WO2018064498A1

WO2018064498A1 - Methods of treating epilepsy and related neurological conditions

Info

Publication number: WO2018064498A1
Application number: PCT/US2017/054338
Authority: WO
Inventors: Gregory R. Stewart; Matthew Fox; Bryant GAY; J. Michael ANDRESEN; Talia ATKIN; Chani MAHER; Steven Petrou; David Goldstein
Original assignee: Pairnomix LLC
Current assignee: Pairnomix LLC
Priority date: 2016-09-30
Filing date: 2017-09-29
Publication date: 2018-04-05
Anticipated expiration: 2019-03-30

Abstract

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

Description

METHODS OF TREATING EPILEPSY AND RELATED

NEUROLOGICAL CONDITIONS

Cross-Reference to Related Applications

This application claims the benefit of the filing date of U.S. application Serial No. 62/402,637, filed on September 30, 2016, the disclosure of which is incorporated by reference herein.

Background

In the US, rare diseases are defined 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 worldwide 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 (EpiP Consortium, 2015). Epilepsy affects 4% of the 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, However, some patients with epilepsy are refractory to pharmacological treatment, e.g., 25-30% of those diagnosed with an epileptic condition are refractory to currently prescribed pharmacologics (Novy et al„ 2010; Mayer et al., 2002).

Summary

Genetic mutations, e.g., somatic mutations, can impact protein function which mutations may in turn be associated 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., sodium voltage-gated channel (SCN) activity. In one embodiment, those molecules are useful in downregulating 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 variant channel protein).

As described herein, a patient was diagnosed with early infantile epileptic encephalopathy, combined with global developmental delay and osteopenia. The epilepsy was multidrug resistant and immunomodulation resistant. Next generation sequencing was earned out on genes associated with severe developmental delay and seizures, and a heterozygous mutation in the SCN8A gene was identified at c.5615G>A, pArg1872Gln (R1872Q). SCN8A encodes voltage-gated sodium channel, Navl .6, which regulates neuronal excitability. SCN8A is one of nine human genes encoding voltage- gated sodium channel alpha subunits. To identify compounds that may alter the activity of the protein encoded by the mutant SCN8A gene, a cell line expressing the patient-specific mutation was screened with a drug library to identify compounds that rescue the mutant phenotype. In particular, the SCN8A R1872Q variant was created by site-directed mutagenesis of wild-type SCN8A plasmid (g5615a; CGG to CAG) and transfected into HEK293 cells. Electrophysiology was conducted to characterize variant and wild-type cells. Following electrophysical characterization of the variant phenotype, a high-throughput drug screening was performed using a 1 ,280 compound library. The R1872Q variant was observed to have a gain-of-function phenotype and 90 compounds inhibited the gain-of- function. Those compounds include sodium-channel blockers as well as FDA-approved compounds that do not report clinical utility in epilepsy or seizure disorders, and non-US-approved compounds that do not report clinical utility in epilepsy or seizure disorders. Moreover, among the 90 compounds, several common structures were identified (e.g., Quinoline/ Isoquinoline/Napthalene, Biaryl and Phenothiazine structures). These compounds may be used prophylactically or therapeutically and for design of related compounds.

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 of any one of formulas (l)-(XXXVI), a compound in Table 3 or 7, or a combination thereof. The method includes, in one embodiment, administering to the mammal an effective amount of a composition a sodium channel blocker, a calcium channel blocker, an alpha adrenergic receptor blocker, a dihydropyridine calcium channel blocker, a cholinergic receptor inhibitor, a muscarinic receptor inhibitor, a serotonin-norepinephrine receptor inhibitor, a histamine receptor inhibitor, an acetylcholine receptor inhibitor, a dopamine receptor inhibitor, or a combination thereof.

Also provided is a method to prevent, inhibit or treat one or more symptoms associated with gain- of-function in a sodium or calcium voltage-gated 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 formulas (l)-(XXXVI), a compound in Table 3 or 7, or a pharmaceutically acceptable salt thereof. The method includes, in one embodiment, administering to the mammal an effective amount of a composition an alpha adrenergic receptor blocker, a dihydropyridine calcium channel blocker, a cholinergic receptor inhibitor, a muscarinic receptor inhibitor, a serotonin-norepinephrine receptor, a histamine receptor inhibitor, an acetylcholine receptor inhibitor, a dopamine receptor inhibitor, or a combination thereof. In one embodiment, the mammal is a human. In one embodiment, the composition comprises a compound that is an alpha adrenergic receptor blocker, a dihydropyridine calcium channel blocker, a cholinergic receptor inhibitor, a muscarinic receptor inhibitor, or a serotonin-norepinephrine receptor inhibitor. In one embodiment, the composition comprises a compound that binds, blocks or inhibits a histamine receptor. In one embodiment, the composition comprises a compound that binds, blocks or inhibits an acetylcholine receptor. In one embodiment, the composition comprises a compound that binds, blocks or inhibits a dopamine receptor. In one embodiment, the composition comprises a compound that binds, blocks or inhibits an adrenergic receptor. In one embodiment, the compound is not tetrodotoxin (TTX). In one embodiment, the compound is not saxitoxin. In one embodiment, the compound is not neosaxitoxin. In one embodiment, the compound is not dibucaine. In one embodiment, the compound is not dyclonine hydrochloride. In one embodiment, the compound is not oxethazaine. In one embodiment, the compound is not benoxinate hydrochloride. In one embodiment, the compound is not diperodon hydrochloride. In one embodiment, the compound is not moricizine hydrochloride. In one embodiment, the compound is not propafenone hydrochloride. In one embodiment, the compound is not carbamazepine. In one embodiment, the compound is not phenytoin. In one embodiment, the compound is not oxcarbazepine. In one embodiment, the compound is not eslicarbazepine. In one embodiment, the compound is not lamotrigine. In one embodiment, the compound is not zonisamide. In one embodiment, the compound is not lacosamide. In one embodiment, the composition is orally, intravenously, intramuscularly, subcutaneously, transdermal^, intrathecally, intracerebrovasculariy, intraparenc ymally, e.g., all forms of direct delivery to the eye, or rectally administered. In one embodiment, the administration of the composition prevents, inhibits or treats seizures, developmental delay, cognitive impairment, ataxia, osteopenia, or any combination thereof. In one embodiment, the administration of the composition inhibits delayed inactivation, decreases frequency of action potentials, decreases sodium, calcium or potassium currents, 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. In one embodiment, the composition is useful to prevent, inhibit or treat epilepsy or symptoms thereof, or regaled disorders, and comprises administering to a mammal such as a human or non-human mammal an effective amount of clemastine fumarate, carvediol, loperamide, fendiline hydrochloride, dyclonine hydrochloride, mebeverine hydrochloride, racecadotril, drofenine hydrochloride, dimethisoquin hydrochloride, bepridril hydrochloride, prenylamine lactate, methyl benethonium chloride, cloperastine hydrochloride, or combinations thereof. In one embodiment, compounds including but not limited to fendiline hydrochloride, dyclonine hydrochloride, drofenine hydrochloride, dimethisoquin hydrochloride, bepridril hydrochloride, prenylamine lactate, methyl benethonium chloride or cloperastine hydrochloride may be employed to prevent, inhibit or treat epilepsy, e.g., Early Infantile Epileptic Encephalopathy (EIEE), e.g., EIEE 43 or El EE 43, or Epilepsy Childhood Absence 5, Lennox-Gastaut Syndrome, Autism spectrum disorder including Asperger syndrome, or ataxia.

In one embodiment, compounds that inhibit SCN8A channel activity may be useful to prevent, inhibit, or treat disorders including but not limited to seizure disorders/epilepsy, e.g., in gain-of-functnn disorders, ataxia, ADHD, hypotonia, movement disorders, pain (inflammatory and non-inflammatory, or neuropathic), central inflammatory syndromes , e.g., inflammatory damage in the CNS secondary to disease (e.g., MS), injury (e.g., TBI), vascular insults (e.g., stroke) or genetic disorders (e.g., Krabbe disease and other storage disorders affecting the brain and spinal cord), or cancer, e.g., where inhibitors may help to decrease motility, migration, or metastasis.

In one embodiment, compounds that enhance SCN8A channel activity may be useful to prevent, inhibit, or treat disorders including seizure disorders/epilepsy, e.g., loss-of-function disorders, intellectual disability/Autism spectrum disorders, Parkinson's disease, Multiple sclerosis, Guillain-Barre and other disorders related to node of Ranvier dysfunction, chronic inflammatory neuropathies (including CIDP), cardiotoxicity, or bone resorption.

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.

Also provided herein are compositions having an effective amount of the compounds disclosed herein for use in a method to prevent, inhibit or treat disorders including epilepsy. Thus, the disclosure provides for the use of a composition comprising one or more compounds having, e.g., one of formula (I)- (XXXVI), pharmaceutically acceptable salts thereof, or a combination thereof, for the treatment of diseases including seizure disorders/epilepsy, ataxia, ADHD, hypotonia, movement disorders, pain (inflammatory and non-inflammatory, or neuropathic), central inflammatory syndromes, injury, vascular insults, genetic disorders , or cancer. The compounds disclosed herein may be useful to prevent or treat epilepsy or related conditions in veterinary applications.

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

Brief Description of Figures

Figures 1 A-D. A) Conductance-voltage relationship for R1872Q SCN8A activation. V0.5 of channel activation is slightly hyperpolarized for R1872Q. V0.5 is -26 mV for WT and -30 mV for R1872Q. Data are statistically significant (P<0.05). B) R1872Q variant displays small window current. Overlap of GV and SSI curves for WT and R1872Q SCN8A channels. Depolarization of steady-state inactivation results in small window current. The difference between V0.5 of activation and inactivation is 31 mV for R1872Q and 35 mV for WT. C) Representative comparative traces illustrating the readily apparent slowing of activation at a test potential of 0 mV. In B-C), the rate of inactivation is slower in R1872Q variant. Representative comparative traces illustrating the readily apparent slowing of activation at a test potential of 0 mV. D) Scatter plots with mean ± SEM for time constants of inactivation. The decay phase was best fit by a single exponential and R1872Q rates were significantly slower (P<0,05) than wild type in both Phase I and Phase II studies.

Figures 2A-B. A) Frequency-dependence of inactivation is similar between R1872Q and WT SCN8A. R1872Q and WT SCN8A channels were tested for frequency-dependence using protocol shown on left. Graphs show mean ± SEM responses normalized to the first pulse of the stimulus train. B) Current amplitude distribution of WT and R1872Q SCN8A. Amplitudes are derived from a 500 msec pulse to 0 mV from a holding potential of -140 mV. Stable pools are required for this study to control for differences in integration sites. R1872Q and WT distributions were not statistically significant (P>0.05, ANOVA).

Figures 3A-D. A) Veratridine stimulated increase in Na+ fluorescence in SCN8A R1872Q expressing HEK cells (ICLN-1475). Cells were loaded with 4 μΜ ANG2 and stimulated with increasing concentration of veratridine (meantSEM, n=4). B) 10 pt CRC of classical small molecule channel blockers on 100 μΜ veratridine stimulated Na+ fluorescence in SCN8A R1872Q expressing HEK cells (ICLN-1 75). Full concentration dependent inhibition was observed for amitriptyline, tetracaine, flecainide and mexilitine (meantSEM, n=4). C) 10 pt CRCs of tetracaine on 100 μΜ veratridine stimulated Na+ fluorescence in SCN8A R1872Q expressing HEK cells (ICLN-1475). CRCs were fit to a logistic equation with floating IC50 and slope. Response was stable and reproducible across plates with a median IC50 value of 2.4 μΜ and a 95% CI between 1.1 μΜ and 3.0 μΜ demonstrating assay stability. D) Plate statistic for the validation plate - ZPRIME and S/B (signal over baseline) was robust and consistent across plates

Figure 4. PatchXpress protocol to determine voltage-dependence of channel activation and inactivation.

Figures 5A-G. Alignment of human SCN proteins (SEQ ID NOs:1-9).

Figure 6. Alignment of human SCN8A and human calcium voltage-gated channel proteins. Figures 7A-F. Test Drug Evaluation in the PentylenetetrazoHnduced Seizure Model: Time to Tonic Seizures. Latency to tonic seizures following PTZ administration. Test drugs were administered 30 minutes prior to PTZ challenge and time to tonic seaizure was measured (seconds). Amitripytiline, cloperastine and R-duloxetine significantly increased tonic latency in a dose-related manner.Data was analyzed using a one way ANOVA followed by Dunnett's test for multiple comparisons. 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 elemenf 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 ΟΉ) in any combination. Similarly, any carbon atom or set thereof in a molecule can be any of the isotopic form of carbons, such as ¹C, ¹²C, ³C, or ^UC, or any nitrogen atom or set thereof in a molecule can be any of the isotopic forms of nitrogen, such as ³N, "N, or ¹⁵N. A molecule can include any combination of isotopic forms in the component atoms making up the molecule, the isotopic form of every atom forming the molecule being independently selected. In a multi-molecular sample of a compound, not every individual molecule necessarily has the same isotopic composition. For example, a sample of a compound can include molecules containing various different isotopic compositions, such as in a tritium or ¹ C 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 ⁴N and ⁵N, ^SS 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,⁴C and ³H can be prepared using neutrons generated in a nuclear reactor. Following nuclear transformation, ⁴C 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. ., 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-dimethoxybenzyloxycarbonyl, 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, phenytthiocarbonyl 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-biphenyly0-1-methylethoxycarbonyl, a,a-dimethyl-3,5- dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl (Boc),

adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenytthiocarbonyl 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',

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 0 forms a carbonyl group, C=0, which can also be written as "CO", "C(O)", or "C(=0)", wherein the C and the 0 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 0 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 0 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 (CHzOn 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(O)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 "carboxamkte." When a C(O) group is bound to two nitrogen atoms, the functional group is termed a urea. When a S(O)2 group is bound to one carbon and one nitrogen atom, the resulting unit is termed a "sulfonamide." When a S(O)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, orspirocyclic. 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, norbornyl, 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- or2,6-disubstituted cyclohexyl groups or mono-, dh ortri-substituted norbornyl 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 independently be a cycloalkyl ring, a cycloalkenyl ring, or an aryl ring.

(CycloalkyQalkyl 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(CH.)=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, bomyl, 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.

(Cycloalkeny 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. EExamples include, but are not limited to -C^CH, -C≡C(CH₃), -C=C(CH₂CH₃), -CH₂CsCH, -CH₂CsC(CH₃), and

-CH₂C≡C(CH₂CH₃) among others.

The term "heteroalkyl" by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group. EExamples include: -O-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 0, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. Up to two heteroatoms may be placed consecutively. [Examples include -CH=CH-0-CH₃, -CH=CH-CH₂-OH, -CH₂-CH=N-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 alkyt group is replaced with a bond to an aryl group as defined above. Representative aralkyl groups include benzyl and phenylethyl groups and fused (cycloalkylaryljalkyl groups such as -ethyi-indanyl. 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, 0, 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 C2- 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 C*-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 benzdnxolanyl 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, thiophenyi, 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, 0, 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 C*-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, thiophenyi,

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-anthracenyO, 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-imidazolyQ, triazolyl (1 ,2,3-triazoH-yl, 1 ,2,3-triazol-2-yl 1 ,2,3-triazol-4-yl, 1,2,4-triazol-3-y0, 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]furany , 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]thk)phenyl), 4-(2,3-dihydro-benzo[b]thiophenyl),

5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro-benzo[b]thnpheny0, 7-(2,3-dihydro- benzo[b]thiophenyl), indolyl (1 -indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyO, 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,f]azepine (5H- dibenz[b,f]azepin-1 -yl, 5H-dibenz[b,f]azepine-2-yl, 5H-dibenz[b,fJazepine-3-yl, 5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,fJazepine-5-yl), 10,11 -dihydro-5H-dibenz[b,f]azepine (10,11 -dihydro-5H-dibenz[b,f]azepine-1 - yl, 10,11-dihydro-5H-dibenz[b,f]azepine-2-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-3-yl, 10,11-dihydro-5H- dibenz[b,f]azepine-4-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-5-yl), and the like.

Heterocyclylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an 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. EExamples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. EExamples 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-difluoropropyl, 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 "(C*-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-C_y)perfluoroalkyl is -(Ci-Ce)perfluoroalkyl. In one embodiment, (Cx-C_y)perfluoroalkyl is -(Ci-C3)perfluoroalkyl. In one embodiment, (Cx-Cy)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 -(Ci-Ce)perfluoroalkylene. In one embodiment, (Cx-Cy)perfluoroalkylene is -(Ci-C3)perfluoroalkylene. In one embodiment, (Cx-Cy)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 cycbalkyl, 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-Nhb, for example, alkylamines, arylamines, alkylarylamines; f¾NH 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, alkyldiarylamines, 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 -NR_⁺, 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 NrV, but unless otherwise specified, it also includes any protonated or quaternarized forms of amines. Thus, trimethylammonium hydrochloride and tetramethylammonium chloride are both ammonium ions, and amines, within the meaning herein.

The term "amide" (or "amido") includes C- and N-amide groups, i.e., -C(O)NR2, and -NRC(O)R groups, respectively. Amide groups therefore include but are not limited to primary carboxamide groups (-C(O)NH₂) and formamkJe groups (-NHC(O)H). A "carboxamido" group is a group of the formula C(O)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 azkJe (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 (NO.-) anion.

The term "urethane" ("carbamoyl" or "carbamyl") includes N- and O-urethane groups, i.e., -NRC(O)OR and -OC(O)NR∑- 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(O)(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 NIV 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 tetrafluoroborates.

Suitable pharmaceutically acceptable base addition salts of compounds include, for example, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, W,/V-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) 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), Int J. Pharm., 33, 201-217, incorporated by reference herein.

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

A "solvate" is a similar composition except that a solvent other that water replaces the water. For example, methanol or ethanol can form an "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.

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, e.g., EIEE13, Angelman Syndrome, Benign Rolnadic Epilepsy, CDKL5 disorder, Childhood Ansence 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 Epilepsye, 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 voltage-gated sodium channel, e.g., SCN8A. 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 delayed inactivation of open channels, increased frequency of action potential, increased sodium, calcium or potassium currents, increased spontaneous firing, increased neuronal excitation, or increased hyperpolarized shifts in voltage- dependence of activated 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 sodium or calcium channel activity, including but not limited to sodium 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 sodium voKage-gated channel activity in a mammal. In certain embodiments, methods are provided for altering or modulating voltage- gated calcium channel activity in a mammal. In various embodiments, the methods comprise administering to the mammal a composition having one or more of formulas (l)-(XXXVI), a compound in Table 3 or 7, 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, a composition comprises a compound of formula (I):

In one specific embodiment, X = C or N. In one specific embodiment, Y = C or N. In one specific embodiment, R¹ = H, alkyl, cycloalkyl or aromatic. In one specific embodiment, R² = H, alkyl, cycloalkyl, or aromatic. In one specific embodiment, R³ = H, alkyl, cycloalkyl or aromatic. In one specific embodiment, R* = H, alkyl, cycloalkyl or aromatic.

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

In one specific embodiment, R¹ = H or halogen. In one specific embodiment, R² = H or halogen. In one specific embodiment, R³ = alkyl, cycloalkyl or aromatic. In one specific embodiment, R* = alkyl, cycloalkyl or aromatic. In one embodiment, a composition comprises a compound of formula (III):

In one specific embodiment, X = C, N, S, or 0. In one specific embodiment, Y = C, N, S, or 0. In one specific embodiment, R = halogen, alkyl, cycloalkyl, or aromatic. In one specific embodiment, R² = halogen, alkyl, cycloalkyl, or aromatic. In one specific embodiment, R³ = halogen, alkyl, cycloalkyl, or aromatic. In one specific embodiment, R⁴ = halogen, alkyl, cycloalkyl, or aromatic. In one specific embodiment, R⁵ = halogen, alkyl, cycloalkyl, or aromatic. In one specific embodiment, R^a = halogen, alkyl, cycloalkyl, or aromatic.

In one embodiment, the compound has formula (IV):

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, CO₂H, CO₂C1-3 saturated or unsaturated alkyl, aryl or heteroaryl, CI, Br, F, I, OH, NH₂, CN, CF₃, NHC1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl, or N( C_1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl)₂ In one embodiment, each R² independently = H, OC1- 6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, CI, Br, F, I, OH, NH₂, CN, CO₂H, CO₂C1. β saturated or unsaturated alkyl, aryl or heteroaryl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl, or N( C_1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl. In one embodiment, each X independently = CH₂, NH, NHC_1-6saturated, unsaturated alkyl, or cycloalkyl, 0, S, SO, or SO₂. In one embodiment, n = 0-6. In one specific embodiment, n = 0-4. In one specific embodiment, each X independently = C, CH, S, N, or NH. In one specific embodiment, each R¹ independently = H or halogen. In one specific embodiment, each R² independently² H or C1-C3 alkyl. In one embodiment, n = 0-4, each X independently = C, CH, S, N, or NH, each R independently = H or halogen, and each R² independently = H orC1-C3 alkyl.

In one embodiment, the compound has formula (V):

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, CO₂H, CO₂C_1-6 saturated or unsaturated alkyl, aryl or heteroaryl, CI, Br, F, I, OH, NH₂, CN, CF₃, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl, or N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl)2 In one embodiment, R² = H, OCLB saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, CI, Br, F, I, OH, NH₂, CN, CO₂H, CO₂C1-3 saturated or unsaturated alkyl, aryl or heteroaryl, NH C_1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl, or N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl)₂

In one embodiment, each X = CH₂, NH, NHCi-esaturated, unsaturated alkyl, or cycloalkyl, 0, S, SO, or SO₂. In one embodiment, each n independently = 0-6.

In one specific embodiment, each n independently = 0-4. In one specific embodiment, each X independently = C, S, SH, N, NH₂, 0, or OH. In one specific embodiment, each R¹ independently = H or halogen. In one specific embodiment, each n independently = 0-4, each X independently = C, S, SH, N, NH₂, 0, or OH, and each R independently = H or halogen.

In one embodiment, the compound has formula (VI):

In one embodiment, formula (VI) is:

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, Ci-a saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, CO₂H, C -C_1-6 saturated or unsaturated alkyl, aryl or heteroaryl, CI, Br, F, I, OH, NH₂, CN, CF₃, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl, or N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl)₂. In one embodiment, R² = H, OCLB saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, CI, Br, F, I, OH, NH₂, CN, CO₂H, CO₂C_1-6 saturated or unsaturated alkyl, aryl or heteroaryl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl, or N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl)2.

In one specific embodiment, each X independently = C, S, N, or O. In one specific embodiment, each R¹ independently = H or halogen. In one specific embodiment, R² = H or C1-C3 alkyl. In one specific embodiment, each X independently = C, S, N, or O, each R independently = H or halogen, and R² = H or C1-C3 alkyl

In one embodiment, the compound has formula (VII):

In one embodiment, each R independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, CO₂H, CO₂C1-3 saturated or unsaturated alkyl, aryl or heteroaryl, CI, Br, F, I, OH, NH₂, CN, CF₃, NHC1.6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl, or N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl)₂ In one embodiment, each R² independently = H, OC1- 6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, Ci-s saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, CI, Br, F, I, OH, NH₂, CN, CO₂H, CO₂C1. β saturated or unsaturated alkyl, aryl or heteroaryl, NHC1.6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl, or N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl)₂ In one embodiment, each X independently = CH₂, NH, NHCi-esaturated, unsaturated alkyl, or cycloalkyl, 0, S, SO, or SO In one specific embodiment, each X independently = C, S, SH, N, NH₂, O, or OH. In one specific embodiment, each R¹ independently = H or halogen. In one specific embodiment, each R² independently = H or C1-C3 alkyl. In one specific embodiment, each X independently = C, S, SH, N, NH₂, 0, or OH, each R¹ independently = H or halogen, and each R² independently = H or C1-C3 alkyl.

In one embodiment, the compound has formula (VIII):

In one embodiment, formula (VIII) is:

In one embodiment, each R¹ independently = OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, &-s saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, CF₃, NH₂, CN, CO₂H, CO₂C_1-6 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, or N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl. In one embodiment, each X

independently = CH₂, NH, NHCi-esaturated, unsaturated alkyl, or cycloalkyl, 0, S, SO, or SO₂ln one specific embodiment, each X independently = C, S, N, or 0. In one specific embodiment, each R¹ ⁱndependently = H, C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, or CF₃. In one specific embodiment, each X independently = C, S, N, or 0 and each R¹ = H, C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, or CF₃.

In one embodiment, the compound has formula (IX):

For example, formula (XIX) is:

In one embodiment, R¹ independently = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl,

cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CO₂H, or CO₂C1-3 saturated or unsaturated alkyl. In one embodiment, each R² independently OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, CF₃, NH₂, CN, CO₂H, CO₂C1.6 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, or N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)₂ In one embodiment, X independently CH₂, NH, NHCi-esaturated, unsaturated alkyl, or cycloalkyl, 0, S, SO, or SO₂.

In one embodiment, each n independently = 0-6. In one specific embodiment, each n independently = 0- 4. In one specific embodiment, each R¹ independently = H or C1-C3 alkyl. In one specific embodiment, each R² independently = H, C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, or CF₃. In one specific embodiment, each n independently = 0-4, each R¹ independently = H or C1-C3 alkyl, and each R² independently = H, C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, or CF₃.

In one embodiment, the compound has formula (X):

In one embodiment, each R independently H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CO₂H, CO₂C_1-6 saturated or unsaturated alkyl, CI, Br, F, I, OH, NH₂, CN, CF₃, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl. In one embodiment, each R² independently = OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, H, CI, Br, F, I, OH, NH₂, CN, CO₂H, CO₂C1-3 saturated or unsaturated alkyl, or NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2. In one embodiment, each X independently = CH₂, NH, NHC_1-6saturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO₂.ln one embodiment, each n independently 0-6. In one specific embodiment, each n independently = 0-4. In one specific embodiment, each X independently = C, S, N, or 0. In one specific embodiment, each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃. In one specific embodiment, each R² independently = H or C1-C3 alkyl. In one specific embodiment, each n independently = 0-4, each X independently = C, S, N, or 0, each R independently = H, C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, or CF₃. and each R² independently = H or C1-C3 alkyl.

In one embodiment, the compound has formula (XI):

In one embodiment, each R¹ independents H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, CF₃, NH₂, CN, CO₂H, CO₂C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, or N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)₂ In one embodiment, each X

independently CH₂, NH, NHC_1-6saturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO₂. In one embodiment, each n independently= 0-6. In one specific embodiment, each n independently = 0-4. In one specific embodiment, each X = C, S, N, or 0. In one specific embodiment, each R independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃. In one specific embodiment, each n independently = 0-4, X = C, S, N, or O, and each R independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃

In one embodiment, the compound has formula (XII):

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CO₂H, CO₂C1.6 saturated or unsaturated alkyl, CI, Br, F, I, OH, IMH₂, CN, CF₃, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, or N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)₂ In one embodiment, R² = H, O C_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, NH₂, CN, CO₂H, CO₂C_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 In one embodiment, X = CH₂, NH, NHC_1-6saturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO₂. In one embodiment, n = 0-6. In one specific embodiment, n = 0-4. In one specific embodiment, X = C, S, N, or O. In one specific embodiment, each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃. In one specific embodiment, R² = H or C1-C3 alkyl. In one specific embodiment, n = 0-4, X = C, S, N, or 0, each R¹ independently = H, C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, or CF₃. and R² = H or C1-C3 alkyl.

In one embodiment, the compound has formula (XIII):

In one embodiment, each R¹ independently = H, OC_1-8 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, CF₃, NH₂, CN, CO₂H, CO₂C_1-6 saturated or unsaturated alkyl, NH C_1-6 saturated, unsaturated alkyl, or cycloalkyl, or N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl. In one embodiment, each X

independently = CH₂, NH, NHCi-esaturated, unsaturated alkyl, or cycloalkyl, 0, OH, S, SO, or SOz In one embodiment, n = 0-6. In one specific embodiment, n = 0-4. In one specific embodiment, each X independently = C, S, N, or 0. In one specific embodiment, each R¹ independently = H, C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, or CF₃ In one specific embodiment, n = 0-4, each X independently = C, S, N, or 0, and each R¹ independently = H, C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, or CF₃.

In one embodiment, the compound has formula (XIV):

In one embodiment, formula (XIV) is:

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, CF₃, NH₂, CN, CO₂H, or CO₂C_1-6 saturated or unsaturated alkyl. In one embodiment, R² = OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, NH₂, CN, CO₂H, CO₂C_1-6 saturated or unsaturated alkyl, NH&-S saturated, unsaturated alkyl, or cycloalkyl, or N( C_1-6 saturated, unsaturated alkyl, or cycloalkyl)₂ In one embodiment, each X independently = CH₂, NH, NHCi-esaturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO₂. In one specific embodiment, each X independently = C, S, N, or 0. In one specific embodiment, each R¹ independently = H, C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, or CF₃. In one specific embodiment, R² = OCH₂C6H5 orm-BrCs^N. In one specific embodiment, X independently = C, S, N, or O, each R¹ independently = H, C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, or CF₃, and R² = OCH₂C8H5 or m- BrCsH4N. In one embodiment, the compound has formula (XV):

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH.CF₃, NH₂, CN, CO₂H, CO₂C_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 In one embodiment, each X independently = CH₂, NH, NHCi-esaturated, unsaturated alkyl, or cycloalkyl, 0, S, SO, or SO₂. In one embodiment, each n independently = 0-6. In one specific embodiment, each n independently = 0-4. In one specific embodiment, X independently = C, S, N, or 0. In one specific embodiment, each R¹ independently = H, C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, or CF₃. In one specific embodiment, each n independently = 0-4, each X independently = C, S, N, or 0, and each R¹ independently = H, C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, or CF₃

In one embodiment, the compound has formula (XVI):

In one embodiment, each R¹ = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, CF₃, NH₂, CN, CO₂H, CO₂C1-3 saturated or unsaturated alkyl, NHC-.6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)₂ In one embodiment, each X independently = CH₂, NH, NHCi- esaturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO₂. In one embodiment, each n independently = 0-6. In one specific embodiment, each n independently = 0-4. In one specific embodiment, each X independently = C, S, N, or 0. In one specific embodiment, each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃. In one specific embodiment, each n independently = 0-4, each X independently = C, S, N, or O, and each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or

CF₃.

In one embodiment, the compound has formula (XVII):

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, CF₃, NH₂, CN, CO₂H, or CO₂C1-3 saturated or unsaturated alkyl. In one embodiment, R² = OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl. cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, NH₂, CN, CO₂H, CO₂C1-3 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, or N(Ci-a saturated, unsaturated alkyl, or cycloalkyl)₂ In one embodiment, each X independently = CH₂, NH, NHCi-esaturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO₂. In one embodiment, each n independently = 0-6. In one specific embodiment, each n independently = 0-4. In one specific embodiment, each X independently = C, S, N, or 0. In one specific embodiment, each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃. In one specific embodiment, R² = OH, NH2, or SH. In one specific embodiment, each n independently = 0-4, each X independently = C, S, N, or O, each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃, and R² = OH, NH2, or SH.

In one embodiment, the compound has formula (XVIII):

In one embodiment, formula (XVIII) is:

In one embodiment, each R¹ independently = OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, NH₂, CF₃, CN, CO₂H, or CO₂C_1-6 saturated or unsaturated alkyl. In one embodiment, each R² independently = OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, CF₃, NH₂, CN, CO₂H, CO₂C1-3 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 X = CH₂, NH, NHCi-esaturated, unsaturated alkyl, or cycloalkyl, 0, S, SO, or SO₂. In one embodiment, each n independently = 0-6. In one specific embodiment, each n independently = 0-4. In one specific embodiment, each X independently = C, S, N, or 0. In one specific embodiment, each R independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃. In one specific embodiment, each R² = OH, NH₂, or SH. In one specific embodiment, each n independently = 0-4, each X

independently = C, S, N, or 0, each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃. and R² = OH, NH₂, or SH.

In one embodiment, the compound has formula (XIX):

In one embodiment, formula (XIX) is:

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, NH₂, CF₃, CN, CO₂H, or CO₂C_1-6 saturated or unsaturated alkyl. In one embodiment, each R² independently = OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, CF₃, NH₂, CN, CO₂H, CO₂C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)₂. In one embodiment, each X independently = CH₂, NH, NHC_1-6saturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO₂. In one embodiment, each n independently = 0-6. In one specific embodiment, each n independently = 0-4. In one specific embodiment, each X independently = C, S, N, or O. In one specific embodiment, each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃. In one specific embodiment, each n independently = 0-4, each X independently = C, S, N, or 0 , and each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃.

In one embodiment, the compound has formula (XX):

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, CF₃, NH₂, CN, CO₂H, CO₂C_1-6 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, or N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)₂. In one embodiment, each X

independently = CH₂, NH, NHC_1-6saturated, unsaturated alkyl, or cycloalkyl, 0, S, SO, or SO₂. In one embodiment, each n independently = 0-6. In one specific embodiment, each n independently = 0-4. In one specific embodiment, each X independently = C, S, N, or O. In one specific embodiment, each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃. In one specific embodiment, each n independently = 0-4, each X independently = C, S, N, or 0, and each R independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃.

In one embodiment, the compound has formula (XXI):

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, CF₃, NH₂, CN, CO₂H, CO₂C_1-6 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, or N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2. In one embodiment, each X

independently = CH₂, NH, NH C_1-6saturated, unsaturated alkyl, or cycloalkyl, 0, S, SO, or SO₂. In one embodiment, n = 0-6. In one specific embodiment, n = 0-4. In one specific embodiment, each X independently = C, S, N, or O. In one specific embodiment, each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃ In one specific embodiment, n = 0-4, each X independently = C, S, N, or 0, and each R¹ independently = H, C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, or CF₃.

In one embodiment, the compound has formula (XXII):

In one embodiment, formula (XXII) is:

In one embodiment, each R¹ independently = H, O C_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, CF₃, NH₂, CN, CO₂H, CO₂ C_1-6 saturated or unsaturated alkyl, NHC_1-6saturated, unsaturated alkyl, or cycloalkyl, or N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)₂ In one embodiment, each X independently = CH₂, NH, NHC1-8saturated, unsaturated alkyl, or cycloalkyl, 0, S, SO, or SO₂. In one embodiment, each n independently = 0-6. In one specific embodiment, each n independently = 0-4. In one specific embodiment, each X independently = C, S, N, or O. In one specific embodiment, each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃. In one specific embodiment, each n independently = 0-4, each X independently = C, S, N, or 0, and each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃.

In one embodiment, the compound has formula (XXIII):

In one embodiment, formula (XXIII) is:

In one embodiment, each X independently = C, S, N, O. In one embodiment, each R¹ independently = OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl CI, Br, F, I, OH, CF₃, NH₂, CN, CO₂H, CO₂C1-3 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl. or N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)₂

In one embodiment,

O C_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, CF₃, NH₂, CN, CO₂H, CO₂ C_1-6 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2. In one embodiment, each X independently = CH₂, NH, NHC_1-8saturated, unsaturated alkyl, or cycloalkyl, 0, S, SO, or SO₂. In one embodiment, n = 0-6. In one specific embodiment, n = 0-4. In one specific embodiment, each X independently = C, S, N, or 0. In one specific embodiment, each R¹ independently = H, C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, or CF₃. In one specific embodiment,

In one specific embodiment n = 0-4, each X independently = C, S, N, or 0, each R¹ independently C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, or CF₃, and

In one embodiment, the compound has formula (XXIV):

For example, formula (XIV) is:

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CO₂H, CO₂C_1-6 saturated or unsaturated alkyl, CI, Br, F, I, OH, NH₂, CN, CF₃, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, orN(C1-6 saturated, unsaturated alkyl, or cycloalkyl)₂ In one embodiment, R² = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, NH₂, CN, CO₂H, CO₂C_1-6 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, orN(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)₂ one embodiment, each X independently = CH₂, NH, NHC_1-6saturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO₂. In one embodiment, each n independently = 0-6. In one specific embodiment, each n independently = 0-4. In one specific embodiment, each X independently = C, S, N, or 0. In one specific embodiment, each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃. In one specific embodiment, R² = C1-6 alkyl, C5-C7 cyclic alkyl or heteroalkyl. In one specific embodiment, each n independently = 0-4, each X independently = C, S, N, or 0, each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃. and R² = C1-6 alkyl, C5-C7 cyclic alkyl or heteroalkyl

In one embodiment, the compound has formula (XXV):

In one embodiment, each R¹ = H, OC1-3 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, CF₃, NH₂, CN, CO₂H, CO₂C_1-6 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, or N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)₂ In one embodiment, each X independently = CH₂, NH, NHCi- esaturated, unsaturated alkyl, or cycloalkyl, 0, S, SO, or SC¾. In one embodiment, each n independently = 0-6. In one specific embodiment, each n independently = 0-4. In one specific embodiment, each X independently = C, S, N, or 0. In one specific embodiment, each R¹ independently = H, C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, or CF₃. In one specific embodiment, each n independently = 0-4, each X independently = C, S, N, or 0 and each R independently = H, C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, or CF₃.

In one embodiment, the compound has formula (XXVI):

In one embodiment, each R¹ = H, O C_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CI, Br, F, I, OH, 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)2or SC1-3 saturated, unsaturated alkyl, or cycloalkyl. In one embodiment, each X independently = CH₂, NH, NHC_1-6saturated, unsaturated alkyl, or cycloalkyl, or O. In one embodiment, each n independently = 0-6. In one specific embodiment, each X independently = C, S, N, or O. In one specific embodiment, R¹ = OH, NH(C1-3 alkyl), N(C1-3 alkyl), NH₂, or SH. In one specific embodiment, each X independently = C, S, N, or O andR¹ = OH, NH(C1-3 alkyl), N(C1-3 alkyl), NH₂, or SH.

In one embodiment, the compound has formula (XXVII):

For example, formula (XXVII) is:

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, CF₃, NH₂, CN, CO₂H, CO₂ C_1-6 saturated or unsaturated alkyl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, or N(Ci-a saturated, unsaturated alkyl, or cycloalkyl)₂. In one embodiment, each X independently = CH₂, NH, NHC_1-6saturated, unsaturated alkyl, or cycloalkyl, 0, S, SO, or SO₂. In one embodiment, each n independently = 0-6. In one specific embodiment, each n independently = 0-4. In one specific embodiment, each X independently = C, S, N, or O. In one specific embodiment, each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃. In one specific embodiment, each n independently = 0-4, each X independently = C, S, N, or 0, and each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃.

In one embodiment, the compound has formula (XXVIII):

In one embodiment, each R¹ independently = H, OC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl, CO₂H, CO₂C1-S saturated, unsaturated alkyl, aryl, or heteroaryl CI, Br, F, I, OH, NH2, CN, CF₃, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, or N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)₂ In one embodiment, R² = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl, CI, Br, F, I, OH, NH₂, CN, CO₂H, CCfcC_1-6 saturated, unsaturated alkyl, aryl, or heteroaryl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, or N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)₂ In one embodiment, R³ = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl, CI, Br, F, I, OH, NH₂, CN, CO₂H, CO₂C_1-6 saturated, unsaturated alkyl, aryl or heteroaryl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)₂ In one embodiment, each X independently = CH₂, NH, NHCi- esaturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO₂.. In one embodiment, n = 0-6. In one specific embodiment, n = 0-4. In one specific embodiment, each X independently = C, S, N, or 0. In one specific embodiment, each R independently = H, C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, or CFi ln one specific embodiment, R² = C1-6 alkyl, C3-C7 cyclic alkyl or heteroalkyl. In one specific embodiment, R³ = OH, NH(C1-3 alkyl), NH₂, or SH. In one specific embodiment, n = 0-4, each X independently = C, S, N, or O, each R independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃, R² = C1-6 alkyl, C3-C7 cyclic alkyl or heteroalkyl, and R³ = OH, NH(C1-3 alkyl), NHz, or SH.

In one embodiment, the compound has formula (XXIX):

In one embodiment, each R¹ independently = H, OC1.8 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl CO₂H, CO₂C1-3 saturated or unsaturated alkyl, aryl, or heteroaryl, CI, Br, F, I, OH, NH2, CN, CF₃, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, or N(Ci-a saturated, unsaturated alkyl, or cycloalkyl)₂. In one embodiment, R² = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl, C1-3 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl, CI, Br, F, I, OH, NH₂, CN, CO₂H, CO₂C_1-6 saturated or unsaturated alkyl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, orN(C_1-6 saturated, unsaturated alkyl, or cycloalkyl)2. In one embodiment, each X independently = CH₂, NH, NHC_1-6saturated, unsaturated alkyl, or cycloalkyl, 0, S, SO, or SO₂. In one specific embodiment, each X independently = C, S, N, or 0. In one specific embodiment, each R¹ independently = H, C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, or CF₃. In one specific embodiment, R² = OH, NH(C1-3 alkyl), NHz, or SH. In one specific embodiment, each X independently = C, S, N, or 0, each R independently = H, C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, or CF₃. and R² = OH, NH(C1-3 alkyl), NH₂, or SH.

In one embodiment, the compound has formula (XXX):

In one embodiment, each R independently = H, OC saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, CI, Br, F, I, OH, CF₃, NH₂, CN, CO₂H, CO₂C_1-6 saturated or unsaturated alkyl, aryl or heteroaryl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl, orN(C1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl)₂. In one embodiment, each X independently = CH₂, NH, NHC_1-6saturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO₂. In one embodiment, each n independently = 0-6. In one specific embodiment, each n independently = 0-4. In one specific embodiment, each X independently = C, S, N, or O. In one specific embodiment, each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃. In one specific embodiment, each n independently = 0- 4, each X independently = C, S, N, or 0, and each R¹ independently = H, C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, or CF₃.

In one embodiment, the compound has formula (XXXI):

In one embodiment, formula (XXXI) is:

In one embodiment, each R¹ independently = H, OCi-a saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, CI, Br, F, I, OH, CF₃, NH₂, CN, CO₂H, CO₂C_1-6 saturated or unsaturated alkyl, aryl or heteroaryl, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl, or N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl)₂ In one embodiment, each X independently = CH₂, NH, NHCi-6saturated, unsaturated alkyl, or cycloalkyl, 0, S, SO, or SO₂. In one embodiment, each n independently = 0-6. In one specific embodiment, each n independently = 0-4. In one specific embodiment, each X independently = C, S, N, or O. In one specific embodiment, each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, CF₃, OH, NH(C1-3 alkyl), NH₂, or SH. In one specific embodiment, each n independently = 0-4, each X independently = C, S, N, or 0, and each

R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, CF₃, OH, NH(C1-3 alkyl), NH₂, or SH.

In one embodiment, the compound has formula (XXXII):

For example, formula (XXXII) is:

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl.aryl or heteroaryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, CO₂H, CO₂C1-3 saturated or unsaturated alkyl, aryl or heteroaryl, CI, Br, F, I, OH, NH₂, CN, CF₃, NHC1-3 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl, or N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl)₂ In one embodiment, each R² independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, CI, Br, F, I, OH, NH₂, CN, CO₂H, COzC_1-6 saturated or unsaturated alkyl, aryl or heteroaryl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl, or N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl)2 In one embodiment, X = CH₂, NH, NHC_1-6saturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO₂. In one embodiment, n = 0-6. In one specific embodiment, n = 0-4. In one specific embodiment, X = C, S, N, or O. In one specific embodiment, each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, CF₃, OH, NH(C1-3 alkyl), NH₂, or SH. In one specific embodiment, each R² independently = C1-C6 alkyl, cycloalkyl, or hetercycloalkyl. In one specific embodiment, n = 0-4, X = C, S, N, or O, each R¹ independently = H, C1- C3 alkyl, OC1-C3 alkoxy, CI, Br, F, CF₃, OH, NH(C1-3 alkyl), NH₂, or SH, and each R² independently = C1-C6 alkyl, cycloalkyl, or hetercycloalkyl.

In one embodiment, the compound has formula (XXXIII):

In one embodiment, formula (XXXIII) is:

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, &-a saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, CO₂H, CO₂C1-3 saturated or unsaturated alkyl, aryl or heteroaryl, CI, Br, F, I, OH, NH₂, CN, CF₃, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl, orN(C_1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl)2. In one embodiment, each R² independently = H, OC1- β saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, CI, Br, F, I, OH, NH₂, CN, CO₂H, CO₂C1. 6 saturated or unsaturated alkyl, aryl or heteroaryl, NHC1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl, or N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl)2. In one embodiment, each X independently = CH₂, NH, NHC_1-6saturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or SO₂.

In one embodiment, each n independently = 0-6. In one specific embodiment, n independently = 0-4. In one specific embodiment, X = C, S, N, or O. In one specific embodiment, each R¹ independently = H, C1- C3 alkyl, OC1-C3 alkoxy, CI, Br, F, CF₃, OH, NH(C1-3 alkyl), NH₂, or SH. In one specific embodiment, each R² independently = C1-C6 alkyl, cycloalkyl, or hetercycloalkyl, CF₃, OH, NH(C1-3 alkyl), NH₂, SH, or CN. In one specific embodiment, n independently = 0-4, X = C, S, N, or O, each

R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, CF₃, OH, NH(C1-3 alkyl), NH₂, or SH, and each R² independently = C1-C6 alkyl, cycloalkyl, or hetercycloalkyl, CF₃, OH, NH(C1-3 alkyl), NH₂, SH, or CN.

In one embodiment, the compound has formula (XXXIV):

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, CO₂H, CO₂C1-3 saturated or unsaturated alkyl, aryl or heteroaryl, CI, Br, F, I, OH, NH₂, CN, CF₃, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl, or N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl)2. In one embodiment, R² = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, CI, Br, F, I, OH, NH2, CN, CF3, CO₂H, C0₂C_1-6 saturated or unsaturated alkyl, aryl or heteroaryl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl, N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl)₂ In one embodiment, each X = CH₂, NH, NHC_1-6saturated, unsaturated alkyl, or cycloalkyl, 0, S, SO, or SOz In one embodiment, each n independently = 0-6. In one specific embodiment, each n independently = 0-4. In one specific embodiment, each X independently = C, S, N, or O. In one specific embodiment, each R independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, CF₃, OH, NH(C1-3 alkyl), NH₂, or SH. In one specific embodiment, R² = C1-C6 alkyl, cycloalkyl, or hetercycloalkyl, CF₃, OH, NH(C1-3 alkyl), NH₂, SH, or CN. In one specific embodiment n independently = 0-4, each X independently = C, S, N, or 0 , each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, CF₃, OH, NH(C1-3 alkyl), NH₂, or SH, andR² = C1-C6 alkyl, cycloalkyl, or hetercycloalkyl, CF₃, OH, NH(C1-3 alkyl), NH₂, SH, or CN.

In one embodiment, the compound has formula (XXXV):

In one embodiment, each R¹ independently = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, C_1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, CO₂H, CO₂C_1-6 saturated or unsaturated alkyl, aryl or heteroaryl, CI, Br, F, I, OH, NH2, CN, CF₃, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl, or N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl)2. In one embodiment, R² = H, OC_1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, C-i-e saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, CI, Br, F, I, OH, NH2, CN, CF₃, CO₂H, C0₂C_1-6 saturated or unsaturated alkyl, aryl or heteroaryl, NHC_1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl, or N(C_1-6 saturated, unsaturated alkyl, or cycloalkyl, aryl or heteroaryl)₂. In one embodiment, each X independently = CH₂, NH, NHC_1-6saturated, unsaturated alkyl, or cycloalkyl, O, S, SO, SO₂. In one embodiment, each n independently = 0-6. In one specific embodiment, each n independently = 0-4. In one specific embodiment, X independently = C, S, N, or 0. In one specific embodiment, each R¹ independently = H, C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, CF₃, OH, NH(C1-3 alkyl), NH₂, or SH. In one specific embodiment, R² = C1-C6 alkyl, cycloalkyl, or hetercycloalkyl, CF₃, OH, NH(C1-3 alkyl), NH₂, SH, or CN. In one specific embodiment, each n independently = 0-4, each X independently = C, S, N, or O, each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, CF₃, OH, NH(C1-3 alkyl), NH₂, or SH, and R² = C1-C6 alkyl, cycloalkyl, or hetercycloalkyl, CF₃, OH, NH(C1-3 alkyl), NH₂, SH, or CN.

In one embodiment, each R¹ independently = OH, NH₂, CN, OC_1-6 saturated or unsaturated alkyl, aryl or heteroaryl, CO₂H, COiC_1-6 saturated or unsaturated alkyl, aryl or heteroaryl, NHC1-3 saturated, unsaturated alkyl, cycloalkyl, aryl or heteroaryl, or N(C_1-6 saturated, unsaturated alkyl, cycloalkyl, aryl or heteroaryl,)2. In one embodiment, each X independently = CH₂, NHCi-.saturated, unsaturated alkyl, or cycloalkyl, O, S, SO, or S0₂. In one embodiment, n = 0-6. In one specific embodiment, n = 0-4. In one specific embodiment, each X independently = C, S, N, or 0. In one specific embodiment, each R¹ independently = C1-C6 alkyl, cycloalkyl, hetercycloalkyl, aryl, heteroaryl, CF_, OH, NH(C1-3 alkyl), NH₂, SH, or CN. In one specific embodiment, n = 0-4, each X independently = C, S, N, or 0 and each R¹ independently = C1-C6 alkyl, cycloalkyl, hetercycloalkyl, aryl, heteroaryl, CF₃, OH, NH(C1-3 alkyl), NH₂, SH, or CN.

The compounds described herein may thus be employed 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 tie 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. While the SCN8A mutation of an individual patient was modeled, other patients with mutations in this gene may benefit from the same compounds that were identified. In various embodiments, compositions and methods are provided for mitigating in a mammal one 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 voltage-gated sodium or calcium 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 voltage-gated sodium or calcium channel activity in a mammal. In certain embodiments, compositions and methods are provided for altering function of voltage-gated sodium or calcium channels in a mammal.

The methods described herein are based, in part, on the surprising discovery that compounds including an adrenergic receptor alpha inhibitor, a voltage-gated L-type channel inhibitor and a selective serotonin receptor inhibitor, among other drugs with different activities targets, were effective to downregulate a sodium voltage-gated channel. Thus, one or more of the compounds in Example 2 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)-(XXXVI), a compound in Table 3 or 7, may be useful to modulate, in one embodiment, voltage-gated sodium or calcium channels.

Accordingly, in various embodiments, a compound of formula (l)-(XXXVI), a compound in Table 3 or 7, 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, delays inactivation, or spontaneous firing of a sodium or calcium channel, or 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 sodium or calcium channel, of a mammal are also provided. In certain embodiments, methods of directly or indirectly impacting sodium or calcium voltage- gated channel, in a mammal are provided.

Typically each of these methods involve administering one or more compounds or formulations thereof and/or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomer 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 voltage-gated sodium or calcium channel activity.

Pharmaceutical Compositions

Pharmaceutical compositions having one or more of the compounds described herein, suitable for administration, e.g., nasal, parenteral, central nervous system, or oral administration, such as by intravenous, intramuscular, topical, intrathecal, or subcutaneous routes, 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. acromol. 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 pharmacopeiae 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, akjinic 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 also be administered intravenously or intraperitoneally by infusion or injection.

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 filter sterilization.

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 nontoxic 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. Most repurposing candidates relied on literature review following the evaluation of one or a few candidate compounds; e.g., the use of quinidine for KCNT1 and memantine for GRIN2A positive epilepsy. This suggests that safer and more effective drugs may exist amongst approved drugs that remain unidentified. Here, candidate drugs were identified to repurpose for a rare genetic disease, focusing on gain of function mutations in SCN8A causing severe epilepsy. The mutation was found in a patient with a mutation in a sodium channel gene, SCN8A with early infantile epileptic encephalopathy resistant to multiple drugs. SCN8A encodes a voltage-gated sodium channel Navl .6 essential in regulating neuronal excitability (Amarouch & Abriel, 2015). A compound library of 1,280 FDA approved drugs was tested for activity in a heterologous expression system expressing the mutated SCN8A channels. Using FLIPR based screening strategies, 90 candidate compounds were identified that inhibit the gain of function associated with the pathogenic SCN8A mutation, 90 compounds that produced greater than 63% inhibition of drug induced stimulation (> 2 standard deviations away from the mean inhibition), many with acceptable safety profile and brain blood barrier penetration, making them attractive candidates to evaluate in patients with SCN8A positive epilepsy. Three compounds were profiled for activity against the wild type NaV1.6 channel. These results identify new candidates therapies for epilepsy patients with SCN8A mutations and illustrate the value of this new paradigm for drug screening, comprehensive repurposing effectiveness screening (CRES or CRS)_: as a strategy to identify candidate repurposed drugs to treat rare genetic diseases. Rare diseases/disorder affect fewer than 200,000 people in the U.S., or affect more than 200,000 persons but are not expected to recover the costs of developing and marketing a treatment drug. 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.

Exemplary sodium channels the activity of which in a mammal may be altered by compounds disclosed herein, are shown below.

In one embodiment, sodium 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:1-9. In one embodiment, voltage gated ion channels such as voltage gated sodium or calcium channels, the activity of which may be altered by compounds described herein, include those having an amino acid residue other than lie at a residue corresponding to residue 1327 in SEQ ID NO:6, other than Arg at a residue corresponding to residue 1878 in SEQ ID NO:6, other than Arg at a residue corresponding to residue 1617 in SEQ ID NO:6, other than Asn at a residue corresponding to residue 984 or 1768 in SEQ ID NO:6, or other than Thr at a residue corresponding to residue 767 in SEQ ID NO:6. For example, the compounds may have particular use for mammals with an amino acid residue in a sodium channel, such as SCN8A, other than 11327, R1872, R1617, N984, N1768, or T767, e.g., the mammal has at position 1327 V, A or T; at position 1892 or 1617 L, I, A, V, T, Q, E, or W; at position 984 or 1768, K or R; or at position 767 I, V, A or G (e.g., compounds useful in mammals having SCN8A with the following substitutions lle1327V, R1872L, R1872Q, R1872W, R1617Gln, N984K, N1768D, or T1716l).

Moreover, since there are structural homologies with voltage-gated calcium channels and voltage-gated sodium channels; the compounds disclosed herein may interact with a conserved region in these ion channels or otherwise indirectly influence the activity of that ion channel. For example, Figure 6 shows an alignment of one domain (S4) of four calcium channels and SCN8A voltage-gated calcium channel alpha subunits 1A (CACNA1A), 1C (CACNA1C), 1D (CACNA1D) and

1S (CACNA1S).

In one embodiment, the composition comprises formula (I):

wherein X = C or N; wherein Y = C or N; wherein R¹ = H, alkyl, cycloalkyl, or aromatic; wherein R² = H, alky], cycloalkyl, or aromatic; wherein R³ = H, alkyl, cycloalkyl, or aromatic; and wherein R⁴ = H, alkyl, cycloalkyl or aromatic.

In one embodiment, the composition comprises formula (la):

wherein X = C or N; wherein Y = C or N; wherein n = 0-4; and wherein R¹ = H, C1-C4 alkyl, or cycloalkyl including an aliphatic heterocycle.

In one embodiment, the composition comprises formula (lb):

wherein X = C or N; wherein Y = C or N; wherein n = 0-1 ; wherein R¹ = heteroaromatic; wherein R² = H or OH; wherein R³ = H, C1-C2 alkyl, or cycloalkyl (aliphatic heterocycle); or R* = H, C1-C2 alkyl, or cycloalkyl (aliphatic heterocycle).

In one embodiment, the composition comprises formula (lc):

wherein X = C or N; wherein Y = C or N; wherein n = 1-2; wherein R¹ = cyclyalkyl (aliphatic heterocycle); wherein R² = H or C1-C2 alkyl; wherein R³ = H or C1-C2 alkyl; wherein R⁴ = H or C1-C2 alkyl; or wherein R⁵ = H or C1-C2 alkyl.

In one embodiment, the composition comprises formula (Id):

wherein X = C or N; wherein Y = C or N; wherein R¹ = aromatic; wherein R²

wherein R³ = H or C1-C2 alkyl.

In one embodiment, the composition comprises formula (II):

wherein R¹ = H or halogen; wherein R² = H or halogen; wherein R³ = alkyl, cycloalkyl, or aromatic; or wherein R⁴ = alkyl, cycloalkyl, or aromatic.

In one embodiment, the composition comprises formula (IIa):

wherein n = 1-2; wherein R¹ = H or halogen; wherein R² = H or halogen; wherein R³ = aromatic or heteroaromatic; wherein R* = H or OH; wherein R⁵ = H or C1-C3 alkyl; or wherein R⁶ = H or C1-C3 alkyl.

In one embodiment, the composition comprises formula (lib):

wherein n = 1-3; wherein X = C or O; wherein R¹ = H or halogen; wherein R² = H or halogen; wherein R³ = H or CH3; wherein R* = C1-C2 alkyl or aromatic; or wherein R⁵ = H or C1-C3 alkyl.

In one embodiment, the composition comprises formula (III):

wherein X = C, N, S, or 0; wherein Y = C, N, S, or 0; wherein R¹ = halogen, alkyl, cycloalkyl, or aromatic; wherein R² = halogen, alkyl, cycloalkyl, or aromatic; wherein R³ = halogen, alkyl, cycloalkyl, or aromatic; wherein R⁴ = halogen, alkyl, cycloalkyl, or aromatic; wherein R⁵ = any halogen, alkyl, cycloalkyl, or aromatic; wherein R⁸ = any halogen, alkyl, cycloalkyl, or aromatic.

In one embodiment, the composition comprises formula (Ilia):

wherein X = C, N, S, or 0; wherein Y = C, N, S, or 0; wherein Z = N or 0; wherein n = 0-1 ; wherein R¹ H or C1-C2 alkyl; wherein R² = H or C1-C3 alcohol; or wherein R³ = H or C1-C2 thiol, or CF3.

In one embodiment, the composition comprises formula (lllb):

wherein X = C, N, S, or 0; wherein Y = C, N, S, or 0; wherein Z = C or N; wherein n = 0-1 ; or wherein R¹ = C1-C2 alkyl.

In one embodiment, the composition comprises formula (lllc):

wherein X = C, N, S, or 0; wherein Y = C, N, S, or 0; wherein Z = H or 0; or wherein R¹ = C1-C3 alkyl.

Specific substituents in formula (I) include:

Specific substituents in formula (II) include:

Specific substituents in formula (III) include:

Another specific embodiment of formula (I) is:

wherein R¹ is C(O)NHR⁵, C_1-10-alkyl, C_1-4-alkoxy,C_3-6-heterocycloalkyl, or C_6-10-aryl, wherein C_1-10- alkyl is optionally branched and substituted with one or more substituents independently selected from hydroxyl, C_1-4-aikoxy-N(C_1-2-alkyl)₂-N- C_6-10-aryl, and C_1-7-alkyl-C(O) C_1-4-alkoxy-N(C_1-2-alkyl)2, and wherein R⁵ is C_1-4-alkyl-N-(C_1-2alkyl)2;

wherein R² is C(O)NHR⁸, C_1-4 alkyl, or C_1-4-alkoxy, wherein R⁸ is selected from -C_1-4-alkyl-N(C_1-2- alkyl)2-N- C_6-10-aryl,or - C_1-4-alkyl-N(C_1-2-cycloalkyl)2-N-C_6-10-aryl;

wherein R³ is H or C_1-3-alkoxy; and

wherein R⁴ is H or C_1-3-alkoxy.

Another specific embodiment of formula (II) is:

wherein R¹ is selected from H or halogen;

wherein R² is selected from H or halogen;

wherein R³ is selected from H, hydroxyl, C_1-4-alkyl, or C(O)NR⁵, wherein R⁵ is selected from H or C_1-4-alkyl, C_1-6-cycloalkyl;

wherein R⁴ is selected from optionally branched C_1-10-alkyl, C_1-4-aikyl-C_3-7-heterocycloalkyl, C_1-4- alkoxy-C_3-7-heterocycloalkyl,C_3-7-heterocycloalkyl-C_1-8-alkyl, C_3-7-heterocycioalkyl- C_1-6-alkyl-C_6-10-aryl, and wherein C_1-10-alkyl is optionally branched C_1-5-alkyl-C_6-10-aryl, C_1-5-alkyl-N-C_3-6-heterocycloalkyl, C_1-5-alkyl- N-C_3-6-heterocycloalkyl-C_3-6-aryl, C_1-4-alkoxy-C_3-6-heterocycloaklyl,-N(C_1-2-alkyl)₂-C_1-4-alkyl-C_6-10-aryl, or C(O)O C_1-4-alkyl-N C_1-4-alkyl.

Another specific embodiment of formula (III) is:

wherein R¹ is selected from optionally branched C_1-10-alkyl, C_1-4-alkyl-C_3-6-heterocycloalkyl,or Ci. 4-alkyl-C_3-6-heterocycloalkyl- C_1-6-alkyl; and

wherein R² is selected from -H,-halogen - C_1-4-thioether, -fluoro-C_1-4-alkyl, -C(O) C_1-4alkoxy, or - NC(O)0-C_1-4-alkyl.

In one embodiment, the compound has formula (IV):

In one embodiment, n = 0-4, each X independently = C, CH, S, N, or NH, each R¹ independently = H or halogen, and each R² independently = H or C1-C3 alkyl.

In one specific embodiment, a compound of formula (IV) is clomipramine, cyproheptadine, amitriptyline, nortriptyline, dosulepin, imipramine, ortrimipramine.

In one embodiment, the compound has formula (V):

In one specific embodiment, each n independently = 0-4, each X independently = C, S, SH, N, NH₂, 0, or OH, and each R¹ independently = H or halogen.

In one specific embodiment, a compound of formula (V) is opopramol.

In one embodiment, the compound has formula (VI):

In one specific embodiment, each X independently = C, S, N, or O, each R¹ independently = H or halogen, and R² = H or C1-C3 alkyl

In one specific embodiment, a compound of formula (VI) is pizotifen.

In one embodiment, the compound has formula (VII):

In one specific embodiment, each X independently = C, S, SH, N, NH₂, 0, or OH, each R¹ independently = H or halogen, and each R² independently = H or C1-C3 alkyl.

In one specific embodiment, a compound of formula (VII) is asenapine.

In one embodiment, the compound has formula (VIII):

In one specific embodiment, each X independently = C, S, N, or O and each R¹

alkoxy, CI, Br, F, or CF₃.

In one specific embodiment, a compound of formula (VIII) is veratridine.

In one embodiment, the compound has formula (IX):

In one specific embodiment, each n independently = 0-4, each R¹ independently

each R² independently = H, C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, or CF₃.

In one specific embodiment, a compound of formula (IX) is alverine.

In one embodiment, the compound has formula (X):

In one specific embodiment, each n independently = 0-4, each X independently = C, S, N, or O, each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃ and each R² independently = H or C1- C3 alkyl.

In one specific embodiment, a compound of formula (X) is oxethazine.

In one embodiment, the compound has formula (XI):

In one specific embodiment, each n independently = 0-4, X = C, S, N, or O, and each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃

In one specific embodiment, a compound of formula (XI) is deptropine.

In one embodiment, the compound has formula (XII):

In one specific embodiment, n = 0-4, X = C, S, N, or 0, each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃, and R² = H or C1-C3 alkyl.

In one specific embodiment, a compound of formula (XII) is sertraline or indatraline.

In one embodiment, the compound has formula (XIII):

In one specific embodiment, n = 0-4, each X independently = C, S, N, or O, and each R¹ independently H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃.

In one specific embodiment, a compound of formula (XIII) is quinkJine.

In one embodiment, the compound has formula (XIV):

In one specific embodiment, X independently = C, S, N, or 0, each R¹ independently = H, C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, or CF₃, and R² = OChfeCeHs or m-BrCst-UN.

In one specific embodiment, a compound of formula (XIV) is metergoline or nicergoline.

In one embodiment, the compound has formula (XV):

In one specific embodiment, each n independently = 0-4. In one specific embodiment, X independently = C, S, N, or 0. In one specific embodiment, each R¹ independently = H, C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, or CF₃. In one specific embodiment, each n independently = 0-4, each X independently = C, S, N, or O, and each R¹ independently = H, C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, or CF₃.

In one specific embodiment, a compound of formula (XV) is spiperone.

In one embodiment, the compound has formula (XVI):

In one specific embodiment, each n independently = 0-4, each X independently

R independently = H, C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, or CF₃.

In one specific embodiment, a compound of formula (XVI) is bepridil.

In one embodiment, the compound has formula (XVII):

In one specific embodiment, each n independently = 0-4, each X independently = C, S, N, or O, independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃.and R² = OH, NH2, or SH.

In one specific embodiment, a compound of formula (XVII) is haloperidol.

In one embodiment, the compound has formula (XVIII):

In one specific embodiment, each R² = OH, NH₂, or SH. In one specific embodiment, each n independently = 0-4, each X independently = C, S, N, or 0, each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃. and R² = OH, NH₂, or SH.

In one specific embodiment, a compound of formula (XVIII) is fluvoxamine.

In one embodiment, the compound has formula (XIX):

In one specific embodiment, each n independently = 0-4, each X independently = C, S, N, or 0, and each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃.

In one specific embodiment, a compound of formula (XIX) is perospirone.

In one embodiment, the compound has formula (XX):

In one specific embodiment, each n independently = 0-4, each X independently

R¹ independently = H, C1-C3 alkyi, 0C1-C3 alkoxy, CI, Br, F, or CF₃.

In one specific embodiment, a compound of formula (XX) is fipexide.

In one embodiment, the compound has formula (XXI):

In one specific embodiment, n = 0-4, each X independently = C, S, N, or O , and each R¹ independently = H, C1-C3 alkyi, OC1-C3 alkoxy, CI, Br, F, or CF₃.

In one specific embodiment, a compound of formula (XXI) is benztropine.

In one embodiment, the compound has formula (XXII):

In one specific embodiment, each n independently = 0-4, each X independently

R independently = H, C1-C3 alkyi, OC1-C3 alkoxy, CI, Br, F, or CF₃.

In one specific embodiment, a compound of formula (XXII) is clemizole.

In one embodiment, the compound has formula (XXIII):

In one specific embodiment n = 0-4, each X independently = C, S, N, or O, each R¹ independently = H, C1-C3 alkyi, OC1-C3 alkoxy, CI, Br, F, or CF₃. and

In one specific embodiment, a compound of formula (XXIII) is benperidol or domperidone. In one embodiment, the compound has formula (XXIV):

In one specific embodiment, each n independently = 0-4, each X independently = C, S, N, or 0, each R¹ independently = H, C1 -C3 alkyl, 0C1 -C3 alkoxy, CI, Br, F, or CF₃. and R² = C1 -6 alkyl, C5-C7 cyclic alkyi or heteroalkyl

In one specific embodiment, a compound of formula (XXIV) is propafenone.

In one embodiment, the compound has formula (XXV):

In one specific embodiment, each n independently = 0-4, each X independently = C, S, N, or 0 and each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃.

In one specific embodiment, a compound of formula (XXV) is diperodon.

In one embodiment, the compound has formula (XXVI):

In one specific embodiment, each X independently = C, S, N, or O andR¹ = OH, NH(C1-3 alkyl), N(C1-3 alkyl), NH₂, or SH.

In one specific embodiment, a compound of formula (XXVI) is 8-azaguanine.

In one embodiment, the compound has formula (XXVII):

In one specific embodiment, each n independently = 0-4, each X independently = C, S, N, or 0, and each R¹ independently = H, C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, or CF₃

In one specific embodiment, a compound of formula (XXVII) is nefazodone.

In one embodiment, the compound has formula (XXVIII):

In one specific embodiment, n = 0-4, each X independently = C, S, N, or O, each R¹ independently = H, C1-C3 alkyi, OC1-C3 alkoxy, CI, Br, F, or CF₃. R² = C1-6 alkyl, C3-C7 cyclic alkyi or heteroalkyl, and R³ = OH, NH(C1-3 alkyl), NH₂, or SH.

In one specific embodiment, a compound of formula (XXVIII) is lorazepam or prazepam. In one embodiment, the compound has formula (XXIX):

In one specific embodiment, each X independently = C, S, N, or O, each R¹ independently

alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃ and R² = OH, NH(C1-3 alky)), NH₂, or SH.

In one specific embodiment, a compound of formula (XXIX) is pyrimethamine.

In one embodiment, the compound has formula (XXX):

In one specific embodiment, each n independently = 0-4, each X independently = C, S, N, or 0, and each R¹ independently = H, C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, or CF₃.

In one specific embodiment, a compound of formula (XXX) is donepezil.

In one embodiment, the compound has formula (XXXI):

In one specific embodiment, each n Independently = 0-4. In one specific embodiment, each X independently = C, S, N, or O. In one specific embodiment, each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, CF₃, OH, NH(C1-3 alkyl), NH₂, or SH. In one specific embodiment, each n independently = 0-4, each X independently = C, S, N, or 0, and each

R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, CF₃, OH, NH(C1-3 alkyl), NH₂, orSH.

In one specific embodiment, a compound of formula (XXXI) is salmeterol.

In one embodiment, the compound has formula (XXXII):

In one specific embodiment, n = 0-4, X = C, S, N, or 0, each R¹ independently = H, C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, CF₃, OH, NH(C1-3 alkyl), NH₂, or SH, and each R² independently = C1-C6 alkyl, cycloalkyl, or hetercycloalkyl.

In one specific embodiment, a compound of formula (XXXII) is tolterodine.

In one embodiment, the compound has formula (XXXIII):

In one specific embodiment, n independently = 0-4, X = C, S, N, or O, each

R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, CF₃, OH, NH(C1-3 alkyl), NH₂, orSH, and each R² independently = C1-C6 alkyl, cycloalkyl, or hetercycloalkyl, CF₃, OH, NH(C1-3 alkyl), NH₂, SH, or CN.

In one specific embodiment, a compound of formula (XXXIII) is verapamil.

In one embodiment, the compound has formula (XXXIV):

In one specific embodiment, R² = C1-C6 alkyl, cycloalkyl, or hetercycloalkyl, CF₃, OH, NH(C1-3 alkyl), NH₂, SH, or CN. In one specific embodiment n independently = 0-4, each

X independently = C, S, N, or 0 , each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, CF₃, OH, NH(C1-3 alkyl), NH₂, or SH, andR² = C1-C6 alkyl, cycloalkyl, or hetercycloalkyl, CF₃, OH, NH(C1-3 alkyl), NH₂, SH. or CN.

In one specific embodiment, a compound of formula (XXXIV) is flavoxate.

In one embodiment, the compound has formula (XXXV):

In one specific embodiment, each n independently = 0-4, each X independently = C, 5, N, or 0, each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, CF₃, OH, NH(C1-3 alkyl), NH₂, or SH, and R² C1-C6 alkyl, cycloalkyl, or hetercycloalkyl, CF₃, OH, NH(C1-3 alkyl), NH₂, SH, or CN.

In one specific embodiment, a compound of formula (XXXV) is(-)-eticlopride.

In one embodiment, the compound has formula (XXXVI):

In one specific embodiment, n = 0-4, each X independently = C, S, N, or O and each R¹ independently C1-C6 alkyl, cycloalkyl, hetercycloalkyl, aryl, heteroaryl, CF₃, OH, NH(C1-3 alkyl), NH₂, SH, or CN.

In one specific embodiment, a compound of formula (XXXVI) is ritonavir.

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, GR1N2A, HCN1, KCNB1, KCNQ2, KCNT1, KIAA1279, LGI1, MAGI2, MDBS, 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.

HEK293 cell line generation

The SCNBA R1872Q variant was created by site-directed mutagenesis of wild-type SCN8A plasmid (g5615a; CGG to CAG) and transfected into HEK293. The resulting stable pool (ICLN-1431) was maintained in growth media containing 400 pg/mL G418 for selection. The clonal cell line. ICLN-1435, was selected from dilution cloning of ICN-1431. HEK-293 cells expressing either wild-type hSCN8A or hSCN8A containing the R1872Q point mutation were cultured in DMEM High glucose containing 10% FBS, 2 mM Sodium Pyruvate, 10mM HEPES, and 400 pg mL G418 at 37°C in the presence of 10% C02. Cells were routinely passaged every 3-5 days to maintain < 80% confluency. All studies were completed within passages 7-9.

Biophysical experiments were performed using the Molecular Devices PatchXpress automated patch clamp platform. The biophysical properties of the 1872Q SCN8A stable pool (ICLN-1431) and clone (ICLN-1435) were compared with those of wild type SCN8A (ICLN-901). Phase I experiments were conducted across multiple days and ICLN-1431 and ICLN-901 test groups were interleaved on days of testing. For Phase II, ICLN-1435 was tested to confirm the differences observed in Phase I and was compared to the WT properties already established as part of Phase I.

PatchXpress protocol and analysis to determine voltage-dependent properties

Upon reaching stable whole cell configuration, cells were held at a membrane potential of -140 mV and the protocol shown in Figure 3 was run to determine voltage-dependent properties. The peak currents from the Δ10 mV (500 msec) steps were used to calculate current-voltage (IV) relationships. To derive conductance-voltage relationship (GV), the calculated Erev of +72 mV was used such that conductance=(current (test potential-reversal potential)) The peak currents from the second 0 mV (20 msec) step were used to determine voltage-dependent properties of steady-state inactivation (SSI) by plotting as a function of the Δ1 OmV (500 msec) pre-pulse voltage. Both GV and SSI curves were individually fit in GraphPad Prism 6 to the Boltzmann equation to derive V0.5, slope, min and max Individual relationships were normalized in Excel such that fractional current = (current amplitude/(fitted Emax-frtted Emin)). These normalized data were averaged, plotted as meantSEM values and fit to the Boltzmann equation to yield 95% confidence intervals in addition to V0.5, slope, min and max.

PatchXpress protocol and analysis to determine frequency-dependent properties

Frequency-dependence was tested using the protocols shown in Figure 4. The 20 msec step protocol provided longer stimulus duration with a maximum frequency of 30 Hz. The 9 msec step protocol allowed for greater stimulus frequency up to 100 Hz. For analysis, data were individually normalized as percent of the 1st pulse amplitude and plotted as mean ± SEM.

Compounds and reagents for FLIPR

For reference compound CRC curves, 15 μΙ of 10 mM compound stocks were added to 35 μΙ of DMSO. Serial dilutions were performed by transferring 25 μΙ of top compound concentration to 25 μΙ of DMSO and mixed. Dilutions were continued to generate 10 point dose response curves. Final assay DMSO concentration was 0.5%. All compounds were tested on the clonal R1872Q SCN8A cell line, ICLN-1475.

For FLIPR experiment

The day prior to testing, cells were harvested in growth media and plated on 384 well, PDL- coated black walled with clear bottom microplates (Greiner). 25 pL of 0.9 x 10^s cells per ml were seeded into the plates. Plates were incubated at 37°C, 10% C02 overnight until used. Prior to testing, growth media was removed from the plate and 10 μΙ of 4 μΜ Asante Natrium Green (Teflabs) was added (mixed with equal volume of 20% Pluronic F127). Cells were incubated for 60-90 minutes at room temperature, protected from light. After incubation, the dye was removed from the plates and replaced with 10 pL of EBSS (142 mM NaCI, 0.8 mM MgCI2, 1.8 mM CaCI2, 5.4 mM KCI, 10 mM HEPES, 5 mM Glucose, pH = 7.4, osmolarity=300 mOsm). Cell and assay plates were loaded onto the FLIPR and the 5_min_5_min 384 protocol was run. 10 pL of a pre-incubation plate containing EBSS + valinomycin either with or without test compound were added to the cells. Images were taken for 5 minutes to monitor effects on basal Na+ fluorescence. After the 5 minute incubation, 20 μΙ_ of EBSS + veratridine (with or without test compounds) was added and fluorescence responses were monitored for an additional 5 minutes. Data were exported as max-min over the 5 minute veratridine addition. ICso testing was done using 100 μΜ veratidine as the stimulus.

Results

Clinical Description and Identification of mutation

The patient was diagnosed with early infantile epileptic encephalopathy, combined with global developmental delay and osteopenia. The epilepsy was multidrug resistant and immunomodulation resistant. The patient was sent for genetic sequencing. Next generation sequencing was carried out on 66 genes associated with severe developmental delay and seizures, and a heterozygous mutation in the SCN8A gene was identified at c.5615G>A, pArgl 872Lys. This de novo mutation caused the early infantile epileptic encephalopathy (EIEE13).

Characterization of the SCN8A R1872Q variant cell lines

To recapitulate the patient's mutation in a cell model amenable to high throughput sequencing, HEK293 cell lines that have been utilized for high throughput screening extensively were used (Chen et al., 2015). A copy of the SCN8A gene containing a point mutation at the R1872Q site as found in the patient was introduced to the HEK293 cells. The SCN8A R1872Q variant was created by site-directed mutagenesis of wild-type SCN8A plasmid (g5615a; CGG to CAG) and transfected into HEK293. The DNA sequences and plasmid expression levels of all generated recombinant cell lines were confirmed by RT- PCR. A clonal line was established and characterization was performed on both pooled and clonal line populations.

A comprehensive characterization of the SCN8A R1872Q variant cell lines compared with WT cell lines was then carried out. The conductance-voltage relationship for R1872Q SCN8A activation revealed no difference between the V0.5 of channel activation in pooled population expressing lines. V0.5 of channel activation is slightly hyperpolarized for R1872Q in a clonal population, with constant level of channel expression between cells (Figure 1 A). This small but significant shift (-4 mV) impacts activation properties of the channel. These findings agree with prior studies (Wagnon et al.. 2015) and support the use of clonal populations for characterization and screening studies.

Next, the voltage-dependence of R1872Q steady-state inactivation was investigated. In stable pools of R1872Q SCN8A expressing lines, steady-state inactivation was depolarized by 7 mV compared to wild type (PO.05) demonstrating a slower inactivation of the R1872Q SCN8A and a greater probability of channel opening, however, in the clonal line this was not significant. When directly testing inactivation using a second method, the rate of inactivation was slower in R1872Q variant in both the pooled cells and clonal lines. The decay phase was best fit by a single exponential and R1872Q rates were significantly slower (P<0.05) than wild type (Figure 1C-D). When steady state inactivation was slowed, this resulted in persistent sodium currents. This disruption of inactivation was predicted to cause prolonged bursts of action potentials, correlating to the severe epilepsy in the patient.

Next, the effect of the mutation on window currents was measured. This was determined using the overlap of G and SSI curves for WT and R1872Q SCN8A channels. The R1872Q variant displayed a reduced window current in both clonal and pool lines. In the R1872Q lines the window current was decreased by 4-7 mV in R1872Q compared to WT (Figure 1 D). The difference between V0.5 of activation and inactivation was 28 mV for R1872Q and 35 mV for WT in the pooled lines, and 31 mV for R1872Q and 35 mV for WT in the clones.

Finally, the frequency dependence of activation and the current amplitude distribution were determined. Frequency dependence remained unchanged across 1 , 3, 10, 30 and 100 Hz stimulation protocols. Current amplitude distribution was measured by measuring amplitudes derived from a 500 msec pulse to 0 mV from a holding potential of -140 mV and no significant difference was found (Figure 2).

Following the assessment of the properties of the R1872Q SCN8A variant expressing lines, the clonal cell lines were developed for use in high throughput screening.

Screening of a library of approved druos

Having identified key effects of the mutation, a screen was developed to identify compounds that revert key effects of the mutant channel. High throughput screening was carried out using stimulus activated fluorescence-based Na⁺flux using FLIPR technology. Compounds were tested at 10 μΜ at n=2 against a background of veratridine stimulation. To optimize this, verartidine concentration response curves were generated on clonal cell lines producing a potency and dynamic range consistent with historical data generated on the clonal wild type SCN8A cell line by assessing classical sodium channel small molecule channel blockers. ICso testing with 100 μΜ veratridine as a stimulus yielded ICso values consistent with historic values for wild type hSCN8A. All plate statistics (ZPRIME, S/B, and dynamic range) were above limits signifying a robust high throughput assay fit for screening of R1872Q SCNBA inhibitor molecules. Run to run variability was assessed using Tetracaine as a control compound. Lastly, assay sensitivity was assessed in single point screening mode by successful detection of TTX and Tetracaine at relevant screening concentrations. Upon confirmation, screening of 1280 compounds was initiated. The average inhibition of the negative control (DMSO) was < 2% and the positive control, 30 μΜ Tetracaine showed an inhibition effect of 99%. The median % inhibition for the screening set was 11%. 2SD and 3SD from the mean was 63% and 89%, respectively. Ninety test compounds produced >2SD inhibition, with an additional 80 producing >40% block. Of those 90 compounds of >2SD inhibition, 5 were known sodium channel blockers (5.5%) and 10 (11.1 %) were described as known channel blockers (including calcium channels). See Table 1.

A more complete exploration of the compounds revealed that of the top compounds with the highest % inhibition, several compounds were candidates for repurposing due to blood brain barrier permeability probability and a favorable toxicity profile (these candidates are underlined).

Table 1. Inhibition Effects on the SCN8A R1872Q.

Table 2. Characterization of known sodium channel inhibitors for selectivity to R1872Q

These compounds were assessed with concentration response curves to confirm findings from high throughput screening. All compounds demonstrated efficacy of as inhibitors of veratridine stimulation under this stimulation protocol. Next it was examined whether the FLIPR assay results were recapitulated in an electrophysiological assay.

Finally, it was tested if any of these compounds strongly inhibited the WT Navl .6 channels. This assessed specificity that could affect the safety of these drugs at doses required for therapeutic effect in addition to revealing whether compounds could be applicable for rescue of other mutations in the SCN8A gene.

Discussion

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 new patient specific indications for approved drugs. While the mutation of an individual patient was modeled, many patients with mutations in this gene could benefit from the same treatment. The assay was able to efficiently and accurately determine the effects of 1280 compounds on veratridine agonism in the HEK293 model system containing the R1872Q form of SCN8A. Veratridine causes fast transient inward voltage-gated Na+ currents by shifting the channel into a long-lasting open state in NaV1.1-7. Sodium influx was monitored using a sodium indicator. 90 drugs showed a statistically significant ability to reduce this sodium influx, including drugs that act at histamine, acetylcholine, dopamine and adrenergic receptors in addition to sodium and calcium channels. While the present findings provide opportunities for therapies, they also suggest alternate mechanisms through which these compounds may act, or other pathways by which sodium influx may be modulated. The specificity of these compounds to the mutation containing SCN8A was compared with the WT, these findings indicated. Finally, to evaluate safety and applicability of these drugs and to see how broadly these drugs affect sodium channel currents, lead compounds were tested against NaV1.5.

Lastly, the feasibility of these compounds for clinical use was addressed. Many of these compounds show acceptable safety profiles, cross the brain blood barrier, and appear attractive candidates to evaluate in epilepsy patients with SCN8A mutations. The most promising of these candidates are in clinical use, including Carvedilol (antihypertensive), Nilvadipine (antianginal) and

Trihexyphenidyl-D,L Hydrochloride (antiparkinsonian). Notably, none of these candidates primarily target sodium channels. Carvedilol inhibits the α-adrenergic receptor, Nilvadipine is a voltage-gated L-type calcium channel blocker and Trihexyphenidyl-D,L Hydrochloride is a M1 muscarinic acetylcholine receptor antagonist. Thus these drugs may treat rare genetic diseases. The number of potentially viable candidates from a screen of 1280 compounds demonstrates the value of this paradigm of comprehensive repurposing effectiveness screening to reveal promising new drug candidates, with immediate clinical potential, e.g., in a disease area where no approved therapies. In conclusion, the present work emphasizes the importance of exhaustively assessing repurposing opportunities to provide new therapeutic avenues for patients with rare genetic disorders.

Example 2

Table 3

Example 3

Table 4. Compounds Identified in Screen that are FDA Approved

The Table below (Table 5) shows the % inhibition and the ICso values (half maximal inhibition) of the leading anti epileptic drugs and the top 90 compounds shown to cause a significant inhibitory effect on the SCN8A R1872Q cellular model and the SCN8A wild type cellular model using FLIPR high throughput screening techniques. Data is shown as the average % inhibition of sodium influx at that receptor compared with 30 μΜ tetracaine (100%) or DMSO control (0%).

Table 5

The results above are supported by docking data (see Table 6) obtained using an in silico model, e.g., a homology model prepared using MOE (Molecular Operating Environment version 2016.08, using the Amber10:MHT force-field) from CCG (Chemical Computing Group Inc). Forthe docking, Gold (GoldSuite v5.4.1 2016) from CCDC (Cambridge Crystallographic Data Centre) and Flare (version 1.0.0) from Cresset BioMolecular Discovery Ltd.

Table 6

Example 4

Compounds that inhibited the activity of SCN8A are shown in Table 7:

Table 7. Compounds that inhibit SCN8A wild type activity

There are several substructure patterns that emerge when analyzing the compounds that inhibit the SCN8A wild-type sodium ion channel (see Table 8). Table 8A. Phenthiazine

Table 8D. Naphihalene/lsoquinoline:

Table 9. Summary of Relative Activities

Example 5

Pentvlenetetrzole Testing in Adult mice

From the compounds that were active in the high-throughput in vitro screens with mutant or wild-type SCN8A cell models, a subset were chosen for testing in vivo, for efficacy in an acute, chemical-induction seizure model using pentylenetetrazole (PTZ) dosing. PTZ is a GABAergic antagonist which reproducibly produces myoclonic seizures when administered to adult mice and has been widely used in epilepsy research and development of anti-epileptic drugs (LOscher, 2011 ; Yuen and Troconiz, 2015).

The six compounds selected for in vivo testing are shown in Table 10 below:

Table 10

For this study, adult (8 to 10 weeks of age) male, CD-1 mice were used as subjects. Test compounds were formulated in 5% hydroxypropyl-beta-cyclodextrin (HPbCD) in saline; pre-formulation testing indicated this was a suitable vehicle for all test compounds. The treatment groups for the study (12 animals/group) are shown in Table 8. Controls groups consisted of vehicle alone (negative control) and Diazepam (positive control); Diazepam was administered at 30 mg/kg, orally (10ml/kg dose volume), a dose known to be sufficient to consistently suppress PTZ seizures. Test compounds were administered intraperitoneally (ip) at one of three pre-determined doses (see Table 8), 30 minutes prior to PTZ administration; diazepam was also administered 30 minutes prior to PTZ administration. Animals were then given PTZ at a dose of 100 mg/kg, ip. The main endpoints of the study were time to clonic seizure (minutes) and time to tonic seizure (minutes). Gross behavioral assessment was also made on the animals over the course of testing.

Across the 6 drugs tested, none demonstrated activity against clonic seizures (data not shown). However, R-duloxetine, amitriptyline and cloperastine produced a dose-related increase in latency to tonic hindlimb seizures (See Figure 7). Cloperastine (80mg/kg) and R-duloxetine (40mg/kg) at the highest dose tested significantly increased latency times. Amitriptyline had significantly increased latencies at all test doses (20, 40 and 80 mg/kg). These results demonstrate evidence for efficacy of these agents in the PTZ model, a model that is considered a useful tool for drug development and predictive for clinical efficacy against epileptic seizures (Yuen and Troconiz, 2015). These findings also serve to confirm the utility of comprehensive drug repurposing screening to identify compounds with heretofore unappreciated potential application for epilepsy.

Table 11. Group Assignments for PTZ Testing:

Notes:

1) all test drugs formulated in 5% hydroxypropyl-beta-cyclodextrin (HPbCD).

2) all drugs (including controls) were administered by intraperitoneal (ip) injection.

3) there were 12 animals/group; 240 animals total.

4) test drugs were administered 30 minutes prior to PTZ challenge.

Example 6

In one embodiment, the disclosure provides for 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 any one of formulas (l)-(XXXVI), a compound in Table 3 or 7, a pharmaceutically acceptable salt thereof, or a combination thereof. In one embodiment, the compound is a compound in any one of Tables 3- 8. In one embodiment, the mammal is a human. In one embodiment, the compound is an alpha adrenergic receptor blocker, a dihydropyridine calcium channel blocker, a cholinergic receptor inhibitor, a muscarinic receptor inhibitor, or a serotonin-norepinephrine receptor inhibitor.

In one embodiment, the composition has a compound of formula (I)

wherein X and Y independently are C or N; and

wherein R¹, R², R³, and R⁴ are independently are H, alkyl, cycloalkyl or aromatic. In one embodiment, R¹ in formula (I) is

In one embodiment, R² in formula (I) is

In one embodiment, R³ or R⁴ in formula (I) independently are H or OEt.

In one embodiment, the composition has a compound of formula (II)

wherein R¹ and R² are independently H or halogen; and

wherein R³ and R⁴ are independently alkyl, cycloalkyl or aromatic.

In one emboidment, R⁴ in formula (II) is

In one embodiment, R¹ and R² in formula (II) are independently H, CI, or F.

In one embodiment, the composition has a compound of formula (III)

wherein X and Y are independently C, N, S, or 0; and

wherein R¹, R², R³, R⁴, R⁵, and R^s are independently halogen, alkyl, cycloalkyl, or aromatic.

In one embodiment, R¹ in formula (III) is

In one embodiment, the compound inhibits sodium channel activity, .calcium channel activity, or both.

Also provided is a method to screen for drugs useful to alter sodium voltage- gated channel activity in a mammal. The method includes a) providing isolated mammalian cells, the genome of which encodes a variant sodium voltage-gated channel with at least 80% amino acid identity to one of SEQ ID Nos. 1-9, which variant channel has at least one amino acid residue that differs from the amino acid sequence in the one of SEQ ID Nos. 1-9 and which variant has delayed inactivation or a hyperpolarizing shift in voltage dependent activation relative to the one of SEQ ID Nos. 1-9; b) contacting the isolated mammalian cells with one or more compounds that include an alpha adrenergic receptor blocker, a dihydropyridine calcium channel blocker, a cholinergic receptor inhibitor, a muscarinic receptor inhibitor, a serotonin- norepinephrine receptor inhibitor, a calcium channel blocker, a sodium channel blocker, any one of formulas (l)-(XXXVI), a compound in Table 3 or 7, or a pharmaceutically acceptable salt thereof; and c) detecting one or more compounds that inhibit the delayed inactivation or hyperpolarizing shift in voltage dependent activation. In one embodiment, the mammal is a human. In one embodiment, the at least one amino acid residue that is different corresponds to a residue at position 757 to 787, 964 to 987, 1317 to 1337, 1605 to 1627, 1758 to 1778, or 1862 to 1882 in SEQ ID NO:6.

References

Amarouch & Abriel, H. Frontiers in Physiology, 6:45 (2015).

Black and Waxman, Multiple Scler. 19:532 (2013).

Blanchard et al., J. Med Genet.. 52:330 (2015).

Chen et al. , Biomol. Screen. 20:242 (2015) .

Chen et al., Cerebellum, 8:192 (2009).

EpiPM Consortium, Lancet. 14:1219 (2015).

Loscher et al., Seizure. 20:359 (2011).

Mastrangelo, Neuroped.. 48:143 (2017). McTague et al., Lancet Neurol.. 15:304 (2016).

Meisler et al., Epilepsia. 57:1027 (2016).

Patel et al., Plos One. 10 :e0133485 (2015).

Stessman et al., Am. J. Hum. Genet.. 98:541 (2016).

Trudeau et al., J. Med. Genet.. 43:527 (2006).

Wagnon et al., Annals Clin. Transl. Neurology. 3:114 (2015).

Warrier et al., Mol. Autism. 4:48 (2013).

Yuen and Troconiz, Seizure. 24:21 (2015). 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 formulas (I)- (XXXVI), or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 wherein the compound is a compound in Table 3 or 7.

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

4. The method of any one of claim 1 , 2 or 3 wherein the compound is an alpha adrenergic receptor blocker, a dihydropyridine calcium channel blocker, a cholinergic receptor inhibitor, a muscarinic receptor inhibitor, or a serotonin-norepinephrine receptor inhibitor.

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

wherein X and Y independently are C or N; and

wherein R¹, R², R³, and R⁴ are independently are H, alkyl, cycloalkyl or aromatic.

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

wherein R¹ and R² are independently H or halogen; and

wherein R³ and R⁴ are independently alkyl, cycloalkyl or aromatic.

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

wherein X and Y are independently C, N, S, or O; and

wherein R¹, R², R³, R⁴, R⁵, and R⁶ are independently halogen, alkyl, cycloalkyl, or aromatic.

8. The method of any one of claims 1 to 3 or 5 to 7 wherein the compound inhibits sodium channel activity.

9. The method of any one of claims 1 to 3 or 5 to 8 wherein the compound inhibits calcium channel activity.

10. The method of claim 5 wherein R¹ in formula (I) is

11. The method of any one of claim 5 or 10 wherein R² in formula (I) is

12. The method of any one of claims 5, 10 or 11 wherein R³ or R⁴ in formula (I) independently are H or OEt.

13. The method of claim 6 wherein R⁴ in formula (II) is

14. The method of any one of claim 6 or 13 wherein R³ in formula (II) is

15. The method of any one of claims 6, 13 or 14 wherein R¹ and R² in formula (II) are independently H, CI, or F.

16. The method of claim 7 wherein R¹ in formula (III) is

17. The method of any one of claim 7 or 16 wherein R² in formula (III) is H, SMe, CI,

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

wherein n = 0-4, each X independently = C, CH, S, N, or NH, each R¹ independently = H or halogen, and each R² independently = H orC1-C3 alkyl.

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

wherein each n independently = 0-4, each X independently = C, S, SH, N, NH₂, 0, or OH, and each R¹ independently = H or halogen.

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

Wherein each X independently = C, S, N, or O, each R¹ independently = H or halogen, and R² = H or C1-C3 alkyl.

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

wherein each X independently = C, S, SH, N, NH₂, 0, or OH, each R¹ independently = H or halogen, and each R² independently = H or C1-C3 alkyl.

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

wherein each X independently = C, S, N, or 0 and each R¹ = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃.

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

wherein each n independently = 0-4, each R¹ independently = H or C1-C3 alkyl, and each R² independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃.

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

wherein each n independently = 0-4, each X independently = C, S, N, or O, each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃. and each R² independently = H or C1-C3 alkyl.

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

wherein each n independently = 0-4, X = C, S, N, or O, and each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃

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

wherein n = 0-4, X = C, S, N, or 0, each R¹ independently = H, C1-C3 a Iky 1, 0C1-C3 alkoxy, CI, Br, F, or CF₃ and R² = H or C1-C3 alkyl.

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

wherein n = 0-4, each X independently = C, S, N, or 0, and each R¹ independently = C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃.

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

X independently = C, S, N, or 0, each R¹ independently = H, C1-C3 alkyl, 0C1-C3 alkoxy, CI, Br, F, or CF₃.and R² = OCH₂C₆H₅ or m-BrC₅H₄N.

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

wherein each n independently = 0-4, each X independently = C, S, N, or O, and each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃.

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

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

wherein each n independently = 0-4, each X independently = C, S, N, or O, each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃. and R² = OH, NH2, or SH.

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

wherein each R² = OH, NH₂, or SH. In one specific embodiment, each n independently = 0-4, each X independently = C, S, N, or O, each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃. and R² = OH, NH₂, or SH.

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

wherein each n independently = 0-4, each X independently = C, S, N, or O, and each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃

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

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

wherein n = 0-4, each X independently = C, S, N, or O , and each R¹ independently C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃.

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

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

wherein n = 0-4, each X independently = C, S, N, or O, each R independently C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃, and

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

wherein each n independently = 0-4, each X independently = C, S, N, or O, each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃, and R² = C1-6 alkyl, C5-C7 cyclic alkyl or heteroalkyl.

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

wherein each n independently = 0-4, each X independently = C, S, N, or O and each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃.

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

wherein each X independently = C, S, N, or O andR¹ = OH, NH(C1-3 alkyl), N(C1-3 alkyl), NH₂, or SH.

41. The method of any one of claims 1 to 4 whereinthe compound has formula (XXVII):

42. The method of any one of claims 1 to 4 wherein the compound has formula

(XXVIII):

wherein each n = 0-4, each X independently = C, S, N, or O, each R¹ independently H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃. R² = C1-6 alkyl, C3-C7 cyclic alkyl heteroalkyi, and R³ = OH, NH(C1-3 alkyl), NH₂, or SH.

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

wherein each X independently = C, S, N, or O, each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, or CF₃, and R² = OH, NH(C1-3 alkyl), NH₂, or SH.

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

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

wherein each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, CF₃, OH, NH(C1-3 alkyl), NH₂, or SH. In one specific embodiment, each n independently = 0-4, each X independently = C, S, N, or O, and each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, CF₃, OH, NH(C1-3 alkyl), NH₂, or SH.

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

wherein = 0-4, X = C, S, N, or O, each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, CF₃, OH, NH(C1-3 alkyl), NH₂, or SH, and each R² independently = C1-C6 alkyl, cycloalkyl, or hetercycloalkyl.

47. The method of any one of claims 1 to 4 wherein the compound has formula (XXXI 11):

wherein each n independently = 0-4, X = C, S, N, or 0, each R¹ independently = H, C1- C3 alkyl, OC1-C3 alkoxy, CI, Br, F, CF₃, OH, NH(C1-3 alkyl), NH₂, or SH, and each R² independently = C1-C6 alkyl, cycloalkyl, or hetercycloalkyl, CF₃, OH, NH(C1-3 alkyl), NH₂, SH. or CN.

48. The method of any one of claims 1 to 4 wherein the compound has formula

(XXXIV):

wherein R² = C1-C6 alkyl, cycloalkyl, or hetercycloalkyl, CF₃, OH, NH(C1-3 alkyl), NH₂, SH, or CN. In one specific embodiment n independently = 0-4, each X independently = C, S, N, or O , each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, CF₃, OH, NH(C1-3 alkyl), NH_2| or SH, andR² = C1-C6 alkyl, cycloalkyl, or hetercycloalkyl, CF₃. OH, NH(C1-3 alkyl), NH₂, SH, or CN.

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

wherein each n independently = 0-4, each X independently = C, S, N, or O, each R¹ independently = H, C1-C3 alkyl, OC1-C3 alkoxy, CI, Br, F, CF₃, OH, NH(C1-3 alkyl), NH₂, or SH, and R² = C1-C6 alkyl, cycloalkyl, or hetercycloalkyl, CF₃, OH, NH(C1-3 alkyl), NH₂, SH. or CN.

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

wherein n = 0-4, each X independently = C, S, N, or O and each R¹ independently = C1- C6 alkyl, cycloalkyl, hetercycloalkyl, aryl, heteroaryl, CFi, OH, NH(C1-3 alkyl), NH₂, SH, or CN.

51. The method of any one of claims 1 to 50 wherein the composition is orally, intravenously, intramuscularly, subcutaneously, transdermally, intrathecally, intracerebrovascularly, intraparenchymally, or rectally administered.

52. The method of any one of claims 1 to 51 wherein the amount administered is about 1 mg to about 75 mg per day, about 10 mg to about 50 mg per day, about 20 mg to about 40 mg per day, or about 5 mg to about 50,000 mg per day.

53. A method to screen for drugs useful to alter sodium voltage-gated channel activity in a mammal, comprising:

a) providing isolated mammalian cells, the genome of which encodes a variant sodium voltage-gated channel with at least 80% amino acid identity to one of SEQ ID Nos. 1-9, which variant channel has at least one amino acid residue that differs from the amino acid sequence in the one of SEQ ID Nos. 1-9 and which variant has delayed inactivation or a hyperpolarizing shift in voltage dependent activation relative to the one of SEQ ID Nos. 1-9;

b) contacting the isolated mammalian cells with one or more compounds that include an alpha adrenergic receptor blocker, a dihydropyridine calcium channel blocker, a cholinergic receptor inhibitor, a muscarinic receptor inhibitor, a serotonin- norepinephrine receptor inhibitor, a calcium channel blocker, a sodium channel blocker, a compound of any one of formulas (l)-(XXXVI), a compound in Table 3 or 7, or a pharmaceutically acceptable salt thereof; and

c) detecting one or more compounds that inhibit the delayed inactivation or hyperpolarizing shift in voltage dependent activation.

54. The method of claim 53 wherein the mammal is a human.

55. The method of any one of claim 53 or 54 wherein the at least one amino acid residue that is different corresponds to a residue at position 757 to 787, 964 to 987, 1317 to 1337, 1605 to 1627, 1758 to 1778, or 1862 to 1882 in SEQ ID NO:6.