (1989); Howard et ai. , J. Neurosurg ., H: 105 (1989)). Other controlled release systems are discussed in the review by Langer (Science, 249:1 527 (1990)).

The pharmaceutical compositions having one or more of the compounds described herein comprise a therapeutically effective amount of compounds, for instance, those identified by the screening methods, and a pharmaceutically acceptable carrier, in a specific embodiment, the term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeiaes for use in animals, and more particularly in humans. The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the pharmaceutical composition is administered . Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable

pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin , malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monosfearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, efhanoi and the like. These compositions can take the form of solutions, suspensions, emulsion , tablets, pills, capsules, powders, sustained-release formulations and the like. These compositions can be formulated as a suppository. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E. W. Martin. Such compositions will contain a therapeutically effective, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration.

The compositions may be systemically administered, e.g. , orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent. For oral administration, the compound(s) may be combined with one or more excipients and used in the form of ingesiible capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions should contain at least 0.1 % of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such useful compositions is such that an effective dosage level will be obtained.

The compositions may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients 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 may be added. Various other materials may be present. For instance, a syrup or elixir may contain the 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, including sustained-release preparations or devices, should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.

The composition can also be delivered by intravenous, intraperitoneal, intra-arterial, intrathecal, intraparenchymal or intracerebroventricular infusion or injection, or any other route of administration where delivery of a liquid formulation is suitable or appropriate for drug delivery. Solutions of the compound(s) can be prepared in water or a suitable buffer, 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 contain a preservative to prevent the growth of undesirable microorganisms.

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, in ail cases, 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 polyoi (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. The prevention of the action of undesirable microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chiorobutanol, 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.

Sterile injectable solutions are prepared by incorporating the compound(s) in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by irradiation, steam (heat) or filter sterilization or any other preparatory method that results in a formulation thai is essentially free of bacterial and/or viral contamination.

Useful liquid carriers include water, alcohols or glycols or water-aicohol/giycol blends, in which the present compound(s) 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.

Useful dosages of the compositions can be determined by comparing their in vitro activity and in vivo activity in animal models.

Exemplary Embodiments

There is increasing interest in repurposing FDA approved drugs to treat rare genetic conditions with several recent examples emerging, particularly in epilepsy. Here, candidate drugs were identified for repurpose, focusing on gain of function mutations in KCNT1 , A small molecule chemical library of 1 ,320 compounds including FDA approved drugs and drugs approved outside the United States (e.g., by E A and other foreign regulatory agencies) was tested for activity in a heterologous expression system expressing the mutated P924L KCNT1 channels. 41 candidate compounds were identified that significantly inhibited the gain of function associated with the respective pathogenic mutation, in one embodiment, certain compounds that produced greater than 10%, 20%, 30% or more inhibition (> 2 standard deviations away from the mean inhibition). These results identify new candidate therapies for epilepsy and cardiac dysfunction patients with KCNT1 mutations and illustrate the value of comprehensive repurposing effectiveness screening (CRES or CRS), as a strategy to identify candidate repurposed drugs. These findings show the power of developing personalized cellular models for human disease linked mutations and utilizing CRES to identify new putative therapeutic options.

The sequence of exemplary potassium channels, the activity of which in a mammal may be altered by compounds, are shown in Figure 1 . in one embodiment, potassium channels, the activity of which may be altered, e.g., inhibited, by compounds described herein, include those having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity to one of SEQ ID NOs:1 -2. in one embodiment, ion channel activity of which may be altered by compounds described herein, include those having an amino acid residue other than proline at a residue corresponding to residue 924 in SEQ ID NO:1 or other than argsnsne at a residue corresponding to residue 398. For example, the compounds may have particular use for mammals with an amino acid residue in KCNT1 , other than P924, e.g., at position 924 in KCNT1 the mammal has L, S, A, i, V, G, or T, or other than R398, e.g., at position 398 in KCNT1 the mammal has Q, N, L, S, A, L V, G, or T. it is also envisioned that the compounds disclosed herein alter the activity of other variants of KCNT1 , e.g., other gain-of-fu notion variants, e.g., KCNT1 proteins having 1 , 2, 3, 5 10 or up to 20 amino acid substitutions relative to one of SEQ ID Nos. 1 -2.

The invention will be further described by the following non-limiting examples.

Exampje 1

Materials and Method

A cellular model of a patient's KCNT1 P924L mutation was generated in CHO cells. The cellular model contains a replica of the KCNT1 P924L mutation identified in the patient's sequencing report. This was done by genetically altering a healthy KCNT1 DNA sequence to the mutant KCNT1 P924L sequence (C.27710T) and then inserting this mutant DNA sequence into cells in a controlled laboratory environment.

A rubidium efflux assay was used a proxy for potassium to measure ion flow through the Slack channel. Rubidium (Rb) ions have the same charge as potassium ions, are nearly the same size, and move freely through many potassium channels, including Slack. Cells loaded initially with radioactive rubidium (⁸⁶Rb) can subsequently be stimulated to open Slack channels and allow efflux of the ⁸⁶Rb to the outside of the ceil. An ⁸⁶Rb efflux assay of this type was developed to characterize how the wild-type and mutant channels respond to added compounds.

The ⁸⁶Rb efflux assay was used to test both variant and wild-type cellular models with increasing concentrations of ioxapine, a known activator of Slack channels (Figure 2). The mutant cellular model displayed stronger ^S6Rb+ efflux in response to channel opening by Ioxapine than the wild-type cellular model: the EDso for the P924L cell model was 1 .7 μΜ, which was six-fold lower than the wild-type cell model with an EDso of 10.5 μΜ. Having confirmed thai the P924L mutation confers a gain-of-function to Slack channels (see also illigan et al, 2014), HTS was performed to search for compounds that might inhibit mutant Slack channel activity. Because the P924L mutation causes a gain of function in Slack channels, the KCNT1 P924L mutant cellular model was used to test for compounds that decrease potassium currents. These inhibitors of channel function could be useful therapeutic options for evaluation in patients with such KCNT1 mutations,

A library of about 1 ,290 compounds was screened in the P924L mutant cellular model to identify compounds that significantly inhibited ⁸⁶Rb efflux. The inhibitory activities for all of the 1 ,290 compounds in the ^8eRb efflux assay are plotted by rank in order of activity in Figure 3. Each compound is represented by a blue dot. A total of 41 compounds had activity above 2 standard deviations (SD; orange line), and 20 of those were also above 3 SD (green line). Most compounds (>95%) had activity below the 2 SD line and were considered statistically insignificant.

Table 1 A shows results from the high-throughput screen listing the 41 compounds with inhibition that was greater than 2 standard deviations from the group mean (3.9% ± 13.7%). Screening was based on incubation of ceils with 10 μ of each compound. In follow-on testing the hit compounds from the screening study were evaluated across a series of concentration ranging from 0.03 μΜ to 100 μΜ. From this experiment, concentration-response curves (CRC) could be generated that served to confirm the inhibitory activity of the compound at the KCNT1 P924L channel and measure the EDso (concentration at which the compound yielded 50% of maximal inhibitory activity), an indicator of potency and maximal effectiveness (greatest level of inhibition). The results from CRC testing are shown in Table 1 B using the rubidium ion efflux assay as well as electrophysiology. The latter used patch clamp methodology across a series of concentrations ranging from 0.03 μΜ to 300 μΜ to derive a measure of ED50 and maximal effectiveness. Table 1 A shows results from the high-throughput screen listing the 41 compounds with inhibition that was greater than 2 standard deviations from the group mean (3.9% ± 13,7%). Screening was based on incubation of ceils with 10 μΜ of each compound. In follow-on testing the hit compounds from the screening study were evaluated across a series of concentration ranging from 0,03 μ to 100 μΜ. From this experiment, concentration-response curves (CRC) could be generated that served to confirm the inhibitory activity of the compound at the KCNT1 P924L channel and measure the EDso (concentration at which the compound yielded 50% of maximal inhibitory activity), an indicator of potency and maximal effectiveness (greatest level of inhibition). The results from CRC testing are shown in Table 1 B using the rubidium ion efflux assay as well as electrophysiology. The latter used patch clamp methodology across a series of concentrations ranging from 0.03 μΜ to 300 μΜ to derive a measure of EDso and maximal effectiveness.

Table 1 A. Compounds with significant inhibitory activity from the P924L KCNT1 HEK293 High Throughput Screen

Compound Inhibition at 10 μΜ (%)

Ritonavir 81.9

Hexestrol 76.1

Racecadotril 75.1

Doxazosin mesylate 74.3

Eeonazole nitrate 66.1

Carvedi!ol 65.8

fvlometasorse furoate 59.0

Dienestrol 56.4

Lomeriziree hydrochloride 55.6

Ezetimibe 52.3

Loteprednol etabonate 49.0

aititrexed 49.0

Nicergoiirse 48.2

Vinpocetine 47.5

Triclosars 46.8

Estradiol-17 beta 46.5

eifinavir mesylate 45.7

Fenofibrate 45.7

Sulconazole nitrate 42.5

Sertacorsazole nitrate 40.5

Mifepristone 40.1

Thonzonium bromide 39.0

Mafenide hydrochloride 38.9

Halcinonide 38.6

Bromhexine hydrochloride 38.1

Tegaserod rnaieate 37.5

Aiprostadil 36.1

Saquinavir mesylate 35.2

Sarafloxacin 35.2

Pinaverium bromide 35.2

Prenylamine lactate 35.1

Miconazole 34.3

Clobetasoi propionate 33.5

Fulvestrant 33.3

Bifonazole 32.9

Zafirlukast 32.3

Fluspiriien 32.3

Vatalanib 31.5

Compounds in Bold are >3 standard deviation above the group mean (45% or greater); compounds in plain text are >2 standard deviations above the group mean (31 to 44%).

Table 1 B. Results from CRC testing of P924L KCNT1 HEK293 using patch clamp eiectrophysiology and the rubidium efflux assay Electrophysiology Rubidium Efflux Assay

Compound EDso Max Effect EDso Max Effect

(μΜ) (%) (μ ) (%)

Carvediloi 0.5 101.7 1.4 114.2

Loperamide hydrochloride 0.9 103.0 0.4 105.8

Raloxifene hydrochloride 1.7 100.3 0.6 108.2

Doxazosin mesylate 3.3 101.5 1.6 105.4

Diethylstilbestro! 5.0 87.8 0.7 117.2

Ezetimibe N/A 69.7 2.4 106.4

Mometasone furoate N/A 68.5 1.7 86.4

Econazoie nitrate N/A 68.2 2.5 97.2

Fenofibrate N/A 67.5 3.2 100.2

Hexestrol N/T N/T 0.8 114.4

Racecadotril N/T N/T 1.8 89.5

Sulconazole nitrate N/T N/T 3.0 105,5

Dienesfrol N/T N/T 3.2 108.5

Ritonavir N/T N/T 3.5 110.9

Sertaconazo!e nitrate N/r N/T 3.7 102.0

Bifonazole N/r N/T 3.8 112.7

Nelfinavir mesylate N T N/T 5.0 81.2

Estradiol-17 beta N/T N/T 5.5 94.5

Miconazole N/T N/T 5.5 91.7

Nicergoline N/T N/T 7.1 104.6

Lomerizine hydrochloride N/T N/T 9.4 127.2

N/A = not measurable due to linear curve across the series of compound concentrations; N/T = not tested.

Example 2

A second model with a different KCNT1 mutation (R398Q) using different host cell (Xenopus oocytes) for electrophysiology was also tested (see Table 2), The R398Q mutation was shown previously to be a gain -of-f u n ctio n mutation (Milligan et ai, 2014). The R398Q mutation is in an entirely different region of the KNCT1 protein than the P924L mutation from Example 1 with a different structural alteration, but still results in a gain-of-function mutation. The test system was Xenopus Oocyt.es that are a convenient model for transiently expressing a mutation and evaluating the effect with electrophysiology using methods standard to the field. For this study, a smaller, select library of 62 drugs were evaluated including compounds that had shown inhibitory activity in the KCNT1 P924L and/or WT model, a panel of 20 AEDs. Of the 82 drugs evaluated for inhibitory activity at 100 μΜ, 13 showed some measurable level of inhibition ranging from 2.7 to 109.6% (Table 2). These 13 compounds were evaluated further across a concentration series (ranging from 0.01 μ to 100 μΜ) to confirm their activity and determine an EDso and maximal effectiveness (Table 2). Five drugs had a measurable EDso with Loperamide demonstrating greatest potency (EDSO = 1 .3 μΜ) and activity (Maximal Effect = 95.1 %). Notably, Loperamide was also one of the most potent compounds in the P924L model above.

Table 2. Results for testing of drugs for inhibitory activity in the R398Q KCNT1 Xenopus oocyte model Single

Concentration-Response Curve Testing Concentration

Inhibition at

Compound CRC ED₅₀ (μΜ) Max effect (%)

100 μΜ (%)

Loperamide hydrochloride 77.6 1.3 95.1

Flunarizine dihydrochloride 109.6 1.5 46.1

Doxazosin mesylate 21.0 9.7 76.4

Oxethazaine 48.8 16.6 62.8

Nicergoline 33.7 34.8 76.9

Pridinol methanesulfonate salt 18.2 N/A 32.8

Mexiletine hydrochloride 46.7 N/E N/E

Retigabine 32.1 N/E N/E

Valproic acid 32.0 N/E N/E

Nitrendipine 22.3 N/E N/E

Clobazam 8.4 N/T N/T

Gabapentin 3.0 N/E N/E

Vigabatrin hydrochloride 2.7 N/E N/E

not available due to linear curve, N/E = no effect, N/T = not tested. in reviewing the compounds with activity from the KCNT1 P924L screen (Tabie 1 A), two

structural/mechanistic classes stand out. They are the synthetic estrogens (see Table 3) and imidazole antifungals (see Tabie 4). These structures give insight into requirements for inhibiting the KCNT1 channel. There are even some similarities between the aromaticity of the aromatic rings of the two classes.

Table 3. Synthetic Estrogens from the screening library that inhibited activity in the P924L KCNT1 variant cell model.

Table 4. Imidazoles from the screening library that inhibited activity in the P924L KCNT1 variant ceil

The drug library was also used to screen normal or wild-type KCNT1 wild-type for inhibitors using the same methods as described in Example 1 . A total of 56 out of 1 ,320 compounds (4.2%) that were screened demonstrated significant inhibitory activity on ion flow or conductance, defined as inhibition that was greater than two standard deviations from the overall mean inhibition of all compounds tested (8.0% ± 20.2%); see Table 5A. As in the above examples, compounds with significant activity on the drug screen were then evaluated by CRC testing to confirm activity and derive an ED50 and maximal effectiveness. Results for CRC testing are shown in Tabie 5B based on the rubidium efflux assay and patch clamp electrophysiology.

Table 5A. WT CNT1 HEK293 HTS

Compound inhibition at 10 μ ( )

Mometasone furoate 92.8

Loperamide hydrochloride 91.7

Miconazole 90.6 acecadotril 89.7

Acetazolamide 88.3

Avermectin Bl 86.0

Doxazosin mesylate 85.1

Fulvestrant 81.2

Algestone acetophenide 79.2

Liranaftate 78.9

Fenofibrate 77.6

Dienestrol 77.0

Cromolyn disodium salt 75.5

Diacerein 74.4

Raloxifene hydrochloride 71.1

Dichlorphenamide 70.9

Mitotarse 70.7

Ne rapine 69.3

Nitrofural 67.9

THIP Hydrochloride 66.3

Fentiazac 66.2

Thiabendazole 66.0

Mevalonic-D, L acid lactone 66.0

Fluspirilen 63.8

Triciosan 62.0

Flubendazol 61.9

Suloctidil 61.9

Clotrimazole 60.9

Bromhexine hydrochioride 60.4

Stanozolol 59.8

Nisoldipine 59.6

Ceftazidime pentahydrate 59.2

Halcinonide 58.9

Loratadine 58.1

Oxandroione 57.6

Darifenacin hydrobromide 57.5

Amifostine 56.6

Ganaxolone 56.0

Econazo!e nitrate 54.4

Tolperisone hydrochioride 54.0

Trioxsalen 53.7

Dosulepin hydrochloride 52.6

Ethinylestradiol 52.4

Nifurtimox 52.1

Telmisartan 51.8 Compound inhibition at 10 μ ( )

Amprolium hydrochloride 51.4

Amantadine hydrochloride 50.5

Decamethonium bromide 49.3

Terfenadine 49.0

Alprostadil 48.9

Compounds in Bold are >3 standard deviation above the group mean (68% or greater); compounds in plain text are >2 standard deviations above the group mean (48 to 68%).

Table 5B. Results for Concentration-Response Curve Testing of drug for inhibitory activity in the WT

KCNT1 HEK293 cell model

References

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Brown et al., Nature neuroscience 13, 819-821 , doi:10.1038/nn.2563 (2010).

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All publications, patents and patent applications are incorporated herein by reference. While in the foregoing specification, this invention has been described in relation to certain preferred embodiments thereof, and many details have been set forth for purposes of illustration, it will be apparent to those skilled in the art that the invention is susceptible to additional embodiments and that certain of the details herein may be varied considerably without departing from the basic principles of the invention.

Claims

WHAT IS CLAIMED IS:

1 , A method to prevent, inhibit or treat one or more symptoms associated with epilepsy, encephaiopathies or cardiac dysfunction in a mammal, comprising: administering to the mammal an effective amount of a composition comprising a compound of formula (l)-(LXXXXIII), a compound in Tabie 1 , 2, 3, 4, or 5, or a pharmaceutically acceptable salt thereof, or any combination thereof.

2. The method of claim 1 wherein the composition comprises a compound of formula (I):

wherein each R¹ independently = Aryl or heteroaryl; wherein R² = CONffe,

or OCi ssaturated, unsaturated alkyl, cycloalkyl, or heterocycloalkyl; wherein R³ = OH, CN, NH2, OCi-esaturated or unsaturated alkyl, NHCi-asatu rated or unsaturated alkyl, or N(Ci-ssaturated or unsaturated aiky)2; wherein R⁴ = Aryl, heteroaryl, or 4-CI-Cel-U; wherein A = CH or N; and wherein n = 0=6

The method of claim 1 wherein the compound has formula (la):

wherein each R¹ independently is CI, Br, F, I, OH, NH2, CN, CO2H, CO2C1 -8 saturated or unsaturated alkyl, NHC-i-esaturated, unsaturated alkyl, or cycloalkyl, or N(Ci-esatu rated, unsaturated alkyl, or cycloalkyl); wherein R² = CO 62, C02Ci-+alkyl, or OCi -ssaturated, unsaturated alkyl, cycloalkyl, or heterocycloalkyl; wherein R³ = OH, CN, NH2, OCi-esaturated or unsaturated alkyl, NHCi-ssaturated or unsaturated alkyl, or N(C i-gsaturated or unsaturated alky)2; wherein R⁴ = Aryl, heteroaryl, or 4-CI-C8H4; wherein A is CH or N.

and wherein n = 0=8.

4. The method of any one of claims 1 to 3 wherein the composition comprises a compound of formula (II):

(II)

wherein each R¹ independently = CI, Br, F, I, OH, NH2, CN, CO2H, CO2C1-8 saturated or unsaturated alkyi, NHCi-esaturated, unsaturated alkyi, or cydoalkyl, or N(Ci ^saturated, unsaturated alkyl, or cycioaikyl)2; wherein R² = Aryl or heteroaryi, or OCi-ssaturated, unsaturated alkyl, cycioaikyl, or cycloheteroalkyl; wherein R³ = CH2, O, NH, or Nd -ssatu rated, unsaturated alkyi, or cydoalkyl; wherein R⁴ = Aryl or heteroaryi, OCi-esatu rated or unsaturated alkyi; and wherein A = CH2, NH, O, or S.

5. The method of any one of claims 1 to 4 wherein the compound has formula (ila):

wherein each R¹ independently is CI, Br, F, OH, NH2, CN, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHCi-esaturated, unsaturated alkyl, or cydoalkyl, or N(Ci-ssaturated, unsaturated alkyi, or cycioaikyl; wherein R² = Aryl or heteroaryi, or OCi-asaturated, unsaturated alkyl, cycioaikyl, or cycloheteroalkyl; wherein R³ = CH2, O, NH, or NCi-ssatu rated, unsaturated alkyi, or cydoalkyl; wherein R⁴ = Aryl or heteroaryi, OCi-esatu rated or unsaturated alkyi; and wherein A = CH2, NH, O, or S.

6. The method of any one of claims 1 to 5 wherein the composition comprises a compound of formula (ill):

(HI)

wherein each R independent^ CI, Br, F, i, OH, NH₂, CN, CO2H, CO2C1-S saturated or unsaturated alkyi, NHC i-ssaturated, unsaturated alkyi, or cycioaikyl, or N(Ci-₈saturated, unsaturated aikyl, or cycioaikyl; and wherein each R² independently^ Aryl, heteroaryi, OCi-asatu ated, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, or Ci-ssaturated alkyl, unsaturated aikyl, cydoalkyl, or cycloheteroalkyl. 7. The method of claim 6 wherein R¹ is CI, Br, OH, NH₂, CN, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated aikyl, or cycioaikyl, or N(Ci-e saturated, unsaturated alkyi, or cycioaikyl)2.

8. The method of claim 7 wherein R² is OC1-6 saturated, unsaturated aikyl, cydoalkyl, or

cycloheteroalkyl, or Ci-e saturated aikyl, unsaturated alkyl, cydoalkyl, or cycloheteroalkyl.

9. The method of any one of claims 1 to 8 wherein the composition comprises a compound of formula (IV):

(IV)

wherein R¹ = Ci, Br, F, I , OH, NH2, CN, CO2H, CO2C1-8 saturated or unsaturated aikyi, NHCi-ssaturated, unsaturated alkyi, or cycioaikyl, or N(Ci-ssaturated, unsaturated aikyl, or cycloalkyi^;

wherein R² = Aryi, heteroaryi, GCi-ssaturated, OC5-8 aryl or heteroaryl, unsaturated alkyi, cycloalkyi, cycioheteroaikyi, or Ci-ssaturated alkyi, unsaturated aikyl, cycioaikyl, or cycioheteroaikyi; wherein each A independents CH , CH2, N, NH, or NCi-ssaturated, unsaturated alkyi, or cycloalkyi, S, SO, SO2 or O; and n = 0-10, 10. The method of any one of claims 1 to 8 wherein the compound has formula (IVa):

wherein each A independently is = CH2, O, NH, or NC1-6 saturated, unsaturated alkyi, or cycioaikyl; wherein R² is Aryl, heteroaryl, OC1-6 saturated, OCs-β aryl or heteroaryi, unsaturated alkyi, cycioaikyl, cycioheteroaikyi, or Ci-ssaturated aikyl, unsaturated alkyi, cycioaikyl, or cycioheteroaikyi; wherein R¹ is OH , NH2, CN, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHCi-e saturated, unsaturated alkyi, or cycloalkyi, or N(Ci ^saturated, unsaturated aikyi, or cycioaikyl)?; and n = 0-10.

1 1 , The method of any one of claims 1 to 10 wherein the composition comprises a compound of formula (V):

wherein each R independently^ CI, Br, F, i, OH , NH2, CN , OCi-a saturated or unsaturated alkyi, CO2H, CO2C1-8 saturated or unsaturated aikyl, NHCi-oSaturated , unsaturated aikyl, or cycloalkyi, or N(Ci- ssaturated, unsaturated aikyi, or cycloalkyi^; wherein R² = CH2, O, NH , or NCi-ssaturated, unsaturated aikyl, or cycioaikyl; and wherein each A independently = CH, CH2, N, NH, or NCi-asaturated, unsaturated alkyi, or cycioaikyl, O S, SO, or SO2.

12. The method of claim 1 1 wherein each R¹ is independently = CH2, O, NH, or NCi-ssaturated, unsaturated alkyi, cycloalky, or cycioheterocyioalkyl. 13, The method of claim 1 1 or 12 wherein each A independently is CH, Ch , O, N, or NCi-ssaturated, unsaturated aikyi, or cycioalkyl.

The method of any one of claims 1 to 13 wherein the composition comprises a compound of (VI):

wherein each R¹ independently= Ch½, O, NH, NCi-ssaturated, unsaturated aikyi, cycloalky, or cycloheterocyloalkyl; wherein each R² independently^ CI, Br, F, I, OH, Nh , CN, OCi-s saturated or unsaturated alkyl, CO2H, CQ2C1 -S saturated or unsaturated alkyl, NHCi-ssatu rated, unsaturated alkyl, or cycioalkyl, or N(Ci-esaturated, unsaturated aikyi, or cycioalkyl^; wherein R^s = Aryi, heteroaryl, OC1- ssaiuraied, OC5-8 aryi or heteroaryl, unsaturated alkyl, cycioalkyl, cycloheteroalkyl, or Ci-esaturated alkyl, unsaturated alkyl, cycioalkyl, or cycloheteroalkyl; and wherein A = CH2, NH, NCi-ssaturated, unsaturated alkyl, or cycioalkyl, O or S, SO, or SO2.

15. The method of claim 14 wherein each R² independently is OH, NH2, CN, OC1-8 saturated or unsaturated aikyi, CO2H, CO2C1-8 saturated or unsaturated alkyl, NHCi-ssaturated, unsaturated alkyl, or cycioalkyl, or N(Gi-8saturated, unsaturated aikyi, or cycioalkyl)2.

The method of any one of claims 1 to 15 wherein the composition comprises a compound of 1 (Vii):

(VII)

wherein each R independentiy= CI, Br, F, I, OH, NH2, CN, OC1-8 saturated or unsaturated alkyl, CO2H, CO2C 1-S saturated or unsaturated alkyl, NHC i-ssaturated, unsaturated alkyl, or cycioalkyl, or N(Ci- esaturated, unsaturated alkyl, or cycioalkyl; wherein each R² = CH2, O, NH, NCi-ssaturated, unsaturated alkyl, cycloalky, or cycloheterocyloalkyl; wherein each A independents CH2, NH, NCi-esaturated, unsaturated aikyi, or cycioalkyl, O or S, SO, or S02; and each n independently= 0-10.

wherein R¹ is OH, NH2, CN, OCi-e saturated or unsaturated aikyi, NHCi-e saturated, unsaturated alkyl, or cycloalkyi, or N(Ci-e saturated, unsaturated alkyl, or cycloalkyl)2; wherein each A independently is CH2, NH, NCi-esaturated, unsaturated alkyl, or cycloalkyi, O, or S, SO, or SOz; wherein each R² independently is CH2, O, NH, NC1-6 saturated, unsaturated aikyl, cycloalky, or cycloheterocyloalkyl; and each n independents 0-10.

The method of any one of claims 1 to 17 wherein the composition comprises a compound of ί (VIII):

R^{2 1} R¹ R²

R R¹ R² R¹

(VI I i)

wherein each R^¾ independently³ CI, Br, F, I, OH, NH2, CN, OCi-s saturated or unsaturated alkyl, CO2H, CO2C1-8 saturated or unsaturated aikyl, NHCi-esaturated , unsaturated aikyl, or cycloalkyi, or N(Ci- esaiuraied, unsaturated alkyl, or cycloalkyi^; wherein each R² independently³ CH2, O, NH, NCi- esaturated, unsaturated aikyl, cycloalky, or cycloheterocyloalkyl; and wherein each A independently³ CH2 NH, NCi-esaturated, unsaturated aikyl, or cycloalkyi, O o S, SO, or S02.

19. The method of claim 18 wherein each R¹ independently is = OH, NH2, CN, OC1-3 saturated or unsaturated alkyl, CO2H , CO2C1-3 saturated or unsaturated alkyl, NHC1 -8 saturated, unsaturated alkyl, or cycloalkyi, or N(Ci-e saturated, unsaturated aikyl, or cycloalkyl)2.

20. The method of claim 18 or 19 wherein each A independently is CH2, NH, NCi-ssaturated, unsaturated alkyl, or cycloalkyi, O, o S.

21 . The method of any one of claims 1 to 20 wherein the composition comprises a compound of formula (IX):

(IX)

wherein each R independently³ H, F, CI, Br, OH, CF3, C1-6 Aryloxy, Ci-e saturated alkyl, CO2H, CO2C1-4 aikyl, SO2NH2, SO2NHC1-6 saturated alkyl, aryl orheteroaryl, S0₂N(Ci.-6 saturated alkyl, aryl orheteroaryl)2, or Cs-e aryl/heteroaryl; and wherein each A independently = CH2, NH, O, S, SO, or SO2.

22. The method of claim 21 wherein each R¹ independently is H, CI, Br, OH, CF3, C1 6 Aryloxy, C1-6 saturated alkyl, CO2H, CQ2C1-4 alkyl, SO2NH2, SO2NHC1-6 saturated aikyl, aryl or heteroaryl, S02N(Ci-6 saturated alkyl, aryl or heteroaryl)2, or C5-6 aryl or heteroaryl. 23, The method of any one of claims 1 to 22 wherein the composition comprises a compound of formula (X):

wherein each R¹ independently^ CI, Br, F, I, OH , NH2, CN , OCi-s saturated or unsaturated aikyi, CO2H, CO2C1-8 saturated or unsaturated aikyl, NHCi-esaturated , unsaturated aikyl, or cycioaikyi, or N(Ci- esaturated, unsaturated aikyi, or cycioaikyi^; wherein each R² independently^ CH2, O, NH, NCi- esaturated, unsaturated aikyi, cycloalky, or cycioheterocyioaikyl; wherein each A independently = CH2, NH, N, NCi-esaturated , unsaturated alkyi, or cycioaikyi, S, SO, SO2 or O; and n = 0-10.

wherein n = 0-6; wherein each R¹ independently is = Br, Ci, F, CN, OCi-s saturated or unsaturated alkyi, CO2H, CO2C1-8 saturated or unsaturated aikyl, NHCi-esaturated , unsaturated aikyl, or cycioaikyi, or N(Ci- esaiuraied, unsaturated aikyl, or cycioaikyi^; and wherein each A independently is CH2, NH, N, NCi- esaiuraied, unsaturated aikyl, or cycioaikyi, O, or S, SO, SO2. 25. The method of any one of claims 1 to 24 wherein the composition comprises a compound of formula (XI):

(XI)

wherein each R¹ independently = Aryl, heteroaryl, OC1 -esaturated, OCs-e aryl or heteroaryi, unsaturated alkyi, cycioaikyi, cydoheteroaikyi, C1 -8saturated aikyl, unsaturated alkyi, cycioaikyi, or cydoheteroaikyi; wherein R² = CI, Br, F, i, OH, NH2, CN, OC1-8 saturated or unsaturated aikyl, CO2H , CO2G1-8 saturated or unsaturated alkyi, NHCi-ssaturated, unsaturated alkyi, or cycioaikyi, or N(Ci- ssaturated, unsaturated aikyl, or cycloalky^; wherein R³ = CH2, O, NH , NCi-ssaturated, unsaturated aikyi, cydoaiky, or cycioheterocyioaikyl; wherein A = CH, N, or NCi-ssaturated, unsaturated aikyi, or cycioaikyi; and wherein n = 0-10. 26, The method of any one of claims 1 to 24 wherein the compound has formula (Xia):

wherein each R¹ independently is CI, Br, F, OH, NH2, CN, OCi-esatu rated, OC5-8 aryi or heteroaryl, unsaturated alkyi, cycloalkyl, cycioheteroalkyi, or Ci-ssaturated alkyi, unsaturated aikyl, cycloalkyl, or cycloheteroalkyl; wherein A is CH or N; wherein R² is OH, OC1-8 saturated or unsaturated aikyl, CO2H , CO2G1-8 saturated or unsaturated alkyi, NHd-ssaturated, unsaturated alkyi, or cycloalkyl, or N(Ci- ssaturated, unsaturated aikyl, or cycloalkyl)2.; and wherein each n independently = 0-6.

27. The method of any one of claims 1 to 26 wherein the composition comprises a compound of formula (Xii):

(XII)

wherein each R independently = Aryi, heteroaryl, OCi-ssaturated, OCs-e aryl or heteroaryl, unsaturated alkyi, cycloalkyl, cycioheteroalkyi, or Ci-asaturated aikyl, unsaturated alkyi, cycloalkyl, or cycloheteroalkyl; wherein each R² independently = CH2, O, NH, or Nd-ssaturated, unsaturated alkyi, cycioalky, or cycloheterocyioaikyi; wherein each R³ independently = Ci, Br, F, I, OH, NH2, GN, OC1-8 saturated or unsaturated aikyl, GO2H , CO2G1-8 saturated or unsaturated alkyi, NHCi-asaturated, unsaturated alkyi, or cycloalkyl, or N(Ci-ssaturated, unsaturated aikyl, or cycloalkyl^; wherein each A independently = CH2, CH, NH, N, NCi-ssaturated, unsaturated aikyl, or cycloalkyl, S, SO, SO2 or O; and wherein each n = 0-10.

28. The method of claim 27 wherein each R¹ independently is H2, NHCi-ssatu ated, unsaturated aikyl, or cycloalkyl, or N(Ci-ssaturated, unsaturated aikyl, or cycloalkyl, OCi-e saturated, OC5-8 aryi or heteroaryl, unsaturated alkyi, cycloalkyl, cycloheteroalkyl, or Ci-e saturated aikyl, unsaturated alkyi, cycloalkyl, or cycloheteroalkyl,

29. The method of claim 27 or 28 wherein each A independently is CH2, O, CH, NH, N, or NC1-6 saturated, unsaturated alkyi, or cycloalkyl. 30, The method of any one of claims 27 to 29 wherein each R² independently is CH2, O, NH, or NC1-6 saturated, unsaturated alkyi, cycioaiky, or cydoheterocyioaikyl.

31 , The method of any one of claims 27 to 30 wherein each R³ independently is OH , NH2, CN, OCi-e saturated or unsaturated alkyi, NHCi-e saturated, unsaturated alkyi, or cye!oa!kyl, or N(Ci-e saturated, unsaturated alkyi, or cycioalkyl)2.

32. The method of any one of claims 27 to 31 wherein n = 0-8.

33. The method of any one of claims 1 to 32 wherein the composition comprises a compound formula (XIII):

(XIII)

wherein each R¹ independently = Aryl, heteroaryl, Od-esaturated, OCs s ary! or heteroaryi, unsaturated alkyi, cycioaikyl, cycioheteroaikyl, or Ci-esaturated aikyl, unsaturated alkyi, cycloalkyl, or cycloheteroalkyi wherein R² = CH2, O, NH, NCi-esaturated, unsaturated alkyi, cycioaiky, or cydoheterocyioaikyl; wherein each R³ independently = CI, Br, F, 1, OH, NH₂, CN, OC1-8 saturated or unsaturated aikyl, CO2H , CO2C1-8 saturated or unsaturated aikyl, NHCi-esaturated, unsaturated aikyl, or cycloalkyl, or N(Ci-ssaturated, unsaturated aikyl, or cycloalkyl^; and wherein each A independently = CH2, CH, NH, N, NCi-ssaturated, unsaturated alkyi, or cycioaikyl, S, SO, SO2 or O.

34. The method of any one of claims 1 to 32 wherein the compound has formula (Xiila):

R³

wherein each R¹ independently is OC1-6 saturated, OCs-s aryl or heteroaryl, unsaturated alkyi, cycloalkyl, cycloheteroalkyi, orCi-e saturated alkyi, unsaturated alkyi, cycloalkyl, or cycloheteroalkyi; wherein each A independently is CH2, CH, O, NH, N, or NCi-esaturated, unsaturated aikyl, or cycloalkyl; wherein each R³ independently = CI, Br, F, I, OH, NH2, CN, OC1-8 saturated or unsaturated alkyi, CO2H, CO2C1-8 saturated or unsaturated alkyl, HCi-asatu rated, unsaturated alkyl, or cycloaikyi, or N(Ci-8saturated, unsaturated alkyl, or cycloaikyi^; wherein R² is = Ch , O, NH, or NC1-6 saturated, unsaturated alkyl, cycloalky, or cycloheterocyloalkyl. 35, The method of any one of claims 1 to 34 wherein the composition comprises a compound of formula (XIV):

(XIV)

wherein each R¹ independently = Aryl, heteroaryl, Od-esaturated, OCs s ary! or heteroaryl, unsaturated alkyl, cycloaikyi, cycloheteroalkyl, or Ci-esaturated alkyl, unsaturated alkyl, cycloaikyi, or cycloheteroalkyl; wherein R² = CH2, O, NH, NCi-esaturated, unsaturated alkyl, cycloalky, or cycloheterocyloalkyl; wherein each R³ independently = CI, Br, F, I, OH, NH₂, CN, OC 1-8 saturated or unsaturated alkyl, CO2H , CO2C1 -8 saturated or unsaturated alkyl, NHCi-esaturated, unsaturated alkyl, or cycloaikyi, or N(Ci-ssaturated, unsaturated alkyl, or cycloalky^; wherein each A independently = CH or N; and wherein each n independently = 0-10.

36. The method of any one of clai the compound has formula (XiVa):

wherein each R¹ independently is OC1-6 saturated, OCs-s aryl or heteroaryl, unsaturated alkyl, cycloaikyi, cycloheteroalkyl, or C1-6 saturated alkyl, unsaturated alkyl, cycloaikyi, or cycloheteroalkyl wherein each A independently is CH or N; wherein R² is = CH2, O, NH, or NC1-6 saturated, unsaturated alkyl, cycloalky, or cycloheterocyloalkyl; wherein each R³ independently = Ci, Br, F, i, OH, NH2, CN, QCt-e saturated or unsaturated alkyl, CO2H , CO2C1-8 saturated or unsaturated alkyl, NHCi-esaturated, unsaturated alkyl, or cycloaikyi, or N(Ci ^saturated, unsaturated alkyl, or cycloalkyl)2; and wherein n = 3.

37, The method of any one of claims 1 to 36 wherein the composition comprises a compound of formula (XV):

(XV) wherein each R¹ independently = H, hydroxy!, Aryi, heteroaryi, OCi-ssaturated, OC5-8 aryl or heteroaryl, unsaturated alkyl, cycloalky!, cyc!oheteroalky!, or Ci-ssaturated alkyl, unsaturated a!kyi, cycloaikyi, or cycloheteroaikyi; and wherein n = 0-10.

38, The method of claim 37 wherein each R¹ independently is H, OH , OCi-ssaturated, OC5-8 aryi heteroaryl, unsaturated alkyl, cycloaikyi, or cycloheteroaikyi, or Ci-i3saturated alkyl, unsaturated alkyl cycloaikyi, or cycloheteroaikyi.

39. The method of claim 37 or 38 wherein n = 0-4.

40. The method of any one of claims 1 to 39 wherein the composition comprises a compound of formula (XVI):

(XVI)

wherein each R independently = Aryl, heteroaryl, QCi-esaturated, OC5-8 aryl or heteroaryl, unsaturated alkyl, cycloaikyi, cycloheteroaikyi, d-8saturated alkyl, unsaturated alkyl, cycloaikyi, cycloheteroaikyi, CI, Br, F, I, OH, NH2, CN, OC i-s saturated or unsaturated alkyl, CO2H , CO2C1-8 saturated or unsaturated alkyl, HCi-ssatu rated, unsaturated alkyl, or cycloaikyi, or N(Ci-ssaturated, unsaturated alkyl, or cycloaikyi^; wherein R² = CH2, O, NH, NCi-ssaturated, unsaturated alkyl, cycioalky, or cycloheterocyloalkyl; wherein each A independently = CH2, CH, C, NH, N, or NCi-ssaturated, unsaturated alkyl or cycloaikyi, O, or S, SO, SO2; and wherein each n independently = 0-10.

wherein each R¹ independently is OCi-e saturated, OCs-s aryi or heteroaryl, unsaturated alkyl, cycioaikyi, cycioheteroalkyi, Ci-e saturated aikyi, unsaturated aikyl, cycioaikyi, cycioheteroalkyi, CI, Br, F, I, OH, NH2, CN, OC1-6 saturated or unsaturated aikyl, CO2H, CO2C1-6 saturated or unsaturated aikyi, NHC1-6 saturated, unsaturated alkyi, or cycioaikyi, or N(Ci-8saturated, unsaturated aikyi, or cycloalkyl)2; wherein each A independently is CH2, CH, C, NH, N, NC1-6 saturated, unsaturated alkyi, or cycioaikyi, O, or S, SO, or SO2; and wherein each n independently = 0-6.

42. The method of any one of claims 1 to 41 wherein the composition comprises a compound of formula (XVII):

(XVII)

wherein each R¹ independently = Aryi, heteroaryl, Od-esaturated, OC5-8 aryi or heteroaryl, unsaturated alkyi, cycioaikyi, cycioheteroalkyi, Ci-esaturaied aikyl, unsaturated aikyl, cycioaikyi, cycioheteroalkyi, CI, Br, F, i, OH, NH2, CN, OC1-8 saturated or unsaturated aikyl, CO2H, CO2C1-8 saturated or unsaturated alkyl, NHCi-esaturated, unsaturated alkyl, or cycioaikyi, or N(Ci-8saturated, unsaturated alkyi, or cycioaikyl)2; wherein each R² independently = CH2, O, NH, NCi-esaturated, unsaturated alkyl, cycloalky, or cycloheterocyloalkyi; and wherein each A independently = CH2, CH , C, NH, N, NCi-esatu rated, unsaturated alkyi, or cycioaikyi, O, or S, SO, SO2. 43. The method of any one of claims 1 to 41 wherein the compound has formula (XVila):

wherein each A independently is CH2, NH, NC1-8 saturated, unsaturated alkyi, or cycioaikyi, O, o S, SO, or SO2: and wherein each R¹ independently is = OC1-6 saturated, OC5-8 aryi or heteroaryl, unsaturated alkyl, cycioaikyi, cycioheteroalkyi, C1-8 saturated alkyl, unsaturated aikyi, cycioaikyi, cycioheteroalkyi, CI, Br, F, I, OH, NH2, CN, OCi-e saturated or unsaturated aikyl, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated alkyl, or cycioaikyi, or N(Ci-e saturated, unsaturated aikyi, or cycloalkyl)2.

44. The method of any one of claims 1 to 43 wherein the composition comprises a compound of formula (XVIII):

(XVIII) wherein each R¹ independently = Aryi, heteroaryi, GCi-esaturated, OC5-8 aryi or heteroaryi, unsaturated aikyl, cydoalkyl, cycloheteroalkyl, Ci-ssaturated aikyl, unsaturated alkyi, cydoalkyl, cycloheteroalkyl, Ci, Br, F, I, OH, NH2, CN, OC1-8 saturated or unsaturated aikyl, CO2H, C02Ci-e saturated or unsaturated alkyi, NHCi-esaturated , unsaturated alkyi, or cydoalkyl, or N(Ci-esaturated, unsaturated aikyl, or cydoalkyl; wherein each A independently = CH2, CH, C, NH, N, NCi-esaturated, unsaturated aikyl, or cydoalkyl, O, or S; and wherein each n independently = 0-10.

The method of any one of claims 1 to 43 wherein the compound has formula (XV

wherein each R¹ independently is = OC1-6 saturated, QC5-8 aryi or heteroaryi, unsaturated aikyl, cydoalkyl, cycloheteroalkyl, C i-s saturated aikyl, unsaturated alkyi, cydoalkyl, cycloheteroalkyl, CI, Br, F, I , OH, NH2, CN, OC1-6 saturated or unsaturated aikyl, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated alkyi, or cydoalkyl, or N(Ci-e saturated, unsaturated aikyl, or cycloalkyl)2_; wherein each R² independently is = CI, Br, or I; wherein each A independently is CH2, CH , C, NH, N , NHCi-e saturated, unsaturated alkyi, or cydoalkyl, O, or S and wherein each n independently = 0-6,

46. The method of any one of claims 1 to 45 wherein the composition comprises a compound of formula (XIX):

(XIX)

wherein each R independently = Aryi, heteroaryi, OCi-ssaturated, OC5-8 aryi or heteroaryi, unsaturated alkyi, cydoalkyl, cycloheteroalkyl, Ci-asaturated aikyl, unsaturated alkyi, cydoalkyl, cycloheteroalkyl, Ci, Br, F, I, OH, NH2, CN, OC1-8 saturated or unsaturated aikyl, COi , CO2C1-8 saturated or unsaturated aikyl, NHCi-ssaturated, unsaturated aikyl, or cydoalkyl, or N(C i-ssatu rated, unsaturated alkyi, or cycioaiky^; wherein each A independently = CH2, CH, C, NH, N, NCi-ssatu rated, unsaturated alkyi, or cydoalkyl, O, S, SO, or SO2; and wherein n = 0-10.

47 The method of any one of claims 1 to 45 wherein the compound has formula (XiXa):

wherein each R¹ independently is = OC5-6 aryl or heteroaryl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1 -6 saturated alky!, unsaturated a!kyi, cycloalkyl, cycloheteroalkyl, CI, Br, F, OH, NH2, CN, OC1-6 saturated or unsaturated alkyl, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHC1-6 saturated, unsaturated alkyl, or cycloalkyl, or N(Ci-6saturated, unsaturated alkyi, or cycloalkyl; wherein A is CH2, NH, NCi. saturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO2 and wherein n = 0-6.

48. The method of any one of claims 1 to 47 wherein the composition comprises a compound of formula (XX):

(XX)

wherein each R¹ independently = Aryl, heteroaryl, Od-ssaturated, OC5-8 aryl or heteroaryl, unsaturated alkyi, cycloalkyl, cycloheteroalkyl, Ci-ssaturated alkyl, unsaturated alkyi, cycloalkyl, cycloheteroalkyl, Gi, Br, F, 1 , OH, NH2, CN, OC1-3 saturated or unsaturated alkyl, CO2H, CG2C1-8 saturated or unsaturated alkyl, NHCi-ssaturated, unsaturated alkyl, or cycioaikyi, or N(Ci-esaturated, unsaturated alkyi, or cycioaikyi; wherein each A independently = CH2, CH , C, NH, N, NCi-ssatu rated, unsaturated alkyl, or cycloalkyl, O, S, SO, or S02; and wherein n = 0-10.

49. The method of any one of claims 1 to 47 wherein the compound has formula (XXa):

wherein each R¹ independently is OC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, NH₂, CN, CO2H , CO2C1-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycloalkyl, or N(Ci-e saturated, unsaturated alkyl, or cycloalkyl)2; wherein each A independently is CH2, CH, NH, N, NCi-esaturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO2 and wherein n = 0-8.

50. The method of any one of claims 1 to 49 wherein the composition comprises a compound of formula (XXI):

(XX!)

wherein each R ¹ independently = Aryi, heteroaryi, GCi ^saturated, OCs-s aryl or heteroaryl, unsaturated aikyl, cycloalkyl, cycloheteroalkyi, Ci-ssaturated aikyl, unsaturated alkyi, cycloalkyl, cycloheteroalkyi, CI, Br, F, I , OH , N H2, CN , OCi -s saturated or unsaturated aikyl, CO2H , CQ2C1-8 saturated or unsaturated aikyl, NHCi-ssaturated, unsaturated aikyl, or cycloalkyl, or N(Ci ^saturated, unsaturated alkyi, or cycloalkyl; wherein each A independently = CH2, CH , C, NH , N , NCi-ssaturated, unsaturated alkyi, or cycloalkyl, O, S, SO, or S02; and wherein n = 0-10.

51 . The method of any one of claims 1 to 49 wherein the compound has formula (XXia):

wherein each R¹ independently is OCi-e saturated, unsaturated aikyl, cycloalkyl, cycloheteroalkyi, Ci-e saturated aikyl, unsaturated aikyl, cycloalkyl, cycloheteroalkyi, CI , Br, F, I , OH , NH₂, CN , CO2H , C02Ci-₆ saturated or unsaturated alkyi, N HCi -e saturated, unsaturated aikyl, or cycloalkyl, or N(Ci-e saturated, unsaturated aikyl, or cycioalkyl)2; wherein each A independently is CH2, CH , NH , N , NCi-esaturated, unsaturated alkyi, or cycloalkyl, O, or S, SO, SO2; and wherein n = 0-6,

52. The method of any one of claims 1 to 51 wherein the composition comprises a compound of formula (XXI I) :

(XXii

wherein each R¹ independently = Aryl, heteroaryi, QCi-ssaturated, OC5-8 aryl or heteroaryl, unsaturated aikyl, cycloalkyl, cycloheteroalkyi, Ci-ssaturated aikyl, unsaturated alkyi, cycloalkyl, cycloheteroalkyi, CI, Br, F, I, OH , NH2, CN , OCi-e saturated or unsaturated aikyl, CO2H , CO2C1-3 saturated or unsaturated aikyl, NHCi-ssaturated, unsaturated aikyl, or cycloalkyl, or N(Ci-ssaturated, unsaturated aikyl, or cycloalkyl^; wherein R² = CH2, O, NH , NCi-ssaturated, unsaturated aikyl, cycloalky, or cycloheterocyloalkyl; wherein each A independently = CH2, CH , C , NH , N , NCi-ssaturated, unsaturated alkyi, or cycloalkyl, O, S, SO, or SO2; and wherein each n independently = 0-10.

53. The method of any one of claims 1 to 51 wherein the compound has formula (XXila):

wherein each R ¹ independently is OC1-6 saturated, unsaturated alkyl, cycioaikyi, cycloheteroalkyi, C1-6 saturated alky!, unsaturated a!kyi, cycioaikyi, cycloheteroalkyi, CI , Br, F, I , OH , NH₂, CN , CO2H , C02Ci-₆ saturated or unsaturated alkyl, N HCi -e saturated, unsaturated alkyl, or cycioaikyi, or N(Ci-e saturated, unsaturated aikyi, or cycloalkyl)2; wherein A is CH2, NH , NC1 -6 saturated, unsaturated alkyi, or cycioaikyi, O, S, SO, or SO2; and wherein n = 0-6.

The method of any one of claims 1 to 53 wherein the composition comprises a compound of (XXIII):

(XXI 11)

wherein each R¹ independently = Aryi, heteroaryi, OC-i-esaturated, OC5-8 aryl or heteroaryl, unsaturated alkyi, cycioaikyi, cycloheteroalkyi, Ci-ssaturaied aikyi, unsaturated aikyi, cycloalkyl, cycloheteroalkyi, CI, Br, F, i, OH , N H₂, CN , OC1-8 saturated or unsaturated aikyi, CO2H , CO2C 1-8 saturated or unsaturated alkyl, NHCi-esaturated, unsaturated alkyl, or cycloalkyl, or N(Ci-8saturated, unsaturated alkyi, or cycioaikyi^; wherein each R² independently = CH₂, O, N H , NCi-esaturated, unsaturated alkyl, cycloalky, or cycloheterocyloalkyi; and wherein each n independently = 0-10.

55. The method of claim 54 wherein each R¹ independently is OCi-e saturated, unsaturated aikyi, cycloalkyl, cycloheteroalkyi, Ci-e saturated alkyl, unsaturated alkyi, cycioaikyi, cycloheteroalkyi, Ci, Br, F, I , OH, NH2, CN, OCi-e saturated or unsaturated aikyi, CO2H , CO2C1-6 saturated or unsaturated alkyl, N HC1-6 saturated, unsaturated alkyl, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl^

56. The method of claim 54 or 55 wherein each R² independently is CH₂, O, NH, or NCi-ssaturated, unsaturated alkyi, cycloalky, or cycloheterocyloalkyi.

57. The method of claim 54, 55 or 56 wherein n is 0-6.

58. The method of any one of claims 1 to 57 wherein the composition comprises a compound of formula (XXIV):

(XXIV)

wherein each R¹ independently = Aryl, heteroaryl, Od-esaturated, OCs s aryl or heteroaryl, unsaturated alkyl, cycloalkyl, cycloheteroalkyi, Ci-ssaturated alkyl, unsaturated alkyi, cycloalkyl, cycloheteroalkyi, Ci, Br, F, i, OH, NH2, CN, OC1-3 saturated or unsaturated aikyl, CO2H, CG2C1-8 saturated or unsaturated alkyl, NHCi-esaturated, unsaturated aikyl, or cycioaikyi, or N(Ci ^saturated, unsaturated alkyl, or cycioaikyi; wherein each R² independently = CH2, O, NH, NCi-esaturated, unsaturated alkyl, cydoalky, or cycloheterocyioaikyi; and wherein each A independently = CH2, CH, C, NH, N, NCi-esaturated, unsaturated aikyl, or cycioaikyi, O, S, SO, or SO2.

59, The method of claim 58 wherein R² is CH2, O, NH, or NCre saturated, unsaturated alkyl, cydoalky, or cycloheterocyioaikyi.

80. The method of any one of claim the compound has formula (XXiVa):

wherein each R¹ independently is OCi-e saturated, unsaturated aikyl, cycioaikyi, cydoheteroaikyi, Ci-e saturated alkyl, unsaturated aikyl, cycioaikyi, cydoheteroaikyi, CI, Br, F, I, OH, NH₂, CN, C0₂H, C02Ci- saturated or unsaturated alkyl, NHCi-esatu rated, unsaturated aikyl, or cycioaikyi, or N(Ci-e saturated, unsaturated aikyl, or cycioalkyl)_2; and wherein each A independently is CH2, CH, NH, N, NCi-esaturated, unsaturated aikyl, or cycioaikyi, N, O, S, SO, or S02.

81 . The method of any one of claims 1 to 60 wherein the composition comprises a compound of formula (XXV):

(XXV)

wherein each R¹ independently = Aryl, heteroaryl, OCi-esatu rated, OC5-8 aryi or heteroaryl, unsaturated alkyi, cycioaikyi, cydoheteroaikyi, Ci-ssaiuraied alkyl, unsaturated aikyl, cycioaikyi, cydoheteroaikyi, CI, Br, F, I, OH, NH₂, CN, OC1-8 saturated or unsaturated alkyi, C0₂H, CO2C1-8 saturated or unsaturated alkyi, NHCi-esaturated, unsaturated alkyi, or cycioaikyi, or N(Ci-esaturated, unsaturated alkyi, or cycioaikyi^; wherein each A independently = CH2, CH, C, N, NH, NCi-esaturated, unsaturated alkyi, or cycioaikyi, O, S, SO, or SO2; and wherein each n independently = 0-10.

The method of any one of claims 1 to 60 wherein the compound has formula (XXVa):

wherein each A independently is CH2, C, N, NH, NC1-6 saturated, unsaturated aikyi, or cycioaikyi, O, S, SO, or SO2; wherein each R^¾ independently is = OCi-e saturated, unsaturated aikyi, cycioaikyi, cydoheteroaikyi, Ci-e saturated alkyl, unsaturated aikyi, cycioaikyi, cydoheteroaikyi, CI, Br, F, I, OH, NH2, CN, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycioaikyi, or N(Ci-6 saturated, unsaturated alkyl, or cycioaikyi^; wherein each R² independently is = CI, Br, I, F; and wherein each n independently = 0-10.

63. The method of any one of claims 1 to 62 wherein the composition comprises a compound of formula (XXVI):

R¹ F

(XXVi)

wherein each R^¾ independently = Aryl, heteroaryl, OCi-ssaturated, OC5-8 aryi or heteroaryi, unsaturated aikyi, cycioaikyi, cydoheteroaikyi, Ci-ssaiuraied alkyl, unsaturated aikyi, cycioaikyi, cydoheteroaikyi, CI, Br, F, I, OH, NH₂, CN, OC1-8 saturated or unsaturated alkyl, CO2H, CO2C1-8 saturated or unsaturated alkyl, NHd-esaturated, unsaturated alkyl, or cycioaikyi, or N(Ci-esatu rated, unsaturated alkyl, or cycioaikyl)2; and wherein each A independently = CH2, CH, NH, N, NCi-ssaturated, unsaturated alkyl, or cycioaikyi, O, or S. 64. The method of any one of claims 1 to 62 wherein the compound has formula (XXVia):

wherein each A independently is CH, N, O, or S; and each R independently = Aryl, heteroaryl, OC1- esaturated, OC5-8 aryl or heteroaryl, unsaturated alkyl, cycioaikyi, cydoheteroaikyi, Ci-ssaturated alkyl, unsaturated aikyi, cycioaikyi, cydoheteroaikyi, CI, Br, F, I, OH, NH2, CN, OC1-8 saturated or unsaturated alkyl, CO2H, CO2C1-8 saturated or unsaturated alkyl, NHCi-ssaturated, unsaturated alkyl, or cycioaikyi, or N(Ci-8saturated, unsaturated alkyl, or cycloaikyi)2. 65, The method of any one of claims 1 to 64 wherein the composition comprises a compound of formula (XXVII):

(XXVII)

wherein each R independently = Aryl, heteroaryl, OCi-asaturated, OC5-8 aryi or heteroaryi, unsaturated alkyl, cycloalkyi, cycloheteroalkyi, Ci-asaturated alkyl, unsaturated alkyi, cycloalkyi, cycloheteroalkyi, Ci, Br, F, I, OH, NH2, GN, OC1-8 saturated or unsaturated alkyi, GQ2H , CO2G1-8 saturated or unsaturated alkyi, NHd-ssatu rated, unsaturated alkyi, or cycloalkyi, or N(Ci-esaturated, unsaturated alkyi, or cycioaikyl)2; and wherein each A independently = CH2, GH, C, NH, N, NCi-esaturated, unsaturated alkyi, or cycloalkyi, O, or S, SO, SO2.

wherein each R independently = Aryi, heteroaryi, OCi-esaturated, OC5-8 aryl or heteroaryl, unsaturated alkyl, cycloalkyi, cycloheteroalkyi, Ci-asaturated alkyl, unsaturated alkyi, cycloalkyi, cycloheteroalkyi, Ci, Br, F, 1, OH, NH2, CN, OCi-s saturated or unsaturated alkyl, CO2H, CO2C1-8 saturated or unsaturated alkyl, NHCi-asaturated, unsaturated aikyl, or cycloalkyi, or N(Ci-ssaturated, unsaturated alkyl, or cycloalkyi^; and wherein each A independently is = CH2, CH, NH, N, NCi-ssaturated, unsaturated aikyl, or cycloalkyi,

67. The method of claim 65 or 66 wherein each R¹ independently is OC1-6 saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyi, C1-6 saturated alkyl, unsaturated alkyi, cycloalkyi, cycloheteroalkyi, CI, Br, F, I, OH, NH2, CN, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHCi-e saturated, unsaturated aikyl, or cycloalkyi, or N(Ci-6 saturated, unsaturated alkyi, or cycioaikyl)2.

68. The method of any one of claims 1 to 67 wherein the composition comprises a compound of formula (XXVIII):

R (XXVI II)

wherein each R¹ independently = Aryi, heteroaryl, OCrssaturated, OC5-8 aryi or heteroaryl, unsaturated alkyl, cycioaikyl, cycioheieroaikyl, Ci-ssaturated alkyl, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, CI, Br, F, I, OH, NH2, CN, OC1-8 saturated or unsaturated alkyl, CO2H , CO2C1-8 saturated or unsaturated alkyl, NHCi-esaturated, unsaturated alkyl, or cycioaikyl, or N(Ci-esaturated, unsaturated alkyl, or cycioaikyl; wherein each R² independently = CH2, O, NH, NCi-ssaturated, unsaturated alkyl, cycioalky, or cycloheterocyloalkyl; wherein each A independently = CH2, CH, C, NH, N, NCi-esaturated, unsaturated alkyl, or cycioaikyl, O, S, SO, or SO2; and wherein n = 0-10.

89. The method of any one of claim the compound has formula (XXVII la):

wherein each A independently is CH2, CH, N, NH, NC1 -6 saturated, unsaiuraied alkyl, or cycioaikyl, O, S, SO, or SO2; wherein R² is CH2, O, NH, or NCi-e saturated, unsaturated alkyl, cycioalky, or

cycloheterocyloalkyl; and wherein each R¹ independently is OCi-s saiuraied, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, Ci-s saiuraied alkyl, unsaturated alkyl, cycioaikyl, cycioheieroaikyl, CI, Br, F, I, OH, NH2, CN, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaiuraied alkyl, or cycioaikyl, or N(Ci-6 saturated, unsaturated alkyl, or cycioalky^

70. The method of any one of claims 1 to 69 wherein the composition comprises a compound of formula (XXIX):

(XXIX)

wherein each R independently = Aryl, heteroaryl, OCi-asaturated, OC5-8 aryi or heteroaryl, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, Ci-8saturated alkyl, unsaturated aikyi, cycioaikyl, cycloheteroalkyl, CI, Br, F, I, OH, NH2, GN, OC1-8 saturated or unsaturated alkyl, CO2H , CO2G1-8 saturated or unsaturated alkyl, HCi-ssatu rated, unsaturated alkyl, or cycioaikyl, or N(Ci-ssaturated, unsaturated alkyl, or cycioaikyl^; wherein R² = CH2, O, NH, NCi-ssaturated, unsaturated alkyl, cycioalky, or cycloheterocyloalkyl; wherein each A independently = CH3, CH2, CH, C, NH2, NH, N, NHCi-ssaturated, unsaturated aikyi, or cycioaikyl, O, OH, S, SH, SO, SO2; and wherein each n independently = 0-10.

71 . The method of any one of claims 1 to 70 wherein the compound has formula (XXiXa):

wherein each A independently is CHs, CH2, CH, N, NH, NH2, NHC1-6 saturated, unsaturated alkyi, or cycloalkyi, O, OH, S, SH, SO, or SO2; wherein each R² independently is CH2, O, NH, or NC1-6 saturated, unsaturated alkyl, cycioaiky, or cycloheterocyloalkyl; wherein each R¹ independently is OC1-6 saturated, unsaturated alkyi, cycioaiky!, cycloheteroalkyl, Ci-e saturated alkyl, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, CI, Br, F, I, OH, NH₂, CN, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHC1-6 saturated, unsaturated alkyl, or cycloalkyi, or N(Ci-6 saturated, unsaturated alkyl, or cycloalkyi; and wherein each n independently = 0-6,

72. The method of any one of claims 1 to 71 wherein the composition comprises a compound of formula (XXX):

wherein each R^¾ independently = H, CI, Br, F, I , OH, NH₂, CN, OCi-e saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, or aryl, SCi-s saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, or aryl, Ci-e saturated alkyl, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHCi-e saturated, unsaturated alkyl, or cycloalkyi, N(Ci-e saturated, unsaturated alkyl, or cycloalkyi, or Cs-7aryl or heteroaryl; R² = OC1-6 saturated, unsaturated alkyl, cycloalkyi,

cycloheteroalkyl, SC 1-8 saturated, unsaturated alkyi, cycloalkyi, cycloheteroalkyl, o aryl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, or Cs-raryi or heteroaryl; and wherein each X independently = C, CH, or N.

73. The method of any one of claims 1 to 72 wherein the composition comprises a compound of formula (XXXI):

wherein each R independently = H, OC1-6 saturated, unsaturated alkyi, cycloalkyi,

cycloheteroalkyl, or ary!, SCi-e saturated, unsaturated alkyi, cycloalkyi, cycloheteroalkyl, or aryi, C1 -6 saturated alkyl, unsaturated alkyi, cycloalkyi, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NGa, CF3, NHa, CN, C0₂H, CO2C1-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycloalkyi, N(Ci-e saturated, unsaturated alkyl, or cycloaikyl)₂, or Cs-yaryi or heteroaryl; wherein each X independently = C, CH₂, N, NH, NCi-esaturated, unsaturated alkyl, or cycloalkyi, O, or S; and wherein each n independently ^: 0-6.

The method of any one of claims 1 to 73 wherein the composition comprises a compound of

wherein each R¹ independently = CH2, O, N H , NCi ^saturated, unsaturated alkyi, cycloalky, or

cycloheterocyloalkyl; wherein each R² independently = H, CI, Br, F, I, OAc, NO2, CF3, OH, N H2, CN , C1-6 saturated alkyl, unsaturated alkyl, cycloalky!, cycloheteroaikyl, OC1-6 saturated or unsaturated a!kyl, SC1-6 saturated or unsaturated alkyl, CO2H , CO2C1 -6 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated aikyl, or cycloalkyl, N(Ci-e saturated, unsaturated alkyi, or cycloalkyl)2, or Cs-7aryl or heteroaryl; and wherein each X independently = CH2, NCi-ssaturated, unsaturated alkyl, or cycloalkyl, or

75. The method of any one of claims 1 to 74 wherein the composition comprises a compound of

(XXX 111):

wherein each R¹ independently = H, Ci, Br, F, I, OH, OAc, CF3, NH2, CN, OCi-e saturated, unsaturated alkyi, cycloalkyl, cycloheteroaikyl, or aryi, SC1-6 saturated, unsaturated alkyi, cycloalkyl, cycloheteroaikyl, or aryi, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroaikyl, CO2H , CO2C1-6 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated alkyi, or cycloalkyl, N(Ci-e saturated, unsaturated alkyi, .or cycloalkyl, or Cs-7aryl or heteroaryl; wherein each X independently = C, CH2, N, NH, O, S, SO, or SO2; and wherein each n independently = 0-6. 76, The method of any one of claims 1 to 75 wherein the composition comprises a compound of formula (XXXIV):

wherein each R¹ = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated aikyl, cycloalkyl, cycloheteroaikyl, o aryi, SCi-e saturated, unsaturated alkyi, cycloalkyl, cycloheteroaikyl, or aryi, C1-6 saturated alkyl, unsaturated alkyi, cycloalkyl, cycloheteroaikyl, CO2H, CO2C1-8 saturated or unsaturated alkyl, NHC1-8 saturated, unsaturated alkyi, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalky^, orCs v-aryl or heteroaryl; each R² = CH2, S, O, NH, NC1-3 saturated, unsaturated aikyl, cycloalky, or cycloheterocyloalkyl; wherein each X = C, CH, CH2, N, NCi-asaturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SOa; and wherein each n = 0-6. The method of any one of claims 1 to 76 wherein the composition comprises a compound of

wherein each R¹ independently = H, Ci, Br, F, I , OH, OAc, CFs, NH2, CN, OC i-e saturated, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, or aryl, SC1 -5 saturated, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, or aryl, C1 -6 saturated alkyl, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, CO2H , CQ2C1 -5 saturated or unsaturated alkyl, NHC-i-e saturated, unsaturated alkyl, or cycioaikyl, N(Ci-6 saturated, unsaturated alkyl, or cycloalkyl)2, or Cs-jaryi or heteroaryl; R² = CH2, S, O, NH, NCi-asaturated, unsaturated alkyl, cycloalky, or cycloheterocyloalkyl; wherein each X independently = C, CH, CH2, N , NCi-esaturated, unsaturated alkyl, or cycioaikyl, O, SO, or SO2; and wherein each n independently = 0-6.

78. The method of any one of claims 1 to 77 wherein the composition comprises a compound of (XXXVI) :

wherein each R = H, CI, Br, F, i, OH, OAc, CF3, NH2, CN, OCi-e saturated, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, or aryl, SC1-6 saturated, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, or aryl, Ci-e saturated alkyl, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, C02H, C02C1 -6 saturated or unsaturated alkyl, NHCi-s saturated, unsaturated alkyi, or cycioaikyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl)2, Cs-7aryi or heteroaryl; wherein each X = C, CH , CH2, NH, N, NCi-esaturated, unsaturated alkyi, or cycioaikyl, O, S, SO, or SO2; and wherein each n = 0-10.

79. The method of any one of claims 1 to 78 wherein the composition comprises a compound of (XXX VI I) :

wherein each R¹ independently = H, Ci, Br, F, I, OH, OAc, CF3, NH2, CN, OCi-e saturated, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, or aryl, SC1-6 saturated, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, or aryl, C i-s saturated alkyl, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHC1 -5 saturated, unsaturated alkyi, or cycioaikyl, NiCs-s saturated, unsaturated alkyl, or cycioaikyl, or Cs-7aryl or heteroaryl; wherein each X independently = C, CH, CH2, NH, N, NHC1- esaturated , unsaturated alkyi, or cycioaikyl, O, S, SO, or S02_; and wherein n = 0-10. 80, The method of any one of claims 1 to 79 wherein the composition comprises a compound of formula (XXXVIII):

wherein each R¹ independently = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OCi-e saturated, unsaturated alkyi, cycioaikyi, cycloheteroalkyl, or aryi, SC1-6 saturated, unsaturated alkyi, cycioaikyi, cycioheteroalkyi, or aryi, Ci-e saturated alkyi, unsaturated aikyl, cycioaikyi, cycioheteroalkyi, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHC-i-e saturated, unsaturated aikyl, or cycioaikyi, N(Ci-6 saturated, unsaturated alkyi, or cycloalkyi)2, o Cs-raryl or heteroaryl; each R² independently = CH2, S, O, NH, NCi-esaturated, unsaturated alkyi, cycloalky, or cycloheterocyloalkyl; and wherein each X independently = CH, CH2, S, SO, SO2, NH, NCi-ssaturated, unsaturated alkyi, or cycioaikyi, or O.

81 . The method of any one of claims 1 to 80 wherein the composition comprises a compound of formula (XXXIX):

wherein each R independently = H, OCi-e saturated, unsaturated alkyi, cycioaikyi, cycioheteroalkyi, or aryi, SC1-6 saturated, unsaturated alkyi, cycioaikyi, cycioheteroalkyi, or aryi, Ci-e saturated alkyi, unsaturated aikyl, cycioaikyi, cycioheteroalkyi, CI, Br, F, I, OH, OAc, N0_2> CF₃, NH_2> CN, CO2H, C0₂Ci-_S saturated or unsaturated alkyi, NHCi-e saturated, unsaturated aikyl, or cycioaikyi, N(Ci-e saturated, unsaturated alkyi, or cycioaikyi^, or Cs yaryl or heteroaryl; and wherein each X independently = C, CH2, N,

82. The method of any one of claims 1 to 81 wherein the composition comprises a compound of formula (XXXX):

wherein each R¹ independently = CI, Br, F, I, OH, NH2, CN, CO2H, CO2C1-8 saturated or unsaturated alkyi, NHCi-esaturated, unsaturated alkyi, or cycioaikyi, N(Ci-8saturated, unsaturated alkyi, or cycioalkyl)2, C5- yaryl or heteroaryl, or 4-CI-C₆H4_; each R² independently = CI, Br, F, I, OH, CO2H , CN, NH₂, CON e₂, C02Ci- alkyl, OCi-ssatu rated, unsaturated alkyi, cycioaikyi, heterocycloalkyl, NHCi-ssaturated or unsaturated aikyl, N(Ci-ssaturated or unsaturated alky)2, or Cs-raryi or heteroaryl; wherein each R³ independently = C5-7 aryl or heteroaryl, 4-CI-C₆H₄, C0₂H, ON, NH_2> CON e₂, C0₂Ci-4aikyi, OC1- esaturated , unsaturated a!kyl, cycloalkyl, heterocycloalkyl, NHCi-esaturated or unsaturated alkyl, N(Ci- ssaturated or unsaturated alky)₂, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl; and wherein each X independently = C, CH, CH₂, S, SO, S0₂, N, NH, NCi-ssaturated, unsaturated alkyl, or cycloalkyl, or O.

83, The method of any one of claims 1 to 82 wherein the composition comprises a compound of formula (XXXXI):

wherein each R¹ independently = H, CI, Br, F, I, OH, NH₂, CN, C0₂H, CO2C1-6 saturated or unsaturated alkyl, NHCi-esaturated , unsaturated alkyl, or cycloalkyl, N(Ci-esaturated, unsaturated alkyl, or cycloalkyl^, OC1-6 saturated , unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, SC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-6 saturated alkyl, unsaturated aikyi, cycloalkyl, or cycloheteroalkyl, C5-7 aryl or heteroaryl; wherein each X independently = C, CH, CH₂, S, SO, SO2, N, NH, NCi-ssaturated, unsaturated alkyl, or cycloalkyl, or O; and wherein n = 0-6.

84. The method of any one of claims 1 to 83 wherein the composition comprises a compound of formula (XXXXI I):

wherein each R¹ independently = H, CI, Br, F, I, OH, OAc, CFs, NH₂, CN, OCi-e saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, SC1 -5 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1 -6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CO2H, CQ2C1 -5 saturated or unsaturated alkyl, NHCi-e saturated, unsaturated alkyl, or cycloalkyl, N(Ci-6 saturated, unsaiuraied alkyl, or cycloalkyi)₂, or Cs-raryl or heteroaryl; and wherein each X independently = C or N.

85. The method of any one of claims 1 to 84 wherein the composition comprises a compound of formula (XXXXIII):

wherein each R¹ independently = H, CI, Br, F, I, OH, OAc, CFs, NH₂, CN, OCi-e saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, SC1 -5 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryi, C1-6 saturated alkyl, unsaturated alkyi, cycloalkyi, cycioheteroalkyi, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycloalkyi, N(Ci-e saturated, unsaturated alkyl or cycloalkyi^, or Canary! or heteroaryl; and wherein each X independently = CH, CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated alkyl, or cycloalkyi, or O.

86, The method of any one of claims 1 to 85 wherein the composition comprises a compound of formula (XXXXIV):

wherein each R¹ independently = H, OC1-6 saturated, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, Ci- saturated alkyl, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, CI, Br, F, I, OH, OAc, Ac, CF3, NH2, CN, NO2, C(0)CH20Ac, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, cycloalkyi, N(Ci-6 saturated, unsaturated alkyl, or cycloalkyi, or Cs-yaryl or heteroaryl; wherein each X independently =CH, CH2, NH, NCi -esaturated, unsaturated alkyl, or cycloalkyi, O, S, SO, or SO?; and wherein n = 0-6.

87. The method of any one of claims 1 to 86 wherein the composition comprises a compound of formula (XXXXV):

wherein each R¹ independently = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OCi-e saturated, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, o aryi, SC1-6 saturated, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, or aryi, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycloalkyi, N(Ci-6 saturated, unsaturated alkyi, or cycloalkyi, or Cs-7aryl or heteroaryl; wherein each X independently = CH, CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated alkyl, or cycloalkyi, or O; and wherein n = 0-6.

88. The method of any one of claims 1 to 87 wherein the composition comprises a compound of formula (XXXXVI):

wherein each R independently = H, Ci, Br, F, I, OH, OAc, CF3, NH2, CN, OCi-e saturated, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, or aryi, SCi-e saturated, unsaturated alkyi, cycloalkyi, cycioheteroalkyi. or aryi, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, CO2H, CO2G1-6 saturated or unsaturated alkyi, NHCI-B saturated, unsaturated alkyi, or cycloalkyi, N(Ci-e saturated, unsaturated alkyi, or cycloalkyi)₂, or Cs-yaryl or heteroaryl; R² = CI, Br, F, i, OH, CO2H , CN, NH₂, CON e₂,

OCi-8saiu rated, unsaturated alkyl, cycloalkyi, heterocycloalkyl, NHCi-esaturated or unsaturated alkyl, N(Ci-esaturated or unsaturated alky)2, or Cs yaryl or heteroaryl; wherein each X independently = C, CH, CH2, S, SO, SO2, N, NH, NC i-ssatu rated, unsaturated alkyl, or cycloalkyi, or O; and wherein each n independentiy = 0-6,

89, The method of any one of claims 1 to 88 wherein the composition comprises a compound of formula (XXXXVII):

wherein each R¹ independentiy = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, or aryl, SC1-6 saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyi, or aryl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, CO2H , CO2C1-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycloalkyi, N(Ci-s saturated, unsaturated alkyl, or cycloalkyl)₂, or Cs-yaryl or heteroaryl; R² = H, CI, Br, F, 1, OH, OAc, CF₃, NH₂, CN, OCi-₆ saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, or aryl, SCi-e saturated, unsaturated aikyl, cycloalkyi, cycloheteroalkyl, or aryl, C1-6 saturated alkyl, unsaturated aikyl, cycloalkyi, cycloheteroalkyl, CO2H , CO2C1- 6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycloalkyi, N(Ci-e saturated, unsaturated aikyl, or cycioalkyl)2, or Cs-yaryl or heteroaryl; wherein each X independently = C , CH, CH2, S, N, NH, NCi-esaturated , unsaturated alkyl, or cycloalkyi, or O; and wherein each n independently = 0-8.

90. The method of any one of claims 1 to 89 wherein the composition comprises a compound of formula (XXXXVII I):

wherein each R¹ independently = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OC i-s saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, o aryl, SCi-e saturated, unsaturated aikyl, cycloalkyi, cycloheteroalkyl, or aryl, C i-s saturated alkyl, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, CO2H , CO2C1-6 saturated or unsaturated alkyl, NHC1 -5 saturated, unsaturated alkyl, or cycloalkyi, NiCs-s saturated, unsaturated alkyl, In one embodiment, or cycloalkyi^, or Cs-yaryl or heteroaryl; and wherein each X independently = C, CH, CH₂, S, SO, SO2, N, NH, NCi-esaturated, unsaturated alkyl, or cycloalkyi, or O.

91 . The method of any one of claims 1 to 90 wherein the composition comprises a compound of formula (XXXXIX) :

wherein each R¹ independently = H, Ci, Br, F, i, OH, OAc, CFs, NH2, CN, OC1-6 saturated, unsaturated alkyi, cycioaikyl, cycioheteroaikyi, or aryi, SC1-6 saturated, unsaturated alkyi, cycioalkyi, cycioheteroalky!, or aryi, C1-6 saturated aikyl, unsaturated alkyi, cycioalkyi, cycioheteroaikyi, CO2H, CO2C 1-8 saturated or unsaturated alkyi, NHC1-6 saturated, unsaturated alkyi, or cycioalkyi, N(Ci-s saturated, unsaturated alkyi, or cycioalkyi, or Cs-7aryl or heteroaryl; wherein each X independently = C, CH, CH2, S, SO, SO?, N, NH, NCi-esaturated, unsaturated alkyi, or cycioalkyi, or O; and wherein n = 0-6,

92, The method of any one of claims 1 to 91 wherein the composition comprises a compound of formula (L):

wherein each R¹ independently = H, CL Br, F, I, OH, OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated alkyl, cycioalkyi, cycioheteroaikyi, or aryi, SC1-6 saturated, unsaturated alkyi, cycioalkyi, cycioheteroaikyi, or aryi, C1-6 saturated alkyl, unsaturated aikyl, cycioalkyi, cycioheteroaikyi, CO2H, CO2C1-B saturated or unsaturated alkyi, NHC1-6 saturated, unsaturated alkyi, or cycioalkyi, N(Ci-e saturated, unsaturated alkyl, or cycioalkyi, or Cs-jaryi or heteroaryl; wherein each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated alkyl, or cycioalkyi, or O; and wherein each n independently = 0-6.

93, The method of any one of claims 1 to 92 wherein the composition comprises a compound of formula (LI):

wherein each R independently = H, Ci, Br, F, I, OH, OAc, CF3, NH2, CN, OCi-s saturated, unsaturated alkyl, cycioalkyi, cycioheteroaikyi, o aryi, SCi-e saturated, unsaturated alkyl, cycioalkyi, cycioheteroaikyi, or aryi, Ci-s saturated alkyl, unsaturated alkyl, cycioalkyi, cycioheteroaikyi, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHCI-B saturated, unsaturated alkyi, or cycioalkyi, N(Ci-e saturated, unsaturated alkyl, or cycloalkyi)2, or Cs-v-ary! or heteroaryl; wherein each X independently = C, CH, CH2, S, SO, SO2, NH2, NH, N, NCi-ssaturated, unsaturated alkyl, or cycioaikyl, or O; and each n independently = 0-6.

94. The method of any one of claims 1 to 93 wherein the composition comprises a compound of formula (Lll):

Ri

wherein each R¹ = H, CI, Br, F, I, OH, OAc, CFs, NH2, CN, OCi-e saturated, unsaturated alkyl, cycioaikyi, cycloheteroalkyl, or aryl, SC1-6 saturated, unsaturated alkyl, cycioaikyi, cycloheteroalkyl, or aryi, C1-6 saturated alkyl, unsaturated alkyl, cycioaikyi, cycloheteroalkyl, CO2H , CChCi-s saturated or unsaturated alkyl, NHCi-s saturated, unsaturated alkyl, or cycioaikyi, N(Ci-6 saturated, unsaturated alkyl, or cycioaikyi, or C^ary! or heteroaryl; wherein each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-esaturated , unsaturated alkyl, or cycioaikyi, or O; and each n independently = 0-6.

95, The method of any one of claims 1 to 94 wherein the composition comprises a compound of formula (Ll ll):

wherein each R¹ independently = H, CI, Br, F, I, OH, OAc, CF3, NH₂, CN, OC1 -6 saturated, unsaturated alkyl, cycioaikyi, cycloheteroalkyl, o aryl, SC1 -5 saturated, unsaturated alkyl, cycioaikyi, cycloheteroalkyl, or aryl, C1 -6 saturated alkyl, unsaturated alkyl, cycioaikyi, cycloheteroalkyl, CO2H , CQ2C1 -5 saturated or unsaturated alkyi, NHCi-e saturated, unsaturated alkyi, or cycioaikyi, N(C i-s saturated, unsaturated alkyl, or cycioaikyi, or Cs-raryl or heteroaryl; wherein each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-ssaturated, unsaturated alkyi, or cycioaikyi, or O; and each n independently = 0-6.

96. The method of any one of claims 1 to 95 wherein the composition comprises a compound of formula (LIV):

wherein each R¹ independently = H, CI , Br, F, I, OH, OAc, C Fs, NH2, C N , OC1-6 saturated, unsaturated alkyl, cycioaikyi, cycloheteroalkyl, o aryl, SC1-6 saturated, unsaturated alkyl, cycioaikyi, cycloheteroalkyl, or aryl, C1-6 saturated alkyl, unsaturated alkyl, cycioaikyi, cycloheteroalkyl, CO2H , CO2C1-6 saturated, unsaturated alkyl, or aryl, CONH2, CO2NHC1 -8 saturated, unsaturated alkyi or aryl, C02N(Ci -8 saturated, unsaturated alkyl or aryik, NHCi-e saturated, unsaturated alkyl, or cycioaikyi, N(Ci-6 saturated, unsaturated alkyl, or cycloalkyl)2, or Cs- aryl or heteroaryl; and each X independently = C , CH , CH2, S, SO, SO2, N, NH, NCi-ssaturated, unsaiiirated alkyi, or cycloalkyi, or O; and wherein each n independently

= 0-6.

97, The method of any one of ciaims 1 to 96 wherein the composition comprises a compound of (LV):

wherein R independently = H, CI, Br, F, I , OH, OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated alkyi, cycloalkyi, cycloheteroaikyl, or aryl, SC i-s saturated, unsaturated alkyi, cycloalkyi, cycloheteroalkyl, or aryl, C1-6 saturated alkyi, unsaturated alkyi, cycloalkyi, cycloheteroalkyl, CO2H, COC1-8 alkyi unsaturated alkyi, or aryl, CO2C1-6 saturated, unsaturated alkyi, o aryl, CONH2, CO2NHC1-6 saturated, unsaturated aikyl or aryl, C02 (Ci-6 saturated, unsaturated alkyi or aryi)2, NHC1 -8 saturated, unsaturated alkyi, or cycloalkyi, N(Ci-6 saturated, unsaturated alkyi, or cycloalkyi^, or Cs^aryl or heteroaryl; wherein each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-ssaturated, unsaturated alkyi, or cycloalkyi, or O; and wherein each n independently = 0-6.

The method of any one of ciaims 1 to 97 wherein the composition comprises a compound of formula (LVI):

wherein each R¹ independently = H, CL Br, F, I, OH, OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated alkyi, cycloalkyi, cycloheteroalkyl, o aryl, SC1-6 saturated, unsaturated alkyi, cycloalkyi, cycloheteroalkyl, or aryl, C1-6 saturated alkyi, unsaturated aikyl, cycloalkyi, cycloheteroalkyl, CO2H, COC1-8 alkyi unsaturated alkyi, or aryl, CO2C1-B saturated, unsaturated alkyi, or aryl, CONH2, CO2NHC1-8 saturated, unsaturated alkyi or aryl, C02N(Ci-6 saturated, unsaturated alkyi or aryfb, NHCI-B saturated, unsaturated aikyl, or cycioaikyl, N(Ci-e saturated, unsaturated aikyl, or cycloalkyi, or Cs-7aryl or heteroaryl; wherein each X independently = C, CH, CH2, S, SO, SO2, N, NH, NC i-ssaturated, unsaturated alkyi, or cycioaikyl, or O; and each n independently = 0-6.

99. The method of any one of ciaims 1 to 98 wherein the composition comprises a compound of formula (LVH):

wherein each R¹ independently = H, CL Br, F, i, OH, OAc, CFs, Nh , CN, OC1-6 saturated, unsaturated alkyl, cycioaikyi, cycloheteroalkyl, or aryl, SC1-6 saturated, unsaturated alkyi, cycioaiky!, cycloheteroalkyl, or ary!, C1-6 saturated alkyi, unsaturated alkyl, cycioaikyi, cycloheteroalkyl, CO2H, COCi-s a!kyi unsaturated alkyi, or aryl, CO2C1-6 saturated, unsaturated alkyi, or aryl, CONH2, CO2NHC1 -8 saturated, unsaturated alkyi or aryi, C02lM(Ci-6 saturated, unsaturated aikyl or aryi)2, NHC1-6 saturated, unsaturated alkyl, or cycioaikyi, N(Ci-e saturated, unsaturated alkyl, or cycloalkyi)2, or C5-7aryl or heteroaryl; wherein each X = C, CH, CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated alkyl, or cycioaikyi, or O; and each n independently = 0-6.

100. The method of any one of claims 1 to 99 wherein the composition comprises a compound of formula (LVIII):

wherein each R independently = H, Ci, Br, F, I, OH, OAc, CF3, NH2, CN, OCi-s saturated, unsaturated alkyi, cycioaikyi, cycloheteroalkyl, o aryl, SCi-e saturated, unsaturated alkyi, cycioaikyi, cycloheteroalkyl, or aryi, C1-6 saturated alkyl, unsaturated alkyl, cycioaikyi, cycloheteroalkyl, GO2H, COC1-8 alkyl unsaturated alkyi, or aryl, CO2G1-6 saturated, unsaturated alkyi, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyi or aryi, C02N(Gi-8 saturated, unsaturated alkyi or aryl)2, NHd-e saturated, unsaturated alkyi, or cycioaikyi, N(Ci-e saturated, unsaturated alkyl, or cycloalkyi)2, or Cs-v-aryl or heteroaryl: wherein each R² independently = CI, Br, i: wherein each X independently = C, CH, or N; and n = 0-6.

101 . The method of any one of claims 1 to 100 wherein the composition comprises a compound of formula (LIX):

wherein each R = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated alkyl, cycioaikyi, cycloheteroalkyl, or aryl, SC1-6 saturated, unsaturated alkyi, cycioaikyi, cycloheteroalkyl, or aryl, Ci-e saturated alkyl, unsaturated alkyi, cycioaikyi, cycloheteroalkyl, CO2H, COC1-8 alkyl unsaturated aikyl, or aryi, CO2C1-6 saturated, unsaturated alkyl, or aryl, CONH2, CG2NHC1-6 saturated, unsaturated aikyl or aryl, C02 (Ci-6 saturated, unsaturated alkyl or aryl)2, NHC1-6 saturated, unsaturated aikyl, or cycioaikyi, N(Ci-6 saturated, unsaturated alkyl, or cycioaikyi, or Cs-7aryi or heteroaryl; and wherein each X = C, CH, CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated alkyl, or cycioaikyi, or O.

102. The method of any one of claims 1 to 101 wherein the composition comprises a compound of formula (LX):

wherein each R¹ independently = H, CI, Br, F, i, OH, OAc, CFs, Nh , CN, OC1-6 saturated, unsaturated alkyi, cycioaikyl, cycioheteroaikyi, or aryi, SC1-6 saturated, unsaturated alkyi, cycioalkyi, cycioheteroalkyi, or aryi, C1-6 saturated aikyl, unsaturated alkyi, cycioalkyi, cycioheteroalkyi, CO2H, COC1-8 alkyi unsaturated alkyi, or aryl, CO2C1-6 saturated, unsaturated alkyi, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyi or aryi, C02lM(Ci-6 saturated, unsaturated alkyi or aryi)2, NHC1-6 saturated, unsaturated alkyi, or cycioaikyl, N(Ci-e saturated, unsaturated alkyi, or cycloaikyi)2, or Cs-7aryl or heteroaryl; and each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated aikyl, or cycioaikyl, or O. 103, The method of any one of claims 1 to 102 wherein the composition comprises a compound of formula (LXI):

wherein each R¹ independently = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated alkyi, cycioaikyl, cycioheteroalkyi, or aryi, SC1-6 saturated, unsaturated alkyi, cycioalkyi, cycioheteroalkyi, or aryl, C1-6 saturated aikyl, unsaturated aikyl, cycioalkyi, cycioheteroalkyi, CO2H, COC1-8 aikyl unsaturated alkyi, or aryi, CO2C1-6 saturated, unsaturated alkyi, or aryi, CONH2, C02 HCi-s saturated, unsaturated alkyi or aryi, C02 (Ci -s saturated, unsaturated aikyl or aryi)2, NHC1-6 saturated, unsaturated aikyl, or cycioaikyl, N(Ci-e saturated, unsaturated aikyl, or cycioaikyl, or C5-7aryi or heteroaryl; wherein each R² independently = CI, Br, I; wherein each X independently = C, CH2, S, SO, SO2, N, NH, NCi- ssaturated, unsaturated alkyi, or cycioalkyi, or O; and each n independently = 0-6.

104, The method of any one of claims 1 to 103 wherein the composition comprises a compound of formula (LXI I):

wherein each R¹ independently = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated alkyi, cycioaikyl, cycioheteroalkyi, or aryi, SC1-6 saturated, unsaturated alkyi, cycioalkyi, cycioheteroalkyi, or aryl, C1-6 saturated alkyi, unsaturated alkyi, cycioalkyi, cycioheteroalkyi, CO2H, COC1-8 alkyi unsaturated alkyi, or aryi, CO2C1-6 saturated, unsaturated alkyi, or aryi, CONH2, C02 HCi-s saturated, unsaturated alkyi or aryi, C02lM(Ci-6 saturated, unsaturated aikyl or aryi)2, NHC1-6 saturated, unsaturated aikyl, or cycioaikyl, N(Ci-e saturated, unsaturated alkyi, or cycioaikyl, or Canary! or heteroaryl; wherein each X independently = C, CH, CHa, S, SO, SOa, N, NH, NC i-ssaturated, unsaturated alkyl, or cycloalkyl, or O; and wherein each n independently = 0-6,

105, The method of any one of claims 1 to 104 wherein the composition comprises a compound of formula (LXIII):

wherein each R independently = H, Ci, Br, F, I, OH, OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, SCi-e saturated, unsaturated aikyi, cycloalkyl, cycloheteroalkyl, or aryl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, G02H, COC1 -8 alkyl unsaturated alkyl, or aryl, CO2G1-6 saturated, unsaturated alkyl, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyl or aryl, C02 (Ci-s saturated, unsaturated alkyl or aryi)2, NHC1-6 saturated, unsaturated alkyl, or cycloalkyl, N(Ci-6 saturated, unsaturated alkyl, or cycloalkyl, or Cs-yary! or heteroaryl; wherein each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated alkyl, or cycloalkyl, or O; and wherein n = 0-6,

106. The method of any one of claims 1 to 105 wherein the composition comprises a compound of formula (LXIV):

wherein each R¹ independently = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, SC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CO2H, COC1-8 alkyl unsaturated alkyl, or aryl, CO2C1-B saturated, unsaturated alkyl, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyl or aryl, C02N(Ci-6 saturated, unsaturated alkyl or aryfb, NHCI-B saturated, unsaturated alkyl, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl^, or Cs-jaryl or heteroaryl; wherein each X independently = C, CH, CH2, S, SO, S02, N, NH, NC i-ssaturated, unsaturated alkyl, or cycloalkyl, or O; and n = 0-6.

107, The method of any one of claims 1 to 106 wherein the composition comprises a compound of formula (LXV):

wherein each R ¹ = H, CI, Br, F, I , OH, OAc, CFs, NH2, CN, OCi-e saturated, unsaturated alkyi, cycioaikyi, cycloheteroalkyl, o aryi, SC1-6 saturated, unsaturated aikyl, cycloalkyl, cycioheteroalkyi, o aryi, C1-6 saturated alkyl, unsaturated aikyl, cycloalkyl, cycioheteroalkyi, CO2H , COC1 -8 alkyi unsaturated aikyl, or aryi, CO2C1 -6 saturated, unsaturated alkyi, o aryi, CONH2, CO2NHC1-6 saturated, unsaturated alkyl or aryi C02lM(Ci-e saturated, unsaturated aikyl or aryl)2, NHC1-6 saturated, unsaturated aikyl, or cycloalkyl, N(Ci-e saturated, unsaturated alkyi, or cycloalkyl^, or Cs-yaryi or heteroaryi; wherein each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated aikyl, or cycloalkyl, o O; and wherein each n independently = 0-8.

108. The method of any one of claims 1 to 107 wherein the composition comprises a compound of formula (LXVI) :

wherein each R¹ independently = H, CI, Br, F, I, OH, OAc, C Fs, NH2, CN, OC1-6 saturated, unsaturated alkyi, cycloalkyl, cycioheteroalkyi, o aryi, SC1-6 saturated, unsaturated alkyi, cycloalkyl, cycioheteroalkyi, or aryi, C i-s saturated alkyl, unsaturated aikyl, cycloalkyl, cycioheteroalkyi, CO2H , COC i-s alkyi unsaturated aikyl, or aryi, CO2C1-6 saturated, unsaturated aikyl, or aryi, CONH2, CO2NHC1 -8 saturated, unsaturated aikyl or aryi, CQ2N(C i-s saturated, unsaturated alkyl or aryik, NHC-i-e saturated, unsaturated alkyl, or cycloalkyl, N(C 1 -6 saturated, unsaturated alkyl, or cycloalkyl^, or Cs-raryl or heteroaryi; and each X independently = C, CH, CH₂, S, SO, SO2, N, NH, NCi-esaturated, unsaturated aikyl, or cycloalkyl, or O; and wherein n is independently 0-6.

109. The method of any one of claims 1 to 108 wherein the composition comprises a compound of formula (LXVI I) :

wherein each R¹ independently³ H, CI, Br, F, I, OH, OAc, CF3, NH2, CN , OCi-e saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryi, SC1-6 saturated, unsaturated alkyi, cycloalkyl, cycioheteroalkyi, or aryi, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycioheteroalkyi, CO2H , COC1-8 alkyl unsaturated alkyi, or aryi, CO2C1-6 saturated, unsaturated alkyi, or aryi, CONH2, C02NHCi-s saturated, unsaturated alkyi or aryi, C02lM(Ci-6 saturated, unsaturated alkyl or aryl)2, NHC1-6 saturated, unsaturated alkyl, or cycioaikyi, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl^, or Cs jaryi or heteroaryi; wherein each X independently = C, CH , CH2, S, SO, SO2, N , N H , NCi-esaturated, unsaturated alkyi, or cycioaikyi, or O; and n = 0-6. 1 10, The method of any one of claims 1 to 109 wherein the composition comprises a compound of formula (LXVIl!):

wherein R each = H, CI, Br, F, I, OH, OAc, CFa, NH2, CN, OC1-6 saturated, unsaturated alkyl, cycloaikyi, cycloheteroaiky!, or aryl, SC1-6 saturated, unsaturated alkyl, cycloaikyi, cycioheteroalkyi, or aryi, C1-6 saturated alkyl, unsaturated alkyl, cycloaikyi, cycioheteroalkyi, CO2H, COC1-8 alkyl unsaturated alkyl, or aryl, CO2C1-6 saturated, unsaturated alkyl, or aryi, CONH2, CO2NHC1-6 saturated, unsaturated alkyl or aryl, C02N(Ci-6 saturated, unsaturated alkyl or aryl)2, NHC1-6 saturated, unsaturated aikyl, or cycloaikyi, N(Ci-6 saturated, unsaturated alkyl, or cycloaikyi, or Cs-7aryi or heteroaryl; wherein each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated alkyl, or cycloaikyi, o O; and wherein n = 0-6.

1 1 1 . The method of any one of claims 1 to 1 10 wherein the composition comprises a compound of formula (LXIX):

wherein each R¹ independently = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated alkyl, cycloaikyi, cycioheteroalkyi, or aryi, SC1-6 saturated, unsaturated alkyl, cycloaikyi, cycioheteroalkyi, or aryl, C1-6 saturated alkyl, unsaturated aikyl, cycloaikyi, cycioheteroalkyi, CO2H, COC1-8 alkyl unsaturated aikyl, or aryl, CO2C1-B saturated, unsaturated alkyl, or aryl, CONH2, CO2NHC1-8 saturated, unsaturated alkyi or aryi, C02 (Ci-s saturated, unsaturated alkyl or aryi)2, NHC1-6 saturated, unsaturated alkyi, or cycloaikyi, N(Ci-e saturated, unsaturated alkyl, or cycloaikyi, or Cs-7aryl or heteroaryl; wherein each X independently = C, CH, CH2, S, SO, SO2, N, NH, NC i-ssaturated, unsaturated alkyi, or cycloaikyi, or O; and each n independently = G-6.

1 12. The method of any one of claims 1 to 1 1 1 wherein the composition comprises a compound of formula (LXX):

wherein each R independently = H, Ci, Br, F, I, OH, OAc, CF₃, NH₂, CN, ONO2, OC1-6 saturated, unsaturated alkyi, cycloaikyi, cycioheteroalkyi, or aryi, SCi-e saturated, unsaturated aikyl, cycloaikyi, cycioheteroalkyi, or aryl, C1-6 saturated alkyi, unsaturated aikyl, cycloaikyi, cycioheteroalkyi, CO2H, COC1 alkyl unsaturated aikyl, or aryl, CO2C1-6 saturated, unsaturated aikyl, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyi or aryi, C02N(Ci-s saturated, unsaturated alkyi or aryi)2, NHCi-s saturated, unsaturated alkyi, or cycloaikyi, N(Ci-6 saturated, unsaturated alkyl, or cycloaikyi, or Cs-yaryi or heieroaryi; wherein each X independently = Ch , S, SO, SO2, NH, NC i-ssaturated, unsaturated alkyi, or cycloalkyl, or O and wherein each n independently = 0-8.

1 13, The method of any one of claims 1 to 1 12 wherein the composition comprises a compound of formula (LXXI):

wherein each R¹ independently = H, CI, Br, F, I, OH, OAc, CFs, NH₂, CN, NO2, OC1-6 saturated, unsaturated aikyi, cycioaikyl, cycioheteroaikyl, or aryl, SC1-6 saturated, unsaturated alkyi, cycloalkyl, cycloheteroalkyl, or aryl, C1-6 saturated alkyl, unsaturated aikyi, cycloalkyl, cycioheteroaikyl, CO2H, COC1-8 alkyl unsaturated alkyl, or aryl, CQ2C1-6 saturated, unsaturated alkyl, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyi or aryl, C02N(Ci-8 saturated, unsaturated alkyl or aryi)2, NHC1-8 saturated, unsaturated alkyl, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl, or Cs-Taryi or heteroaryl; and wherein each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-esatu rated, unsaturated alkyl, or cycloalkyl, or O.

1 14. The method of any one of claims 1 to 1 13 wherein the composition comprises a compound of formula (LXXI 11):

wherein each R¹ independently = H, Ci, Br, F, I, OH, OAc, CFs, NH2, CN, NO2, OCi-e saturated, unsaturated aikyi, cycloalkyl, cycioheteroaikyl, or aryl, SC1-6 saturated, unsaturated alkyl, cycloalkyl, cycioheteroaikyl, or aryl, C1-6 saturated alkyi, unsaturated alkyl, cycloalkyl, cycioheteroaikyl, CO2H, COC1-8 alkyl unsaturated alkyi, or aryl, CO2C1-6 saturated, unsaturated alkyl, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyl or aryl, C02 (Ci-s saturated, unsaturated alkyl or aryi)2, NHCi-s saturated, unsaturated alkyi, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl, OR Cs-7aryl or heteroaryl; wherein each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-asaturated, unsaturated alkyi, or cycioaikyl, or O; and wherein n = 0-6,

1 15, The method of any one of claims 1 to 1 14 wherein the composition comprises a compound of formula (LXXIV):

wherein each R independently = H, Ci, Br, F, I, OH, OAc, CF₃, NH₂, CN, NO2, OC1-6 saturated, unsaturated alkyi, cycloalkyl, cycioheteroaikyl, or aryl, SC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, Ci-e saturated alkyl, unsaturated alkyl, cycloalkyl, cycioheteroaikyl, CO2H, COC1-8 alkyi unsaturated alkyi, or aryl, CO2C1-6 saturated, unsaturated alkyl, or aryl, CONH2, CO2NHC1-B saturated, unsaturated a!kyl or aryl, C02 (Ci-s saturated, unsaturated a!kyl or aryl)2, NHCi-s saturated, unsaturated alkyl, or cycloalkyi, N(Ci-e saturated, unsaturated aikyL or cycloalkyl)2, Cs-yaryl or heteroaryl; and wherein each X independently = C, CH, CH2, S, SO, SO2, N, NH, NC-i-ssafurated, unsaturated alkyl, or cycloalkyi, or O.

1 16, The method of any one of claims 1 to 1 15 wherein the composition comprises a compound of formula (LXXV):

wherein each R¹ independently = H, CI, Br, F, I, OH, OAc, CFs, NH₂, CN, NO2, OC1-6 saturated, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, or aryl, SC1-6 saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, or aryl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, CO2H, COC i-s alkyl unsaturated alkyl, or aryl, CO2C1-6 saturated, unsaturated alkyl, or aryl, CONH2, CO2NHC1-6

saturated, unsaturated alkyl or aryl, C02N(Ci-8 saturated, unsaturated alkyl or aryi)2, NHC1-8 saturated, unsaturated alkyl, or cycloalkyi, N(Ci-e saturated, unsaturated alkyl, or cycloalkyi, or Cs-yaryi or heteroaryl; wherein each R² = Mono, di, or triglycoside, QC(O) C3-5 alkenyl; wherein each X

independently = CH, CH2, S, SO, SO2, NH, NCi-ssaturated, unsaturated alkyl, or cycloalkyi, or O; and wherein n = 0-6.

1 17. The method of any one of claims 1 to 1 16 wherein the composition comprises a compound of formula (LXXVI):

wherein each R¹ = H, CI, Br, F, I, OH, ONa, OAc, CF₃, NH₂, CN, NO2, OCi-e saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, or aryl, SCi-s saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, or aryl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, CO2H, COC1-8 alkyl unsaturated alkyl, or aryl, CO2C1-6 saturated, unsaturated alkyl, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyl or aryl, C02 (Ci-e saturated, unsaturated alkyl or aryi)2, NHC1-6 saturated, unsaturated alkyl, or cycloalkyi, N(Ci-6 saturated, unsaturated alkyl, or cycloalkyi^, Cs-yaryi or heteroaryl: wherein each X independently = CH, CH2, S, N, NH, NCi-asaturated, unsaturated alkyl, or cycloalkyi, or O; and wherein each n

independently = 0-6.

1 18. The method of any one of claims 1 to 1 17 wherein the composition comprises a compound of formula (LXXVII): X X

wherein each R¹ independently = H, CI, Br, F, I, OH, ONa, OAc, CFs, NH₂, CN, NO2, OC1-6 saturated, unsaturated aikyi, cycloalkyl, cycloheteroalkyl, or aryi, SC1-6 saturated, unsaturated aikyl, cycloalkyl, cycloheteroalkyl, or aryi, C1-6 saturated alkyi, unsaturated aikyl, cycloalkyl, cycloheteroalkyl, CO2H , COC1-8 alkyi unsaturated aikyi, or aryl, CO2C1-6 saturated, unsaturated aikyl, or aryl, CONH2, CO2NHC1-6

saturated, unsaturated alkyi or aryi, C02N(Ci-e saturated, unsaturated alkyi o aryi)2, NHC1-6 saturated, unsaturated aikyi, or cycloalkyl, N(Ci-e saturated, unsaturated alkyi, or cycioaikyl)2, or Cs-7aryl or heteroaryl; and wherein each X independently = C, CH, CH₂, S, SO, SO2, N, NH, NCi-esatu rated, unsaturated alkyi, or cycloalkyl, or O.

1 19. The method of any one of claims 1 to 1 18 wherein the composition comprises a compound of formula (LXXVIII):

wherein each R¹ independently = H, Ci, Br, F, I, OH, ONa, OAc, CF₃, NH₂, CN, NO2, OC1-6 saturated, unsaturated aikyl, cycloalkyl, cycloheteroalkyl, or aryi, SC1-6 saturated, unsaturated aikyl, cycloalkyl, cycloheteroalkyl, or aryl, Ci-e saturated alkyi, unsaturated aikyl, cycloalkyl, cycloheteroalkyl, CO2H, COC1-8 alkyi unsaturated aikyl, or aryl, CO2C1-6 saturated, unsaturated aikyl, or aryl, CONH₂, CO2NHC1-5 saturated, unsaturated alkyi or aryi, C02 (Ci-8 saturated, unsaturated alkyi or aryi)2, NHC1 -8 saturated, unsaturated aikyl, or cycloalkyl, N(Ci-e saturated, unsaturated alkyi, or cycioaikyl)2, or Cs-Taryi or heteroaryl; and wherein each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-esatu rated, unsaturated aikyi, or cycloalkyl, or O.

120. The method of any one of claims 1 to 1 19 wherein the composition comprises a compound of formula (LXXIX):

wherein each R¹ independently = H, CI, Br, F, I, OH, ONa, OAc, CF₃, NH₂, CN, NO2, OC1-6 saturated, unsaturated alkyi, cycloalkyl, cycloheteroalkyl, or aryl, SC1-6 saturated, unsaturated alkyi, cycloalkyl, cycloheteroalkyl, or aryi, C1-6 saturated alkyi, unsaturated aikyl, cycloalkyl, cycloheteroalkyl, CO2H, COC1-8 alkyi unsaturated aikyi, or aryl, CO2C1-6 saturated, unsaturated aikyl, or aryl, CONH2, CO2NHC1-B saturated, unsaturated alkyi or aryl, CQ2N(Ci-8 saturated, unsaturated alkyi or aryi)2, NHC1-8 saturated, unsaturated alkyi, or cycioaikyl, N(Ci-e saturated, unsaturated aikyl, or cycloalkyi)2, or Cs-7aryi or heteroaryl; wherein each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-ssaturated, unsaturated alkyi, or cycioaikyl, or Q; and wherein each n independently = 0-8. 121 , The method of any one of claims 1 to 120 wherein the composition comprises a compound of formula (LXXX):

wherein each R¹ independently = H, CI, Br, F, I, OH, ONa, OAc, CF₃, NH₂, CN, NO2, OC1-6 saturated, unsaturated alkyi, cycioaikyl, cycioheteroalkyi, or aryl, SC1-6 saturated, unsaturated alkyi, cycioaikyl, cycioheteroalkyi, or aryl, C1-6 saturated alkyi, unsaturated aikyl, cycioaikyl, cycioheteroalkyi, CO2H , COC i-s alkyi unsaturated aikyl, or aryl, CO2C1-6 saturated, unsaturated aikyl, or aryl, CONH₂, CO2NHC1-5 saturated, unsaturated alkyi or aryl, C02N(Ci -8 saturated, unsaturated alkyi or aryi)2, NHC1 -8 saturated, unsaturated aikyl, or cycioaikyl, N(Ci-e saturated, unsaturated alkyi, or cycioaikyl, or Cs-Taryi or heteroaryl; and each X independently = C, CH , CH₂, S, SO, SO2, N, NH, NC i-ssaturated, unsaturated alkyi, or cycioaikyl, or O.

122. The method of any one of claims 1 to 121 wherein the composition comprises a compound of formula (LXXXI):

wherein each R¹ independently = H, CI, Br, F, I, OH, ONa, OAc, CF₃, NH₂, CN, NO2, OC1-6 saturated, unsaturated alkyi, cycioaikyl, cycioheteroalkyi, or aryl, SC1-6 saturated, unsaturated aikyl, cycioaikyl, cycioheteroalkyi, or aryl, C1-6 saturated alkyi, unsaturated aikyl, cycioaikyl, cycioheteroalkyi, CO2H, COC i-s alkyi unsaturated alkyi, or aryl, CO2C1-6 saturated, unsaturated aikyl, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyi or aryl, C02N(Ci -8 saturated, unsaturated alkyi or aryi)2, NHC1 -8 saturated, unsaturated aikyl, or cycioaikyl, N(Ci-e saturated, unsaturated alkyi, or cycioaikyl, or Cs-yaryi or heteroaryl; and wherein each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated aikyl, or cycioaikyl, or O.

123. The method of any one of claims 1 to 122 wherein the composition comprises a compound of formula (LXXXII):

wherein each R¹ independently = H, Ci, Br, F, I, OH, ONa, OAc, CF₃, NH₂, CN, N0₂, OCi-₆ saturated, unsaturated alkyi, cycloalkyi, cycloheteroalkyl, or aryl, SC1-6 saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, or aryl, C1-6 saturated alkyl, unsaturated aikyl, cycloalkyi, cycloheteroalkyl, CO2H, COC1- alkyl unsaturated aikyi, or aryl, CO2C1-6 saturated, unsaturated alkyl, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyl or aryl, C02N(Ci -8 saturated, unsaturated alkyl or aryi)₂, NHC1 -8 saturated, unsaturated aikyi, or cycloalkyi, N(Ci-e saturated, unsaturated alkyl, or cycloalkyi, or Cs-yaryi or heteroaryl; wherein each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-ssaturated, unsaturated alkyl, or cycloalkyi, or O; and wherein n is 0-6.

124. The method of any one of claims 1 to 123 wherein the composition comprises a compound of formula (LXXXlii):

wherein each R independently = H, Ci, Br, F, I, OH, ONa, OAc, CF₃, NH₂, CN, NO2, OC1-6 saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, or aryl, SC1-6 saturated, unsaturated aikyl, cycloalkyi, cycloheteroalkyl, or aryl, Ci-e saturated alkyl, unsaturated aikyl, cycloalkyi, cycloheteroalkyl, CO2H, COC1- alkyl unsaturated alkyl, or aryl, CO2C1-6 saturated, unsaturated alkyl, or aryl, CONH₂, CO2NHC1-5 saturated, unsaturated alkyl or aryl, C02N(Ci-6 saturated, unsaturated alkyl or aryi)2, NHC1-6 saturated, unsaturated alkyl, or cycloalkyi, N(Ci-e saturated, unsaturated alkyl, or cycloalkyi, or Cs-yaryi or heteroaryl; and wherein each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-esatu rated, unsaturated alkyl, or cycloalkyi, or O.

125. The method of any one of claims 1 to 124 wherein the composition comprises a compound of formula (LXXXIV):

wherein each R¹ independently = H, Ci, Br, F, I, OH, ONa, OAc, CF3, NH₂, CN, NO2, OC1-6 saturated, unsaturated alkyi, cycloalkyi, cycloheteroalkyl, or aryl, SC1-6 saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, or aryl, C1 -5 saturated alkyl, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, CO2H, COC1- alkyl unsaturated alkyi, or aryl, CO2C1-6 saturated, unsaturated alkyl, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyl or aryl, C02 (C i-s saturated, unsaturated alkyl or aryl)2, NHC i-s saturated, unsaturated alkyi, or cycloalkyi, N(Ci-e saturated, unsaturated alkyl, or cycloalkyi, or C aryl or heteroaryl; and wherein each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-ssaturated, unsaturated alkyi, or cycloalkyi, or O. 126, The method of any one of claims 1 to 125 wherein the composition comprises a compound of formula (LXXII):

wherein each Ri independently = H, Ci, Br, F, i, OH, OAc, CFs, Nh , CN, NO2, OC1-6 saturated, unsaturated alkyi, cycioaikyl, cycioheteroalkyl, or aryi, SC1-6 saturated, unsaturated aikyl, cycloalkyl, cycioheteroalkyi, o aryl, C1-6 saturated a!kyl, unsaturated alkyi, cycioaikyl, cycioheteroalkyl, CO2H , COC1- alkyl unsaturated aikyi, or aryi, CO2C1-6 saturated, unsaturated aikyl, or aryi, CONH2, CO2NHC1-6 saturated, unsaturated alkyi or aryi, C02N(Ci -8 saturated, unsaturated alkyi or aryi)2, NHC1 -8 saturated, unsaturated aikyi, or cycioaikyl, N(Ci-e saturated, unsaturated alkyi, or cycioaikyl, OR Cs-7aryl or heteroaryl; each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated alkyi, or cycioaikyl, or O; and wherein each n is independently 0-6,

127. The method of any one of claims 1 to 126 wherein the composition comprises a compound of formula (LXXXV):

wherein each R¹ independently = H, Ci, Br, F, I, OH, OAc, CF3, NH2, CN, OCi-e saturated, unsaturated alkyi, cycioaikyl, cycioheteroalkyl, o aryl, SC1-6 saturated, unsaturated alkyi, cycioaikyl, cycioheteroalkyi, or aryi, Ci-e saturated alkyi, unsaturated aikyl, cycioaikyl, cycioheteroalkyi, CO2H , COC1 -8 alkyi unsaturated aikyi, or aryl, CO2C1-6 saturated, unsaturated aikyi, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyi or aryi, C02N (Ci -8 saturated, unsaturated alkyi or aryi)2, NHC1 -5 saturated, unsaturated alkyi, or cycioaikyl, N(Ci-e saturated, unsaturated aikyl, or cycioaikyl, or Cs-raryl or heteroaryl; wherein each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated aikyl, or cycioaikyl, or O; and wherein each n = 0-6.

128. The method of any one of claims 1 to 127 wherein the composition comprises a compound of formula (LXXXVI):

wherein each R¹ independently = H, Ci, Br, F, I, OH, ONa, OAc, CF₃, NH₂, CN, ONO2, OC1-6 saturated, unsaturated aikyl, cycioaikyl, cycioheteroalkyl, or aryi, SC1-6 saturated, unsaturated aikyl, cycioaikyl, cycioheteroalkyl, o aryl, Ci-e saturated alkyi, unsaturated aikyl, cycioaikyl, cycioheteroalkyl, CO2H , COC1- alkyl unsaturated aikyl, or aryl, C02C1 -6 saturated, unsaturated alkyi, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated a!kyl or aryl, C02N(Ci-e saturated, unsaturated a!kyl or aryl)2, NHCi-s saturated, unsaturated alkyl, or cycloalkyl, N(Ci-e saturated, unsaturated aikyL or cycloalkyl)2, or Cs-yaryl or heteroaryl; and wherein each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated alkyl, or cycloalkyl, or O,

129, The method of any one of claims 1 to 128 wherein the composition comprises a compound of formula (LXXXVil):

wherein each R¹ independently = H, CI, Br, F, i, OH, ONa, OAc, CF₃, NH₂, CN, ONO2, OC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, SC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyi, CO2H, COC1 - 8 alkyl unsaturated alkyl, or aryl, CO2C1-6 saturated, unsaturated alkyl, or aryl, GONH2, CO2NHC1-6 saturated, unsaturated alkyl or aryl, GQ2N(Ci-s saturated, unsaturated alkyl or aryi)2, NHC1-8 saturated, unsaturated alkyl, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl)2, or Gs-raryi or heteroaryl; and wherein each X independently = G, CH, CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated alkyl, or cycloalkyl, o O,

130, The method of any one of claims 1 to 129 wherein the composition comprises a compound of formula (LXXXVIIi):

R R¹

wherein each R¹ independently = H, CI, Br, F, I, OH, ONa, OAc, CF₃, NH₂, CN, ONO2, OC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, SC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, Ci-e saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CO2H, COC1-8 alkyl unsaturated alkyl, or aryl, CO2C1-6 saturated, unsaturated alkyl, or aryl, CONH2, CO2NHC1-5 saturated, unsaturated alkyl or aryl, C02 (Ci -8 saturated, unsaturated alkyl or aryi)2, NHC1 -8 saturated, unsaturated alkyl, or cycloalkyl, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl, or Cs-Taryi or heteroaryl; and wherein each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-esatu rated, unsaturated alkyl, or cycloalkyl, or O . 131 . The method of any one of claims 1 to 130 wherein the composition comprises employs a compound of formula (LXXXIX):

wherein each R¹ independently = H, CI, Br, F, I, OH, ONa, OAc, CF₃, NH₂, CN, NO2, OC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, SC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryi, Ci-6 saturated a!kyl, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, CO2H, COC i-s alky! unsaturated alkyl, or aryl, CO2C1-6 saturated, unsaturated alkyl, or aryl, CONH2, CO2NHC1 -6 saturated , unsaturated a!kyl or aryl, C02N(Ci -8 saturated , unsaturated a!kyl or aryl)2, NHC1 -8 saturated , unsaturated alkyl, or cycloalkyi, N(Ci-e saturated, unsaturated alkyl, or cycloalkyl)2, or Cs-yaryi or

heteroaryl; and wherein each X independently = CH , CH2, S, SO, SO2, N, NH, NCi-ssatu rated, unsaturated aikyi, or cycloalkyi, or O,

132. The method of any one of claims 1 to 131 wherein the composition comprises a compound of formula (LXXXX):

wherein each R¹ independently = H, CI, Br, F, !, OH, ONa, OAc, CF₃, NH₂, CN, NO2, OC1-6 saturated, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, or aryl, SC1-6 saturated , unsaturated alkyl, cycloalkyi, cycloheteroalkyl, or aryi, C1-6 saturated a!kyl, unsaturated alkyl, cycloalkyi, cycioheteroalkyi, CO2H, COC i-s aikyi unsaturated alkyl, or aryl, CO2C1-6 saturated , unsaturated alkyl, or aryl, CONH2, CO2NHC1-6 saturated , unsaturated alkyl or aryl, CG2 (Ci-s saturated , unsaturated alkyl or aryi)2, NHCi-s saturated , unsaturated alkyl, or cycloalkyi, N(Ci-e saturated, unsaturated alkyl, or cycloalkyi, or Cs-yaryi or

heteroaryl; wherein each X independently = C, CH, CH2, S, SO, SO2, N, NH, NCi-ssaturated, unsaturated alkyl, or cycloalkyi, or O; and wherein n = 0-6, 133, The method of any one of claims 1 to 1 32 wherein the composition comprises a compound of formula (LXXXX!):

wherein each R¹ independently = H, CI, Br, F, I, OH, ONa, OAc, CF₃, NH₂, CN, NO2, OC1-6 saturated, unsaturated aikyi, cycloalkyi, cycioheteroalkyi, or aryl, SC1-6 saturated , unsaturated alkyl, cycloalkyi, cycloheteroalkyl, or aryl, Ci -5 saturated alkyl, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, CO2H, COC1-8 alkyl unsaturated aikyi, or aryl, CO2C1-6 saturated, unsaturated alkyl, or aryl, CONH2, CO2NHC1-6

saturated , unsaturated alkyl or aryl, CQ2N(Ci-s saturated , unsaturated alkyl or aryi)2, NHC1-8 saturated , unsaturated aikyi, or cycloalkyi, N(Ci-e saturated, unsaturated alkyl, or cycioaikyl)2, orCs-v-aryl or heteroaryl; and wherein each X independently = CH, CH2, S, SO, SO2, N, NH, NCi-ssatu rated, unsaturated aikyi, or cycloalkyi, or O.

134. The method of any one of claims 1 to 1 33 wherein the composition comprises a compound of formula (LXXXXI I):

wherein each R¹ independently = H_s CI, Br, F, I, OH, ONa, OAc, CF₃, NH₂, CN, N0₂, OCi-e saturated, unsaturated alkyi, cycloaikyi, cycloheteroalkyl, or aryi, SC1-6 saturated, unsaturated aikyi, cycloalkyl, cycloheteroalkyl, o aryl, C1-6 saturated aikyl, unsaturated aikyi, cycloaikyi, cycloheteroaikyi, CO2H, COC1 alkyi unsaturated aikyi, or aryi, CO2C1-6 saturated, unsaturated aikyl, or aryi, CONH2, CO2NHC1-6 saturated, unsaturated alkyi or aryi, CQ2N(Ci-8 saturated, unsaturated alkyi or aryi)2, NHC1-8 saturated, unsaturated aikyi, or cycioaikyl, N(Ci-e saturated, unsaturated alkyi, or cycioaikyl)2, or Cs-raryi or heteroaryl; wherein each X independently = C, CH, CH², S, N, NH, NC '^saturated, unsaturated alkyi, or cycloaikyi, or O; and wherein each n independently = 0-6.

135. The method of any one of claims 1 to 134 wherein the composition comprises a compound of formula (LXXXXIIi):

wherein each R¹ independently = H, Ci, Br, F, I, OH, ONa, OAc, CF₃, NH₂, CN, NO2, OC1-6 saturated, unsaturated aikyl, cycloalkyl, cycloheteroalkyl, or aryi, SC1-6 saturated, unsaturated aikyl, cycioaikyl, cycloheteroalkyl, o aryl, Ci-e saturated alkyi, unsaturated aikyl, cycloaikyi, cycloheteroalkyl, CO2H, COC1 aikyl unsaturated aikyl, or aryi, CO2C1-6 saturated, unsaturated aikyl, or aryi, CONH2, CO2NHC1-5 saturated, unsaturated alkyi or aryi, C02N(Ci-6 saturated, unsaturated alkyi or aryi)2, NHC1 -8 saturated, unsaturated aikyl, or cycloalkyl, N(Ci-e saturated, unsaturated alkyi, or cycioaikyl)₂, or Cs-Taryi or heteroaryl; wherein each X independently = C, CH, CH2, S, N, NH, NCi-ssaturated, unsaturated alkyi, or cycloaikyi, or O; and wherein n = 0-6.

136. The method of any one of claims 1 to 135 wherein the amount administered is about 1 mg to about 75 mg per day or about 5 mg to about 50,000 mg per day.

137. The method of any one of claims 1 to 136 wherein the composition is systemicaliy administered.

138. The method of any one of claims 1 to 136 wherein the composition is orally administered.

139. The method of claim 138 wherein the composition is a sustained release formulation. 140, The meihod of any one of claims 1 to 136 wherein the administration is intravenous, intra-arterial, subcutaneous, intranasal, intrathecal, intracerebroventricuiar, intraparenchymai, trans-retinal, intramuscular, transdermal, or rectal.

141 , The method of any one of claims 1 to 140 wherein the mammal is a human with EIMFS or autosomal dominant nocturnal frontal lobe epilepsy.

142. The method of any one of claims 1 to 140 wherein the mammal is a human with seizures.

143. The method of any one of claims 1 to 140 wherein the mammal is a human with cardiac arrhythmia, with Brugada syndrome or at risk of myocardial infarction.