WO2018204765A1

WO2018204765A1 - Methods of treating epilepsy and kcnq2 related conditions

Info

Publication number: WO2018204765A1
Application number: PCT/US2018/031057
Authority: WO
Inventors: Gregory R. Stewart; Chani MAHER; Bryant GAY; J. Michael ANDRESEN; Matthew Fox; David Goldstein; Steven Petrou; Slavé PETROVSKI
Original assignee: Pairnomix, Llc
Priority date: 2017-05-05
Filing date: 2018-05-04
Publication date: 2018-11-08

Abstract

The disclosure provides methods to prevent, inhibit or treat one or more symptoms associated with epilepsy or encephalopathies, or other conditions, in a mammal, comprising: administering to the mammal, e.g., a composition having one of more of compounds of formula (I)-(LXXXV).

Description

METHODS OF TREATING EPILEPSY AND KCNQ2 RELATED

CONDITIONS

Cross-Reference to Related Applications

This application claims the benefit of the filing date of U.S. application Serial No. 62/617,778, filed on Janaury 16, 2018, and of U.S. application Serial No. 62/502,035, filed on May 5, 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, millions 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. Personalized medicine provides a new research avenue to identify candidate therapies for these diseases (EpiPM 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

(McTague, Howell, Cross, Kurian, & 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 al., 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 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 KCNQ2 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 encodes a gain-of-function 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 KCNQ2) may also be employed as a therapeutic, e.g., for disorders including but not limited to those characterized by seizures or other encephalopathies.

Likewise, in other embodiments, those molecules are useful in increasing the activity of ion channels, including those for disorders characterized by seizures or other encephalopathies that have descreased activity in those channels, e.g., descreased activity associated with a mutation(s) in a gene encoding those channels (the mutation encodes a loss-of-function variant channel protein). In another embodiment, molecules that are useful in increasing the activity of ion channels that are not mutated (wild-type potassium ion channels such as wild-type KCNQ2) may also be employed as a therapeutic, e.g., for disorders including but not limited to those characterized by seizures or other encephalopathies. As described herein, a patient was diagnosed with early infantile epileptic encephalopathy (El EE).

Next generation sequencing was carried out on genes associated with severe developmental delay and seizures. A heterozygous mutation was identified in the KCNQ2 gene with a thymidine (T) in place of a cytosine (C) at position 607 in the DNA sequence (C.607OT) in one of two copies of the gene.

Expression of that nucleotide substitution results in a KCNQ2 amino acid sequence with cysteine in place of arginine, KCNQ2 Arg201 Cys (R201C). KCNQ2, also referred to as Kv7.2, forms a homotetramerthat provides for a voltage-sensitive potassium channel of four identical subunits. KCNQ2 can also form a heterotetramer with KCNQ3 to form a voltage-sensitive potassium channel of two KCNQ2 subunits and two KCNQ3 subunits. KCNQ2 and KCNQ3 are highly enriched in the nervous system. The

heterotetramer, also referred as the M-channel, may convey more of the total potassium ton flow or current in neurons, also referred to as the M-cunrent, than the homotetramer.

To identify compounds that may alter the activity of the protein encoded by the mutant KCNQ2 gene, a cell line expressing one of those mutations was screened with a drug library to identify compounds that reverse or inhibit the mutant phenotype. In particular, a KCNQ2 R201C variant was created by site-directed mutagenesis of a plasmid containing a wild-type KCNQ2 gene, which plasmid was then transfected into CHO cells along with a wild-type copy of the KCNQ3 gene to create potassium channels with KCNQ2 R201C. Wild-type copies of the KCNQ2 and KCNQ3 genes were transfected into CHO cells to create wild-type potassium channels. Electrophysiology was conducted to characterize variant and wild-type cells. Cells expressing the R201 C variant were observed to have a gain-of-function phenotype resulting in excess outward potassium ion flow or current compared to wild-type potassium channels. Following electrophysiological characterization of the variant phenotype, a high-throughput drug screen was developed and a library of roughly 1 ,300 drugs, including drugs approved in the US and outside the US were evaluated. 36 compounds were identified that inhibited excess potassium channel efflux associated with the gain-of-function KCNQ2 R201C mutation (Tables 1A and 1 B). From the high- throughput screen, 26 compounds (see Tables 3A and 3B) were also identified that inhibited potassium channel efflux through wild-type channels. In addition, 30 different compounds (see Tables 4A and 4B) were identified that increased potassium channel efflux through wild-type channels. 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 prophylactically or therapeutically and for design of related compounds. Compounds that inhibit potassium ion flow through mutant or wild-type channels may be of therapeutic value in treating epilepsy related to KCNQ2 R201C mutations. Compounds that inhibit or increase 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 or reduced potassium ion flow through KCNQ2-bearing channels, respectively.

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 KCNQ2 channel with at least 80%, 85%, 90%, 92%, 94%, 95%, 96%, 97% 98%, or 99% amino acid sequence identity to one of SEQ ID Nos.1-2 and which optionally has at least one amino acid residue that differs from SEQ ID Nos.1-2 (a "variant" KCNQ2) 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-function variant relative to wild-type KCNQ2. In one embodiment, the variant has an amino acid residue at position 201 that is not arginine (R), e.g., the variant has a cysteine (C) at residue

201.

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 formula (l)-(XI) or (LXIII)-(LXXIX), a compound in Tables 1 A-B or 3A-B, a pharmaceutically acceptable salt thereof, or any combination thereof. In one embodiment, the mammal has a KCNQ2 variant having an amino acid residue at position 201 that is not arginine (R). In one embodiment, the mammal is heterozygous for the variant KCNQ2. In one embodiment, the mammal is a human. In one embodiment, the compound is not prednisolone. In one embodiment, the compound is not lithochlolic acid. In one embodiment, the compound is not

benzbromarone. In one embodiment, the compound is not felodipine. In one embodiment, the compound is not norfloxacin. In one embodiment, the compound is not gatifioxacin. In one embodiment, the compound is not cycloheximide. In one embodiment, the compound is not toltrazuril. In one embodiment, the compound is not riluzole hydrochloride. In one embodiment, the compound is not indatraline hydrochloride. In one embodiment, the compound is not dienestrol. In one embodiment, the compound is not acebutolol. In one embodiment, the mammal is identified as having a variant KCNQ2 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 KCNQ2 versus cells with wild-type KCNQ2. In one embodiment, the compound inhibits at least 5%, 10%, 15%, 20%, 50% or more of the activity of a variant KCNQ2. In one embodiment, the compound inhibits up to at least 90% or more of the activity of a variant KCNQ2. In one embodiment, the compound decreases KCNQ2 activity in a mammal having a gain-of- function variant KCNQ2 to an activity that is no greater than 5%, 10% or 15% that of wild-type KCNQ2. In one embodiment, the compound decreases KCNQ2 activity in a mammal having a gain-of-function variant KCNQ2 to an activity that is no less than 5%, 10% or 15% that of wild-type KCNQ2. In one embodiment, the compound increases KCNQ2 activity in a mammal having a loss-of-function variant KCNQ2 to an activity that is no less than 30, 40, 50 or 60% of wild-type KCNQ2. In one embodiment, the compound increases KCNQ2 activity in a mammal having a loss-of-function variant KCNQ2 to an activity that is no less than 70, 80 or 90% or more of wild-type KCNQ2. In one embodiment, the symptom is impaired cognitive function and an effective amount of a compound disclosed herein that treats that symptom improves, e.g., enhances, cognitive function.

In one embodiment, the disclosure further provides a method to prevent, inhibit or treat autism or broad-spectrum developmental delay. The method includes, in one embodiment, administering to the mammal an effective amount of a composition comprising a compound of any one of formula (l)-(XXVIII) or (LXIII)-(LXXXV), a compound in Tables 1 A-B or Tables 3A-B, a pharmaceutically acceptable salt thereof, or any combination thereof. In one embodiment, the mammal is a human. In one embodiment, the compound is not prednisolone. In one embodiment, the compound is not lithochlolic acid. In one embodiment, the compound is not benzbromarone. In one embodiment, the compound is not felodipine. In one embodiment, the compound is not norfloxacin. In one embodiment, the compound is not gatifioxacin. In one embodiment, the compound is not cycloheximide. In one embodiment, the compound is not toltrazuril. In one embodiment, the compound is not riluzole hydrochloride. In one embodiment, the compound is not indatraline hydrochloride. In one embodiment, the compound is not dienestrol. In one embodiment, the compound is not acebutolol.

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 mammal an effective amount of a composition comprising a compound of any one of formula (I)-

(XXVIII) or (LXIII)-(LXXXV), a compound in one of Tables 1A-B or Tables 3A-B, a pharmaceutically acceptable salt thereof, or any combination thereof. In one embodiment, the mammal is a human. In one embodiment, the compound is not prednisolone. In one embodiment, the compound is not lithochlolic acid. In one embodiment, the compound is not benzbromarone. In one embodiment, the compound is not felodipine. In one embodiment, the compound is not norfloxacin. In one embodiment, the compound is not gatifloxacin. In one embodiment, the compound is not cycloheximide. In one embodiment, the compound is not toltrazuril. In one embodiment, the compound is not riluzole hydrochloride. In one embodiment, the compound is not indatraline hydrochloride. In one embodiment, the compound is not dienestrol. In one embodiment, the compound is not acebutolol.

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, 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, autism-spectrum disorders, impaired motor skills, hypotonia, cognitive impairment, ataxia, or any combination thereof. In one embodiment, the administration of the composition inhibits increased sensitivity to activation, delays or decreases M-current, decreases potassium currents, decreases spontaneous firing, increases neuronal excitation, decreases hyperpolarized shifts in voltage- dependence of activated ion channels, or increases the speed of inactivation of open ion channels.

As disclosed herein below, certain compounds were found to inhibit the activity of wild-type KCNQ2 channels. The disclosure further provides a method to inhibit potassium channel (e.g., KCNQ) activity in a mammal, e.g., activity that is not aberrant, with a compound that inhibits that activity, for instance by reducing potassium ion flow through the channel. Thus, the treatment of epilepsy as well as disorders other than epilepsy and related disorders, that benefit by decreasing the flow of potassium ions, such as excess potassium flux, through KCNQ2 channels, both wild-type and/or variant KCNQ2 channels, is envisioned. In one embodiment, the mammal has Parkinson's Disease. In one embodiment, the compound is administered in an amount that enhances dopaminergic neuronal excitability, or improves learning or memory, e.g., such as is observed in Alzheimer's disease, cognitive impairment, benign senescent forgetfulness, or motor coordination, or inhibits hyperprolactinemia, social withdrawal, anhedonia, bipolar disorder, schizophrenia, or attention deficit disorder, or any combination thereof. The method includes, in one embodiment, administering to the mammal an effective amount of a composition comprising a compound of any one of formula (XII)-(XXVIII) or (LXXX)-(LXXXV), a compound in Table 3, a pharmaceutically acceptable salt thereof, or a combination thereof. The method includes, in one embodiment, administering to the mammal an effective amount of a composition comprising a compound of any one of formula (l)-(XI) or (LXIII)-(LXXIX), a compound in Table 1 , a pharmaceutically acceptable salt thereof, or a combination thereof. In one embodiment, the symptom is impaired cognitive function and an effective amount of a compound disclosed herein that treats that symptom improves, e.g., enhances, cognitive function. 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, intracerebroventricular, intraparenchymal, trans-retinal, intra-aural, intramuscular, transdermal, or rectal.

As also disclosed herein below, certain compounds were found to enhance the activity of wild- type KCNQ2 channels. The disclosure thus provides a method to enhance (augment) potassium channel (e.g., KCNQ) activity in a mammal, e.g., activity that is not aberrant, e.g., in a mammal having or at risk of seizure disorders, epilepsy, hypertension, vasospasm, overactive bladder/urinary incontinence, vasodilation, temporomandibular disorders, pain (analgesia), learning and memory disorders, and hearing disorders, e.g., by altering the flow of potassium ions through wild-type KCNQ2 channels or channels with reduced activity due to loss-of-function mutations in the KCNQ2 channel. The method includes, in one embodiment, administering to the mammal an effective amount of a composition comprising a compound of any of formula (XXIX)-(LXII), a compound in Table 4, a pharmaceutically acceptable salt thereof, or a combination thereof. 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, intracerebroventricular, intraparenchymal, trans-retinal, intra-aural, intramuscular, transdermal, or rectal. In one embodiment, the compound is not vinpocetine. In one embodiment, the compound is not niclosamide. In one embodiment, the compound is not merbromin. In one embodiment, the compound is not benzbromarone. In one embodiment, the compound is not leflunomide. In one embodiment, the compound is not zafiriukast. In one embodiment, the compound is not dilazep. In one embodiment, the compound is not alexidine. In one embodiment, the compound is not toltrazuril. In one embodiment, the compound is not apigenin. In one embodiment, the compound is not spiperone. In one embodiment, the compound is not acitretin. In one embodiment, the compound is not 3-alpha-hydroxy-5-beta-androstan- 17-one. In one embodiment, the compound is not astemizole. In one embodiment, the compound is one of benzbromarone, leflunomide, alexidine, toltrazuril or acitretin, or a combination thereof. In one embodiment, the symptom is impaired cognitive function and an effective amount of a compound disclosed herein that treats that symptom improves, e.g., enhances, cognitive function.

The compounds disclosed herein may be employed with other therapeutic compounds.

Brief Description of Figures

Figure 1. Sequence of exemplary human KCNQ2 proteins (SEQ ID NO: 1 and SEQ ID NO: 2). Figure 2. CHO cells carrying the KCNQ2 R201C mutation (red) show increased activation of

Kv7.2-containing potassium channels in comparison to cells carrying the wild-type KCNQ2 gene (black) (see leftward shift in voltage-dependent channel activation). This finding is indicated by greater potassium ion conductance at lower voltages. Wild-type represents the healthy Kv7.2-containing channels conferred by the KCNQ2 gene without the genetic mutation. mV indicates millivolts.

Figure 3. A) Cells carrying the KCNQ2 R201C mutation (R201C-red) show a delayed ability to deactivate after stimulation compared with cells containing wild-type KCNQ2 (WT-black) indicated by a rightward shift in the red electrical trace and an increased time interval for recovery to base-line. Time was measured in milliseconds (ms) and current was measured in nanoamps (nA). B) Decay time to recovery.

Figure 4. Scatterplot of over 1 ,300 compounds screened for their activity on both KCNQ2 R201 C/KCNQ3 and KCNQ2 wikj-type/KCNQ3 cellular model rubidium efflux assays. Compounds that are >2 SDs above the mean are represented with colored symbols as indicated in the legend. Black symbols indicate data points that are <2 SD for both KCNQ2 R201C/KCNQ3 and KCNQ2 wild-type/KCNQ3 cellular models.

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, goats, 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 "therapeutically 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.

All 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 "isotopically labeled form" of the molecule. All 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 (¹H), deuterium ^H), or tritium CH) in any combination. Similarly, any carbon atom or set thereof in a molecule can be any of the isotopic form of carbons, such as ¹¹C, ¹²C, ¹³C, or ¹⁴C, or any nitrogen atom or set thereof in a molecule can be any of the isotopic forms of nitrogen, such as ¹³N, ^UN, 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 isotopically enriched themselves are mixtures of naturally occurring isotopic forms, such as ¹⁴N and ¹⁵N,

³²S and ^MS, and so forth. A molecule as recited herein is defined as including isotopic forms of all its constituent elements at each position in the molecule. As is well known in the art, isotopically labeled compounds can be prepared by the usual methods of chemical synthesis, except substituting an isotopically 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 which 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 acyl groups such as formyl, acetyl, propionyl, pivaloyl, 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; alkoxy- or aryloxy-carbonyl groups (which form urethanes with the protected amine) such as benzyloxycarbonyl (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-dimethoxybenzyloxycarbonyl₁ 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, a,a-dimethyl-3,5- dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl (Boc),

diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethyloxycarbonyl (Teoc), phenoxycarbonyl, 4- nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl,

adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; aralkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Amine protecting groups also include cyclic amino protecting groups such as phthaloyl and

dithiosuccinimidyl, which incorporate the amino nitrogen into a heterocycle. Typically, amino protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, 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 acyl groups such as formyl, acetyl, propionyl, pivaloyl, 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 benzyloxycarbonyl (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-dimethyl-3,5- dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl (Boc),

adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; aralkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. It is well within the skill of the ordinary artisan to select and use the appropriate hydroxyl protecting group for the synthetic task at hand.

In general, "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, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl 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',

Ο0(Ο)Ν^·)₂, CN, NO, N0₂, ONO2, azido, CF₃, OCF₃, R', O (oxo), S (thiono), methylenedioxy, ethylenedioxy, N(R-)2, SR', SOR', S02R", S0₂N(R')2, S0₃R', C(0)R\ C(0)C(0)R\ C(0)CH2C(0)R\ C(S)R', C(0)OR', OC(0)R', Ο(Ο)Ν0*·)2, OC(0)N(R-)2, CiSJNiR^, (CH^oeNfFOCW, (CH2)o-2N(R')N(R')2, N(R')N(R')C(0)R', NiR'JNiR-JCiOJOR", NiR'JNiR'JCONiR^, N(R¹)S02R^, _I N(R¹)S0₂N(R^,)2, Ν^·)0(Ο)Ο^, N(R')C(0)R', NiR'JCiSJR', NiR-JCiOJNiR^, N^C^N^, NiCOR'JCOR', NiOR'JR', C(=NH)N(R')2, C(0)N(OR')R', or C(=NOR')R' wherein R' can be hydrogen or a carbon-based moiety, and wherein the carbon-based moiety can itself 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 carbonyl group, C=0, which can also be written as "CO", "C(0)", or "C(=0)ⁿ, 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]-oxabicyclo system. Further, any substituent can be bonded to a carbon or other atom by a linker, such as (CH2)n or (CR'2)n wherein n is 1 , 2, 3, or more, and each R' is independently selected. Similarly, a methylenedioxy group can be a substituent when bonded to two adjacent carbon atoms, such as in a phenyl ring.

C(O) 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 "sulfamate."

Substituted alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl 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 carbonyl (oxo), carboxyl, ester, amide, imide, urethane, and urea groups; and nitrogen in imines, hydroxyimines, oximes, hydrazones, amidines, guanidines, and nitriles.

Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyl and heteroaryl 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 cycloalkyl, aryl, heterocyclyl and heteroaryl groups can also be substituted with alkyl, alkenyl, and alkynyl groups as defined herein.

By a "ring system" 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 "spirocyclic" 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 sterically impractical and/or synthetically non-feasible. In addition, the compounds of this disclosed subject matter include all stereochemical isomers arising from the substitution of these compounds.

Selected substituents 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 substituents, 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 substituents 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 that recursive substituents 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 cycloalkyl 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-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. [Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and

2.2- dimethylpropyl 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.

Cycloalkyl groups are cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl 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. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbomyl, adamantyl, bomyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above. Representative substituted cycloalkyl 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- ortri-substrtuted norbomyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term "cycloalkenyl" alone or in combination denotes a cyclic alkenyl group.

The terms "carbocyclic," "carbocyclyl," and "carbocycle" denote a ring structure wherein the atoms of the ring are carbon, such as a cycloalkyl 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 carbocyclic ring can be substituted with as many as N-1 substituents wherein N is the size of the carbocyclic ring with, for example, alkyl, alkenyl, alkynyl, amino, aryl, hydroxy, cyano, carboxy, heteroaryl, heterocyclyl, nitro, thio, alkoxy, and halogen groups, or other groups as are listed above. A carbocyclyl ring can be a cycloalkyl ring, a cycloalkenyl ring, or an aryl ring. A carbocyclyl can be monocyclic or polycyclic, and if polycyclic each ring can be independently be a cycloalkyl ring, a cycloalkenyl ring, or an aryl ring.

(Cycloalkyl)alkyl groups, also denoted cycloalkylalkyl, are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkyl group as defined above.

Alkenyl groups include straight and branched chain and cyclic alkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Thus, alkenyl 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, -CH=CH(CH₃), -CH=C(CH₃)2, -C(CH₃)=CH₂, -C(CH₃)=CH(CH₃), -C(CH₂CH₃)=CH₂, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others.

Cycloalkenyl groups include cycloalkyl groups having at least one double bond between 2 carbons. Thus for example, cycloalkenyl groups include but are not limited to cyclohexenyl,

cyclopentenyl, and cyclohexadienyl groups. Cycloalkenyl 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. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbomyl, adamantyl, bornyl, camphenyl, isocamphenyl, 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. Cycloalkenyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above.

(Cycloalkenyl)alkyl 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 cycloalkenyl group as defined above.

Alkynyl groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl 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(CH₃), -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 quatemized. 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: -0-CH2-CH2-CH₃, -CH2-CH2CH2-OH, -CH2-CH2-NH-CH₃, -CH2-S-CH2-CH₃, -CH2CH2-S(=0)-CH₃, and -CH2CH2-O-CH2CH2-O-CH3. Up to two heteroatoms may be consecutive, such as, for

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

A "cycloheteroalkyl" ring is a cycloalkyl ring containing at least one heteroatom. A

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

The term "heteroalkenyl" by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain monounsaturated or 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 heteroatom may optionally be quatemized. Up to two heteroatoms may be placed consecutively. Examples

include -CH=CH-0-CH₃, -CH=CH-CH2-OH, -CH2-CH=N-OCH₃, -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 aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl 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 naphthyl groups, which can be substituted with carbon or non-carbon groups such as those listed above.

Aralkyl 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 aryl group as defined above. Representative aralkyl groups include benzyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyMndanyl. Aralkenyl group are alkenyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl 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 cycloheteroalkyl, 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 C_t- heterocyclyl 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 dioxolanyl ring and a benzdioxolanyl 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, quinuclidyl. Heterocyclyl groups can be unsubstituted, or can be substituted as discussed above. Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.

Representative substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with groups such as those listed above.

Heteroaryl groups are aromatic 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, heteroaryl rings can have 5 to about 8-12 ring members. A heteroaryl group is a variety of a heterocyclyl group that possesses an aromatic electronic structure. A heteroaryl 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 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. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.

Heteroaryl groups can be unsubstituted, or can be substituted with groups as is discussed above.

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

Additional examples of aryl and heteroaryl 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-thienyl), furyl (2-furyl, 3- furyl) , indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5- imidazolyl), triazolyl (1 ,2,3-triazoI-I-1-yl, 1 ,2,3-triazol-2-yl 1 ,2,3-triazol-4-yl, 1 ,2,4-triazol-3-yl), oxazolyl (2- oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3- pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7- isoquinolyl, 8-isoquinolyl), 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-dihydro- 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]thiophenyl, 6- benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl, (2-(2,3-dihydro- benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro-benzo[b]thiophenyl), 5-(2,3- dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro-benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1 -indolyl, 2-indolyl, 3-indolyl, 4-indolyl, S-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl,

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

8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1 -benzothiazolyl, 2- benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1- carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz[b,fJazepine (5H-dibenz[b,fJazepin-1-yl, 5H- dibenz[b,fJazepine-2-yl, 5H-dibenz[b,fJazepine-3-yl, 5H-dibenz[b,fJazepine-4-yl, 5H-dibenz[b,f]azepine-5- yl), 10,11-dihydro-5H-dibenz[b,fJazepine (10,11-dihydro-5H-dibenz[b,f|azepine-1-yl, 10,11-dihydro-5H- dibenz[b,fJazepine-2-yl, 10,11-dihydro-5H-dibenz[b,fJazepine-3-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-4- yl, 10,11-dihydro-5H-dibenz[b,fJazepine-5-yl), and the like.

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

Representative heterocyclyl alkyl groups include, but are not limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.

Heteroarylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined above.

The term "alkoxy" refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined above. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. [Examples of cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy 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 allyloxy group is an alkoxy group within the meaning herein. A methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy 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 "haloalkyl" group includes mono-halo alkyl groups, poly-halo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro. Examples of haloalkyl include trifluoromethyl, 1 ,1-dichloroethyl, 1 ,2- dichloroethyl, 1 ,3-dibromo-3,3-dif!uoropropyl, perfluorobutyl, and the like.

A "haloalkoxy" group includes mono-halo alkoxy groups, poly-halo alkoxy groups wherein all halo atoms can be the same or different, and per-halo alkoxy groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro. Examples of haloalkoxy include trifluoromethoxy, 1 ,1-dichloroethoxy,

1 ,2-dichloroethoxy, 1 ,3-dibromo-3,3-difluoropropoxy, perfluorobutoxy, and the like.

The term "(Cx-C_y)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, (Cx-Cy)perfluoroalkyl is -(C₁-Ce)perfluoroalkyl. In one embodiment, (Cx-Cy)perfluoroalkyl is -(C₁-C3)perfluoroalkyl. In one embodiment, (Cx-C_y)perfluoroalkyl is -CF₃.

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 all hydrogen atoms are replaced by fluorine atoms. In one embodiment, (Cx-C_y)perfluoroalkylene is -(C₁-Ce)perfluoroalkylene. In one embodiment, (Cx-Cy)perfluoroalkylene is -(C₁-C3)perfluoroalkylene. In one embodiment, (Cx-C_y)perfluoroalkylene is -

CF2-.

The terms "aryloxy" and "arylalkoxy" refer to, respectively, an aryl 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 alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like. In the special case wherein the carbonyl carbon atom is bonded to a hydrogen, the group is a "formyl" 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 carbonyl group. An acyl group can include double or triple bonds within the meaning herein. An acryloyl 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, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and the like. When the group containing the carbon atom that is bonded to the carbonyl 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)3 wherein each group can independently be H or non-H, such as alkyl, aryl, and the like. Amines include but are not limited to R-NH2, for example, alkylamines, arylamines, alkylarylamines; R2NH wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R3N wherein each R is independently selected, such as trialkylamines,

dialkylarylamines, alkyidiarylamines, triarylamines, and the like. The term "amine" also includes ammonium ions as used herein.

An "amino" group is a substituent of the form -NH2, -NHR, -NR2, -NR3⁺, 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

"alkylamino" group includes a monoalkylamino, dialkylamino, and trialkylamino group.

An "ammonium" ion includes the unsubstituted ammonium ion NhU*, but unless otherwise specified, it also includes any protonated or quatemarized 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(O)H). A "carboxamido" group is a group of the formula C(0)NR2, wherein R can be H, alkyl, aryl, etc.

The term "azido" refers to an N3 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 "urethane" ("carbamoyl" or "carbamyl") includes N- and O-urethane groups, i.e., -NRC(0)OR and -OC(0)NR2 groups, respectively.

The term "sulfonamide" (or "sulfonamido") includes S- and N-sulfonamide groups, i.e., -SO2NR2 and -NRSO2R groups, respectively. Sulfonamide groups therefore include but are not limited to sulfamoyl groups (-SO2NH2). An organosulfur 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)NR2. 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 carboxylic acid, a sulfonic acid, or an amine, in ionic form, in combination with a counterion. 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 crystallinity, 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, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic,

cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric, salicylic, galactaric and galacturonic acid. Examples of pharmaceutically unacceptable acid addition salts include, for example, perchlorates and tetrafluoro borates.

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-methykjlucamine) 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 recrystallization. All 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 al., Salt Selection for Basic Drugs (1986), IntJ. 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 "alcoholate", 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 carboxylic acid groups, which can be hydrolyzed 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 forX being bromine and claims forX 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 forX 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 toss 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 "epilepsy" as your search term in the Rare Disease Database.) Epilepsy can also occur as part of larger genetic syndromes. Types of epilepsy or disorders associated with epilepsy include Rett syndrome, Autism Spectrum Disorders, Angleman syndrome, Dravet syndrome, and West syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)

Ohtahara syndrome (OS) is a rare type of EIEE that typically becomes apparent during the first 1 to 3 months of life. It is characterized by frequent tonic seizures that are difficult to treat. Tonic seizures appear as stiffening of a limb or the body. The disorder is also characterized by a severely abnormal electroencephalogram (EEG) called "burst-suppression" in which short periods of abnormal brain activity are separated by several seconds of quiet. Otahara syndrome is considered an epileptic encephalopathy because the abnormal brain activity is thought to contribute to the cognitive and behavioral impairments associated with the disorder. Most children will go on to develop additional seizure types such as infantile spasms or Lennox-Gastaut syndrome as they grow older. There are many causes of this epilepsy syndrome including metabolic disorders, genetic, and structural brain malformations or injuries.

Lennox-Gastaut syndrome (LGS) is a rare type of epilepsy that typically becomes apparent during infancy or early childhood. The disorder is characterized by frequent episodes of uncontrolled electrical disturbances in the brain (seizures) and, in many cases, delays in the acquisition of skills require the coordination of mental and muscular activity (psychomotor retardation). Individuals with the disorder may experience several different types of seizures including drop attacks, tonic seizures, absence, and convulsions. Lennox-Gastaut syndrome may be due to, or occur in association with, a number of different underlying disorders or conditions. (For more information on this disorder, choose "Lennox-Gastaut" as your search term in the Rare Disease Database.)

Symptoms of EIEE7 that are caused by KCNQ2 mutations are characterized by seizures, tonic, seizures, clonic, generalized stiffening, automatisms (repetitive actions performed unconsciously), delayed development, intellectual disability, hypotonia (low muscle tone), dystonia (abnormal muscle tone), spastic quadriparesis, EEG shows burst suppression pattern, EEG shows multifocal epileptic activity, hyperintensities in the basal ganglia and/or thalamus on MRI, thin corpus callosum (in some patients), reduced posterior white matter volume (in some patients), onset of seizures in infancy, multiple seizures daily at onset, seizure frequency decreases during early childhood, most patients become seizure-free by age 3 or 4 years, variable severity of seizures seen in family members and can be inherited, mutations may also occur de novo (not seen in either parent), or seizures are often

unresponsive to treatment.

KCNQ2

Ion channels are protein-lined pores in the cell membrane that selectively allow charged atoms (ions) to flow into and out of cells. These pores, or channels, can open and close in response to different stimuli, such as a change in the membrane potential, and play a key role in a cell's ability to generate and transmit electrical signals. Most ion channels allow only a specific type of charged particle (positive or negative) to pass into or out of the cell when open. KCNQ2 forms part of a voltage-gated potassium channel and is sometimes abbreviated Kv7.2. KCNQ2 facilitates the flow of potassium ions out of the cell according to their concentration gradient when the channel is open. While there are twelve distinct families of potassium channels (Kvl - Kv12), KCNQ genes encode five subunits of the Kv7 potassium channel (Kv7.1-Kv7.5). Only four subunits are required to form a functional potassium ion channel, however, and channels can be formed from four of the same type of subunit or from four different types of subunits. In the case of KCNQ2, four Kv7.2 subunits together can form a homotetrameric channel that permits a low level of potassium ion flow (also called 'current"). Alternatively, Kv7.2 subunits can also combine with Kv7.3 subunits (encoded by the KCNQ3 gene) to generate a channel that allows for greater potassium ion flow, referred to as the M-current.

Kv7.2-containing potassium channels are found in the brain and peripheral ganglia and play a key role in stabilizing a cell's electrical state through the production of a potassium current called the M- current. The M-current provides a membrane voltage-regulated steady outward current of potassium ions from the cell, which helps maintain the electrical resting state of the cell and prevent subthreshold generation of action potentials. At the molecular level, an action potential is essentially a collection of charged ions flowing into and out of the cell in an orderly fashion according to their concentration gradients through the opening of ion-specific channels. These action potentials are the main component for communication along neurons and for them to coordinate and execute biological processes. M- currents therefore help to regulate normal neuronal communication patterns, but are not directly involved in the generation or the immediate recovery from an action potential; instead, other types of ion specific potassium channels are involved with these functions, notably voltage-gated sodium channels.

M-currents are also important for regulating a cell's response to repetitive stimulation. If a Kv7.2- containing channel is open during a cell's recovery from an action potential, the exit of potassium ions from the cell will keep the cell in a more negatively charged, or hyperpolarized, state. Similar to the effect described above where the M-current can help prevent subthreshold generation of action potentials, the M-current can also help prevent repetitive stimulation that might otherwise allow the cell to generate many action potentials, a state that is described as being "hyperexcitable." In this way, M-currents can be considered protective by preventing cellular hyperexcitability and its functional consequences, one of which may be the development of seizures.

Mutations in the KCNQ2 gene cause a spectrum of disease that ranges from benign seizures in infancy to epileptic encephalopathy, likely based on the degree of dysfunction in this channel. Some of these mutations prompt loss-of-function consequences while others induce gain-of-function

consequences. Loss-of-function mutations are characterized by a reduced potassium M-current exiting the cell; because the M-current normally provides a stabilizing effect on the electrical resting state of the cell, a decrease in the functionality of this current usually leads to increased excitability of cells. As described above, increased cellular excitability f hyperexcitability") means that there is a greater likelihood of that cell generating an action potential. Increased cellular excitability is often associated with the development of seizures.

In contrast, gain-of-function mutations are characterized by an enhanced potassium M-current exiting the cell. KCNQ2 gain-of-function mutations are thus associated with seizure activity through a different pathophysiological mechanism that is not yet fully understood. Many potential mechanisms have been proposed for the systemic hyperexcitability that is still associated with gain-of-function mutations. One promising theory suggests that an enhanced M-current functions in an overly protective manner and detrimentally limits the ability of a cell to generate an action potential and communicate with neighboring cells. If inhibitory communication signals cannot reach neighboring cells, then the collective network of cells could become more excited (an example of disinhibition). Despite the lack of understanding of the precise mechanism that underlies the downstream functional consequences of gain-of-function mutations, it is clear that M-currents must be tightly controlled; too little of the M-current and too much of the M- current can be problematic.

-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 epilepsy, epileptic encephalopathies,

Angelman Syndrome, Benign Rolnadic 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-related ID Syndrome, Temporal Lobe Epilepsy, epilepsy associated with neurodevelopment disorders such as autistic spectrum disorder, and epilepsy associated with traumatic brain injury, including symptoms such as seizures, developmental and cognitive disabilities and movement disorders (e.g., hypotonia, dystonia, hyperreflexia, and ataxia). In one embodiment, the compounds directly or indirectly inhibit activity of a potassium channel, e.g., KCNQ2.

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, cognitive impairment, ataxia, osteopenia, or sleep disruption. Methods are also provided for reducing the risk, progression or onset of a pathological condition characterized by increased sensitivity to activation, increased M-current, increased potassium currents, increased spontaneous firing, decreased neuronal excitation, increased hyperpolarized shifts in voltage-dependence of activated ion channels, or decreased speed of inactivation of open ion channels

Methods are also provided for reducing the risk, lessening the severity, or delaying the progression or onset of a pathological condition characterized by aberrant voltage-gated potassium channel activity, including but not limited to potassium channel activity in a mammal having epilepsy, epileptic encephalopathy, dyskinesia, 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)-(XXVW) and (LXIII)-(LXXXV), a compound in Tables 1 and 3, 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. 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 paroxetine such as a compound of formula (I), e.g., a composition having a compound of formula (I):

In one embodiment, each X independently = CH2, NH, O, or S. In one embodiment, In one embodiment, each R¹ independently = H, F, CI, Br, OH, or C_1-6 Aryloxy. In one embodiment, each R¹ independently = H, F, CI, Br, OH, CF₃, C_1-6 Aryloxy, C_1-6 saturated alkyt, COzH, C0₂C_1-4alkyl, SO2NH2, S02NHC_1-6 saturated

Alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6aryl or heteroaryl.

In one embodiment, formula (I) is X = CH2, NH, O, or S; and R¹ = H, F, CI, Br, OH, or C_1-6 Aryloxy.

In one embodiment, formula (I) is X = NH or O, or S; and R¹ = F or CI. In one embodiment, the method employs a compound of formula (II), e.g., a composition having a compound of formula (II):

In one embodiment, X = CH2, NH, N-OH, O, or S. In one embodiment, each R¹ independently = H, C_1-4 saturated alkyl, Cw saturated cycloalkyl, or OH. In one embodiment, R² = H, OH, or C1-3 alykyl or alkynl. In one embodiment, R³ = OH, OAc, C1-2 Alkoxy, C_1-6 saturated branched or unbranched alkyl, COCH2OH, or CHCH2CH2C02H.

In one embodiment, formula (II) is X = CH2, NH, N-OH, O, or S; each R¹ independently = H, C_1-4 saturated alkyl, C_3-6 saturated cycloalkyl, or OH; R² = H, OH, or C1-3 alykyl or alkynl; and R³ = OH, OAc, C1-2 Alkoxy, C1-8 saturated branched or unbranched alkyl, COCH2OH, or CHCH2CH2CO2H. In one embodiment, formula (II) is X = NH, N-OH, or O; each R¹ independently = H, CH3 or OH; R² = H, OH, or C1-3 alykyl; and R³ = OH, OAc, C1-2 Alkoxy, C1-8 saturated branched or unbranched alkyl, COCH2OH, or CHCH2CH2CO2H.

In one embodiment, formula (II) is prednisolone, norgestimate or lithocholic acid.

In one embodiment, the method employs a compound of formula (III), e.g., a composition having a compound of formula (III):

2¹

In one embodiment, each R¹ independently = C1-5 Saturated alkyl, NH2, S, OH, H, or C_1-6 Aryloxy. In one embodiment, each R¹ independently = H, F, CI, Br, OH, CF3, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, SO2NHC1-8 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6aryl or heteroaryl. In one embodiment, each R² independently is H, C1-4 Saturated alkyl or alkenyl, C3-7 Cycloalkyl, aryl, or heteroaryl.

In one embodiment, formula (III) is R¹ = C1-5 Saturated alkyl, NH2 , S, OH, H, or C_1-6 Aryloxy and each R² independently is H, C_1-4 Saturated alkyl or alkenyl, C3-7 Cycloalkyl, aryl, or heteroaryl. In one embodiment, formula (III) is R¹ = NH2, H or OH and each R² independently is H or C_1-4 Saturated alkyl.

In one embodiment, formula (III) is diethylstilbestrol, dienestrol or hexestrol.

In one embodiment, the method employs a compound of formula (IV). e.g., a composition having a compound of formula (IV):

In one embodiment, R¹ = C1-5 Saturated alkyl, NH2, OH, S, or C_1-6 Alkoxy. In one embodiment, X = CH2, NH, O, or S. In one embodiment, each R¹ independently = H, F, CI, Br, OH, NH2, or C_1-6 Aryloxy. In one embodiment, X = CH2, NH, O, or S. In one embodiment, each R¹ independently = H, F, CI, Br, OH, CF3, C_1-6Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-* alkyl, SO2NH2, SO2NHC_1-6 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl.

In one embodiment, formula (IV) is R¹ = C1-5 Saturated alkyl, NH2, OH, S, or C_1-6 Alkoxy; X = CH2, NH, O, or S; each R¹ independently = H, F, CI, Br, OH, NH₂, or C_1-6 Aryloxy; and X = CH₂, NH, O, or S. In one embodiment, formula (IV) is R¹ = C1-5 Saturated alkyl, NH2, or OH; X =NH or O; each R¹

independently = CI or C_1-6 Aryloxy; and X = NH, O, or S.

In one embodiment, formula (IV) comprises is khellin.

In one embodiment, the method employs a compound of formula (V), e.g., a composition having a compound of formula (V):

In one embodiment, each R¹ independently = H, F, CI, Br, OH, or C_1-6 Aryloxy. In one

embodiment, each R¹ independently = H, F, CI, Br, OH, CF3, C_1-6 Aryloxy, C1-3 saturated alkyl, CO2H, CC¾C₁-« alkyl, SO2NH2, SO2NHC1-6 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_-e aryl or heteroaryl. In one embodiment, X = CH2, NH, O, or S.

In one embodiment, formula (V) is isoconazole or miconozole.

In one embodiment, the method employs a compound of formula (VI), e.g., a composition having a compound of formula (VI):

In one embodiment, each R¹ independently = H, F, CI, Br, OH, C₁« saturated alkyl or C_1-6 Aryloxy.

In one embodiment, each R¹ independently = H, F, CI, Br, OH, CF3, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, SO2NHCU1 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6aryl or heteroaryl. In one embodiment, each R¹ independently = H, CM saturated alkyl, C3-8 saturated cycloalkyl, OH, or C_5-6aryl or heteroaryl. In one embodiment, R¹ = H, C_1-6 Saturated alkyl branched or unbranched. In one embodiment, X = CH2, NH, O, or S.

In one embodiment of formula (VI), each R¹ independently = H, F, CI, Br, OH, C1-3 saturated alkyl or C_1-6 Aryloxy; each R¹ independently = H, C1-4 saturated alkyl, C_3-6 saturated cycloalkyl, or OH; R¹ = H, C_1-6 Saturated alkyl branched or unbranched; and X = CH2, NH, O, or S. In one embodiment of formula (VI), each R¹ independently = C_1-6 saturated alkyl or C_1-6 Aryloxy; each R¹ independently = H or C1-4 saturated alkyl; R¹ = H; and Y = NH or O.

In one embodiment, formula (VI) is acetretin.

In one embodiment, the method employs a compound of formula (VII), e.g., a composition having a compound of formula (VII):

In one embodiment, X = CH2, NH, O, S, NHC1-10 Saturated alkyl, cycloalkyl, aryl, or heteroaryl. In one embodiment, R¹ = OH, OAc, C1-2 Alkoxy, C_1-6 saturated branched or unbranched alkyl, COCH2OH, or CHCH2CH2CO2H.

In one embodiment of formula (VII), X = CH2, NH, O, S, NHC1-10 Saturated alkyl, cycloalkyl, aryl, or heteroaryl; and R¹ = OH, OAc, C1-2 Alkoxy, C1-8 saturated branched or unbranched alkyl, COCH2OH, or CHCH2CH2CO2H. In one embodiment of formula (VII), X = NH; and R¹ = OH or OAc.

In one embodiment, formula (VII) is aceclidine.

In one embodiment, the method employs a compound of formula (VIII), e.g., a composition having a compound of formula (VIII):

In one embodiment, each R¹ independently = H, F, CI, Br, OH, or C_1-6 Aryloxy. In one embodiment, each R¹ independently = H, F, CI, Br, OH, CF3, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, SO2NHC_1-6 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6aryl or heteroaryl. In one embodiment, X = CH2, NH, O, or S.. In one embodiment, each R¹ independently = H, F, CI, Br, OH, or C_1-6 Aryloxy. In one embodiment, each R¹ independently = H, F, CI, Br, OH, CF₃, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, SCfcNHC_1-6 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl. In one embodiment, R¹ = OH, OAc, C1-2 Alkoxy, C_1-6 saturated branched or unbranched alkyl, COCH2OH, or CHCH2CH2C02H.

In one embodiment of formula (VIII), each R¹ independently = H, F, CI, Br, OH, or C_1-6 Aryloxy; X = CH2, NH, O, or S; each R¹ independently = H, F, CI, Br, OH, or C_1-6 Aryloxy; and R¹ = OH, OAc, C₁-2 Alkoxy, C1-8 saturated branched or unbranched alkyl, COCH2OH, or CHCH2CH2CO2H. In one embodiment of formula (VIII), each R¹ independently CI, Br, or OH; X = NH or O; each R¹ independently = H, OH, or C_1-6 Aryloxy; and Z = C_1-6 saturated alkyl.

In one embodiment, formula (VIII) is benzbromarone.

In one embodiment, the method employs a compound of formula (IX), e.g., a composition having a compound of formula (IX):

In one embodiment, R² = C1-10 saturated Alkyl, NH, O, S, NHC1-10 Saturated alkyl, cycloalkyl, aryl, or heteroaryl. In one embodiment, each R¹ independents OH, OAc, OCF3, C1-2 Alkoxy, C_1-6 saturated branched or unbranched alkyl, COCH20H, or CHCH2CH2CO2H. In one embodiment, each R² independently = H, F, CI, Br, OH, CF3, C₁ eAryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroary1)2, or C_5-6 aryl or heteroaryl. In one embodiment, each R¹ independently = H, F, CI, Br, OH, CF3, C_1-6Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroary1)2, or C_5-6aryl or heteroaryl.

In one embodiment of formula (IX), R² = C1-10 saturated Alkyl, NH, O, S, NHCMO Saturated alkyl, cycloalkyl, aryl, or heteroaryl; and each R¹ independently² CI, OH, OAc, OCF3, C1-2 Alkoxy, C1-8 saturated branched or unbranched alkyl, COCH2OH, or CHCH2CH2CO2H. In one embodiment of formula (IX), R² = NHC1-10; and each R¹ independents CI or OH.

In one embodiment, formula (IX) is indatraline.

In one embodiment, the method employs a compound of formula (X), e.g., a composition having a compound of formula (X):

J

In one embodiment, each R² independents C1-10 saturated Alkyl, NH, O, S, NHC1-10 Saturated alkyl, cycloalkyl, aryl, or heteroaryl. In one embodiment, each R¹ independently = OH, OAc, C1-2 Alkoxy, C_1-6 saturated branched or unbranched alkyl, COCH2OH, CHCH2CH2CO2H, C02Me, CO2C1-10 Saturated, cycloalkyl, or heterocycloalkyl or aryl. In one embodiment, each R¹ independently = H, F, CI, Br, OH, CF₃, C_1-6Aryloxy, C₁« saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, SO2NHC1-8 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl. In one embodiment, X = NH, 0, S or CH₂.

In one embodiment, formula (X) is benidipine or felodipine.

In one embodiment, the method employs a compound of formula (XI), e.g., a composition having a compound of formula (XI):

In one embodiment, each X independently = CH, CH2, CH3, N, NH, NH2, O, OH, S, or SH. In one embodiment, each R¹ independently = OH, OAc, OCF3, C1-2 Alkoxy, C_1-6 saturated branched or unbranched alkyl, COCH2OH, or CHCH2CH2CO2H. In one embodiment, each R¹ independently = H, F, CI, Br, OH, CF3, C₁ eAryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl,

COCH2OH, or CHCH2CH2C02H. In one embodiment of formula (XI), each X independently = CH, CH2, CH3, N, NH, NH2, O, OH, S, or SH; and each R¹ independently = OH, OAc, OCF3, C1-2 Alkoxy, C1-8 saturated branched or unbranched alkyl, COCH2OH, or CHCH2CH2CO2H. In one embodiment of formula (XI), each X independently =, N,

NH, NH2, or S; and each R¹ independently = OH, OAc, or OCF3.

In one embodiment, formula (XI) is riluzole.

In one embodiment, the composition comprises a compound of formula (LXIII):

In one embodiment, each R¹ independently = H, F, CI, Br, OH, CF3, SCF3, NO2, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl,S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 aryl/heteroaryl, C1-4 saturated alkyl, Cs-β saturated cycloalkyl, or C_5-6 aryl or heteroaryl C_1-6 Saturated alkyl branched or unbranched; each R² independently² Na, K, or Li; each X independently = C, CH, CH2, NH, O, or S; and each n independently = 0-6.

In one embodiment, formula (LXIII) is carbenoxolone.

In one embodiment, the composition comprises a compound of formula (LXIV):

In one embodiment, each R¹ independently = H, F, CI, Br, OH, CF3, SCF3, NO2, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-* alkyl, SO2NH2, S02NHC_1-6 saturated alkyl/aryl/heteroaryl,S02N(C_1-6 saturated alkyl, aryl, or heteroary1)2, C_5-6 aryl/heteroaryl, C_1-4 saturated alkyl, C_3-6 saturated cycloalkyl, OH, or C_5-6 aryl/heteroaryl C_1-6 Saturated alkyl branched or unbranched; and each X independently = C, CH, CH2, NH, O, or S.

In one embodiment, formula (LXIV) is toltrazuril.

In one embodiment, the composition comprises a compound of formula (LXV):

In one embodiment, each R¹ independently = H, F, CI, Br, OH, CF3, SCF3, NO2, C_1-6 Aryloxy, Cm saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, SO2NHC_1-6 saturated alkyl, aryl or heteroaryl,S02N(C_1-6 saturated alkyl, aryl or heteroary1)2, C_5-6 aryl/heteroaryl, C_1-4 saturated alkyl, C_3-6 saturated cycloalkyl, OH, or C_5-6 aryl or heteroaryl C_1-6 Saturated alkyl branched or unbranched; and each X independently = C,

CH, CH₂, NH, O, or S.

In one embodiment, formula (LXV) is phthalylsulfathiazole.

In one embodiment, the composition comprises a compound of formula (LXVI):

In one embodiment, each R¹ independently = H, F, CI, Br, OH, NO2, CF3, SCF3, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl orheteroaryl,S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 arylor heteroaryl, C_1-4 saturated alkyl, C_3-6 saturated cycloalkyl, OH, or C_5-6 aryl or heteroaryl C_1-6 Saturated alkyl branched or unbranched; and each X independently = C, CH, CH₂, NH. O, or S.

In one embodiment, formula (LXVI) is nifenazone.

In one embodiment, the composition comprises a compound of formula (LXVI I):

In one embodiment, each R¹ independently = H, F, CI, Br, OH, NO2, CF3, SCF3, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl,S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 ary lor heteroaryl, C_1-4 saturated alkyl, C_3-6 saturated cycloalkyl, OH, or C5-6 aryl or heteroaryl C_1-6 Saturated alkyl branched or unbranched; and each X independently = C, CH, CH₂, NH, O, S

In one embodiment, formula (LXVI I) is nifuroxazide.

In one embodiment, the composition comprises a compound of formula (LXVI I):

In one embodiment, each R¹ independently = H, F, CI, Br, OH, NO2, CF3, SCF3, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2. S02NHC_1-6 saturated alkyl/aryl/heteroaryl,S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 aryl orheteroaryl, C1-4 saturated alkyl, C_3-6 saturated cycloalkyl, OH, or C_5-6 aryl orheteroaryl C_1-6 Saturated alkyl branched or unbranched; and each X independently = C, CH. CH2, NH. O. or S. In one embodiment, formula (LXVII) is triclabendazole.

In one embodiment, the composition comprises a compound of formula (LXIX):

In one embodiment, each R¹ independently = H, F, CI, Br, OH, CF₃, SCF3, NO2, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C14 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl,S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 aryl or heteroaryl, C_1-4 saturated alkyl, C3-3 saturated cycloalkyl, OH, or C_5-6 aryl or heteroaryl C_1-6 Saturated alkyl branched or unbranched; each X independently = C, CH, CH₂, NH, O, orS; and n = 0-6.

In one embodiment, formula (LXIX) is diphemanil methylsulfate.

In one embodiment, the composition comprises a compound of formula (LXX):

In one embodiment, each R¹ independently = H, F, CI, Br, OH, CF3, SCF3, NO2, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl,S02N(C_1-6 saturated alkyl, aryl or heteroary02, C_5-6 aryl or heteroaryl, C_1-4 saturated alkyl, C_3-6 saturated cycloalkyl, OH, or C_1-6 aryl or heteroaryl C1-3 Saturated alkyl branched or unbranched; and each X independently = C, CH, CH₂, NH. O, or S.

In one embodiment, formula (LXX) is dihydrostreptomycin.

In one embodiment, the composition comprises a compound of formula (LXXI):

In one embodiment, each R¹ independently = H, F, CI, Br, OH, CF₃, SCF₃, NH2, NO2, C1-3 Aryloxy, C1-3 saturated alkyl, CO2H, CO2C1-* alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl,S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 aryl or heteroaryl, C1-4 saturated alkyl, C_3-6 saturated cycloalkyl, OH, orC_5-6 aryl/heteroaryl C_1-6 Saturated alkyl branched or unbranched; each X independently = C, CH, CH₂, NH, O, or S; and n = 0-6.

In one embodiment, formula (LXXI) is pencyclovir.

In one embodiment, the composition comprises a compound of formula (LXXII):

In one embodiment, each R¹ independently = H, F, CI, Br, OH, CF₃, SCF₃, NH2, NO2, C1-3 Aryloxy, C1-3 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl,S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 aryl or heteroaryl, C_1-4 saturated alkyl, C3-3 saturated cycloalkyl, OH, or C_5-6 aryl orheteroaryl C_1-6 Saturated alkyl branched or unbranched; and each X independently = CH, CH2, NH, O, or S.

In one embodiment, formula (LXXII) methylhydantoin-5-(L).

In one embodiment, the composition comprises a compound of formula (LXXIII):

T

In one embodiment, each R¹ independently = H, F, CI, Br, OH, CF3, SCF3, NH2, NO2, C_1-6 Aryloxy, C_1-6 saturated alkyl, OC_1-6 saturated or unsaturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl,S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 aryl or heteroaryl, C1-4 saturated alkyl, C_3-6 saturated cycloalkyl, OH, or C_5-6 aryl or heteroaryl C_1-6 Saturated alkyl branched or unbranched; each X independently = CH, CH2, NH, O, or S; and each n independently = 0-6.

In one embodiment, formula (LXXIII) is mebeverine.

In one embodiment, the composition comprises a compound of formula (LXXIV):

In one embodiment, each R¹ independently = H, F, CI, Br, OH, CF₃, SCF₃, NH2, NO2, C_1-6 Aryloxy, C_1-6 saturated alkyl, OC_1-6 saturated or unsaturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 aryl or heteroaryl, C_1-4 saturated alkyl, C_5-6 saturated cycloalkyl, OH, or C_5-6 aryl orheteroaryl C_1-6 Saturated alkyl branched or unbranched; each X independently = CH, CH2, NH, O, or S; and n = 0-6.

In one embodiment, formula (LXXIV) is lomerizine. In one embodiment, the composition comprises a compound of formula (LXXV):

In one embodiment, each R¹ independently = H, F, CI, Br, OH, CF₃, SCF3, NH2, NO2, C_1-6 Aryloxy, C_1-6 saturated alkyl, OC_1-6 saturated or unsaturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl,S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 aryl or heteroaryl, C_1-4 saturated alkyl, C_3-6 saturated cycloalkyl, OH, C_5-6 aryl or heteroaryl C1-5 Saturated alkyl branched or unbranched; each X independently = CH, CH2, NH, O, or S; and each n independently = 0-6.

In one embodiment, formula (LXXV) is acebutolol.

In one embodiment, the composition comprises a compound of formula (LXXVI):

In one embodiment, each R¹ independently = H, F, CI, Br, OH, CF3, SCF3, NH2, NO2, C1-3 Aryloxy, C1-3 saturated alkyl, OC_1-6 saturated or unsaturated alkyl, CO2H, CQJCI-* alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 aryl or heteroaryl, C_1-4 saturated alkyl, C_3-6 saturated cycloalkyl, OH, or C_5-6 aryl orheteroaryl C1-3 Saturated alkyl branched or unbranched; and each X independently = CH, CH2, NH, O, or S.

In one embodiment, formula (LXXVI I) is tolfenamic acid.

In one embodiment, the composition comprises a compound of formula (LXXVI I):

In one embodiment, each R¹ independently = H, F, CI, Br, OH, CF3, SCF3, NH2, NO2, C_1-6 Aryloxy, OC_1-6 saturated or unsaturated alkyl, CO2H, CO2C1-1 alkyl, SO2NH2, SO2NHC_1-6 saturated alkyl, aryl or heteroaryl,S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 aryl or heteroaryl, C_1-4 saturated alkyl, C_3-6 saturated cycloalkyl, OH, or C_5-6 aryl or heteroaryl C_1-6 Saturated alkyl branched or unbranched; each X independently = CH, CH2, NH, O, or S; and n = 0-6.

In one embodiment, formula (LXXVI I) is norfloxacin or gatifloxacin.

In one embodiment, the composition comprises a compound of formula (LXXVI 11):

In one embodiment, each R¹ independently = H, F, CI, Br, OH, CF₃, SCF₃, NH2, NO2, C1-3 Aryloxy, OC_1-6 saturated or unsaturated alkyl, CO2H, C02C_1-4 alkyl, SO2NH2, SO2NHC_1-6 saturated alkyl, aryl or heteroaryl,S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 aryl or heteroaryl, C_1-4 saturated alkyl, C_3-6 saturated cycloalkyl, OH, or C_5-6 aryl or heteroaryl C_1-6 Saturated alkyl branched or unbranched; each X independently = CH, CH2, NH, O, or S; and each n independently = 0-6.

In one embodiment, formula (LXXVIII) is cycloheximide.

In one embodiment, the composition comprises a compound of formula (LXXIX):

In one embodiment, each R¹ independently = H, F, CI, Br, OH, CF3, SCF3, NH2, NO2, ONO2, C_1-6 Aryloxy, OC_1-6 saturated or unsaturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, SO2NHC1-S saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 aryl or heteroaryl, C1-4 saturated alkyl, C_3-6 saturated cycloalkyl, OH, or C_5-6 aryl or heteroaryl C1-5 Saturated alkyl branched or unbranched; each X independently = CH, CH2, NH, O, or S; and each n independently = 0-6.

In one embodiment, formula (LXXIX) is isosorbide dinitrate.

In one embodiment, the composition comprises a compound of formula (LXIII):

In one embodiment, each R¹ independently = H, F, CI, Br, OH, CF₃, SCF3, NH2, NO2, ONO2, C1-8 Aryloxy, OC_1-6 saturated or unsaturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl,S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 aryl or heteroaryl, satCur1a-4ted alkyl, C_3-6 saturated cycloalkyl, OH, or C_5-6 aryl or heteroaryl, C1-3 Saturated alkyl branched or unbranched, NHC_1-6 Saturated alkyl branched or unbranched; each X independently = CH2, CH, NH, NHC_1-6 saturated, unsaturated alkyl, heteroalkyl, cycloalkyl, or cycloheteroalkyl, O, S. SO or SO2; and each n independently = 0-6.

In one embodiment, formula (LXXIX) is Nelfinavir mesylate.

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 activitiesAargets, 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)-(XXVIII) or (LXIII)- (LXXXV), a compound in Table 1 or 3, 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)-(XI) or (LXIII)-(LXXXIX), a compound in Table 1 , 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. In various embodiments, a compound of formula (XII)-(XXVIII) or (LXXX)-(LXXXV), a compound in Table 3, 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 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 pathological condition characterized by seizures, developmental delay or cognitive impairment, or hyperpolarizing activity, delayed inactivation, or spontaneous firing of a potassium channel, and delaying or preventing the onset of said symptoms. In certain embodiments, methods of reducing the risk, lessening the severity, or delaying the progression or onset of a disease characterized by seizures, developmental delay or cognitive impairment, or hyperpolarizing activity, delays in activation, or spontaneous firing of a potassium channel, of a mammal are also provided. In certain embodiments, methods of directly or indirectly impacting potassium channels, in a mammal are provided.

The compounds described below may be employed to inhibit the activity of KCNQ channels , e.g., wild-type KCNQ channels including those present in an individual that is a KCNQ2 heterozygote, such as an individual that expresses wild-type KCNQ2 and a variant KCNQ2 protein that has an arginine at position 201 , or an individual that is homozygous for wild-type KCNQ2 channels. In addition to epilepsy, the compounds may, in one embodiment, be administered in an amount that enhances dopaminergic neuronal excitability, or improves learning or memory, e.g., such as is observed in Alzheimer's disease, improves cognitive impairment or benign senescent forgetfulness, improves motor coordination, inhibits hyperprolactinemia, or inhibits one or more symptoms associated with social withdrawal, anhedonia, bipolar disorder, schizophrenia, or attention deficit disorder. The compounds may also be useful to inhibit or treat one or more symptoms associated with epilepsy or related conditions, or other conditions associated with excess potassium flux, as the compounds decrease the activity of wild-type KCNQ2 or act to counteract the aberrant behavior of other ionotrophic channels. Thus, compounds that alter potassium flow through KCNQ2-bearing channels may be useful in treating conditions caused by dysfunction of non-

KCNQ2-bearing potassium channels as well as ion channels that allow movement of sodium, chloride and other charged ions.

In one embodiment, the method employs a compound of formula 0(11), e.g., a composition having a compound of formula (XII):

In one embodiment for formula (XII), X = CH2, NH, N-OH, O, OH, S, or SH. In one embodiment, R¹ = H, C1-4 Saturated alkyl, C_3-6 Saturated cycloalkyl, or OH. In one embodiment, R² = H, OH, C1-3 alykyl or alkynl. In one embodiment, R³ = OH, OAc, Acetyl, C1-2 Alkoxy, C1-8 saturated branched or unbranched alkyl, COCH2OH, or CHCH2CH₂C0₂H.ln one embodiment of formula (XII), X = CH₂, NH, N-OH, O, OH, S, or SH; R¹ = H, C1-4 Saturated alkyl, C3-6 Saturated cycloalkyl, or OH; R² = H, OH, C1-3 alykyl or alkynl; and R³ = OH, OAc, Acetyl, C1-2 Alkoxy, C1-8 saturated branched or unbranched alkyl, COCH2OH, or

CHCH2CH2CO2H.

In one embodiment, the compound is pregnenolone. In one embodiment, the compound is tibolone.

In one embodiment, the method employs a compound of formula (XIII), e.g., a composition having a compound of formula (XIII):

In one embodiment of formula (XIII), X = C, CH, or N. In one embodiment, R¹ = H, F, CI, Br, OH, CF3, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, C02 C_1-4 alkyl, SO2NH2, SO2NHC1-8 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl, X = CH2, CH, NH, N, O, or S.

In one embodiment of formula (XIII), X = C, CH, or N; R¹ = H, F, CI, Br, OH, CF3, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl; and X = CH2, CH, NH, N, O, or S.

In one embodiment, the compound is naphazoline.

In one embodiment, the method employs a compound of formula (XIV). e.g., a composition having a compound of formula (XIV):

In one embodiment, R² = OH, OC₁-t saturated alkyl, NH2, or NHC1-4 alkyl. In one embodiment, R¹ = H, F, CI, Br, OH, CF3, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl. In one embodiment, R³ = CH3, NH2, NHC1-5 saturated alkyl, OH, OC_1-6 saturated alkyl, or SH.

In one embodiment for formula (XIV), R² = OH, OC1-4 saturated alkyl, ΝH2,ΟΓ NHC1-4 alkyl, R¹ = H, F, CI, Br, OH, CF₃, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, SO2NHC_1-6 saturated alkyl, aryior heteroaryl, S02N(C_1-6 saturated alkyl/aryl/heteroaryl)2, or C_5-6 aryl or heteroaryl, R³ = CH3, NH2. NHC1-S saturated alkyl, OH, OC_1-6 saturated alkyl, or SH.

In one embodiment, the compound is salbutamol.

In one embodiment, the method employs a compound of formula (XV), e.g., a composition having a compound of formula (XV):

In one embodiment, R² = C_1-6 Saturated alkyl, or H, R¹ = H, F, CI, Br, OH, CF3, C_1-6 Aryloxy, C1-3 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated, alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 aryl or heteroaryl. In one embodiment, X = CH2, NH, NC_1-6 saturated alkyl, O, or S, R³ = N-C1-8 saturated alkylpyrrolidine or pyrrole, pyrrolidine, pyrrole, or NHCH2CH2C_5-6aryl or heteroaryl.

In one embodiment of formula (XV), R² = C_1-6 Saturated alkyl, or H, R¹ = H, F, CI, Br, OH, CF3, C₁- β Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated, alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 aryl or heteroaryl. In one embodiment, X = CH2, NH, NC_1-6 saturated alkyl, O, S, R³ = N-C_1-6 saturated alkylpyrrolidine or pyrrole, pyrrolidine, pyrrole, or NHCH2CH2C_5-6aryl or heteroaryl.

In one embodiment, the compound is clemastime or prenylamine.

In one embodiment, the method employs a compound of formula (XVI), e.g., a composition having a compound of formula (XVI):

In one embodiment, R¹ = H, F, CI, Br, OH, CF3. C_1-6 Aryloxy, C1-3 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl. In one embodiment, X = CH2, NH2, NH, NHC1-3 saturated alkyl, O, OH, S, SH, OCONH2, OCONHC_1-6 saturated alkyl, aryl, or heteroaryl.

In one embodiment of formula (XVI), R¹ = H, F, CI, Br, OH, CF3, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl; X = CH2, NH2, NH, NHC_1-6 saturated alkyl, O, OH, S, SH, OCONH2, OCONHC_1-6 saturated alkyl, aryl, or heteroaryl.

In one embodiment, the compound is methocarbamol.

In one embodiment, the method employs a compound of formula (XVII), e.g., a composition having a compound of formula (XVII):

In one embodiment, R³ = C_1-6 Saturated alkyl chain or CF3. In one embodiment, R¹ = H, F, CI, Br, OH, CF3, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, C02C_1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl. In one embodiment, X = CH2, NH2, NH, NHC_1-6 saturated alkyl, O, OH, S, SH. In one embodiment, R² = CC-C_3-6 cycloalkyl, or CC-C_5-6 aryl or heteroaryl.

In one embodiment for formula (XVII), R³ = C_1-6 Saturated alkyl chain or CF3; R¹ = H, F, CI, Br, OH, CF3, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-* alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl, or C_5-6 aryl or heteroaryl; and X = CH2, NH2, NH, NHC1-8 saturated alkyl, O, OH, S, SH, R² = CC-C_3-6 cycloalkyl, or CC-C_5-6 aryl or heteroaryl.

In one embodiment, the compound is efavirenz.

In one embodiment, the method employs a compound of formula (XVIII), e.g., a composition having a compound of formula (XVIII):

In one embodiment, each X independently = CH2, NH, O, or S. In one embodiment, each R¹

independently = H, F, CI, Br, OH, CF3, or C_1-6 Aryloxy. In one embodiment, each R¹ independently = H, F, CI, Br, OH, CF3, C1-3 Aryloxy, C1-3 saturated alkyl, CO2H, C02C_1-4 alkyl, SO2NH2, SO2NHC1-8 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl. In one embodiment, X = CH₂, NH2, NH, NHC_1-6 saturated alkyl, O, OH, S, SH, CC-C_3-6 cycloalkyl, or CC-C_5-6 aryl or heteroaryl.

In one embodiment of formula (XVIII), X = CH2, NH, O, or S;; and R¹ = H, F, CI, Br, OH, CF₃, or C₁^ Aryloxy.

In one embodiment, the method employs a compound of formula (XIX), e.g., a composition having a compound of formula (XIX):

In one embodiment, each R¹ independently = H, F, CI, Br, OH, CF₃, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2,or C_5-6 aryl or heteroaryl. In one embodiment, each X independently = CH2, NH, O, or S.

In one embodiment, the method employs a compound of formula (XX), e.g., a composition having a compound of formula (XX):

In one embodiment, each X independently = CH2, NH, NC_1-6 saturated alkyl, O, or S. In one embodiment, each R¹ independently² CH2C34 cycloalkyl, CH2C_5-6 aryl or heteroaryl, C_1-6 saturated alky, or C_5-6 aryl or heteroaryl.

In one embodiment, the compound is antipyrene.

In one embodiment, the method employs a compound of formula (XXI), e.g., a composition having a compound of formula (XXI):

In one embodiment, each R¹ independently = H, F, CI, Br, OH, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, C02C₁~t alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl. In one embodiment, X = CH2, NH, NC_1-6 saturated alkyl, O, or S. In one embodiment each R² independently = CH2C_3-6 cycloalkyl, CCN, CH2C_5-6 aryl or heteroaryl, or C_1-6 saturated alkyl.

In one embodiment, the compound is verapamil.

In one embodiment, the method employs a compound of formula (XXII), e.g., a composition having a compound of formula (XXII):

In one embodiment, each R¹ independently² H, F, CI, Br, OH, CF3, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, C02 C_1-4 alkyl, SO2NH2, SO2NHC1-8 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl. In one embodiment, each X independently² CH2, NH, NHC1- β saturated alkyl, O, or S. In one embodiment, R² = CH2C_3-6 cycloalkyl, CH2C_5-6 aryl or heteroaryl, or C_1-6 saturated alkyl.

In one embodiment, the compound is nalbuphine.

In one embodiment, the method employs a compound of formula (XXIII), e.g., a composition having a compound of formula (XXIII):

In one embodiment, each R¹ independently = H, F, CI, Br, OH, CF₃, C1-5 Aryloxy, CO2H, CO2C1-4 alkyl, SO2N or heteroaryl)2, or C_5-6 aryl or heteroaryl. In one embodiment, each R¹ independently² H, F, CI, Br, OH, CF3, C_1-6 Aryloxy, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl. In one embodiment, each X independently² CH2, NH, NC_1-6 saturated alkyl, O, or S.

In one embodiment, the compound is thioproperazine.

In one embodiment, the method employs a compound of formula (XXIV), e.g., a composition having a compound of formula (XXIV):

In one embodiment, each R¹ independently = H, F, CI, Br, OH, CF₃, C_1-6 Aryloxy, C1-3 saturated alkyl, CO2H, C02 C_1-4 alkyl, SO2NH2, SO2NHC1-8 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl. In one embodiment, X = CH2, NH, NC_1-6 saturated alkyl, O, or S. In one embodiment, R¹ = H, F, CI, Br, OH, CF3, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2,C_5-6 aryl or heteroaryl; and X = CH2, NH, NC_1-6 saturated alkyl, O, or S.

In one embodiment, the compound is crotamiton.

In one embodiment, the method employs a compound of formula (XXV), e.g., a composition having a compound of formula (XXV):

In one embodiment, each R¹ independently = H, F, CI, Br, OH, CF₃, CN, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2. S02NHC_1-6 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl. In one embodiment, each X independently = CH2, NH, NC_1-6 saturated alkyl, O, or S. In one embodiment, R¹ = H, F, CI, Br, OH, CF3, CN, C1-3 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-* alkyl, SO2NH2, SO2NHC1-3 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl; and X = CH2, NH, NC_1-6 saturated alkyl, O, or S.

In one embodiment, the compound is citalopram.

In one embodiment, the method employs a compound of formula (XXVI), e.g., a composition having a compound of formula (XXVI):

In one embodiment, each R¹ independently = H, C_1-6 Alkoxy, C_1-6 saturated alkyl, CH2CH2NHCHNH, CO2H, or CO2C1-4 alkyl. In one embodiment, X = H, F, CI, Br, OH, or C_1-6 Alkoxy. In one embodiment, R¹ = H, C_1-6 Alkoxy, C_1-6 saturated alkyl, CH2CH2NHCHNH, CO2H, C02C_1-4 alkyl; and X = H, F, CI, Br, OH, or C_1-6 Alkoxy.

In one embodiment, the compound is imipenem.

In one embodiment, the method employs a compound of formula (XXVII), e.g., a composition having a compound of formula (XXVII):

In one embodiment, each R¹ independently = H, F, CI, Br, OH, CF3, C1-3 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, SO2NHC1-S saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl. In one embodiment, each X independently = CH2, NH, NH2, NC_1-6 saturated alkyl, O, OH, S, or SH.

In one embodiment of formula (XVII), R¹ = H, F, CI, Br, OH, CF3, C_1-6 Aryloxy, C_1-6 saturated alkyl,

CO2H, C02C_1-4 alkyl, SO2NH2, SO2NHC1-8 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl, or C_5-6 aryl or heteroaryl; and X = CH2, NH, NH2, NC_1-6 saturated alkyl, O, OH, S, or SH

In one embodiment, the compound is leflunomide. In one embodiment, the method employs a compound of formula (XXVIII), e.g., a composition having a compound of formula (XXVI 11):

In one embodiment, each R¹ independently = H, F, CI, Br, OH, CF₃, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl. In one embodiment, each X independently = CH2, NH2, NHC_1-6 saturated alkyl, N, N(C_1-6 saturated alkyl)2, OH, or SH.

In one embodiment of formula (XXVIII), R¹ = H, F, CI, Br, OH, CF3, C_1-6 Aryloxy, C1-5 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, SOzNHC_1-6 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 aryl or heteroaryl; and X = CH2, NH2, NHC_1-6 saturated alkyl, N, N(C_1-6 saturated alkyl)2, OH, or SH.

In one embodiment, the compound is trimethoprim.

In one embodiment, the composition comprises a compound of formula (LXXX):

In one embodiment, each R¹ independently = H, F, CI, Br, OH, CF3, SCF3, NH2, NO2, C_1-6 Aryloxy, C1-6 saturated alkyl, OC_1-6 saturated or unsaturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl,S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 aryl or heteroaryl, C1-4 saturated alkyl, C34 saturated cycloalkyl, OH, orC_5-6 aryl or heteroaryl C_1-6 Saturated alkyl branched or unbranched; each X independently = C, CH, CH2, NH, O, or S; and n = 0-6.

In one embodiment, formula (LXXX) is bosentan.

In one embodiment, the composition comprises a compound of formula (LXXXI):

In one embodiment, each R¹ independently = H, F, CI, Br, OH, CF₃, SCF3, NH2, NO2, C_1-6 Aryloxy, C_1-6 saturated alkyl, OC_1-6 saturated or unsaturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, SO2NHCU1 saturated alkyl, aryl or heteroaryl,S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 aryl or heteroaryl, C1-4 saturated alkyl, C_3-6 saturated cycloalkyl, OH, or C_5-6 aryl or heteroaryl C_1-6 Saturated alkyl branched or unbranched; and each X independently = C, CH, CH2, NH, O, or S.

In one embodiment, formula (LXXXI) is ambrisentan

In one embodiment, the composition comprises a compound of formula (LXXXI I):

In one embodiment, each R¹ independently = H, F, CI, Br, OH, CF₃, SCF3, NH2, NO2, C_1-6 Aryloxy, C_1-6 saturated alkyl, OC_1-6 saturated or unsaturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl/aryl/heteroaryl,S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 aryl or heteroaryl, C1-4 saturated alkyl, C_3-6 saturated cycloalkyl, OH, or C_5-6 aryl or heteroaryl C_1-6 Saturated alkyl branched or unbranched; and each X independently = C, CH, CH2, NH, O, S, CI, Br, or I.

In one embodiment, formula (LXXXI I) is pralidoxime chloride.

In one embodiment, the composition comprises a compound of formula (LXXXI 11):

In one embodiment, each R¹ independently = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, SC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CO2H, COC1 8 alkyl unsaturated alkyl, or aryl, CO2C1-5 saturated, unsaturated alkyl, or aryl, CONH2, CC^NHC_1-6 saturated, unsaturated alkyl or aryl, C02N(C_1-6 saturated, unsaturated alkyl or aryl)2, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or Cs-7aryl or heteroaryl; each X independently = C, CH, CH2, S, SO, SO2, N, NH, NC_1-6saturated, unsaturated alkyl, or cycloalkyl, or O; and each n independently = 0-6.

In one embodiment, formula (LXXXI 11) is alprostadil.

In one embodiment, the composition comprises a compound of formula (LXXXI V): Λ Α

In one embodiment, each R¹ = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, SC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CO2H, COC1-8 alkyl unsaturated alkyl, or aryl, C02C_1-6 saturated, unsaturated alkyl, or aryl, CONH2, CC^NHC_1-6 saturated, unsaturated alkyl or aryl, C02N(C_1-6 saturated, unsaturated alkyl or aryl)2, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or Cs-7aryl or heteroaryl; and each X independently =

C, CH, CH2, S, SO, SO2, NH, NC_1-6saturated, unsaturated alkyl, or cycloalkyl, or O.

In one embodiment, formula (LXXXIV) is torsemide. In one embodiment, the composition comprises a compound of formula (LXXXV):

In one embodiment, each R¹ independently = H, CI, Br, F, I, OH, OAc, CF₃, NH2, CN, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, SC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CO2H, COC1-8 alkyl unsaturated alkyl, or aryl, CO2CI-6 saturated, unsaturated alkyl, or aryl, CONH2, CO2NHC1-8 saturated, unsaturated alkyl or aryl, C02N(C_1-6 saturated, unsaturated alkyl or aryl)2, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl; and each X = independently C, CH, CH2, S, SO, SO2, NH, NC_1-6saturated, unsaturated alkyl, or cycloalkyl, or O.

In one embodiment, formula (LXXXV) is etodolac.

The methods described herein are also based, in part, on the discovery that certain compounds, including those with other different activities/targets, were effective to increase the activity of a potassium channel, e.g., by increasing potassium ion flow through the channel. Compounds that enhance KCNQ2 activity, e.g., wild-type KCNQ2 activity, include, but are not limited to, those having formula (XXIX)-(LXII).

In one embodiment, the method employs a compound of formula (XXIX), e.g., a composition having a compound of formula (XXIX):

In one embodiment, each R¹ independently = OC_1-6 saturated, OC_5-6 aryl or heteroaryl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, or cycloheteroalkyl. In one embodiment, R² = CH2, 0, NH, or NC_1-6 saturated, unsaturated alkyl, cycloalkyl, or

cycloheterocycloalkyl.

In one embodiment, R³ = CN, C1-8 saturated or unsaturated alkyl, OC_1-6 saturated or unsaturated alkyl, NHC1-8 saturated, unsaturated alkyl, or cycloalkyl, or N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2. In one embodiment, each X independently = CH or N. In one embodiment, n = 0-6.

In one embodiment, formula (XXIX) is vinpocetine.

In one embodiment, each R¹ independently = OC_1-6 saturated, OC_5-6 aryl or heteroaryl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, or cycloheteroalkyl; R² = CH2, O, NH, or NC_1-6 saturated, unsaturated alkyl, cycloalkyl, or

cycloheterocycloalkyl; R³ = CN, C_1-6 saturated or unsaturated alkyl, OC_1-6 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, or N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2; each X independently = CH or N; and n = 0-6. In one embodiment, each R¹ independently = H, CI, Br, F, I, OH, NH2, CN, OH, OAc, OC1-3 saturated, OC_5-6 aryl or heteroaryl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl R2 = CH2, O, NH, NC1-3 saturated, unsaturated alkyl, cycloalky, or cycloheterocyloalkyl R3 = CN, C1-3 saturated or unsaturated alkyl, OC1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, or N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl; each X independently =CH or N; and n = 0-3.

In one embodiment, the method employs a compound of formula (XXX), e.g., a composition having a compound of formula (XXX):

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF₃, NH2, CN, CO2H, CO2C_1-6 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl. In one

embodiment, each X independently = CH2, N, O, S, SO, or SO2.

In one embodiment, formula (XXX) is niclosamide.

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF₃, NH2, CN, CO2H, CO2C_1-6 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or Cs yaryl or heteroaryl; and each X independently = CH2, N, O, S, SO, or SO2.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF₃, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C1-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7ary! or heteroaryl; and each X independently = CH2, N, O, S, SO, or SO2

In one embodiment, the method employs a compound of formula (XXXI), e.g., a composition having a compound of formula (XXXI):

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF3, NH2, CN, NO2, C(0)CH20Ac, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl. In one embodiment, each X independently = CH2, N, NH, NC_1-6saturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO2 In one embodiment, formula (XXXI) is retigabine.

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF₃, NH2, CN, NO2, C(0)CH20Ac, CO2H, CO2C_1-6 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl; and each X independently = CH2, N, NH, NC₁ esaturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO2

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF₃, NH2, CN, NO2, C(0)CH20Ac, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl)2, or Cs-7aryl or heteroaryl; each X independently = CH2, N, NH, NC1-3saturated, unsaturated alkyl, or cycloalkyl, O, S, SO, S or O2; and n = 0-3.

In one embodiment, the method employs a compound of formula (XXXII), e.g., a composition having a compound of formula (XXXII):

R¹

R¹ 1

Ri

R¹ -U

XT U._XJ

A "R¹

In one embodiment, each R¹ independently = H, OC1-8 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, CF3, NH2, CN, CO2H, CO2C1-S saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, or N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2. In one embodiment, each M

independently = Na, K, Li, Hg, or Zn. In one embodiment, each X independently = CH2, NH, O, S, SO, or SO2.

In one embodiment, formula (XXXII) is merbromin.

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, CF3, NH2, CN, CO2H, C02C₁« saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, or N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2; M independently = Na, K, Li, Hg, or Zn; and each X independently = CH2, NH, O, S, SO, or SO2.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, CF₃, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, or N(C1-3 saturated, unsaturated alkyl, or cycloalkyl)2, each M independently = Na, K, Li, Hg, or Zn; and each X independently = CH2, NH, O, S, SO, or SO2.

In one embodiment, the method employs a compound of formula (XXXIII), e.g., a composition having a compound of formula (XXXIII):

In one embodiment, R¹ = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, CF₃, NH2, CN, CO2H, CO2C14 saturated or unsaturated alkyl, NHC₁-a saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C5-7 aryl or heteroaryl. In one embodiment, X = CH2, NH, O, S, SO, or SO2.

In one embodiment, formula (XXXIII) is bithionol or hexachlorophene.

In one embodiment, R¹ = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, CF3, NH2, CN, CO2H, CO2C1-5 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or Cs-7 aryl or heteroaryl and X = CH2, NH, O, S, SO, or SO2.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, CF3, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalky02, or C5-7 aryl or heteroaryl; and

each X independently = CH2, NH, O, S, SO, or SO2.

In one embodiment, the method employs a compound of formula (XXXIV), e.g., a composition having a compound of formula (XXXIV):

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-8 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl In one embodiment, each X independently = CH, CH2, N, O, S, SO, or SO2.

In one embodiment, formula (XXXIV) is benzbromarone.

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, C02C_1-6 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl; and each X independently = CH, CH2, N, O, S, SO, or SO2.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl C1.3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C1-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroary and each X independently = CH, CH2, N, O, S, SO, or SO2. In one embodiment, the method employs a compound of formula (XXXV), e.g., a composition having a compound of formula (XXXV):

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C_1-6 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl. In one embodiment, each X independently = CH, CH2, N, O, S, SO, or SO2.

In one embodiment, formula (XXXV) is prankulast.

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C_1-6 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl; and each X independently = CH, CH2, N, O, S, SO, or SO2.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C1-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C₁-7aryl or heteroaryl; and each X independently = CH, CH2, N, O, S, SO, or SO2.

In one embodiment, the method employs a compound of formula (XXXVI), e.g., a composition having a compound of formula (XXXVI):

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl. In one embodiment, each X independently = CH, CH2, N, O, S, SO, or SO2.

In one embodiment, formula (XXXVI) is leflunomide.

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C_1-6 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl; and each X independently = CH, CH2, N, O, S, SO, or SO2. In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I,

OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl; and each X independently = CH, CH2, N, O, S, SO, or SO2.

In one embodiment, the method employs a compound of formula (XXXVII), e.g., a composition having a compound of formula (XXXVII):

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, CF3, NH2, CN, CO2H, CO2C_1-6 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C5-7 aryl or heteroaryl. In one embodiment, each X independently = CH, CH2, NH, O, S, SO, or SO2.

In one embodiment, formula (XXXVII) is zafirlukast.

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, CF₃, NH2, CN, CO2H, CO2C1-8 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C5-7 aryl or heteroaryl, and each X independently = CH, CH2, NH, O, S, SO, or SO2.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, CF₃, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl)2,or C5-7 aryl or heteroaryl; and each X independently = CH, CH2, NH, O, S, SO, or SO2.

In one embodiment, the method employs a compound of formula (XXXVIII), e.g., a composition having a compound of formula (XXXVIII):

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF₃, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl. In one embodiment, each X independently = C, CH2, N, NH, O, S, SO, or SO2.

In one embodiment, formula (XXXVIII) is diclazuril. In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C_1-6 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl; and each X independently = C, CH2, N, NH, O, S, SO, or SO2.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl)2, or Cs-7aryl or heteroaryl; and each X independently = C, CH2, N, NH, O, S, SO, or SO2.

In one embodiment, the method employs a compound of formula (XXXIX), e.g., a composition having a compound of formula (XXXIX):

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH.OAc, NO2, CF3, NH2, CN, CO2H, C02C_1-6 saturated or unsaturated alkyl, NHC1-8 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl 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, formula (XXXIX) is dilazep.

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-S saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or Cs-7aryl or heteroaryl; each X independently = C, CH2, N, NH, O, S, SO, or SO2; and each n independently = 0-6.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl)2, or Cwaryl or heteroaryl; each X independently = C, CH2, N, NH, O, S, SO, or SO2; and each n independently = 0-3.

In one embodiment, the method employs a compound of formula (XXXX), e.g., a composition having a compound of formula (XXXX):

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C_1-6 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl. In one embodiment, each X independently = CH, CH2, N, NH, O, S, SO, or SO2. In one embodiment, each n independently = 0-6.

In one embodiment, formula (XXXX) is alexidine.

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-8 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or Cs-7aryl or heteroaryl; each X independently = CH, CH2, N, NH, O, S, SO, or SO2; and each n independently = 0-6.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C1-3 saturated, unsaturated alkyl, or cycloalkyl)2, or Cs-7aryl or heteroaryl; each X independently = CH, CH2, N, NH, O, S, SO, or SO2; and each n independently = 0-3.

In one embodiment, the method employs a compound of formula (XXXXI), e.g., a composition having a compound of formula (XXXXI):

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, C02C_1-6 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl. In one embodiment, each X independently = CH, CH2, N, NH, O, S, SO, or SO2. In one embodiment, n = 0-6.

In one embodiment, formula (XXXXI) is tiratricol.

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, C02C_1-6 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl; each X independently = CH, CH2, N, NH, O, S, SO, or SO2 ; and n = 0-6.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl, or Cs- 7aryl or heteroaryl; each X independently = CH, CH2, N, NH, O, S, SO, or SO2; and n = 0-3.

In one embodiment, the method employs a compound of formula (XXXXI I), e.g., a composition having a compound of formula (XXXXII):

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or Cs-7aryl or heteroaryl. In one embodiment, each X independently = CH, CH2, N, NH, O, S, SO, orSOj> In one embodiment, each n independently = 0-6.

In one embodiment, formula (XXXXII) is bromocriptine.

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C_1-6 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, Cs-7aryl or heteroaryl; each X independently = CH, CH2, N, NH, O, S, SO, SO2; and each n independently = 0-6.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7ary! or heteroaryl; each X independently = CH, CH2, N, NH, O, S, SO, or SO2; and each n independently = 0-3.

In one embodiment, the method employs a compound of formula (XXXXII I), e.g., a composition having a compound of formula (XXXXII I):

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, C02C_1-6 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl 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, formula (XXXXII I) is calcipotriene.

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-S saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalky1)2, or Cs-7aryl or heteroaryl; each X independently = C, CH2, N, NH, O, S, SO, or SO2; and each n independently = 0-6.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl; each X independently = C, CH2, N, NH, O, S, SO, or SO2; and each n independently = 0-3.

In one embodiment, the method employs a compound of formula (XXXXIV), e.g., a composition having a compound of formula (XXXXIV):

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, C02C_1-6 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl. In one embodiment, each X independently = C, CH2, N, NH, O, S, SO, or SO2. In one embodiment, n = 0-6.

In one embodiment, formula (XXXXIV) is fentiazac.

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-S saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or Cs-7aryl or heteroaryl; each X independently = C, CH2, N, NH, O, S, SO, or SO2; and n = 0-6.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl; each X independently = C, CH2, N, NH, O, S, SO, or SO2; and n = 0-3.

In one embodiment, the method employs a compound of formula (XXXXV), e.g., a composition having a compound of formula (XXXXV):

In one embodiment, each R1 independently = H, OC_1-6 saturated, unsaturated alkyl, cyclolalkyl, cycloheteroalkyl, or aryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyf, cycloheteroalkyl, CI, Br, F, I,

OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C_1-6 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl. In one embodiment, each X independently = C, CH2, N, NH, O, S, SO, or SO2. In one embodiment, n = 0-6.

In one embodiment, formula (XXXXV) is telmisartan.

In one embodiment, each R1 independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-8 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or Cs-7aryl or heteroaryl; each X independently = C, CH2, N, NH, O, S, SO, or SO2; and n = 0-6.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C1-3 saturated, unsaturated alkyl, or cycloalkyl)2, or Cs-7aryl or heteroaryl; each X independently = C, CH2, N, NH, O, S, SO, or SO2 and n = 0-3.

In one embodiment, the method employs a compound of formula (XXXXVI), e.g., a composition having a compound of formula (XXXXVI):

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl. In one embodiment, each X independently = C, CH2, N, NH, O, S, SO, or SO2. In one embodiment, n = 0-6.

In one embodiment, formula (XXXXVI) is stanozolol.

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, C02C_1-6 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl; each X independently = C, CH2, N, NH, O, S, SO, or SO2; and n = 0-6.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl)2, or Cs-7aryl or heteroaryl; each X independently = C, CH2, N, NH, O, S, SO, or SO2; and n = 0-3. In one embodiment, the method employs a compound of formula (XXXXVII), e.g., a composition having a compound of formula (XXXXVII):

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, SCF3, NH2, CN, CO2H, CO2C1-S saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl, or Cs-7aryl or heteroaryl. In one embodiment, each X independently = C, CH, CH2, N, NH, O, S, SO, or SO2. In one embodiment, n = 0-6.

In one embodiment, formula (XXXXVII) is toltrazuril.

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, SCF₃, NH2, CN, CO2H, CO2C1-S saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl; each X independently = C, CH, CH2, N, NH, O, S, SO, or S02_; and n = 0-6.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, SCF₃, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalky02, or C_5-7aryl or heteroaryl; each X independently = C, CH, CH2, N, NH, O, S, SO, or SO2; and n = 0-3.

In one embodiment, the method employs a compound of formula (XXXXVII I), e.g., a composition having a compound of formula (XXXXVII I):

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-5 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl. In one embodiment, each X independently = C, CH2, N, NH, O, S, SO, or SO2. In one embodiment, n = 0-6.

In one embodiment, formula (XXXXVII I) is dicumarol.

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalky02, or Cs-7aryl or heteroaryl; each X independently = C, CH2, N, NH, O, S, SO, or SO2; and n = 0-6. In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I,

OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl; each X independently = C, CH2, N, NH, O, S, SO, or SO2; and n = 0-3.

In one embodiment, the method employs a compound of formula (XXXXIX), e.g., a composition having a compound of formula (XXXXIX):

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-5 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl. In one embodiment, each X independently = C, CH2, N, NH, O, S, SO, or SO2.

In one embodiment, formula (XXXXIX) is apigenin.

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-5 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl; and X independently = C, CH2, N, NH, O, S, SO, or SO2.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl)2, or Cs-7aryl or heteroaryl; and each X independently = C, CH2, N, NH, O, S, SO, or SO2

In one embodiment, the method employs a compound of formula (L), e.g., a composition having a compound of formula (L):

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C_1-6 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl 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, formula (L) is spiperone. In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C_1-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or Cs-7aryl or heteroaryl; each X independently = C, CH2, N, NH, O, S, SO, or SO2; and each n independently = 0-6.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl)2, or Cs-7aryl or heteroaryl; each X independently = C, CH2, N, NH, O, S, SO, or SO2; and each n independently = 0-3.

In one embodiment, the method employs a compound of formula (LI), e.g., a composition having a compound of formula (LI):

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C_1-6 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl 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, formula (LI) is acitretin.

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, C02C_1-6 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl; each X independently = C, CH2, N, NH, O, S, SO, or SO2 and each n independently = 0-6.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C1-3 saturated, unsaturated alkyl, or cycloalkyl)2, orC_5-7aryl or heteroaryl; each X independently = C, CH2, N, NH, O, S, SO, or SO2, and each n independently = 0-3.

In one embodiment, the method employs a compound of formula (LI I), e.g., a composition having a compound of formula (LI I):

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or Cs-7aryl 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, formula (LI I) is rostiglitazone or pioglitazone.

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-8 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or Cs-7aryl or heteroaryl; each X independently = C, CH2, N, NH, O, S, SO, or SO2; and each n independently = 0-6.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1 3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7ary! or heteroaryl; each X independently = C, CH2, N, NH, O, S, SO, or SO2 and each n independently = 0-3.

In one embodiment, the method employs a compound of formula (LI 11), e.g., a composition having a compound of formula (LI 11):

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C_1-6 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl. In one embodiment, each X independently = C, CH2, N, NH, O, S, SO, or SO2.

In one embodiment, formula (LIN) is flufenamic acid. In one embodiment, formula (LI 11) is not mefenamic acid.

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-8 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or Cs-7aryl or heteroaryl; and each X independently = C, CH2, N, NH, O, S, SO, or SO2

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C1-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl; and each X independently = C, CH, CH2, N, NH, O, S, SO, or SO2.

In one embodiment, the method employs a compound of formula (LIV), e.g., a composition having a compound of formula (LIV):

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF₃, NH2, CN, C(0)CH20Ac, CO2H, CO2C_1-6 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl. In one embodiment, each R² independently = H, OH, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, OAc, CF₃, NH2, CN, C02H,C(0)CH20Ac, C(0)C_1-6saturated, unsaturated, cyloalkyl, cycloheteralkyl, or aryl, CO2C1 8 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or Cs-7aryl or heteroaryl. In one embodiment, each X independently = CH2, C, NH, NC₁-asaturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO2. In one embodiment, n = 0- 6.

In one embodiment, formula (LIV) is rimexolone.

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF₃, NH2, CN, C(0)CH20Ac, CO2H, CO2C1-8 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalky02, or Cs-7aryl or heteroaryl; each R² independently = H, OH, OC1-6 saturated, unsaturated alkyl, cycloalkyl,

cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, OAc, CF₃, NH2, CN, C02H,C(0)CH20Ac, C(0)C_1-6saturated, unsaturated, cyloalkyl, cycloheteralkyl, or aryl, C02C_1-6 saturated or unsaturated alkyl, NHC1-8 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl, or C_5-7aryl or heteroaryl; each X independently = CH2, C, NH, NC_1-6saturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO2; and n = 0-6.

In one embodiment, each R² independently = H, OH, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, OAc, CF₃, NH2, CN, C02H,C(0)CH2oAc, C(0)C₁-3saturated, unsaturated, cyloalkyl, cycloheteralkyl, or aryl, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or In one embodiment, cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl)2, or Cs-7aryl or heteroaryl; X = CH2, C, NH, NC₁- ssaturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO2; and n= 0-3.

In one embodiment, the method employs a compound of formula (LV), e.g., a composition having a compound of formula (LV):

A

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF₃, NH2, CN, CO2H, CO2C_1-6 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl 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, formula (LV) is tazobactam.

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C_1-6 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or Cs-7aryl or heteroaryl; each X independently = C, CH2, N, NH, O, S, SO, or SO2; and each n independently = 0-6.

In one embodiment, the method employs a compound of formula (LVI), e.g., a composition having a compound of formula (LVI):

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl. In one embodiment, each X independently = C, CH2, N, NH, O, S, SO, or SO2. In one embodiment, n = 0-6.

In one embodiment, formula (LVI) is oxantel.

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C_1-6 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl; each X independently = C, CH2, N, NH, O, S, SO, or SO2; and n = 0-6.

In one embodiment, the method employs a compound of formula (LVI I), e.g., a composition having a compound of formula (LVI I):

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc,

Ac, CF₃, NH2, CN, C(0)CH20Ac, CO2H, C02C_1-6 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl. In one embodiment, each X independently = CH2, C, NH, NC_1-6saturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO2. In one embodiment, each n independently = 0-6.

In one embodiment, formula (LVII) is 56-androsterone.

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF3, NH2, CN, C(0)CH20Ac, CO2H, C02C_1-6 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or Cs-7aryl or heteroaryl; each X independently = CH2, C, NH, NC_1-6saturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO2; and each n independently = 0-6.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF₃, NH2, CN, C(0)CH20Ac, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl; each X independently = CH2, C, NH, NC1-3saturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO2. and each n independently = 0-3.

In one embodiment, the method employs a compound of formula (LVII I), e.g., a composition having a compound of formula (LVII I):

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, C02C_1-6 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl. In one embodiment, each X independently = C, CH2, N, NH, O, S, SO, or SO2. In one embodiment, n = 0-6.

In one embodiment, formula (LVII I) is zoledronic acid.

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF₃, NH2, CN, CO2H, CO2C_1-6 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl; each X independently = C, CH2, N, NH, O, S, SO, or SO2; and n = 0-6.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalky1)2,or Cs-7aryl or heteroaryl; each X independently = C, CH2, N, NH, O, S, SO, or SO2; and n = 0-3.

In one embodiment, the method employs a compound of formula (LIX), e.g., a composition having a compound of formula (LIX):

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C_1-6 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl. In one embodiment, each X independently = C, CH2, N, NH, O, S, SO, or SO2.

In one embodiment, formula (LIX) is hydroflumethiazide.

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-5 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl; and each X independently = C, CH2, N, NH, O, S, SO, or SO2

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl; and each X independently = C, CH2, N, NH, O, S, SO, or SO2

In one embodiment, the method employs a compound of formula (IX), e.g., a composition having a compound of formula (LX):

In one embodiment, formula (LX) is lomefloxacin.

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, C02C_1-6 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalky1)2, or Cs-7aryl or heteroaryl; each X independently = C, CH2, N, NH, O, S, SO, or SO2; and n = 0-6.

In one embodiment, the method employs a compound of formula (LXI), e.g., a composition having a compound of formula (LXI): r

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C_1-6 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl. In one embodiment, each X independently = C, CH2, N, NH, O, S, SO, or SO2. In one embodiment, n = 0-6.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1 3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl)2, or Cs-7aryl or heteroaryl; each X independently = C, CH2, N, NH, O, S, SO, or SO2; and n = 0-3.

In one embodiment, formula (LXI) is butamben or procaine.

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, C02C_1-6 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl; each X independently = C, CH2, N, NH, O, S, SO, or SO2 ; and n = 0-6.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C1-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl; each X independently = C, CH2, N, NH, O, S, SO, or SO2, and n = 0-3.

In one embodiment, the method employs a compound of formula (LXI I), e.g., a composition having a compound of formula (LXI I): ¹

In one embodiment, each R1 independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl 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, formula (LXII) is astemizole.

In one embodiment, each R1 independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C_1-6 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl; each X independently = C, CH2, N, NH, O, S, SO, or SO2; and each n independently = 0-6.

In one embodiment, each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl; and each X independently = C, CH, CH2, N, NH, O, S, SO, or SO2; and each n independently = 0-3.

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 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 Ball (eds.), Wiley, New York (1984); Ranger & Peppas, J. Macromol. Sci. Rev. Macromol. Chem.. 23:61 (1983); see also Levy et al., Science. 228:190 (1985); During et al., Ann. Neurol.. 25:351 (1989); Howard et al., J. Neurosuro.. 71:105 (1989)). Other controlled release systems are discussed in the review by Langer (Science. 249:1527 (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 monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol 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 ingestible 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, com starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as com 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 intracerebroventicular 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 all 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 polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of undesirable microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride.

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 that is essentially free of bacterial and/or viral contamination.

Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol 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 to repurpose for a rare genetic disease, focusing on a gain of function mutation in KCNQ2 causing severe epilepsy. This mutation was found in a patient with EIEE that was resistant to multiple AEDs. A small molecule chemical library of over 1 ,300 compounds including FDA approved drugs and drugs approved outside the United States (i.e. by EMA and other foreign regulatory agencies) was tested for activity in a heterologous expression system expressing the mutated KCNQ2 channels. Using a fluorescent imaging plate reader-based screening assay, 35 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), many with acceptable safety profile and brain blood barrier penetration, were identified as candidates to evaluate in patients with KCNQ2 positive epilepsy. The same chemical library of compounds was assayed for activity against the respective wild-type channel. Some of the compounds screened were found to inhibit the wild-type channel but not KCNQ2 R201C. The overlap in compounds was surprisingly low; only two compounds inhibited both the wild-type KCNQ2 channel and the variant KCNQ2 channel (Figure 4). These results identify new candidates therapies for epilepsy patients with KCNQ2 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 comprehensive repurposing effectiveness screening (CRES) to identify new putative therapeutic options for a severely underserved patient population.

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 arginine (Arg or R) at a residue corresponding to residue 201 in SEQ ID NO:1. For example, the compounds may have particular use for mammals with an amino acid residue in KCNQ2, other than R201 , e.g., at position 201 in KCNQ2 the mammal has C, S, A, I, V, G or T. It is also envisioned that the compounds disclosed herein alter the activity of other variants of KCNQ2, e.g., other gain-of-function variants, e.g., KCNQ2 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.

Example 1

Materials and Method

Next Generation Sequencing

Agilent SureSelect + MiSeq was carried out. A minimum of 30x coverage was required for confirmation of a variant. 99.71% of coding bases in the genes were covered > 30x. In-house validation attributes a minimum sensitivity of 97.5% (with 95% confidence) for regions covered >30x. Genes covered were ADSL, ALG13, ARHGEF9, ARX, ATP1A3, CBL, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2,

CNTNAP2, CREBBP, CSNK1G1, DNM1, DOCK7, EHMT1, EP300, FASN, FOXG1, GABRA1, GABRB3.

GATAD2B, GRIN2A, HCN1, KCNB1, KCNQ2, KCNT1, KIAA1279, LGI1, MAGI2, MDB5, MECP2,

MEF2C, NRXN1, PCDH19, PIGA, PIGQ, PLCB1, PNKP, POLG, PRRTW, QARS, RYR3, SCN1A,

SCN2A, SCN8A, SLC13A5, SLC16AD, SLC25A22, SLC2A1, SLC35A2, SLC9A6, SMARCA2, SPTAN1,

STXBP1, SYNGAP1, TBC1D24, TCF4, UBE2A, UBE3A, WRD45, ZEB2.

Table 1A. Inhibitory activity of compounds on KCNQ2 R201C/KCNQ3 cell model tested at a 10 μΜ concentration.

3SD hits in bold, 2 - 3 SD in plain text.

Mean = -1.3%

SD = 4.2%

Mean + 2 SD = 7.2%

Mean + 3 SD = 11.5%

Table 1 B Inhibitory activity of selected compounds on KCNQ2 R201 C/KCNQ3 cell model tested across a concentration series from 10 nM to 30 μΜ

N/E=no effect; N/A=not available due to linear curve; N/T=not tested

Table 2A. Exemplary steroids that inhibit KCNQ2 variant.

Table 2B. Exemplary synthetic estrogens that inhibit KCNQ2 variant.

A cellular model of a patient's KCNQ2 R201 C mutation was generated in CHO cell lines. In depth electrophysiological characterization of this cell line indicated that the mutation gave rise to increased sensitivity to activation of Kv7.2-containing potassium channels as well as delayed deactivation kinetics of the channels. The KCNQ2 R201C mutation provides a gain-of-function, leading to increased outward potassium ion flow or currents of the Kv7.2-containing potassium channels. Kv7.2-containing potassium channels are expressed in neurons. Increased potassium channel trafficking correlates with an increased

M-current out of the cell which may contribute to epilepsy pathology.

The cellular model contains a replica of the KCNQ2 R201C mutation identified in the patient's sequencing report. This was done by genetically altering a healthy KCNQ2 DMA sequence to the mutant KCNQ2 C607T sequence (see below) and then inserting this mutant DNA sequence into cells in a controlled laboratory environment. Then the functional effects of the KCNQ2 R201C mutation were examined in voltage clamp experiments.

The KCNQ2 R201C mutation encodes a potassium channel that exhibits both increased sensitivity to activation in response to electrical stimulation of the cell as well as delayed deactivation following electrical stimulation. These changes would result in increased outward flow or efflux of potassium and support the characterization of KCNQ2 R201C as a gain-of-function mutation.

The patient was first identified as having seizures at approximately 6 months of age and received a diagnosis of neonatal epileptic encephalopathy. Clinically, the patient has developmental delay, delayed motor milestones, hypotonia, seizures, abnormal movements, eye anomalies, and vision loss. The KCNQ2 gene in the patient had a point mutation with a thymine (T) in place of the usual cytosine (C) at position 607 in the DNA sequence (C.607OT) in one of the two copies of the KCNQ2 gene (i.e. the patient is heterozygous for the mutation). The substitution of a cytosine nucleic acid for thymine found in the patient causes the patient's cells to then substitute a cysteine (Cys or C) amino acid in place of the usual arginine (Arg or R) amino acid at the 201st position of the protein sequence (p.R201C). As a result, the protein product is altered, resulting in dysfunction. The patient's KCNQ2 R201C mutation was identified as de novo (happening anew in the patient and not detected in either parent) and is thought to be the cause of the patient's neonatal epileptic encephalopathy.

A synthetic strand of KCNQ2 DNA was manipulated to carry the R201C mutation.

The healthy form of the KCNQ2 gene is referred to as the wild-type (WT) and is most commonly found in the general population. Wild-type KCNQ2 DNA was purchased and then altered to replicate the specific KCNQ2 R201C mutation detected in the patient. No blood or tissue specimens were obtained from the patient for this work. Rather, altering the healthy KCNQ2 gene to the mutant form was carried out by a technique called "site-directed mutagenesis". Specifically, at the 607th position of the wild-type KCNQ2 DNA, the nucleic acid cytosine (C) was removed and replaced with a thymine (T). As described earlier, this effect produces a change in the resulting protein wherein the normal amino acid arginine (R) is substituted for cysteine (C) at the 201st position of the protein (R201C).

Generation of a Cellular Model: Insertion of Gene Mutation Replica into a Cell Line

DNA was introduced into the CHO cell line.

In order to characterize a genetic mutation and its effects on cellular processes, the mutated gene must be introduced into cells to see how it behaves in a native cellular environment. CHO cells were selected to host KCNQ2 wild-type or mutated DNA because they are widely used in biology to model cellular function and because they contain few inherent ion channels, which might otherwise affect the assessment of potassium channel function. In addition, CHO cells have been successfully utilized in high throughput drug screening previously. To create cellular models for research studies, either wild-type or mutated KCNQ2 DNA was introduced into CHO cells using standard genetic delivery methods to allow high amounts of the DNA to be present in the cell. Because KV7.2 potassium channel subunits often form functional channels together with Kv7.3 subunits and these combined subunits generate larger currents than channels with Kv7.2 subunits alone, cellular models containing both subunits were created. A gene expression system was created where the KCNQ2 DNA was introduced into cells in a fixed ratio together with wild-type KCNQ3 DNA (which encodes the Kv7.3 channel subunit). This incorporation of

KCNQ2/KCNQ3 wild-type, normal DNA into one pool of CHO cells produced the healthy KCNQ2 wild- type/KCNQ3 cellular model, while the incorporation of KCNQ2 C607T/KCNQ3 wild-type DNA into a separate pool of CHO cells generated a mutated KCNQ2 R201C/KCNQ3 cellular model.

The expression of DNA in the CHO cells was confirmed.

The DNA sequences and their successful introduction into CHO cells were then ascertained by Sanger sequencing. This technique confirmed that both cellular models contained the intended DNA sequences to allow for the expression of Kv7.2 containing potassium channels and Kv7.2-mediated potassium currents. Together, these findings established the cellular models as suitable for

characterization studies.

The R201C mutation in KCNQ2 causes a gain of function in potassium ion conductance.

The KCNQ2 R201C/KCNQ3 cellular model was tested to determine how it compares to the healthy, wild-type KCNQ2 /KCNQ3 cellular model. To test these cells for changes in function, electrophysiological methods were used. The potassium channels created by the Kv7.2/Kv7.3 subunits have two main conformational states: (1) an "open" state in which the channel has been activated and undergoes a physical change that allows for the passage of potassium ions out of the cell and (2) a "closed" state in which the channel has been deactivated and undergoes a physical change that no longer allows for the passage of potassium ions out of the cell. Activation and deactivation kinetics were measured to understand the exact effects of the KCNQ2 R201C mutation on normal channel function and potassium ion passage through the cell (conductance).

Measuring sensitivity to activation

An important feature of wild-type voltage-gated potassium channels is their ability to open only at the appropriate voltage. In order to determine how readily wild-type or mutated Kv7.2-containing channels are activated and opened, cells were electrically stimulated and the resulting current flow recorded. The voltage at which 50% of potassium channels activate is known as "V1/2" and reflects how readily the cells are activated by an electrical stimulus. In the present studies, the V1/2 of potassium channel opening was found to be dramatically lower for mutated Kv7.2-containing cells compared to wild-type Kv7.2-containing cells (Figure 2, left-shift of the red curve, p<0.05). A lower V1/2 indicates that the potassium channels open at lower voltages and are therefore more easily activated. This significant shift in channel opening (- 22 mV, p<0.05) means that mutated Kv7.2-containing potassium channels require a lower amount of membrane depolarization in order to be activated than wild-type Kv7.2-containing potassium channels; these mutated channels are therefore more sensitive to activation and result in greater potassium efflux as the membrane potential of the cell is depolarized. The KCNQ2 R201 C mutation therefore enhances the activity of the M-like current produced in the cell models.

Testing the dynamics of channel closing The effect of the KCNQ2 R201C mutation on channel closure, a process known as "deactivation" was also examined. Deactivation helps to bring about the end of the potassium current. When electrophysiology experiments were carried out to understand how quickly the mutated and wild-type

Kv7.2/Kv7.3 channels close in response to a decrease in membrane potential, there was a clear difference between cells containing mutated Kv7.2/Kv7.3 channels and cells containing wild-type

Kv7.2/Kv7.3 channels. Cells containing the mutated channel were significantly slower to deactivate than cells containing the wildtype channel, as can be seen by the rightward shift in the recordings shown in

Figure 3 (significance, p<0.05). This slowed deactivation allows a prolonged potassium current during the closing phase of the channel than would otherwise occur in a healthy state..

These results confirm KCNQ2 R201C as a gain-of-function mutation in Kv7.2/Kv7.3 voltage-gated potassium channels.

These data also show the generation of a cell line containing the patient's KCNQ2 R201C mutation that is amenable to high throughput screening. Drugs may be tested to identify those with the capability to reverse the enhanced M-current and potentially protect cells from the detrimental effects of the mutation.

Certain compounds were also found to inhibit the wild-type KCNQ2 (see Tables 3A-B below). Those compounds as well as compounds that are structurally related thereto may be employed to inhibit or treat one or more symptoms of Parkinson's Disease or Alzheimer's disease, or treat cognitive impairment, benign senescent forgetfulness, impaired motor coordination, hyperprolactinemia, social withdrawal, anhedonia, bipolar disorder, schizophrenia, or attention deficit disorder. In one embodiment, the compound is administered in an amount that enhances dopaminergic neuronal excitability or improves learning or memory.

Table 3A. Inhibitory activity of compounds on KCNQ2/3 Wild-Type cell model tested at 10 μΜ

concentration.

3SD hits in bold, 2 - 3 SD in plain text.

Mean = -1.0%

SD = 5.0%

Mean + 2 SD = 9.0%

Mean + 3 SD = 14.0%

Table 3B. Inhibitory activity of selected compounds on KCNQ2 Wild-Type cell model tested across a concentration series from 10 nM to 30 μΜ.

N/A = not available due to linear curve

Certain compounds were also found to enhance (e.g., activate or increase ion flow through) the wild-type KCNQ2 channel (see Tables 4A-B below). Those compounds as well as compounds that are structurally related thereto may be employed to enhance (augment) potassium channel, e.g., KCNQ2, activity in a mammal, e.g., activity that is not abberant, for instance, in a mammal having or at risk of seizure disorders, epilepsy, hypertension, vasospasm, overactive bladder/urinary incontinence, vasodilation, temporomandibular disorders, pain (analgesia), learning disorders, memory disorders, or hearing disorders, e.g., by altering flow of potatssium ions through wild-type KCNQ2 channels or channels with reduced activity due to loss-of-function mutation in the KCNQ2 channel.

Table 4A: Activating compounds on the KCNQ2/3 Wild-Type cell model testing at 10 μΜ.

3SD hits in bold, 2 - 3 SD in plain text.

Mean = 0.1%

SD = 10.5%

Mean + 2 SD = 21.2%

Mean + 3 SD = 31.8%

Table 4B Selected activating compounds on the KCNQ2 Wild-Type cell model tested across a concentration series from 10 nM to 30 μΜ.

N/E = no effect, N/A = not available due to linear curve, N/T = not tested

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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 or encephalopathies in a mammal, comprising: administering to the mammal an effective amount of a composition comprising a compound of any one of formula (l)-(LXXXV), a compound in any one of Tables 1 , 2, 3, or 4, or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 wherein the compound is a compound in Table 1.

3. The method of claim 1 or 2 wherein the mammal is a human.

4. The method of any one of claims 1 to 3 wherein the composition has a compound of formula (I)

wherein each X independently = CH2, NH, O, or S; wherein each R¹ independently = H, F, CI, Br, OH, CF₃, C_1-6Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, SO2NHC1-8 saturated Alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl.

5. The method of any one of claims 1 to 4 wherein the composition has a compound of formula (II)

wherein X = CH2, NH, N-OH, O, or S; each R¹ independently = H, C₁~t saturated alkyl, C_-e saturated cycloalkyl, or OH; wherein R² = H, OH, or C1-3 alykyl or alkynyl; and wherein R³ = OH, OAc, C1-2 Alkoxy, C_1-6 saturated branched or unbranched alkyl, COCH2OH, or CHCH2CH2CO2H 6. The method of any one of claims 1 to 5 wherein the composition has a compound of formula (III)

wherein each R1 independently² H, F, CI, Br, OH, CF3, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, SO2NHC_1-6 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl; and wherein each R² independently is H, C_1-4 Saturated alkyl or alkenyl, C3-7 Cycloalkyl, aryl, or heteroaryl

7. The method of any one of claims 1 to 6 wherein the composition has a compound of formula (IV)

wherein R1 = C1-5 Saturated alkyl, NH2, OH, S, or C_1-6 Alkoxy; and wherein X = CH2, NH, O, or S.

8. The method of any one of claims 1 to 7 wherein the composition has a compound of formula (V)

wherein each R1 independently = H, F, CI, Br, OH, CF3, d-β Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl; and X = CH2, NH, O, or S.

9. The method of any one of claims 1 to 8 wherein the composition has a compound of formula (VI)

wherein each R1 independently = H, F, CI, Br, OH, CF3, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, SO2NHC_1-6 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl; and wherein X = CH2, NH, O, or S.

The method of any one of claims 1 to 9 wherein the composition has a compound of formula (VII)

wherein X = CH2, NH, O, S, NHC1-10 Saturated alkyl, cycloalkyl, aryl, or heteroaryl; and whereinRI = OH, OAc, C1-2 Alkoxy, C₁-a saturated branched or unbranched alkyl, COCH2OH, or CHCH2CH2CO2H. The method of any one of claims 1 to 10 wherein the composition has a compound of formula

wherein each R1 independently = H, F, CI, Br, OH, CF3, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl; and wherein X = CH2, NH, O, or S.

The method of any one of claims 1 to 11 wherein the composition has a compound of formula (IX)

wherein each R² independently = H, F, CI, Br, OH, CF3, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, SO2NHC1-8 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl; and wherein each R1 independently = H, F, CI, Br, OH, CF3, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-* alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl.

13. The method of any one of claims 1 to 12 wherein the composition has a compound of formula (X)

wherein each R² independently² C1-10 saturated Alkyl, NH, O, S, NHC1-10 Saturated alkyl, cycloalkyl, aryl, or heteroaryl; wherein each R¹ independently = H, F, CI, Br, OH, CF3, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2. S02NHC_1-6 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl; and wherein X = NH, O, S or CH2. The method of any one of claims 1 to 13 wherein the composition has a compound of formula (XI)

wherein each X independently = CH, CH2, CH3, N, NH, NH2, 0, OH, S, or SH; and wherein each R1 independently = H, F, CI, Br, OH, CF3, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl, COCH2OH, or CHCH2CH2CO2H.

15. The method of claim 1 wherein the composition comprises a compound of any one of formula (XII)-(XXVIII) or (LXXX)-(LXXXV), a compound in Table 3, a pharmaceutically acceptable salt thereof, or a combination thereof.

16. The method of claim 15 wherein potassium ion flux is decreased by at least 10% but no more than 50%.

17. The method of claim 15 or 16 wherein the compound is the compound of formula (XII)

wherein X = CH₂, NH, N-OH, O, OH, S, or SH; wherein R¹ = H, SatCur1a-4ted alkyl, C_3-6

Saturated cycloalkyi, or OH; wherein R² = H, OH, C1-3 alkyl or alkynl; and wherein R³ = OH, OAc, Acetyl, C1-2 Alkoxy, C1-8 saturated branched or unbranched alkyl, COCH2OH, or CHCH2CH2CO2H.

18. The method of any one of claims 15 to 17 wherein the compound is the compound of formula

(XIII)

S

wherein R1 = H, F, CI, Br, OH, CF3, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, SO2NHC1-5 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl; and wherein X = CH2, CH, NH, N, O, or S.

19. The method of any one of claims 15 to 18 wherein the compound is the compound of formula

(XIV)

wherein R¹ = H, F, CI, Br, OH, CF3, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, SO2NHC1-8 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl; wherein X = CH₂, NH₂, NH, NHC_1-6 saturated alkyl, O, OH, S, SH, OCONH2, OCONHC1-8 saturated alkyl, aryl, or heteroaryl; wherein R2 = OH, OC1-4 saturated alkyl, NH2, or NHC1-4 alkyl; and wherein R³= CH3, NH2, NHC_1-6 saturated alkyl, OH, OC_1-6 saturated alkyl, or SH.

20. The method of any one of claims 15 to 19 wherein the compound is the compound of formula (XV)

wherein R² = C_1-6 Saturated alkyl, or H, R¹ = H, F, CI, Br, OH, CF3, C1-6 Aryloxy, C1-3 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated, alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 aryl or heteroaryl; wherein X = CH2, NH, NC_1-6 saturated alkyl, O, or S; and wherein R³ = N-C_1-6 saturated alkylpyrrolidine or pyrrole, pyrrolidine, pyrrole, or NHCH2CH2Cs-8aryl or heteroaryl. 21. The method of any one of claims 15 to 20 wherein the compound is the compound of formula (XVI)

wherein R¹= H, F, CI, Br, OH, CF3, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl; and wherein X = CH₂, NH₂, NH, NHC_1-6 saturated alkyl, O, OH, S, SH, OCONH2, OCONHC1-8 saturated alkyl, aryl, or heteroaryl.

22. The method of any one of claims 15 to 21 wherein the compound is the compound of formula (XVII)

wherein R³ = C_1-6 Saturated alkyl chain or CF3; wherein R¹= H, F, CI, Br, OH, CF3, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, SO2NHC1-8 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl; wherein X = CH2, NH2, NH, NHC₁- β saturated alkyl, O, OH, S, SH; and wherein R² = CC-C34 cycloalkyl, or CC-C_5-6 aryl or heteroaryl.

The method of any one of claims 15 to 22 wherein the compound is the compound of formula

wherein each R¹ independently = H, F, CI, Br, OH, CF3, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H,

CO2C1-4 alkyl, SO2NH2, SO2NHC1-8 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl; and wherein each X = CH2, NH2, NH, NHC_1-6 saturated alkyl, O, OH, S, SH, CC-C3-B cycloalkyl, or CC-C_5-6 aryl or heteroaryl.

The method of any one of claims 15 to 23 wherein the compound is the compound of formula

wherein each R¹ independently = H, F, CI, Br, OH, CF3, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, SO2NHC1-S saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2,or C_5-6 aryl or heteroaryl; and wherein each X independently = CH2, NH, O, or S.

25. The method of any one of claims 15 to 24 wherein the compound is the compound of formula

(XX)

X

wherein each X independently = CH2, NH, NC_1-6 saturated alkyl, O, or S; and wherein each R¹ independently² CH2C_3-6 cycloalkyl, CH2C_5-6 aryl or heteroaryl, C_1-6 saturated alky, or Cs-β aryl or heteroaryl.

wherein each R¹ independently = H, F, CI, Br, OH, C1-8 Aryloxy, C1-8 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl;, wherein X = CH2, NH, NC_1-6 saturated alkyl, O, or S; and wherein each R² independently = CH2C3-e cycloalkyl, CCN, CH2C5-8 aryl or heteroaryl, or C_1-6 saturated alkyl.

27. The method of any one of claims 15 to 26 wherein the compound is the compound of formula (XXII)

wherein each R¹ independently² H, F, CI, Br, OH, CF3, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, SO2NHC1-3 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl; wherein each X independently² CH2, NH, NHC_1-6 saturated alkyl, O, or S; and wherein R² = CH2 C_3-6 cycloalkyl, CH2C5-8 aryl or heteroaryl, or C_1-6 saturated alkyl.

28. The method of any one of claims 15 to 27 wherein the compound is the compound of formula (XXIII)

wherein each R¹ independently = H, F, CI, Br, OH, CF3, C_1-6 Aryloxy, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl, or C_5-6 aryl or heteroaryl; and wherein each X independently² CH2, NH, NC_1-6 saturated alkyl, O, or S. The method of any one of claims 15 to 28 wherein the compound is the compound of formula

(XXIV)

wherein each R independently = H, F, CI, Br, OH, CF3, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1- alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl; and wherein X = CH2, NH, NC_1-6 saturated alkyl, O, or S, or any combination thereof.

30. The method of any one of claims 15 to 29 wherein the compound is the compound of formula (XXV)

wherein each R¹ independently = H, F, CI, Br, OH, CF3, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl; and wherein each X independently = CH2, NH, NC_1-6 saturated alkyl, O, or S, or any combination thereof.

31. The method of any one of claims 15 to 30 wherein the compound is the compound of formula (XXVI)

wherein each R¹ independently = H, C_1-6 Alkoxy, C_1-6 saturated alkyl, CH2CH2NHCHNH, CO2H, or CO2C1 alkyl; and wherein X = H, F, CI, Br, OH, or C1-3 Alkoxy, or any combination thereof.

32. The method of any one of claims 15 to 31 wherein the compound is the compound of formula

(XXVII)

wherein each R¹ independently = H, F, CI, Br, OH, CF₃, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-* alkyl, SO2NH2, SO2NHC1-S saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl; and wherein each X independently = CH2, NH, NH2, NC_1-6 saturated alkyl, O, OH, S, or SH, or any combination thereof.

33. The method of any one of claims 15 to 32 wherein the compound is the compound of formula (XXVIII)

wherein each R¹ independently = H, F, CI, Br, OH, CF3, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, or C_5-6 aryl or heteroaryl; and wherein each X independently = CH2, NH2, NHC_1-6 saturated alkyl, N, N(C_1-6 saturated alkyl)2, OH, or SH, or any combination thereof.

34. The method of any one of claims 4 to 14 wherein the compound is the compound of formula (XXIX)

wherein each R¹ independently = H, CI, Br, F, I, OH, NH2, CN, OH, OAc, OC1-3 saturated, OC_5-6 aryl or heteroaryl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl R² = CH2, O, NH, NC1-3 saturated, unsaturated alkyl, cycloalky, or cycloheterocyloalkyl R³ = CN, C1-3 saturated or unsaturated alkyl, OC1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, or N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2; and wherein each X independently =CH or N; and n = 0-3.

35. The method of any one of claims 4 to 14 or 34 wherein the compound is the compound of formula (XXX)

wherein each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, NO2, CF3, NH2, CN, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-3 saturated, unsaturated alkyl, or cycloalky02, or C5-7aryl or heteroaryl; and wherein each X independently

= CH₂, N, O, S, SO, or SO_z.

36. The method of any one of claims 4 to 14 or 34 to 35 wherein the compound is the compound of formula (XXXI)

wherein each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF3, NH2, CN, NO2, C(0)CH20Ac, CO2H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C1-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C5-7aryl or heteroaryl; wherein each X independently = CH2, N, NH, N C1-3saturated, unsaturated alkyl, or cycloalkyl, O, S, SO, S or O-O; and wherein n = 0-3.

37. The method of any one of claims 4 to 14 or 34 to 36 wherein the compound is the compound of formula (XXXII)

wherein each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, CF3, NH2, CN, C02H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, or N(C₁ 3 saturated, unsaturated alkyl, or cycloalkyl)2; wherein each M independently = Na, K, Li, Hg, or Zn; and wherein each X independently = CH2, NH, O, S, SO, or S02.

38. The method of any one of claims 4 to 14 or 34 to 37 wherein the compound is the compound of formula (XXXIII)

wherein each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, CF3, NH2, CN, C02H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalky02, or C5-7 aryl or heteroaryl; and wherein each X independently

= CH2, NH, O, S, SO, or S02.

39. The method of any one of claims 4 to 14 or 34 to 38 wherein the compound is the compound of formula (XXXIV)

wherein each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl C1.3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, N02, CF3, NH2, CN, C02H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C5-7aryl or heteroaryl; and wherein each X independently = CH, CH2, N, O, S, SO, or S02.

40. The method of any one of claims 4 to 14 or 34 to 39 wherein the compound is the compound of formula (XXXV)

wherein each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, N02, CF3, NH2, CN, C02H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C1-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C5-7aryl or heteroaryl; and wherein each X independently = CH, CH2, N, O, S, SO, or S02.

41. The method of any one of claims 4 to 14 or 34 to 40 wherein the compound is the compound of formula (XXXVI)

wherein each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, N02, CF3, NH2, CN, C02H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C1-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C5-7aryl or heteroaryl; and wherein each X independently = CH, CH2, N, O, S, SO, or S02. The method of any one of claims 4 to14 or 34 to 41 wherein the compound is the compound of

wherein each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, CF3, NH2, CN, C02H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl)2,or C5-7 aryl or heteroaryl; and wherein each X independently = CH, CH2, NH, O, S, SO, or S02. 43. The method of any one of claims 4 to 14 or 34 to 42 wherein the compound is the compound of formula (XXXVIII)

wherein each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, N02, CF3, NH2, CN, C02H, C02C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C5- 7aryl or heteroaryl; and wherein each X independently = C, CH2, N, NH, O, S, SO, or S02.

44. The method of any one of claims 4 to 14 or 34 to 43 wherein the compound is the compound of formula (XXXIX)

wherein each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, N02, CF3, NH2, CN, C02H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C1-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C5- 7aryl or heteroaryl; wherein each X independently = C, CH2, N, NH, O, S, SO, or S02; and wherein each n independently = 0-3

45. The method of any one of claims 4 to 14 or 34 to 44 wherein the compound is the compound of formula (XXXX)

wherein each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1 3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, N02, CF3, NH2, CN, C02H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C5- 7aryl or heteroaryl; wherein each X independently = CH, CH2, N, NH, O, S, SO, or S02; and wherein each n independently = 0-3.

46. The method of any one of claims 4 to 14 or 34 to 45 wherein the compound is the compound of formula (XXXXI)

wherein each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1 3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, N02, CF3, NH2, CN, C02H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C5- 7aryl or heteroaryl; wherein each X independently = CH, CH2, N, NH, O, S, SO, or S02; and wherein n = 0-3.

47. The method of any one of claims 4 to 14 or 34 to 46 wherein the compound is the compound of formula (XXXXI I)

wherein each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1 3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, N02, CF3, NH2, CN, C02H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C5-7aryl or heteroaryl; wherein each X independently = CH, CH2, N, NH, O, S, SO, or S02; and wherein each n independently = 0-3

The method of any one of claims 4 to 14 or 34 to 47 wherein the compound is the compound of (XXXXIII)

wherein each R¹= independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1 3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, N02, CF3, NH2, CN, C02H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C1-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C5-7aryl or heteroaryl; wherein each X independently = C, CH2, N, NH, O, S, SO, or S02; and wherein each n independently = 0-3.

49. The method of any one of claims 4 to14 or 34 to 48 wherein the compound is the compound of formula (XXXXIV)

wherein each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, N02, CF3, NH2, CN, C02H, C02C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C5-7aryl or heteroaryl; wherein each X independently = C, CH2, N, NH, O, S, SO, or S02; and wherein n = 0-3.

50. The method of any one of claims 4 to 14 or 34 to 49 wherein the compound is the compound of formula (XXXXV)

wherein each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1 3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, N02, CF3, NH2, CN, C02H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C1-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C5- 7aryl or heteroaryl; wherein each X independently = C, CH2, N, NH, O, S, SO, or S02; and wherein n = 0-3. The method of any one of claims 4 to 14 or 34 to 50 wherein the compound is the compound of

wherein each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, N02, CF3, NH2, CN, C02H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C5-7aryl or heteroaryl; wherein each X independently = C, CH2, N, NH, O, S, SO, or S02; and wherein n = 0-3. 52. The method of any one of claims 4 to 14 or 34 to 51 wherein the compound is the compound of formula (XXXXVII)

wherein each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1 3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, N02, CF3, SCF3, NH2, CN, C02H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C5-7aryl or heteroaryl; wherein each X independently = C, CH, CH2, N, NH, O, S, SO, or S02; and wherein n = 0-3.

53. The method of any one of claims 4 to 14 or 34 to 52 wherein the compound is the compound of formula (XXXXVII I)

wherein each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1 3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, N02, CF3, NH2, CN, C02H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C5-7aryl or heteroaryl; wherein each X independently = C, CH2, N, NH, O, S, SO, or S02; and wherein n = 0-3.

54. The method of any one of claims 4 to14 or 34 to 53 wherein the compound is the compound of formula (XXXXIX)

wherein each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, N02, CF3, NH2, CN, C02H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C5- 7aryl or heteroaryl; and wherein each X independently = C, CH2, N, NH, O, S, SO, or S02.

55. The method of any one of claims 4 to 14 or 34 to 54 wherein the compound is the compound of formula (L)

wherein each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, N02, CF3, NH2, CN, C02H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C5-7aryl or heteroaryl; wherein each X independently = C, CH2, N, NH, O, S, SO, or S02; and wherein each n independently = 0-3.

56. The method of any one of claims 4 to 14 or 34 to 55 wherein the compound is the compound of formula (LI)

wherein each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, N02, CF3, NH2, CN, C02H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl)2, orC5-7aryl or heteroaryl; wherein each X independently = C, CH2, N, NH, O, S, SO, or S02; and wherein each n independently = 0-3.

57. The method of any one of claims 4 to 14 or 34 to 56 wherein the compound is the compound of formula (LI I)

58. The method of any one of claims 4 to 14 or 34 to 57 wherein the compound is the compound of formula (LIN)

wherein each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1 3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, N02, CF3, NH2, CN, C02H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C5-7aryl or heteroaryl; and wherein each X independently = C, CH, CH2, N, NH, O, S, SO, or S02.

59. The method of any one of claims 4 to 14 or 34 to 58 wherein the compound is the compound of formula (LIV)

wherein each R² independently = H, OH, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, OAc, CF3, NH2, CN,

C02H,C(0)CH20Ac, C(0)C₁-3saturated, unsaturated, cyloalkyl, cycloheteralkyl, or aryl, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C5-7aryl or heteroaryl; wherein X = CH2, C, NH, NC₁-3saturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or S02; and wherein n= 0-3.

60. The method of any one of claims 4 to 14 or 34 to 59 wherein the compound is the compound of formula (LV)

wherein each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, N02, CF3,

NH2, CN, C02H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C5-7aryl or heteroaryl; wherein each X independently = C, CH2, N, NH, O, S, SO, or S02; and wherein each n independently = 0-3

61. The method of any one of claims 4 to 14 or 34 to 60 wherein the compound is the compound of formula (LVI)

wherein each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, N02, CF3, NH2, CN, C02H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C1-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C5-7aryl or heteroaryl; wherein each X independently = C, CH2, N, NH, O, S, SO, or S02; and wherein n = 0-3.

62. The method of any one of claims 4 to 14 or 34 to 61 wherein the compound is the compound of formula (LVI I)

wherein each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, Ac, CF3, NH2, CN, C(0)CH20Ac, C02H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C1-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C5-7aryl or heteroaryl; wherein each X independently = CH2, C, NH, NC1-3saturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or S02; and wherein each n independently = 0-3.

63. The method of any one of claims 4 to 14 or 34 to 62 wherein the compound is the compound of formula (LVI 11)

wherein each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, N02, CF3, NH2, CN, C02H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalky1)2,or C5-7aryl or heteroaryl; wherein each X independently = C, CH2, N, NH, O, S, SO, or S02; and wherein n = 0-3.

64. The method of any one of claims 4 to 14 or 34 to 63 wherein the compound is the compound of formula (LIX)

wherein each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, N02, CF3, NH2, CN, C02H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C5-7aryl or heteroaryl; and wherein each X independently = C, CH2, N, NH, O, S, SO, or S02.

65. The method of any one of claims 4 to 14 or 34 to 64 wherein the compound is the compound of formula (LX)

wherein each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1 3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, N02, CF3, NH2, CN, C02H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C1-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C5-7aryl or heteroaryl; wherein each X independently = C, CH2, N, NH, O, S, SO, or S02; and wherein n = 0-3.

66. The method of any one of claims 4 to 14 or 34 to 65 wherein the compound is the compound of formula (LXI)

67. The method of any one of claims 4 to14 or 34 to 66 wherein the compound is the compound of formula (LXI I)

wherein each R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, OAc, N02, CF3, NH2, CN, C02H, CO2C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C₁-3 saturated, unsaturated alkyl, or cycloalkyl)2, or C5-7aryl or heteroaryl; wherein each X independently = C, CH, CH2, N, NH, O, S, SO, or S02; and wherein each n independently = 0-3.

68. The method of any one of claims 4 to 14 or 34 to 67 wherein the compound is the compound of formula (LXIII)

wherein each R¹ independently = H, F, CI, Br, OH, CF3, SCF3, NO2, C1-5 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, SO2NHC_1-6 saturated alkyl, aryl or heteroaryl,S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 aryl/heteroaryl, C_1-4 saturated alkyl, C_3-6 saturated cycloalkyl, or C_5-6 aryl or heteroaryl C_1-6 Saturated alkyl branched or unbranched; wherein each R² independently² Na, K, or Li; wherein each X independently = C, CH, CH2, NH, O, or S; and wherein each n independently = 0-6.

69. The method of any one of claims 4 to 14 or 34 to 68 wherein the compound is the compound of formula (LXIV)

wherein each R¹ independently = H, F, CI, Br, OH, CF3, SCF3, NO2, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, SO2NHC_1-6 saturated alkyl/aryl/heteroaryl,S02N(C_1-6 saturated alkyl, aryl, or heteroaryl)2, C_5-6 aryl/heteroaryl, C1-4 saturated alkyl, C_3-6 saturated cycloalkyl, OH, or C_5-6

aryl/heteroaryl C_1-6 Saturated alkyl branched or unbranched; and wherein each X independently = C, CH, CH₂, NH, O, or S.

70. The method of any one of claims 4 to 14 or 34 to 69 wherein the compound is the compound of formula (LXV)

wherein each R¹ independently = H, F, CI, Br, OH, CF3, SCF3, NO2, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl,S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 aryl/heteroaryl, C1-4 saturated alkyl, C_3-6 saturated cycloalkyl, OH, or C_5-6 aryl or heteroaryl C_1-6 Saturated alkyl branched or unbranched; and wherein each X independently = C, CH, CH2, NH, O, or S.

71. The method of any one of claims 4 to 14 or 34 to 70 wherein the compound is the compound of formula (LXVI)

wherein each R¹ independently = H, F, CI, Br, OH, NO2, CF3, SCF3, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2. S02NHC_1-6 saturated alkyl, aryl orheteroaryl,S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2. C_5-6 arylor heteroarylC, 1-4 saturated alkyl, C_3-6 saturated cycloalkyl, OH, or C_5-6 aryl or heteroaryl C_1-6 Saturated alkyl branched or unbranched; and wherein each X independently = C, CH, CH2, NH, O, or S.

72. The method of any one of claims 4 to 14 or 34 to 71 wherein the compound is the compound of formula (LXVI I)

wherein each R¹ independently = H, F, CI, Br, OH, NO2, CF3, SCF₃, C1-5 Aryloxy, C1-5 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, SO2NHC1-S saturated alkyl, aryl or heteroaryl,S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 ary lor heteroaryl,C1-4 saturated alkyl, C_3-6 saturated cycloalkyl, OH, or C_5-6 aryl or heteroaryl C_1-6 Saturated alkyl branched or unbranched; and wherein each X independently = C, CH, CH2, NH, O, or S.

73. The method of any one of claims 4 to 14 or 34 to 72 wherein the compound is the compound of formula (LXVIII)

1

wherein each R¹ independently = H, F, CI, Br, OH, NO2, CF3, SCF3, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2. S02NHC_1-6 saturated alkyl, aryl or heteroaryl,S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 ary lor heteroaryl, C_1-6 saturated alkyl, C_3-6 saturated cycloalkyl, OH, or C5-8 aryl or heteroaryl C_1-6 Saturated alkyl branched or unbranched; and wherein each X independently = C, CH, CH2,

NH, O, S.

The method of any one of claims 4 to 14 or 34 to 73 wherein the compound is the compound of (LXIX)

wherein each R¹ independently = H, F, CI, Br, OH, CF3, SCF3, NO2, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl,S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 aryl or heteroaryl, C1-4 saturated alkyl, C_3-6 saturated cycloalkyl, OH, or CM aryl or heteroaryl C_1-6 Saturated alkyl branched or unbranched; wherein each X independently = C, CH, CH2, NH, O, or S; and wherein n = 0-6.

75. The method of any one of claims 4 to 14 or 34 to 74 wherein the compound is the compound of formula (LXX)

wherein each R¹ independently = H, F, CI, Br, OH, CF3, SCF3, NO2, C1-5 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl,S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 aryl or heteroaryl, C1-4 saturated alkyl, C_3-6 saturated cycloalkyl, OH, or C_5-6 aryl or heteroaryl C_1-6 Saturated alkyl branched or unbranched; and each X independently = C, CH, CH2, NH, O, or S.

76. The method of any one of claims 4 to 14 or 34 to 75 wherein the compound is the compound of formula (LXXI)

wherein each R¹ independently = H, F, CI, Br, OH, CF3, SCF3, NH2, NO2, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-* alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl,S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 aryl or heteroaryl, C_1-4 saturated alkyl, C_3-6 saturated cycloalkyl, OH, orCs-e aryl/heteroaryl C_1-6 Saturated alkyl branched or unbranched; each X independently = C, CH, CH2, NH, O, or S; and n = 0-6.

77. The method of any one of claims 4 to 14 or 34 to 76 wherein the compound is the compound of formula (LXXI I)

wherein each R¹ independently = H, F, CI, Br, OH, CF3, SCF3, NH2, NO2, C_1-6 Aryloxy, C_1-6 saturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2. S02NHC_1-6 saturated alkyl, aryl or heteroaryl,S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 aryl or heteroaryl, C_1-6 saturated alkyl, C_3-6 saturated cycloalkyl, OH, or C_5-6 aryl orheteroaryl C_1-6 Saturated alkyl branched or unbranched; and wherein each X independently = CH, CH2,

NH, O, or S.

78. The method of any one of claims 4 to 14 or 34 to 77 wherein the compound is the compound of formula (LXXIII)

wherein each R¹ independently = H, F, CI, Br, OH, CF3, SCF3, NH2, NO2, C_1-6 Aryloxy, C_1-6 saturated alkyl, OC_1-6 saturated or unsaturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, SO2NHC1-5 saturated alkyl, aryl or heteroaryl,S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 aryl or heteroaryl, C1-4 saturated alkyl, C_3-6 saturated cycloalkyl, OH, or C_5-6 aryl or heteroaryl C1-5 Saturated alkyl branched or unbranched; wherein each X independently = CH, CH2, NH, O, or S; and wherein each n independently = 0-6.

79. The method of any one of claims 4 to 14 or 34 to 78 wherein the compound is the compound of formula (LXXIV)

wherein each R¹ independently = H, F, CI, Br, OH, CF3, SCF3, NH2, NO2, C_1-6 Aryloxy, C_1-6 saturated alkyl, OC_1-6 saturated or unsaturated alkyl, CO2H, C02C_1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl,S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 aryl or heteroaryl, C_1-4 saturated alkyl, C_3-6 saturated cycloalkyl, OH, or C_5-6 aryl orheteroaryl C_1-6 Saturated alkyl branched or unbranched; wherein each X independently = CH, CH2, NH, O, or S; and wherein n = 0-6.

80. The method of any one of claims 4 to 14 or 34 to 79 wherein the compound is the compound of formula (LXXV)

wherein each R¹ independently = H, F, CI, Br, OH, CF3, SCF3, NH2, NO2, C_1-6 Aryloxy, C_1-6 saturated alkyl, OC_1-6 saturated or unsaturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, SO2NHC1-5 saturated alkyl, aryl or heteroaryl,S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 aryl or heteroaryl, C1-4 saturated alkyl, C_3-6 saturated cycloalkyl, OH, C_5-6 aryl or heteroaryl C_1-6 Saturated alkyl branched or unbranched; wherein each X independently = CH, CH2, NH, O, or S; and wherein each n independently = 0-6.

81. The method of any one of claims 4 to 14 or 34 to 80 wherein the compound is the compound of formula (LXXVI)

wherein each R¹ independently = H, F, CI, Br, OH, CF3, SCF3, NH2, NO2, C_1-6 Aryloxy, C_1-6 saturated alkyl, OC_1-6 saturated or unsaturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl,S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 aryl or heteroaryl, C1-4 saturated alkyl, C_3-6 saturated cycloalkyl, OH, or C_5-6 aryl orheteroaryl C_1-6 Saturated alkyl branched or unbranched; and wherein each X independently = CH, CH2, NH, O, or S.

82. The method of any one of claims 4 to 14 or 34 to 81 wherein the compound is the compound of formula (LXXVI I)

wherein each R¹ independently = H, F, CI, Br, OH, CF3, SCF3, NH2, NO2, C_1-6 Aryloxy, OC_1-6 saturated or unsaturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl,S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 aryl or heteroaryl, C1-4 saturated alkyl, C_3-6 saturated cycloalkyl, OH, or C_5-6 aryl or heteroaryl C_1-6 Saturated alkyl branched or unbranched; wherein each X independently = CH, CH2, NH, O, or S; and wherein n = 0-6.

83. The method of any one of claims 4 to 14 or 34 to 82 wherein the compound is the compound of formula (LXXVI 11)

,

wherein each R¹ independently = H, F, CI, Br, OH, CF3, SCF3, NH2, NO2, C_1-6 Aryloxy, OC_1-6 saturated or unsaturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl,S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 aryl or heteroaryl, C1-4 saturated alkyl, C_5-6 saturated cycloalkyl, OH, or C_5-6 aryl or heteroaryl C_1-6 Saturated alkyl branched or unbranched; wherein each X independently

= CH, CH2, NH, O, or S; and wherein each n independently = 0-6.

84. The method of any one of claims 4 to 14 or 34 to 83 wherein the compound is the compound of formula (LXXIX)

wherein each R¹ independently = H, F, CI, Br, OH, CF3, SCF3, NH2, NO2, ONO2, C_1-6 Aryloxy, OC_1-6 saturated or unsaturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, S02NHC_1-6 saturated alkyl, aryl or heteroaryl, S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 aryl or heteroaryl, C1-4 saturated alkyl, C_3-6 saturated cycloalkyl, OH, or C_5-6 aryl or heteroaryl C_1-6 Saturated alkyl branched or unbranched; wherein each X independently = CH, CH2, NH, O, or S; and wherein each n independently = 0-6.

85. The method of any one of claims 15 to 33 wherein the compound is the compound of formula

(LXXX)

wherein each R¹ independently = H, F, CI, Br, OH, CF3, SCF3, NH2, NO2, C_1-6 Aryloxy, C_1-6 saturated alkyl, OC1-8 saturated or unsaturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, SO2NHC1-6 saturated alkyl, aryl or heteroaryl,S02N(C_1-6 saturated alkyl, aryl or heteroaryl, C_5-6 aryl or heteroaryl, C_1-4 saturated alkyl, C_3-6 saturated cycloalkyl, OH, or C_5-6 aryl or heteroaryl C_1-6 Saturated alkyl branched or unbranched; wherein each X independently = C, CH, CH2, NH, O, or S; and wherein n = 0-6.

86. The method of any one of claims 15 to 33 or 85 wherein the compound is the compound of formula (LXXXI)

wherein each R¹ independently = H, F, CI, Br, OH, CF3, SCF3, NH2, NO2, C_1-6 Aryloxy, C_1-6 saturated alkyl, OC_1-6 saturated or unsaturated alkyl, CO2H, C02 C_1-4 alkyl, SO2NH2, SO2NHC_1-6 saturated alkyl, aryl or heteroaryl,S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 aryl or heteroaryl, C_1-4 saturated alkyl, C3-5 saturated cycloalkyl, OH, or C_5-6 aryl or heteroaryl C_1-6 Saturated alkyl branched or unbranched; and wherein each X independently = C, CH, CH2, NH, O, or S.

87. The method of any one of claims 15 to 33 or 85 to 86 wherein the compound is the compound of formula (LXXXII)

wherein each R¹ independently = H, F, CI, Br, OH, CF3, SCF3, NH2, NO2, C_1-6 Aryloxy, C_1-6 saturated alkyl, OC_1-6 saturated or unsaturated alkyl, CO2H, CO2C1-4 alkyl, SO2NH2, SO2NHC1-8 saturated

alkyl/aryl/heteroaryl,S02N(C_1-6 saturated alkyl, aryl or heteroaryl)2, C_5-6 aryl or heteroaryl, C1-4 saturated alkyl, C_3-6 saturated cycloalkyl, OH, or C_5-6 aryl or heteroaryl C_1-6 Saturated alkyl branched or unbranched; and wherein each X independently = C, CH, CH2, NH, O, S, CI, Br, or I.

88. The method of any one of claims 15 to 33 or 85 to 87 wherein the compound is the compound of formula (LXXXIII)

wherein each R¹ independently = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, SC1-5 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CO2H, COC1-8 alkyl unsaturated alkyl, or aryl, C02C_1-6 saturated, unsaturated alkyl, or aryl, CONH2, C02NHC_1-6 saturated, unsaturated alkyl or aryl, C02N(C_1-6 saturated, unsaturated alkyl or aryl)2, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl; wherein each X independently = C, CH, CH2, S, SO, SO2, N, NH, NC_1-6saturated, unsaturated alkyl, or cycloalkyl, or O; and wherein each n independently = 0-6.

89. The method of any one of claims 15 to 33 or 85 to 88 wherein the compound is the compound of formula (LXXXIV)

R

wherein each R¹ = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, SC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CO2H, COC1-8 alkyl unsaturated alkyl, or aryl, CO2C1-S saturated, unsaturated alkyl, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyl or aryl, C02N(C_1-6 saturated, unsaturated alkyl or aryl)2, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl; and wherein each X independently = C, CH, CH2, S, SO, SO2, NH, NC_1-6saturated, unsaturated alkyl, or cycloalkyl, or O.

90. The method of any one of claims 15 to 33 or 85 to 89 wherein the compound is the compound of formula (LXXXV)

wherein each R¹ independently = H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, SC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CO2H, COC1-8 alkyl unsaturated alkyl, or aryl, C02C_1-6 saturated, unsaturated alkyl, or aryl, CONH2, C02NHC_1-6 saturated, unsaturated alkyl or aryl, C02N(C_1-6 saturated, unsaturated alkyl or aryl)2, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2, or C_5-7aryl or heteroaryl; and wherein each X = independently C, CH, CH2, S, SO, SO2, NH, NC_1-6saturated, unsaturated alkyl, or cycloalkyl, or O.

91. A method to increase potassium ion flux in a mammal in need thereof, comprising: administering to the mammal an effective amount of a composition comprising a compound of any one of formula (XXIX)-(LXII), a compound in Table 4, a pharmaceutically acceptable salt thereof, or a combination thereof.

92. A method to decrease potassium ion flux in a mammal in need thereof, comprising: administering to the mammal an effective amount of a composition comprising a compound of any one of formula (I)- (XXVIII) or (LXIII)-(LXXXV), a compound in Table 1 , 2 or 3, a pharmaceutically acceptable salt thereof, or a combination thereof.

93. A method to prevent, inhibit or treat one or more symptoms associated with hypertension, vasospasm, overactive bladder/urinary incontinence, vasodilation, temporomandibular disorders, pain, learning disorders, memory disorders, or hearing disorders in a mammal, comprising: administering to the mammal an effective amount of a composition comprising a compound of any one of formula (XXIX)- (LXII), a compound in Table 4, a pharmaceutically acceptable salt thereof, or a combination thereof.

94. A method to prevent, inhibit or treat one or more symptoms associated with Parkinson's Disease, dopaminergic neuronal excitability, learning or memory disorders, Alzheimer's disease, cognitive impairment, benign senescent forgetfulness, motor coordination, hyperprolactinemia, social withdrawal, anhedonia, bipolar disorder, schizophrenia, or attention deficit disorder in a mammal, comprising:

administering to the mammal an effective amount of a composition comprising a compound of any one of formula (l)-(XXVIII) or (LXIII)-(LXXXV), a compound in Table 1 , 2 or 3, a pharmaceutically acceptable salt thereof, or a combination thereof.

95. The method of any one of claims 1 to 94 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.

96. The method of any one of claims 1 to 94 wherein the composition is systemically administered.

97. The method of any one of claims 1 to 94 wherein the composition is orally administered.

98. The method of claim 97 wherein the composition is a sustained release formulation. 99. The method of any one of claims 1 to 98 wherein administration is intravenous, intra-arterial, subcutaneous, intranasal, intrathecal, intracerebroventricular, intraparenchymal, trans-retinal, intramuscular, transdermal, or rectal.

100. The method of any one of claims 1 to 14. 34 to 84, 92, or 94 to 99 wherein the amount inhibits increased sensitivity to activation, delays or decreases M-current, decreases spontaneous firing, decreases neuronal excitation, decreases hyperpolarized shifts in voltage-dependence of activated ion channels, or increases the speed of inactivation of open ion channels, or any combination thereof.

101. The method of any one of claims 1 to 14, 34 to 84, 92, or 94 to 99 wherein the KCNQ2 channels in the mammal are determined to have increased sensitivity to activation, increased M-current, increased spontaneous firing, increased neuronal excitation, hyperpolarized shifts in voltage-dependence of activated ion channels, or decreased speed of inactivation of open ion channels, or any combination thereof. 102. The method of any one of claims 1 , 3, 15 to 33, 85 to 91 , 93, or 95 to 99 wherein the amount increases sensitivity to activation, accelerates or increases M-current, increases spontaneous firing, increases neuronal excitation, increases depolarized shifts in voltage-dependence of activated ion channels, or decreases the speed of inactivation of open ion channels, or any combination thereof. 103. The method of any one of claims 1 , 3, 15 to 33, 85 to 91 , 93, or 95 to 99 wherein the KCNQ2 channels in the mammal are determined to have decreased sensitivity to activation, decreased M-current, decreased spontaneous firing, decreased neuronal excitation, non-hyperpolarized shifts in voltage- dependence of activated ion channels, or increased speed of inactivation of open ion channels, or any combination thereof.