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WO2019018119A1 - Méthodes de traitement de l'épilepsie et d'affections associées à kcnti - Google Patents

Méthodes de traitement de l'épilepsie et d'affections associées à kcnti Download PDF

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Publication number
WO2019018119A1
WO2019018119A1 PCT/US2018/040403 US2018040403W WO2019018119A1 WO 2019018119 A1 WO2019018119 A1 WO 2019018119A1 US 2018040403 W US2018040403 W US 2018040403W WO 2019018119 A1 WO2019018119 A1 WO 2019018119A1
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saturated
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alkyi
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Gregory R. Stewart
Chani MAHER
Bryant GAY
J. Michael ANDRESEN
Matthew Fox
David Goldstein
Steven Petrou
Slavé PETROVSKI
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Pairnomix LLC
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Pairnomix LLC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine

Definitions

  • encephalopathies are a group of rare, severe neurological disorders manifesting in childhood often caused by de novo mutations ( cTague, Howell, Cross, Ku ian, & Scheffer, 2016).
  • Standard treatment of epilepsy consists of anti-epileptic drugs (AEDs).
  • AEDs anti-epileptic drugs
  • many patients with epilepsy are refractory to pharmacological treatment. 25-30% of those diagnosed with an epileptic condition are refractory to currently prescribed AEDs (Novy et ai., 2010; Mayer et al., 2002).
  • Epileptic encephalopathies are particularly resistant to drug treatment, creating a critical unmet need for the development of new therapies
  • Genetic mutations can impact protein function and those mutations may in turn be associated with neural and behavioral symptoms, e.g., symptoms associated with epilepsy, other seizure disorders and epileptic encephalopathies.
  • the methods described herein are based, in part, on the identification of molecules that directly or indirectly modulate ion channel activity, e.g., potassium channel (KCN) activity, e.g., directly or indirectly modulate KCNT1 channel activity.
  • KCN potassium channel
  • those molecules are useful in decreasing the activity of ion channels, including those for disorders characterized by seizures or other encephalopathies that have increased activity in those channels, e.g., increased activity associated with a mutation(s) in a gene encoding those channels (the mutation results in a variant channel protein).
  • molecules that are useful in decreasing the activity of ion channels that are not mutated may also be employed as a therapeutic, e.g., for disorders including but not limited to those characterized by seizures or other encephalopathies.
  • KCNT1 encodes a potassium channel commonly referred to as Slo2.2, KNa1 .1 or Slack (sequence like a calcium-activated K + channel).
  • Slack is an outwardly rectifying, voltage-gated potassium channel, that is activated by sodium, it is widely expressed in brain and contributes to slow after-hyperpoiarization of the neuron by outward flow of potassium sons following action potentials and thereby helps to regulate neuronal firing and activity.
  • Slack is a homotetrameric protein comprised of subunits encoded by KCNT1 , which combine to form a central pore that allows the passage of potassium sons. Each subunit contains a large cytoplasmic sequence with two domains that act to regulate potassium ion flow.
  • a cell line expressing the P924L mutation was screened with a drug library to identify compounds that reverse or inhibit the mutant phenotype of enhanced potassium ion conductance or flow.
  • a cell line expressing Slack channels comprised of a KCNT1 subuniis with a P924L mutation was created by site-directed mutagenesis of a plasmid containing a wild-type KCNT1 gene, which was then transfected into CHO cells to create a mutant P924L cell line.
  • a wild-type copy of the KCNT1 gene was transfected into Chinese Hamster Ovary (CHO) ceils to create a cell line expressing wild-type Slack channels.
  • Patch clamp electrophysioiogy was conducted to characterize cells expressing mutant and wild-type KCNT1 .
  • P924L mutant cells were observed to have a gain-of-function phenotype resulting in excess outward potassium ion flow or current compared to wild-type potassium channels.
  • the mutant ceils were observed to have a greatly enhanced basal potassium current (larger currents and increased current density) compared to wild-type ceils.
  • Compounds that inhibit potassium ion flow through wild-type channels may be of therapeutic value in treating a wider range of epilepsies, other seizure-related disorders, and other nervous system diseases and disorders (described below) associated with excess potassium ion flow through KCNT1 - bearing channels.
  • the disclosure provides a method to prevent, inhibit or treat one or more symptoms associated with epilepsy or other encephalopathies, e.g., associated with seizures, in a mammal.
  • the method includes, in one embodiment, administering to the mammal an effective amount of a composition comprising a compound that alters the activity of a KCNT1 channel with at least 80%, 85%, 90%, 92%, 94%, 95%, 98%, 97% 98%, or 99% amino acid sequence identity to one of SEQ ID Nos.1 -2 and which has at least one amino acid residue that differs from SEQ ID Nos.1 -2 (a "variant" KCNT1 ) that alters the activity of the variant potassium channel relative to SEQ ID NO:1 or 2.
  • the variant is a gain-of-fu notion variant relative to wild-type KCNT1 , in one embodiment, the variant has an amino acid residue at position 924 that is not proline (P), e.g., the variant has a leucine (L) at residue 924.
  • P proline
  • L leucine
  • the disclosure further provides a method to prevent, inhibit or treat one or more symptoms associated with epilepsy or other encephalopathies, e.g., those associated with seizures, in a mammal.
  • the method includes, in one embodiment, administering to the mammal an effective amount of a composition comprising a compound of formula (I), a compound of formula (II), a compound of formula (111), a compound of formula (IV), a compound of formula (V), a compound of formula (VI), a compound of formula (VII), a compound of formula (VIII), a compound of formula (IX), a compound of formula (X), a compound of formula (XI), a compound of formula (XII), a compound of formula (XIII), a compound of formula (XIV), a compound of formula (XV), a compound of formula (XVI), a compound of formula (XVII), a compound of formula (XVIII), a compound of formula (XIX), a compound of formula (XX), a
  • the mammal has a KCNT1 variant having an amino acid residue at position 924 that is not proline (P). in one embodiment, the mammal is heterozygous for the variant KCNT1 . In one embodiment, the mammal is a human. In one embodiment, the compound is not raititrexed. In one embodiment, the compound is not fenofibrate. in one embodiment, the compound is not nelfinavir mesylate. In one embodiment, the compound is not estradioi-17 beta. In one embodiment, the compound is not paclitaxei. In one embodiment, the compound is not diethyistiibestroi. In one embodiment, the compound is not racecadotril.
  • the compound is not mometason furoate. in one embodiment, the compound is not carvediiol. In one embodiment, the compound is not doxazosin mesylate. In one embodiment, the compound is not ritonavir, in one embodiment, the compound is not raloxifene hydrochloride. In one embodiment, the compound is not loperamide hydrochloride, in one embodiment, the mammal is identified as having a variant KCNT1 gene or channel, in one embodiment, the compound to be administered is selected based on in vitro screening of a plurality of compounds in cells with the variant KCNT1 versus ceils with wild-type KCNT1 .
  • the compound inhibits at least 5%, 10%, 15%, 20%, 50% or more of the activity of a variant KCNT1 . In one embodiment, the compound inhibits up to at least 90% or more of the activity of a variant KCNT1 . In one embodiment, the compound decreases KCNT1 activity in a mammal having a gain-of-function variant KCNT1 to an activity that is no greater or no less than 5%, 10% or 15% that of wild-type KCNT1 .
  • the disclosure further provides a method to prevent, inhibit or treat cardiac dysfunction, e.g., prevent, inhibit or treat arrhythmias, Brugada syndrome or myocardial infarction.
  • the method includes, in one embodiment, administering to the mammal an effective amount of a composition comprising a compound of formula (i), a compound of formula (ii), a compound of formula (ill), a compound of formula (IV), a compound of formula (V), a compound of formula (VI), a compound of formula (Vii), a compound of formula (VIII), a compound of formula (IX), a compound of formula (X), a compound of formula (XI), a compound of formula (Xii), a compound of formula (XIII), a compound of formula (XIV), a compound of formula (XV), a compound of formula (XVI), a compound of formula (XVII), a compound of formula (XVIII), a compound of formula (XIX), a compound of formula (X), a compound
  • the mammal is a human, in one embodiment, the compound is not raltitrexed. in one embodiment, the compound is not fenofibrafe. in one embodiment, the compound is not nelfinavir mesylate. In one embodiment, the compound is not estradioi-17 beta.
  • the compound is not paclitaxei, in one embodiment, the compound is not diethylstilbestrol. In one embodiment, the compound is not racecadotril. In one embodiment, the compound is not mometason furoate. in one embodiment, the compound is not carvedilol. In one embodiment, the compound is not doxazosin mesylate. In one embodiment, the compound is not ritonavir. In one embodiment, the compound is not raloxifene hydrochloride. In one embodiment, the compound is not loperamide hydrochloride.
  • the cardiac arrhythmia is tachycardia, including but not limited to atrial flutter/atrial fibrillation/atrial tachycardia, paroxysmal supraventricular tachycardia, accessory pathway tachycardia, V nodal reentrant tachycardia, ventricular tachycardia, ventricular fibrillation, or digitalis-induced arrhythmia.
  • the method includes, in one embodiment, administering to the mammai an effective amount of a composition comprising a compound of formula (1), a compound of formula (II), a compound of formula (111), a compound of formula (IV), a compound of formula (V), a compound of formula (VI), a compound of formula (VII), a compound of formula (VIII), a compound of formula (IX), a compound of formula (X), a compound of formula (XI), a compound of formula (XII), a compound of formula (XIII), a compound of formula (XIV), a compound of formula (XV), a compound of formula (XVI), a compound of formula (XVII), a compound of formula (XVIII), a compound of formula (XIX), a compound of formula (XX), a compound of formula (XX), a compound of formula (XXI), a compound of formula (XI), a compound of formula (XII), a compound of formula (XII), a compound of formula
  • the compound is not fenofibrafe. in one embodiment, the compound is not nelfinavir mesylate, in one embodiment, the compound is not estradiol-"! ? beta, in one embodiment, the compound is not paclitaxei. In one embodiment, the compound is not diethylstilbestrol. In one embodiment, the compound is not racecadotril. In one embodiment, the compound is not mometasone furoate. In one embodiment, the compound is not carvedilol. In one embodiment, the compound is not doxazosin mesylate. In one embodiment, the compound is not ritonavir. In one embodiment, the compound is not raloxifene hydrochloride. In one embodiment, the compound is not loperamide hydrochloride.
  • the composition is administered to a mammal such as a human by routes including but not limited to oral, intravenous, intra-arteriai, subcutaneous, intranasal, intrathecal, intracerebroventricular, intraparenchymal, trans-retinal, intra-aural, intramuscular, transdermal, or rectal.
  • the administration of the composition prevents, inhibits or treats seizures, developmental delay or cardiac dysfunction, in one embodiment, the administration of the composition improves kinestics of slow after-hyperpolarization, decreases potassium ion flow, decreases current density, decreases current, decreases voltage-dependent activation, or improves kinetics of slow reactivation.
  • the disclosure further provides a method to prevent, inhibit or treat one or more symptoms associated with epilepsy or other encephalopathies, e.g., those associated with seizures, in a mammal.
  • the method includes, in one embodiment, administering to the mammal an effective amount of a composition comprising a compound of any one of formulas (XXX)-(LXXXXIII), a compound in Table 5A, a pharmaceutically acceptable salt thereof, or any combination thereof.
  • a composition comprising a compound of any one of formulas (XXX)-(LXXXHi), a compound in Table 5A, a pharmaceutically acceptable salt thereof, or any combination thereof, may also be employed in a method to prevent, inhibit or treat cardiac dysfunction, e.g., prevent, inhibit or treat arrhythmias, Brugada syndrome or myocardial infarction, or to prevent, inhibit or treat symptoms associated with gain-of-function mutations in ion channels.
  • the compound is not hexestrol.
  • the compound is not diethylstilbestrol.
  • the compound is not mometasone furoate.
  • the compound is not loperamide.
  • the compound is not miconazole. In one embodiment, the compound is not racecadotril. In one embodiment, the compound is not doxazosin mesylate, in one embodiment, the compound is not fulvestrant. In one embodiment, the compound is not dienestrol. in one embodiment, the compound is not raloxifene. In one embodiment, the compound is not THiP
  • the compound is not fluspirilen. In one embodiment, the compound is not ezetimibe. In one embodiment, the compound is not triclosan. In one embodiment, the compound is not bromhexine. In one embodiment, the compound is not halcinonide. In one embodiment, the compound is not loratadine. In one embodiment, the compound is not darifenacin hydrobromide. in one embodiment, the compound is not econazole nitrate. In one embodiment, the compound is not dosulepin
  • the compound is not alprostadil. in one embodiment, the compound is not isosorbide dinitrate. In one embodiment, the compound is not fenofibrate. in one embodiment, the compound is not avermectin b1 , In one embodiment, the compound is not nicergoline. in one
  • the compound is not niclosamide. In one embodiment, the compound is not fentiazac. In one embodiment, the compound is not triclabendazole. In one embodiment, the compound is not prenylamine lactate. In one embodiment, the compound is mometasone furoate. In one embodiment, the compound is doxazosin mesylate, in one embodiment, the compound is fulvestrant. in one embodiment, the compound is raloxifene, in one embodiment, the compound is fluspirilen. in one embodiment, the compound is ezetimibe. In one embodiment, the compound is triclosan. In one embodiment, the compound is bromhexine. in one embodiment, the compound is halcinonide.
  • the compound is econazole nitrate, in one embodiment, the compound is isosorbide dinitrate. In one embodiment, the compound is fenofibrate.
  • the cardiac arrhythmia is tachycardia, including but not limited to atrial flutter/atrial fibrillation/atrial tachycardia, paroxysmal supraventricular tachycardia, accessory pathway tachycardia, V nodal reentrant tachycardia, ventricular tachycardia, ventricular fibrillation, or digitalis-induced arrhythmia, in one embodiment, the composition is administered to a mammal such as a human by routes including but not limited to oral, intravenous, intra-arterial, subcutaneous, intranasal, intrathecal, intracerebroventricuiar, intraparenchymai, trans-retinal, intra-aurai, intramuscular, transdermal, or rectal.
  • FIG. 1 Amino acid sequences of exemplary KCNT1 proteins (SEQ ID Nos, 1 -2),
  • Figure 3 Inhibition of efflux by each of the about 1320 compounds (blue circles) are plotted by rank in order of activity from left to right. The orange and green lines cross the x-axis at 2 and 3 standard deviations, respectively. The top 5 inhibitors identified in the HTS are indicated with arrows.
  • an element means one or more than one element.
  • the term "about,” as used herein, means approximately, in the region of, roughly, or around. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. For example, in one aspect, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 20%.
  • the term “about”, when referring to a numerical value or range, allows for a degree of variability in the value or range, for example, within 10%, or within 5% of a stated value or of a stated limit of a range.
  • mammals as used herein, “individual” (as in the subject of the treatment) means both mammals and non-mammals. Mammals include, for example, humans; non-human primates, e.g. apes and monkeys; and non-primates, e.g. dogs, cats, cattle, horses, sheep, goafs, and rodents including rabbits, mice, rats and ferrets. Non-mammals include, for example, fish and birds.
  • an 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.
  • compositions 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.
  • administration of a composition may be for either a "prophylactic” or "therapeutic" purpose.
  • 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.
  • compositions are provided upon the detection of a symptom or clinical sign of disease.
  • composition may be provided either before the onset of disease or a symptom (so as to prevent or attenuate a symptom) or after the initiation of symptoms or clinical signs of disease.
  • a composition is said to be "pharmacologically acceptable” if its administration can be tolerated by a recipient mammal.
  • Such an agent is said to be administered in a "thera eutically effective amount” if the amount administered is physiologically significant.
  • the "protection” provided need not be absolute, i.e., need not be totally prevented or eradicated, if there is a statistically significant improvement compared with a control population or set of mammals. Protection may be limited to mitigating the severity or rapidity of onset of symptoms or clinical signs of the disease.
  • Treating” or “treatment” within the meaning herein refers to an alleviation of symptoms associated with a disorder or disease, or inhibition of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder, or curing the disease or disorder.
  • 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.
  • 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.
  • Ail chiral, diastereomeric, racemic forms of a structure are intended, unless a particular stereochemistry or isomeric form is specifically indicated.
  • Compounds used in the present invention can include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions, at any degree of enrichment. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their
  • an isotopic form of one or more atoms in a molecule that is different from the naturally occurring isotopic distribution of the atom in nature is referred to as an "isofopicaiiy labeled form" of the molecule.
  • Ail isotopic forms of atoms are included as options in the composition of any molecule, unless a specific isotopic form of an atom is indicated.
  • any hydrogen atom or set thereof in a molecule can be any of the isotopic forms of hydrogen, i.e., protium OH), deuterium ( 2 H), or tritium ( 3 H) in any combination.
  • any carbon atom or set thereof in a molecule can be any of the isotopic form of carbons, such as 1 , C, 2 C, i3 C, or 1 C, or any nitrogen atom or set thereof in a molecule can be any of the isotopic forms of nitrogen, such as 13 N, 1 N, or 15 N.
  • 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.
  • a sample of a compound can include molecules containing various different isotopic compositions, such as in a tritium or 14 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 isotopicaliy enriched themselves are mixtures of naturally occurring isotopic forms, such as and 15 N, 32 S and 34 S, and so forth. A molecule as recited herein is defined as including isotopic forms of ail its constituent elements at each position in the molecule. As is well known in the art, isotopicaliy labeled compounds can be prepared by the usual methods of chemical synthesis, except substituting an isotopicaliy labeled precursor molecule.
  • the isotopes 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.
  • 14 C and 3 H can be prepared using neutrons generated in a nuclear reactor. Following nuclear transformation, 14 C and 3 H are incorporated into precursor molecules, followed by further elaboration as needed.
  • amino protecting group or “N ⁇ protected” as used herein refers to those groups intended to protect an amino group against undesirable reactions during synthetic procedures and v/hich can later be removed to reveal the amine. Commonly used amino protecting groups are disclosed in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999).
  • Amino protecting groups include acyi groups such as formyl, acetyl, propionyl, pivaloyi, t-butyiacetyl, 2-chloroacetyi, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chiorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesuifonyl and the like; aikoxy- or aryloxy-carbonyl groups (which form urethanes with the protected amine) such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyi, p-methoxybenzyloxycarbonyl, p-nitrobenzyl
  • diisopropylmethoxycarbonyl isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, aiiyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethyloxycarbonyl (Teoc), phenoxycarbonyi, 4- nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl, adamantyloxycarbonyi, cyclohexyloxycarbonyi, phenylthiocarbonyl and the iike; araikyi groups such as benzyl, triphenyirnethy!, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like.
  • Amine protecting groups also include cyclic amino protecting groups such as phthaioyi and
  • amino protecting groups include formy!, acetyl, benzoyl, pivaioyl, t-butylacetyl, phenyisu!fony!, Alloc, Teoc, benzyl, Fmoc, Boc and Cbz, It is well within the skill of the ordinary artisan to select and use the appropriate amino protecting group for the synthetic task at hand.
  • 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
  • Hydroxyl protecting groups include acyi groups such as formyl, acetyl, propionyi, pivaioyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; acyloxy groups (which form urethanes with the protected amine) such as benzyioxycarbonyl (Cb
  • diisopropylmethoxycarbonyl isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, ai!yloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilyiethyioxycarbony! (Teoc), phenoxycarbonyi, 4- nitrophenoxycarbonyl, fluoreny!-9-methoxycarbonyl (Fmoc), cyclopentyioxycarbony!,
  • adamantyloxycarbonyi cyclohexyloxycarbonyi, phenylthiocarbonyl and the like
  • araikyi groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like
  • siiy! groups such as trimethylsilyl and the like
  • substituted refers to an organic group as defined herein in which one or more bonds to a hydrogen atom contained therein are replaced by one or more bonds to a non-hydrogen atom such as, but not limited to, a halogen (i.e., F, CI, Br, and I); an oxygen atom in groups such as hydroxyl groups, a!koxy groups, aryloxy groups, araikyloxy groups, oxo(carbony!) groups, carboxyi groups including carboxyiic acids, carboxy!ates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alky! and ary!
  • sulfide groups sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups
  • a nitrogen atom in groups such as amines, hydroxylamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines
  • substituents that can be bonded to a substituted carbon (or other) atom include F, CI, Br, i, OR',
  • a substituent 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.
  • a divalent substituent such as O or S can be connected by two single bonds to two different carbon atoms.
  • O a divalent substituent
  • any substituent can be bonded to a carbon or other atom by a linker, such as (CH2)n or (C '2) ri wherein n is 1 , 2, 3, or more, and each R' is independently selected.
  • a methyienedioxy group can be a substituent when bonded to two adjacent carbon atoms, such as in a phenyl ring.
  • C(0) and S(0)2 groups can be bound to one or two heteroatoms, such as nitrogen, rather than to a carbon atom.
  • a C(O) group is bound to one carbon and one nitrogen atom
  • the resulting group is called an "amide” or "carboxamide.”
  • the functional group is termed a urea.
  • a S(0)2 group is bound to one carbon and one nitrogen atom
  • the resulting unit is termed a "sulfonamide.”
  • a S(0)2 group is bound to two nitrogen atoms, the resulting unit is termed a "suifamate.”
  • Substituted aikyl, alkenyi, alkynyl, cycioaikyl, and cycloalkenyi groups as well as other substituted groups also include groups in which one or more bonds to a hydrogen atom are replaced by one or more bonds, including double or triple bonds, to a carbon atom, or to a heteroatom such as, but not limited to, oxygen in carbonyi (oxo), carboxyi, ester, amide, imide, urethane, and urea groups; and nitrogen in imines, hydroxyzines, oximes, hydrazones, amidines, guanidines, and nitriles.
  • Substituted ring groups such as substituted cycioaikyl, aryi, heterocyclyl and heteroaryi groups also include rings and fused ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycioaikyl, aryl, heterocyclyl and heteroaryi groups can also be substituted with aikyl, alkenyi, and alkynyl groups as defined herein.
  • ring sysiem as the term is used herein is meant a moiety comprising one, two, three or more rings, which can be substituted with non-ring groups or with other ring systems, or both, which can be fully saturated, partially unsaturated, fully unsaturated, or aromatic, and when the ring system includes more than a single ring, the rings can be fused, bridging, or spirocyclic.
  • spikerocyciic is meant the class of structures wherein two rings are fused at a single tetrahedral carbon atom, as is well known in the art.
  • any of the groups described herein, which contain one or more substituents it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterica!ly impractical and/or synthetically non-feasible.
  • the compounds of this disclosed subject matter include ail stereochemical isomers arising from the substitution of these compounds.
  • recursive substituent means that a substituent may recite another instance of itself. Because of the recursive nature of such substiiuents, theoretically, a large number may be present in any given claim.
  • One of ordinary skill in the art of medicinal chemistry and organic chemistry understands that the total number of such substituents is reasonably limited by the desired properties of the compound intended. Such properties include, by of example and not limitation, physical properties such as molecular weight, solubility or log P, application properties such as activity against the intended target, and practical properties such as ease of synthesis.
  • Recursive substiiuents are an intended aspect of the disclosed subject matter.
  • One of ordinary skill in the art of medicinal and organic chemistry understands the versatility of such substituents.
  • Alkyl groups include straight chain and branched alkyl groups and cycioaikyi groups having from 1 to about 20 carbon atoms, and typically from 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms.
  • straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyi, n-butyl, n-pentyl, n-hexyi, n-heptyi, and n-octyl groups.
  • branched alkyl groups include, but are not limited to, isopropyl, iso-butyi, sec-butyl, t-butyl, neopentyl, isopentyi, and 2,2-dimethyipropyl groups.
  • Representative substituted alkyl groups can be substituted one or more times with any of the groups listed above, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
  • Cycioaikyi groups are cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyi, cyclohexyl, cycloheptyi, and cyciooctyi groups, in some embodiments, the cycioaikyi group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 4, 5, 6, or 7.
  • Cycioaikyi groups further include polycyclic cycioaikyi groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyi, and carenyl groups, and fused rings such as, but not limited to, decalinyi, and the like. Cycioaikyi groups also include rings that are substituted with straight or branched chain alkyl groups as defined above.
  • Representative substituted cycioaikyi groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substituted norbornyl or cycloheptyi groups, which can be substituted wiih, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
  • cycioaikenyi alone or in combination denotes a cyclic alkenyl group.
  • Carbocyciic denotes a ring structure wherein the atoms of ihe ring are carbon, such as a cycioaikyi group or an aryl group, in some embodiments, the carbocycle has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms is 4, 5, 6, or 7.
  • the carbocyciic ring can be substituted with as many as N-1 substituents wherein N is the size of the carbocyciic ring with, for example, alkyl, alkenyl, alkynyl, amino, aryl, hydroxy, cyano, carboxy, heteroaryi, heterocyclyl, nitro, thio, alkoxy, and halogen groups, or other groups as are listed above.
  • a carbocyclyl ring can be a cycioaikyi ring, a cycioaikenyi ring, or an aryi ring.
  • a carbocyclyi can be monocyciic or poiycyclic, and if poiycyclic each ring can be independently be a cye!oa!kyl ring, a cycioalkenyi ring, or an aryl ring.
  • (Cycloaikyl)alkyi groups also denoted cyc!oalkyialkyl, are aiky! groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycioaikyi group as defined above.
  • Alkenyi groups include straight and branched chain and cyciic alkyl groups as defined above, except that at least one double bond exists between two carbon atoms.
  • aikenyi groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to vinyl,
  • cyclohexenyi cyclopentenyi, cyciohexadienyl, butadienyl, pentadienyl, and hexadienyl among others.
  • Cycioalkenyi groups include cycioaikyi groups having at least one double bond between 2 carbons.
  • cycioalkenyi groups include but are not limited to cyclohexenyi,
  • Cycioalkenyi groups can have from 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 6, or 7.
  • Cycioaikyi groups further include poiycyclic cycioaikyi groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyi, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like, provided they include at least one double bond within a ring.
  • Cycioalkenyi groups also include rings that are substituted with straight or branched chain alkyl groups as defined above.
  • (Cycloalkenyl)alkyi groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycioalkenyi group as defined above.
  • Aikynyi groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms.
  • aikynyi groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to -C CH. -C C(CI ⁇ b) -C C(CH 2 CH 3 ). -CH 2 C CH, -CH 2 C ⁇ C(CH 3 ),
  • heteroalkyl by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized.
  • the heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group. Examples
  • a "cycioheteroalkyl" ring is a cycioaikyi ring containing at least one heteroatom.
  • cycloheteroalkyl ring can also be termed a “heterocyciy!,” described below.
  • heteroalkenyl by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain monounsaturated o di-unsaturated hydrocarbon group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heieroatom may optionally be quaternized. Up to two heteroatoms may be placed consecutively. Examples
  • Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms in the ring.
  • aryi groups include, but are not limited to, phenyl, azuienyl, heptalenyl, biphenyi, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyi, naphthacenyl, chrysenyl, biphenyienyl, anthracenyl, and naphthyi groups.
  • aryi groups contain about 6 to about 14 carbons in the ring portions of the groups.
  • Aryl groups can be unsubstituted or substituted, as defined above.
  • Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or 2-8 substituted naphthyi groups, which can be substituted with carbon or non-carbon groups such as those listed above.
  • Aralkyi groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryi group as defined above.
  • Representative aralkyi groups include benzyl and phenyiethyi groups and fused (cycioalkylaryi)aikyl groups such as 4-ethyl-indanyl.
  • Aralkenyl group are aikenyi groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryi group as defined above.
  • Heterocyclyl groups or the term "heterocyclyl” includes aromatic and non-aromatic ring compounds containing 3 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S.
  • a heterocyclyl can be a cycloheteroaikyl, or a heteroaryl, or if polycyclic, any combination thereof, in some embodiments, heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members.
  • a heterocyclyl group designated as a C 2 - heterocyciyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth.
  • a C4-heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth.
  • the number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms.
  • a heterocyclyl ring can also include one or more double bonds.
  • a heteroaryl ring is an embodiment of a heterocyclyl group. The phrase
  • heterocyclyl group includes fused ring species including those comprising fused aromatic and non- aromatic groups.
  • a dioxoianyi ring and a benzdioxoianyi ring system are both heterocyclyl groups within the meaning herein.
  • the phrase also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuciidyl.
  • Heterocyclyl groups can be unsubstituted, or can be substituted as discussed above.
  • Heterocyclyl groups include, but are not limited to, pyrroiidinyl, piperidinyi, piperazinyl, morpholinyl, pyrrolyi, pyrazolyl, triazolyi, tetrazolyl, oxazolyl, isoxazolyl, ihiazolyi, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyi, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazoiyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyi, imidazopyridinyi, isoxazolopyridinyl, thianaphthaienyi, purinyl, xanthinyl, adeninyi, guansnyi,
  • substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as, but not limited to, piperidinyi or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with groups such as those listed above.
  • Heteroaryi groups are aromaiic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S; for instance, heteroaryi rings can have 5 to about 8-12 ring members.
  • a heteroaryi group is a variety of a heterocyciyi group that possesses an aromatic electronic structure
  • a heteroaryi group designated as a C2-heteroaryl can be a 5- ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth.
  • a C4-heteroaryl can be a 5-ring with one heteroatom, a 8-ring with two
  • heteroaryi groups include, but are not limited to, groups such as pyrrolyi, pyrazolyl, triazolyi, tetrazolyl, oxazolyl, isoxazoiyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyi, indolyl, azaindoiyl, indazoiyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl,
  • benzothiazolyl benzoihiadiazolyi, imidazopyridinyl, isoxazolopyridinyl, thianaphthaienyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinoiinyl, quinoxaiinyl, and quinazolinyl groups.
  • Heteroaryi groups can be unsubstituted, or can be substituted with groups as is discussed above.
  • Representative substituted heteroaryi groups can be substituted one or more times with groups such as those listed above.
  • aryl and heteroaryi groups include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1 -naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1 -anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophenyl (2-thienyl, 3-thienyi), fury!
  • Heterocyclylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyi group as defined above is replaced with a bond to a heierocyc!yi group as defined above.
  • heterocyclyl a!kyi groups include, but are not limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indoi-2-yi propyl.
  • Heteroaryiaikyi groups are alkyi groups as defined above in which a hydrogen or carbon bond of an alkyi group is replaced with a bond to a heteroaryi group as defined above.
  • aikoxy refers to an oxygen atom connected to an alkyi group, including a cycioalkyi group, as are defined above.
  • linear aikoxy groups include but are not limited to methoxy, eihoxy, propoxy, butoxy, pentyloxy, hexyioxy, and the like.
  • branched aikoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyioxy, and the like.
  • cyclic aikoxy examples include but are not limited to cyciopropyioxy, cyciobutyioxy, cyclopentyloxy, cyc!ohexyioxy, and the like.
  • An aikoxy group can include one to about 12-20 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms.
  • an allyioxy group is an aikoxy group within the meaning herein.
  • a methoxyethoxy group is also an aikoxy group within the meaning herein, as is a methyienedioxy group in a context where two adjacent atoms of a structures are substituted therewith.
  • 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.
  • haloalkyi includes mono-halo alkyi groups, poly-halo alkyl groups wherein all halo atoms can be the same or different, and per-haio alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro.
  • haloalkyi include trifluoromethyl, 1 ,1 -dichloroethyl, 1 ,2- dichloroethyl, 1 ,3-dibromo-3,3-difluoropropyl, perfluorobutyi, and the like.
  • haioaikoxy includes mono-halo aikoxy groups, poly-halo aikoxy groups wherein all halo atoms can be the same or different, and per-haio aikoxy groups, wherein ail hydrogen atoms are replaced by halogen atoms, such as fluoro.
  • haioaikoxy include trifluoromethoxy, 1 ,1 -dichloroethoxy, 1 ,2-dichloroethoxy, 1 ,3-dibromo-3,3-difluoropropoxy, perfluorobutoxy, and the like.
  • (Cx-Cy)perfluoroalkyl wherein x ⁇ y, means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein all hydrogen atoms are replaced by fluorine atoms.
  • (C x -C y )perfluoroaikyl is -(Ci-C6)perfluoroalkyl.
  • (Cx-C y )perfluoroalkyl is -(Ci-C3)perfluoroalkyl.
  • (Cx-C y )perfluoroalkyl is -CPs.
  • (Cx-C y )perfluoroalkylene wherein x ⁇ y, means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein ail hydrogen atoms are replaced by fluorine atoms.
  • (Cx-C y )perfluoroalkylene is -(Ci-C6)perfluoroalkylene.
  • (Cx-C y )perfluoroalkylene is -(Ci-C3)perfluoroalkylene.
  • (Cx-C y )perfluoroalkylene is -
  • aryioxy and arylalkoxy refer to, respectively, an ary! group bonded to an oxygen atom and an aralkyl group bonded to the oxygen atom at the alkyl moiety. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy.
  • acyl group refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom.
  • the carbonyl carbon atom is also bonded to another carbon atom, which can be part of an aiky!, aryi, araikyi cycioaikyi, eycioaikylalkyl, heterocyclyi, heterocyciyiaikyi, heteroaryi, heteroaryialkyl group or the like.
  • the group is a "forrnyl” group, an acyl group as the term is defined herein.
  • An acyl group can include 0 to about 12-20 additional carbon atoms bonded to the carbonyi group.
  • An acyl group can include double or triple bonds within the meaning herein.
  • An acryloyi group is an example of an acyl group.
  • An acyl group can also include heteroatoms within the meaning here.
  • a nicotinoyl group (pyridyl ⁇ 3-carbonyl) group is an example of an acyl group within the meaning herein.
  • Other examples include acetyl, benzoyl, phenyiacetyl, pyridylacetyi, cinnamoyl, and acryloyi groups and the like.
  • the group containing the carbon atom that is bonded to the carbonyi carbon atom contains a halogen, the group is termed a "haloacyl" group.
  • An example is a trifluoroacetyl group.
  • amine includes primary, secondary, and tertiary amines having, e.g., the formula N(group)s wherein each group can independently be H or non-H, such as aikyl, aryl, and the like.
  • Amines include but are not limited to R-NH2, for example, alkylamines, aryiamines, alkyiarylamines; R2NH wherein each R is independently selected, such as diaikylamines, diarylamines, aralkyiamines, heterocyciylamines and the like; and R3N wherein each R is independently selected, such as triaikylamines,
  • dialkylaryiamines alky!diaryiamines, triaryiamines, and the like.
  • amine also includes ammonium sons as used herein.
  • amino group is a substituent of the form -NH2, -NHR, -NR2, -NRa + , wherein each R is independently selected, and protonated forms of each, except for -NR3 + , which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine.
  • An “amino group” within the meaning herein can be a primary, secondary, tertiary or quaternary amino group.
  • An "a!kyiamino” group includes a monoalkyiamino, dialkylamino, and triaikyiamino group.
  • ammonium ion includes the unsubstituted ammonium ion but unless otherwise specified, it also includes any protonated or quaternarized forms of amines.
  • trimethylammonium hydrochloride and tetramethylammonium chloride are both ammonium ions, and amines, within the meaning herein.
  • amide includes C- and N-amide groups, i.e., -C(0)NR2, and ⁇ -NRC(0)R groups, respectively.
  • Amide groups therefore include but are not limited to primary carboxamide groups ( ⁇ C(0)NH2) and formamide groups ( ⁇ NHC(0)H).
  • a "carboxamido” group is a group of the formula C(0)NR2, wherein R can be H, alkyl, aryi, etc.
  • azido refers to an 3 group.
  • An “azide” can be an organic azide or can be a salt of the azide (N3 " ) anion.
  • nitro refers to an NO2 group bonded to an organic moiety.
  • nitroso refers to an NO group bonded to an organic moiety.
  • nitrate refers to an ONO2 group bonded to an organic moiety or to a salt of the nitrate (NO3 " ) anion.
  • ureihane (“carbamoyl” or “carbamyl”) includes N- and O-urethane groups, i.e., -NRC(0)QR and -OC(0)NR 2 groups, respectively.
  • sulfonamide includes S- and N-su!fonamide groups, i.e., -SO2NR2 and -NRSO2R groups, respectiveiy. Sulfonamide groups therefore include but are not limited to sulfamoyl groups (-SO2NH2).
  • An organosuifur structure represented by the formula -S(0)(NR)- is understood to refer to a sulfoximine, wherein both the oxygen and the nitrogen atoms are bonded to the sulfur atom, which is also bonded to two carbon atoms.
  • amidine or “amidino” includes groups of the formula -C(NR)N!3 ⁇ 4. Typically, an amidino group is ⁇ C(NH)NH 2 .
  • guanidine or "guanidino” includes groups of the formula ⁇ NRC(NR)NR2. Typically, a guanidino group is ⁇ -NHC(NH)NH2.
  • a “salt” as is well known in the art includes an organic compound such as a carboxyiic acid, a sulfonic acid, or an amine, in ionic form, in combination with a counferion.
  • acids in their anionic form can form salts with cations such as metal cations, for example sodium, potassium, and the like; with ammonium salts such as NhV or the cations of various amines, including tetraalkyl ammonium salts such as tetramethylammonium, or other cations such as trimethylsulfonium, and the like.
  • “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 refers to salts which possess toxicity profiles within a range that affords utility in pharmaceutical applications.
  • compositions of the invention may nonetheless possess properties such as high crystaiiinity, which have utility in the practice of the present invention, such as for example utility in process of synthesis, purification or formulation of compounds of the invention.
  • Suitable pharmaceutically-acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid.
  • inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids.
  • Appropriate organic acids may be selected from aliphatic, cycloaiiphafic, aromatic, araiiphatic, heterocyclic, carboxyiic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, giycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maieic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenyiacefic, mandeiic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, sulfaniiic,
  • cyclohexylaminosulfonic stearic, alginic, ⁇ -hydroxybutyric, salicylic, galactaric and galacturoriic acid.
  • pharmaceutically unacceptable acid addition salts include, for example, perchiorates and tetrafluoroborates.
  • Suitable pharmaceutically acceptable base addition salts of compounds include, for example, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts.
  • Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, /V,/V-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyigiucamine) and procaine.
  • Examples of pharmaceutically unacceptable base addition salts include lithium salts and cyanate salts.
  • salts may be useful, for example as intermediates in the synthesis of compounds, for example in their purification by recrystaliization. Ail of these salts may be prepared by conventional means from the corresponding compound by reacting, for example, the appropriate acid or base with the compound.
  • pharmaceutically acceptable salts refers to nontoxic inorganic or organic acid and/or base addition salts, see, for example, Lit et a!., Salt Selection for Basic Drugs (1986), int J. Pharm., 33, 201 -217, incorporated by reference herein,
  • a “hydrate” is a compound that exists in a composition with water molecules.
  • the composition can include water in stoichiometic quantities, such as a monohydrate or a dihydrate, or can include water in random amounts.
  • 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.
  • a solvent other that water replaces the water.
  • methanol or ethanol can form an "aicoholate", which can again be stoichiometic or non- stoichiometric.
  • 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.
  • prodrug as is well known in the art is a substance that can be administered to a patient where the substance is converted in vivo by the action of biochemicals within the patient's body, such as enzymes, to the active pharmaceutical ingredient.
  • examples of prodrugs include esters of carboxyiic acid groups, which can be hydroiyzed by endogenous esterases as are found in the bloodstream of humans and other mammals. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • 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.
  • 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.
  • Provisos may apply to any of the disclosed categories or embodiments wherein any one or more of the other above disclosed embodiments or species may be excluded from such categories or embodiments.
  • Epilepsy is a group of neurological disorders characterized by abnormal electrical discharges in the brain that result in loss of consciousness, convulsions, spasms, sensory confusion, and disturbances in the autonomic nervous system. There are many different types of epilepsy and seizures and the exact cause is frequently unknown. (For more information on this disorder, choose “epiiepsy” as your search term in the Rare Disease Database.) Epiiepsy can also occur as part of larger genetic syndromes. Types of epilepsy or disorders associated with epiiepsy include Rett syndrome, Autism Spectrum Disorders, Angleman syndrome, Dravet syndrome, and West syndrome.
  • the present disclosure provides methods to prevent or mitigate, e.g., inhibit or treat, in a mammal one or more symptoms associated with conditions such as epiiepsy, epileptic encephalopathies,
  • Angelman Syndrome Benign Roinadic Epilepsy, CDKL5 disorder, Childhood Absence Epilepsy, Doose Syndrome, Dravet Syndrome, Epilepsy with Generalized Tonic-Clonic Seizures Alone, Epilepsy with Myoclonic-Absences, Frontal Lobe Epilepsy, Glutl Deficiency Syndrome, Hypothalamic Hamartoma, Infantile Spasms/West's Syndrome, Juvenile Myoclonic Epilepsy, Lafora Progressive Myoclonus Epilepsy, Landau-Kleffner Syndrome, Lennox-Gastaut Syndrome, Ohtahara Syndrome, Panayuotopoulos
  • KCNT1 potassium channel
  • methods are provided for inhibiting or treating symptoms associated with a disease or condition characterized by seizures or abnormal neural activity or delaying or preventing the onset of symptoms of the disease or condition. Methods are also provided for reducing the risk, progression or onset of a pathological condition characterized by seizures, developmental delay or cognitive impairment. Methods are also provided for reducing the risk, progression or onset of a pathological condition characterized by arrhythmias.
  • compositions and methods are provided for altering or modulating aberrant potassium voltage-gated channel activity in a mammal, in certain embodiments, methods are provided for altering or modulating voltage-gated potassium channel activity in a mammal.
  • the methods comprise administering to the mammal a composition having one or more compounds of formulas (l) ⁇ (LXXXXIil), a compound in one of Tables 1 -5, or a pharmaceutically acceptable salt (or other
  • the compounds are administered in a therapeutically effective or prophylactically effective amount.
  • the method employs a compound of formula (I):
  • R 2 CON ez, C02Ci-*alkyl, or OCi-ssatu rated, unsaturated aikyl, cydoaikyi, or heterocycioaikyi.
  • R 3 OH, CN, NH2, OCi-esatu rated or unsaturated a!kyl, NHC-i-esaturated or unsaturated alkyl, or N(Ci-8saturated or unsaturated alky)2.
  • R 4 Aryl, heteroaryl, o 4-Ci-C6H4.
  • A C, N.
  • R 2 CON ez, C02Ci-*alkyl, or OCi-ssatu rated, unsaturated aikyl, cydoaikyi, or heterocycioaikyi.
  • R 3 OH, CN
  • R 3 OH, CN, NH2, OCi-esatu rated or unsaturated alkyl, NHCi-ssaturated or unsaturated aikyl, or N(Ci-8saturated or unsaturated aiky)2;
  • R 4 Aryl, heteroaryl, or 4-CI-CeH4; and
  • R 1 CI, Br, F, I, OH, NH2, CN, CO2H, CO2C1-8 saturated or unsaturated aikyl, NHC1 ⁇ saturated, unsaturated alkyl, or cydoaikyi, or N(Ci-esaturated, unsaturated aikyl, or cycloalkyi)2.
  • R 2 CON e2, C02Ci-4alkyl, OCi-esatu rated, unsaturated aikyl, cydoaikyi, or heterocycioaikyi.
  • R 3 OH, CN, NH2, OCi-esatu rated or unsaturated aikyl, NHCi-esaturated or unsaiuraied alkyl, N(Ci-esaturated or unsaturated alky)2.
  • R 4 Aryl, heteroaryl, or 4-CI-C8H4.
  • A C, N.
  • n 0-8.
  • R Ci, Br, F, I, OH, NH2, CN, CO2H, CO2C1 -8 saturated or unsaturated alkyl, NHd ssaturaied, unsaturated alkyl, or cydoaikyi, or N(Ci-8saturated, unsaturated aikyl, or cycloalkyi)2 ;
  • R 2 CONMe2,
  • the compound is loperamide.
  • the method employs a compound of formula (II):
  • R 2 Aryl or heteroaryl, or GC ⁇ satu ated, unsaturated alkyl, cydoaikyi, or cycloheteroalkyi.
  • R 3 CH2, O, NH, or NCi-ssaturated, unsaturated aikyi, or cydoaikyi.
  • R 2 Aryl or heteroaryi, or OCi-esaturated, unsaturated alkyl, cycloalkyi, or cycloheteroalkyl;
  • R 3 CH2, O, NH, or NC i-ssaturated, unsaturated alkyi, or cycloalkyi;
  • a compound has formula (iia):
  • R 1 Ci, Br, F, i, OH, NH2, CN, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHd-esaturated, unsaturated alkyi, or cycloalkyi, or N(Ci-ssaturated, unsaturated alkyl, or cycloalkyi)2.
  • R 2 Aryl or heteroaryi, OCi-esatu rated, unsaturated alkyl, cycloalkyi, or cycloheteroalkyl.
  • R 3 CH2, O, NH, NCi- ssaturated, unsaturated alkyi, or cycloalkyi.
  • R 4 Aryl or heteroaryi, OC1-6 saturated or unsaturated alkyl.
  • A CH2, N, O, or S
  • R 1 CI, Br, F, i, OH, NH 2 , CN, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHd-esaturated, unsaturated alkyi, or cycloalkyi, N(Ci -ssaturated, unsaturated alkyl, or cycloalkyi ⁇ ;
  • R 2 Aryl or heteroaryi, OC1 -ssaturated, unsaturated alkyl, cycloalkyi, or cycloheteroalkyl;
  • R 3 CH2, O, NH, NCi ssaturated, unsaturated alkyl, or cycloalkyi;
  • R 4 Aryl or heteroaryi, OC1 -5 saturated or unsaturated alkyi; and
  • A CH2, N, O, or S. in one embodiment, the compound is raloxifene.
  • the method employs a compound of formula (III):
  • each R ! independents CI, Br, F, I, OH, NH 2 , CN, CO2H, CO2C1-8 saturated or unsaturated alkyl, NHCi-ssaturaied, unsaturated alkyl, or cycloalkyi, or N(Ci-8saturated, unsaturated alkyl, or cycloalkyl)2.
  • each R 2 independents Aryl, heteroaryi, OC-i-ssaturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, or Ci-ssaturated alkyl, unsaturated alkyi, cycloalkyi, or cycloheteroalkyl.
  • each R independents CI, Br, F, I, OH, NH2, CN, CO2H, CO2C1 -8 saturated or unsaturated alkyl, NHCi-ssaturated, unsaturated alkyl, or cycloalkyi, or N(Ci-ssaturated, unsaturated alkyi, or cycloalkyi ⁇ ; and each R 2 independents Aryl, heteroaryi, OCi-ssaturated, unsaturated alkyi, cycloalkyi, cycloheteroalkyl, or Ci-asaturated alkyl, unsaturated alkyi, cycloalkyi, or cycloheteroalkyl.
  • a compou has formula (ilia):
  • the compound is diethylstiibestrol, hexestrol or dienestrol.
  • the method employs a compound of formula (IV):
  • R 3 ⁇ 4 CI, Br, F, I, OH, NH2, CN, CO2H, CO2C1-8 saturated or unsaturated alkyi, NHCi-esaiuraied, unsaturated alkyi, or cycioaikyi, or N(Ci-8saturated, unsaturated alkyi, or cycioaikyi ⁇ .
  • R 2 Aryl, heteroaryi, OCi-esaturated, OC5-8 ary!
  • R 1 CI, Br, F, I, OH, NH2, CN, CO2H , CO2G1-8 saturated or unsaturated alkyi, NHCi-ssaturated, unsaturated alkyi, or cycioaikyi, or N(Ci- ssaturated , unsaturated aikyi, or cycioaikyi ⁇ ;
  • R 2 Aryl, heteroaryi, OCi-oSatu rated, OCs-s aryl or heteroaryi, unsaturated alkyi, cycioaikyi, cycioheteroalkyl, or Ci-ssaturated aikyi, unsaturated alkyi, cycioaikyi, or cycioheteroalkyl; each A independently ⁇ CH, CH2, O, N, or NHCi-asaturated, unsaturated alkyi, or cycioaii, or
  • R 1 OH, NH2, CN, CO2H, CO2C1-6 saturated or unsaturated alkyi, NHCi-s saturated, unsaturated alkyi, or cycioaikyi, or N(Ci-esatu rated, unsaturated aikyi, or cycloaikyi)2.
  • R 2 Aryi, heteroaryi, OC1-6 saturated, OC5-6 aryl or heteroaryi, unsaturated aikyi, cycioaikyi, cycioheteroalkyl, Ci-asaturated alkyi, unsaturated alkyi, cycioaikyi, or cycioheteroalkyl.
  • A CH, CH2, O, N, NHC1-6 saturated, unsaturated alkyi, or cycioaikyi.
  • n 0-6.
  • R 1 OH , NH2, CN, CO2H, CO2C1 -8 saturated or unsaturated alkyi, NHCi-e saturated, unsaturated alkyi, or cycioaikyi, or N(Ci-esaturated, unsaturated aikyi, or cycioalkyl) s ;
  • R 2 Aryl, heteroaryi, OC1 -6 saturated , OC5-6 aryl or heteroaryi, unsaturated alkyi, cycioaikyi, cycioheteroalkyl, Ci -ssaturated aikyi, unsaturated alkyi, cycioaikyi, or cycioheteroalkyl;
  • the compound is carvedi
  • the method employs a compound of formula (V):
  • each R independently ⁇ CI, Br, F, i, OH, NH2, CN, OC1-8 saturated or unsaturated alkyl, CO2H , CO2C1-S saturated or unsaturated alkyl, NHCi-ssaturated, unsaturated alkyl, or cycloaikyi, or N(Ci-8saturated, unsaturated alkyi, or cycioalkyl)2.
  • R 2 CH2, O, NH , or NCi-esaturated , unsaturated alkyi, or cycloaikyi, S.
  • each R 1 independentiy CI, Br, F, I, OH, NH2, CN, OC1-8 saturated or unsaturated alkyi, CO2H , CO2C1-8 saturated or unsaturated alkyi, NHCi-ssaturated, unsaturated alkyl, or cycloaikyi, or N(Ci-ssaturated, unsaturated alkyl, or cycloaikyi ⁇ ;
  • a compound of formula (V) has formula (Va):
  • R 1 CH2, O, NH, NCi-ssaturated, unsaturated alkyl, cycloalky, or cycloheterocyloalkyl.
  • R 2 CH2, O, NH, or NCi- ssaturated , unsaturated alkyi, or cycloaikyi.
  • A CH2, O, NH , or NCi- esaturated , unsaturated alkyi, or cycloaikyi, S, SO, or S02.
  • R 1 CI, Br, F, I , OH, NH2, CN, OCi-s saturated or unsaturated alkyl, CO2H, CO2C1-8 saturated or unsaturated alkyl, NHCi-ssaturated, unsaturated alkyl, or cycloaikyi, or N(Ci-esaturated , unsaturated alkyl, or cycloaikyi;
  • R 2 CH2, O, NH, NCi -ssaturated, unsaturated alkyi, cycloalky, or cycloheterocyloalkyl, S; and
  • A CH2, O, NH, or NCi-esaturated, unsaturated alkyl, or cycloaikyi, S, SO, SO2 ,
  • the compound is doxazosin .
  • the method employs a compound of formula (VI):
  • each R independents CH2, O, NH, NCi -ssaturated, unsaturated alkyl, cycloalky, or cycloheterocyloalkyl.
  • each R 2 independently ⁇ CI, Br, F, I , OH, NH2, CN, OC1-8 saturated or unsaturated alkyl, CO2H, CO2C1-8 saturated or unsaturated alkyi, NHCi-esaturated, unsaturated alkyi, or cycloaikyi, or N(Ci-esaturated, unsaturated alkyl, or cycloalkyl)2.
  • R 3 Aryl, heteroaryl, OCi-ssaturated, OC5-8 aryi or heteroaryi, unsaturated alkyl, cycloaikyi, cycloheteroalkyl, or Ci-3saturated alkyi, unsaturated alkyi, cycioaikyl, or cycloheteroalkyl.
  • A CH2, O, NH or NCi-ssatu rated, unsaturated aikyl, or cycioaikyl.
  • R 1 CH2, O, NH, NCi-esaturated, unsaturated aikyl, cycloalky, or cycloheterocyloalkyl.
  • R 2 OH, NH2, CN, OCi-e
  • A CH2, O, NH or NCi-esaturated, unsaturated alkyi, or cycioaikyl.
  • R 1 CH2, O, NH, NCi-asaturated, unsaturated aikyl, cycloalky, or cycioheterocyioaikyi;
  • R 2 OH, NH2, CN, OCi-e saturated or unsaturated aikyl, CO2H , CO2C1-6 saturated or unsaturated aikyl, NHC1-6 saturated , unsaturated alkyi, or cycioaikyl, or N(Ci-e saturated , unsaturated aikyl, or cycioaikyl ⁇ ;
  • A CH2, O, NH or NCi-esaturated, unsaturated aikyl, or cycioaikyl.
  • the compound is mometasone furoate, loieprednoletabonate, mifepristone, halconide, clobetasoi propionate or beciomethasone dipropionate.
  • the method employs a compound of formula (VI I):
  • each R independents CI, Br, F, I, OH, NH2, CN, OC1-8 saturated or unsaturated alkyi, CO2H , CO2C1-8 saturated or unsaturated alkyi, NHCi-ssaturated, unsaturated alkyi, or cycioaikyl, or N(Gi-ssaturated, unsaturated alkyi, or cycioalkyl)2.
  • each R 2 CH2, O, NH, NCi-asaturated, unsaturated aikyl, cycloalky, or cycloheterocyloalkyl.
  • each A independents CH2, O, NH or Nd-ssaturated, unsaturated aikyl, or cycioaikyl, S, SO, SO2; and n 0-10.
  • each R independents CI, Br, F, I, OH, NH2, CN, OCi-s saturated or unsaturated aikyl, CO2H, CO2C1-8 saturated or unsaturated aikyl, NHCi-esaturated, unsaturated alkyi, or cycioaikyl, or N(Ci-3saturated, unsaturated aikyl, or cycloalky ⁇ ; each R 2 CH2, O, NH, NC i-ssaturated, unsaturated aikyl, cycloalky, or cycloheterocyloalkyl; each A independents CH2, O, NH or NCi-esaturated, unsaturated aikyl, or cycloheterocy
  • R 1 OH, NH2, CN, Ci-esaturaied aikyl, unsaturated alkyl, cycloalkyl, or cycloheteroalkyl, OCi-e saturated or unsaturated alkyl, NHd-e saturated , unsaturated alkyl, or cycloalkyl, or N(Ci-e saturated, unsaturated alkyl, or cycioaikyl)2
  • R 2 CH2, O, NH, NC1-6 saturated, unsaturated alkyl, cycloaiky, or cycloheterocyloalkyi.
  • A CH2, NH, NCi-esaturated, unsaturated alkyl, or cycloalkyl, O, S, SO or SO2.
  • n 0-8.
  • R 1 OH, NH2, CN, OCi-e saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated aikyl, or cycloalkyl, or N(Ci-e saturated , unsaturated alkyl, or cycloalkyl ⁇ ;
  • R 2 CH2, O, NH, NC1-6 saturated, unsaturated aikyl, cycloaiky, or cycloheterocyloalkyi;
  • the compound is racecadotril.
  • the method employs a compound of formula (VI II):
  • each R independentiy CI, Br, F, I, OH, NH2, CN, OC1-8 saturated or unsaturated alkyl, CO2H , CO2C1-8 saturated or unsaturated alkyl, NHCi-ssaturated, unsaturated alkyl, or cycloalkyl, or N(Ci-esaturated, unsaturated alkyl, or cycioalkyl)2.
  • each R 2 independentiy CH2, O, NH, NCi-ssatu rated, unsaturated alkyl, cycloaiky, or cycloheterocyloalkyi.
  • each A independents CH2 O, or NHCi-ssatu rated , unsaturated alkyl, or cycloalkyl, S, SO, SO2.
  • each R 1 independently ⁇ CI, Br, F, I , OH, NH2, CN, OCi-s saturated or unsaturated aikyl, CO2H , CO2C1-8 saturated or unsaturated alkyl, NHCi-ssatu rated, unsaturated alkyl, or cycloalkyl, or N(Ci ⁇ saturated, unsaturated aikyl, or cycloalkyl ⁇ ;
  • a compound of formula (VII I) has formula (Vil la):
  • R 1 OH, NH2, CN, OC1 -6 saturated or unsaturated aikyl, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated aikyl, or cycloalkyl, or N(Ci saturated , unsaturated alkyl, or cycloalkyl ⁇ ;
  • R 2 CH2, O, NH, NC1-6 saturated, unsaturated aikyl, cycloaiky, or cycloaiky, or heterocyioalkyl; and
  • A CH2, O, or NHCi-ssaturated, unsaturated alkyl, or cycloalkyl, S, SO, SO2.
  • the compound is ritonavir.
  • the method employs a compound of formula (IX):
  • each R 1 independents H, F, Ci, Br, OH, CF3, C i-e Aryloxy, C1-6 saturated aikyl, CO2H, CO2C1-4 aikyl, SO2NH2, S0 2 NHCi - 5 saturated aikyl, aryi or heteroaryl, S0 2 N(Ci-s saturated aikyl, aryl or heteroaryl)2, or Cs-e aryl/heteroaryl.
  • each A independently CH2, NH, O, or S.
  • a compound of formula (IX) has formula (iXa):
  • the compound is econazole, sulconazole, sertaconazole, or miconazole.
  • the method employs a compound of formula (X):
  • each R 1 independents Ci, Br, F, I, OH, NH2, CN, OC1-8 saturated or unsaturated aikyi, CO2H, CQ2C1-8 saturated or unsaturated alkyi, NHCi-ssaturated, unsaturated alkyi, or cydoaikyi, or N(C i-ssaturated, unsaturated aikyi, or cycioalkyl)2.
  • each R 2 independents Ci, Br, F, I, OH, NH2, CN, OC1-8 saturated or unsaturated aikyi, CO2H, CQ2C1-8 saturated or unsaturated alkyi, NHCi-ssaturated, unsaturated alkyi, or cydoaikyi, or N(C i-ssaturated, unsaturated aikyi, or cycioalkyl)2.
  • each R 2 independents Ci, Br, F, I, OH, NH
  • each A independently CH, CH2, O, N, NH , NCi-ssaturated, unsaturated aikyl, or cydoaikyi, S, SO, SO2.
  • a compound of formula (X) has formula (Xa):
  • R 1 Br, CI, F, CN, OCi-s saturated or unsaturated alkyl, CO2H, CO2C1-8 saturated or unsaturated alky!, NHCi-esaturated , unsaturated alky!, or cycloalky!, or N(Ci- esaturated , unsaturated a!ky!, or cyc!oa!ky!2;
  • the compound is !omer!zine, prenylamirie, fluspirilen, or GBR 12909,
  • the method employs a compound of formula (XI):
  • R 2 CI, Br, F, I , OH, NH2, CN, OC1-8 saturated or unsaturated alkyi, CO2H , CO2C1-8 saturated or unsaturated alkyl, NHCi-ssaturated, unsaturated alkyl, or cycloalkyi, or N(Ci-8saturated, unsaturated alkyi, or cycloalkyl)2.
  • R 3 CH2, O, NH, NCi-esaturated , unsaturated alkyi, cycloalky, or cycioheterocyioaikyl.
  • a compound of formula (XI) has formula (Xla):
  • R 1 CI, Br, F, i, OH, NH2, CN, OCi-ssaturated, OCs s aryi or heteroaryi, unsaturated alkyi, cycloalkyi, cycloheteroalkyl, or Ci-ssaturated alkyl, unsaturated alkyl, cycloalkyi, or cycloheteroalkyl;
  • R 2 OH, OC1-8 saturated or unsaturated alkyl, CO2H , CO2C1-8 saturated or unsaturated alkyi, NHCi-esaturated, unsaturated alkyi, or cycioaikyi, or N(Ci-3saturated, unsaturated aikyl, or cycioaikyi ⁇ ;
  • the method employs a compound of formula (XI I):
  • each R 3
  • each A independently CH2, CH, O, NH, NHCi-esaturated, unsaturated alkyi, or cycioaikyi.
  • each n 0-10.
  • each R 2 CH2, O, NH, or NCi-esaturated, unsaturated alkyi, cycloalky, or cycioheterocyioaikyl;
  • a compound of formula (XII) has formula (Xi la):
  • R ! OC1-6 saturated, OC5-8 aryi or heteroaryl, unsaturated alkyi, cycioaikyi, cycloheteroalkyl, or Ci-e saturated aikyl, unsaturated alkyi, cycioaikyi, or cycloheteroalkyl.
  • R 2 CH2, O, NH, or NC1 -5 saturated, unsaturated alkyi, cycloalky, or cycioheterocyioaikyl.
  • R 3 OH, NH2, CN, OC1 -6 saturated or unsaturated alkyi, NHCi-e saturated , unsaturated alkyi, or cycioaikyi, or N(Ci-e saturated , unsaturated alkyi, or eycioaikyl)2.
  • A CH2, CH, O, NH, or NHCi-e saturated, unsaturated alkyi, or cycioaikyl.
  • n 0-6.
  • R 1 OC1-6 saturated, OC5-8 aryi or heteroaryl, unsaturated alkyi, cycioaikyl, cycloheteroalkyi, or Cre saturated alkyi, unsaturated alkyi, cycioaikyl, cycloheteroalkyi;
  • R 2 CH2, O, NH, or NC1-6 saturated, unsaturated alkyi, cycioaiky, or cyeloheteroeyloalkyi;
  • R 3 OH, NH2, CN, OC1-6 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated alkyi, or cycloalkyi, or N(Ci-e saturated, unsaturated alkyi, or cycloalkyi)?;
  • A CH2, CH, O, NH, NHC1-6 saturated, unsaturated aikyl, or cycloalkyi; and
  • n 0-6.
  • the method employs a compound of formula (XIII):
  • each A independently CH2, CH, O, NH, N, NCi-ssaturated, unsaturated aikyl, or cycloalkyi.
  • R 2 CH2, O, NH, NCi-ssaturated, unsaturated aikyl, cycioaiky, or cyeloheteroeyloalkyi;
  • a compound of formula (Xlii) has formula (XII la):
  • R 1 OCi-e saturated, GC5-6 ary! or heteroaryl, unsaturated alkyi, cydoaikyi, cydoheteroalkyl, orCi-e saturated aikyl, unsaturated alkyi, cydoaikyi, or eycloheteroaikyi.
  • R 2 CH2, O, NH, or NC1-6 saturated, unsaturated aikyl, cycloalky, or eycloheteroeyloalkyi.
  • R 3 Ci, Br, F, I, OH, NH2, CN, OC1-6 saturated or unsaturated aikyl, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated alkyi, or cydoaikyi, or N(C1 -6 saturated, unsaturated aikyl, or eycloaiky!2.
  • R 3 ⁇ 4 OCi-e saturated, OCS-B aryl or heteroaryl, unsaturated aikyl, cydoaikyi, cydoheteroalkyl, or C i-s saturated alkyi, unsaturated aikyl, cydoaikyi, or cydoheteroalkyl;
  • R 2 CH2, O, NH, or NCi-e saturated, unsaturated aikyl, cycloalky, or eycloheteroeyloalkyi;
  • R 3 CI, Br, F, I, OH, NH 2 , CN, OCi-e saturated or unsaturated aikyl, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated alkyi, or cydoaikyi, or N(C1 -6 saturated, unsaturated aikyl
  • the method employs a compound of formula (XIV):
  • R 2 CH2, O, NH, NCi-ssatu rated, unsaturated aikyl, cycloalky, or eycloheteroeyloalkyi.
  • R 2 CH2, O, NH, NCi-asaturated, unsaturated alkyi, cycloalky, or eycloheteroeyloalkyi;
  • a compoun has formula (XVia):
  • R 3 CN, C1-6 saturated or unsaturated alkyi, OC1-6 saturated or unsaturated alkyi, NHCi-e saturated, unsaturated alkyi, or cycloaikyi, or N(Ci-e saturated, unsaturated alkyi, or cycloaikyi)?.
  • R 1 OC1-6 saturated, OCs-e aryl or heieroaryi, unsaturated aikyi, cycloaikyi, cycloheteroaikyi, Ci-e saturated alkyi, unsaturated alkyi, cycloaikyi, cycloheteroaikyi;
  • R 2 CH2, O, NH, or NC1-6 saturated, unsaturated aikyi, cycloaiky, or cycioheterocyioaikyl;
  • R 3 CN, C1-6 saturated or unsaturated alkyi, OC1 -5 saturated or unsaturated alkyi, NHCi-e saturated, unsaturated alkyi, or cycloaikyi, or N(Ci-e saturated, unsaturated aikyi, or
  • the method employs a compound of formula (XV):
  • n 0-10.
  • n 0-10.
  • a compoun has formula (XVa):
  • R 1 H, OH, OCi-esatu rated, OC5-8 aryl or heteroaryi, unsaturated aikyi, cycloaikyi, or cycloheteroaikyi, or Ci-issaturated alkyi, unsaturated aikyi, heteroalkyi, cycloaikyi, or cycloheteroaikyi;
  • A CH or N; and
  • n 0-4. in one embodiment, the compound is estradiol or fluvestrant.
  • the method employs a compound of formula (XVI):
  • R 2 CH2, O, NH, NCi-ssaturated, unsaturated aikyl, cycloalky, or cycloheterocyloalkyl.
  • each A independently CH2, CH, NH,C, N,or NCi- ssaturated, unsaturated alkyi or cycioaikyl, O, or S.
  • each n independently 0-10.
  • R 1 OC1-6 saturated, OC5-6 aryi or heteroaryl, unsaturated alkyi, cycioaikyl, cycloheteroaikyl, C1-6 saturated alkyl, unsaturated alkyi, cydoalkyl, cycioheieroaikyl, CI, Br, F, i, OH, NH2, CN, OCi-e saturated or unsaturated aikyl, CO2H, CQ2C1 6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycioaikyl, or N(Ci-esaturated , unsaturated alkyi, or cycioaikyl ⁇ .
  • R 2 CH2, O, NH, or NCi-ssaturated, unsaturated aikyl, cycloalky, or cycloheterocyloalkyl.
  • A CH2, CH, C, N, NH, NCi-e saturated, unsaturated alkyl, or cycioaikyl, O, or S.
  • n 0-6.
  • the method employs a compound of formula (XVII):
  • each A independently CH2, CH, NH, NCi- esaturated, unsaturated aikyl, or cydoalkyi, O, or S.
  • R OCi-e saturated, OC5-6 aryl or heteroaryi, unsaturated alkyi, cydoalkyi, cydoheteroalkyl, C1-8 saturated aikyl, unsaturated aikyl, cydoalkyi, cydoheteroalkyl, CI, Br, F, I, OH, NH2, CN, OCi-e saturated or unsaturated aikyl, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHCi-6 saturated, unsaturated alkyl, or cydoalkyi, or N(Ci-e saturated, unsaturated alkyi, or cycloalkyl)2.
  • R 2 CH2, O, NH, or NCi-e saturated, unsaturated alkyl, cycioaiky, or cycloheterocyloalkyl.
  • the method employs a compound of formula (XVII I):
  • each A independently CH2, CH, C, N, NH, NCi- ssaturated , unsaturated alkyi, or cycloaikyi, O, or S.
  • each n independently 0-10.
  • each R 1 independently Aryi, heteroaryl, Od-ssaturated, OC5-8 aryl or heteroaryl, unsaturated alkyi, cycloaikyi, cycioheteroalkyi, Ci-ssaturated alkyl, unsaturated alkyi, cycloaikyi, cycioheteroalkyi, CI, Br, F, I, OH, NH2, CN, OC1-8 saturated or unsaturated alkyi, CO2H , C02C i-s saturated or unsaturated alkyi, HCi-asatu rated, unsaturated alkyi, or cycloaikyi, orN(Ci-ssaturated, unsaturated, unsaturated, unsaturated,
  • a compound of formula (XVi il) has formula (XVII la):
  • R 1 OCi-e saturated, OC5-6 aryl or heteroaryl, unsaturated alkyi, cycloaikyi, cycioheteroalkyi, C1 -6 saturated alkyl, unsaturated alkyi, cycloaikyi, cycioheteroalkyi, CI, Br, F, i , OH, NH2, CN, OCi-e saturated or unsaturated alkyl, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHC1-6 saturated, unsaturated alkyl, or cycloaikyi, or N(Ci-e saturated, unsaturated alkyi, or cycloalkyl)2.
  • R 2 CI, Br, or I .
  • A CH2, CH, C, N , NH, NHC1-6 saturated , unsaturated alkyl, or cycloaikyi, O, or S.
  • n 0-8.
  • the compound is thonzon
  • the method employs a compound of formula (XIX):
  • a compound of formula (XIX) has formula (XiXa):
  • the compound is mafenide.
  • the method employs a compound of formula (XX):
  • R 1 OC1-6 saturated, unsaturated alkyl, cycioaikyi, cydoheteroaikyi, C1-6 saturated alkyl, unsaturated aikyi, cycioaikyi, cydoheteroaikyi, CI, Br, F, I , OH, NH2, CN, CO2H, CO2C1-6 saturated or unsaturated alkyl, NHCi-e saturated , unsaturated alkyl, or cycioaikyi, or N(Ci-6 saturated, unsaturated alkyl, or cycloalky ⁇ ;
  • the compound is bromhexine.
  • each R 1 independently Aryl, heteroaryl, OCi-esaturated, OC5-8 aryl or heteroaryl, unsaturated alkyl, cycioaikyi, cydoheteroaikyi, Ci -ssaturated alkyl, unsaturated alkyl, cycioaikyi, cydoheteroaikyi, CI, Br, F, I, OH, NH 2 , CN, OC1-8 saturated or unsaturated aikyi, CO2H , CO2C1-8 saturated or unsaturated alkyl, NHCi-esatu ated, unsaturated alkyl, or cycioaikyi
  • n 0-10.
  • the compound is tegaserod.
  • the method employs a compound of formula (XXII):
  • R 2 CH2, O, NH, NCi-ssaturated, unsaturated aikyl, cycloaiky, or cycloheterocyloalkyi.
  • each A independently CH2, CH, C, ⁇ , ⁇ , NCi- ssaturated, unsaturated aikyl, or cycloalkyi, O, S, SO, or SO2.
  • each n independently 0-1 Q.
  • the method employs a compound of formula (XXIII):
  • a compoun has formula (XXIIIa):
  • the compound is aiprostadii.
  • the method employs a compound of formula (XXIV):
  • a compoun has formula (XXIVa):
  • the method employs a compound of formula (XXV):
  • the compound is pinaverium bromide.
  • the method employs a compound of formula (XXVI):
  • each A independently CH , CH2, N , NH , NCi- esaiuraied, unsaturated alkyl, or cycloalkyi, O, or S.
  • each R 1 independently Aryi, heteroaryi, OC i-oSatu rated, OCs-s aryi or heteroaryi, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, Ci- ssaturated alkyl, unsaturated alkyl, cycioaikyi, cycloheteroalkyl, CI, Br, F, I, OH , NH2, CN , OC1-8 saturated or unsaturated alkyl, C0 2 H , CO2C1-8 saturated or unsaturated alkyl, NHCi-ssaturated, unsaturated alkyl, or cycioaikyi, or N(Ci-ssaturated, unsaturated alkyl,
  • the compound is bifonazoie.
  • the method employs a compound of formula (XXVII):
  • each R 1 independently Aryl, heteroaryl, OCi-esatu rated , OC5-8 aryl or heteroaryl, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, Ci- ssaturated alkyl, unsaturated aikyi, cycloalkyi, cycloheteroalkyl, CI, Br, F, I, OH, NH2, CN, OCi-a saturated or unsaturated alkyl, CO2H, CO2C1-8 saturated or unsaturated alkyl, NHCi-esaturated, unsaturated alkyl, or cycloalkyi, or N(Ci-ssaturated, unsaturated aikyi, or cycloalkyi; and each A
  • a compound of formula (XXVi i) has formula (XXVI la):
  • the compound is vatalanib.
  • the method employs a compound of formula (XXVII I): (XXVIII)
  • n 0-1 Q.
  • a compoun has formula (XXVI I la):
  • R 1 OC1-6 saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, C1-6 saturated alkyl, unsaturated alkyi, cycloalkyi, cycloheteroalkyl, CI, Br, F, I, OH, NH2, CN, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHCi-e saturated, unsaturated alkyl, or cycloalkyi, or N(Ci-6 saturated, unsaturated alkyl, or cycloalkyi ⁇ ;
  • R 2 CH2, O, NH, or NC1-6 saturated, unsaturated alkyl, cycloalky, or cydoheterocyloalkyl;
  • the method employs a compound of formula (XXIX):
  • R 2 CH2, O, NH, NCi-ssaturated, unsaturated aikyl, cycloalky, or cydoheterocyloalkyl.
  • each A independently CH2, CH3, C, NH2, N, CH, NH, NHCi-ssaturated, unsaturated alkyl, or cycloalkyi, O, OH, SH, S, SO, SO2.
  • each n independently 0-10.
  • a compound of formula (XXIX) has formula (XXiXa):
  • Certain compounds were found to inhibit wild-type KCNT1 , e.g. , compounds having formulas (XXX)-(LXXXXil i).
  • the method employs a compound of formula (XXX):
  • R 2 OCi-e saturated, unsaturated aikyl, cycioaikyl, eycioheteroaikyl, SC 1 -6 saturated, unsaturated alkyi, cycioaikyl, eycioheteroaikyl, or aryi, C1-6 saturated aikyl, unsaturated aikyl, cycioaikyl, eycioheteroaikyl, or Canary! or heteroaryl.
  • each X independently C, CH , or N.
  • diethylstilbestrol diethylstilbestrol, hexestrol, or dienestrol.
  • the method employs a compound of formula (XXXI):
  • each X independently C, CH2, N, NH, NCi-esaturated, unsaturated alkyl, or cycioaikyl, O, or S.
  • each n independently 0-8.
  • formula (XXXI) is etrinate.
  • the method employs a compound of formula (XXXII):
  • each X independently CH2, NHd-esaturated, unsaturated alkyl, or cycioaikyl, or O.
  • each R 1 independently CH2, O, NH, NCi-esaturated, unsaturated alkyl, cycloalky, or cycloheterocyioaikyi.
  • formula (XXXII) is mometasone furoate.
  • the method employs a compound of formula (XXXIII):
  • each X independently C, CH2, N, NH, O, S,
  • each n independently 0-6.
  • the method employs a compound of formula (XXXIV): '
  • each R 1 H, Ci, Br, F, I, OH, OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated alkyl, cycioaikyi, cycloheteroalkyl, or aryi, SC1-6 saturated, unsaturated alkyi, cycioaikyi, cycloheteroalkyl, or aryl, C1-6 saturated aikyi, unsaturated alkyl, cycioaikyi, cycloheteroalkyl, CO2H, C02Ci-e saturated or unsaturated aikyi, NHC1-6 saturated, unsaturated alkyi, or cycioaikyi, N(Ci-e saturated, unsaturated alkyl, or cycioaikyi, orC5-7aryl or heteroaryl.
  • each R 2 CH2, S, O, NH, NC1-6 saturated, unsaturated aikyi, cycloalky, or cycioheterocyioalkyl.
  • each X C, CH, CH2, N, NCi- esaturated, unsaturated alkyi, or cycioaikyi, O, S, SO, or SO2.
  • each n 0-6.
  • the method employs a compound of formula (XXXV):
  • R 2 CH2, S, O, NH, NCi-esaturated, unsaturated alkyl, cycloalky, or cycloheterocyloalkyl.
  • each X independently C, CH, CH2, N, NH, NCi-esaturated, unsaturated alkyl, or cycioaikyl, O, SO, or SO2.
  • each n independently 0-6.
  • formula (XXXV) is doxazosin.
  • the method employs a compound of formula (XXXVI):
  • each R 1 H, Ci, Br, F, I, OH, OAc, CF3, NH2, CN, OCi -e saturated, unsaturated alkyi, cycioaikyl, cycloheteroaikyi, or aryl, SCi -e saturated, unsaturated alkyi, cycioaikyl, cycloheteroaikyi, or aryl, C1-6 saturated alkyl, unsaturated alkyi, cycioaikyl, cycloheteroaikyi, C02H, C02C 1 -6 saturated or unsaturated alkyl, NHC1 -5 saturated , unsaturated alkyi, or cycioaikyl, N(C i-e saturated , unsaturated alkyl, or cycloalkyl) 2 , Cs-7aryl or heteroaryl
  • each X C , CH, CH 2 , N
  • each n 0-1 0.
  • the method employs a compound of formula (XXXVI I):
  • each R 1 independentiy H , Ci, Br, F, I , OH , OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryi, SC1-6 saturated , unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroaikyi, CO2H , CO2C1- 6 saturated or unsaturated alkyl, NHCi-s saturated, unsaturated alkyi, or cycloalkyl, N(Ci-6 saturated, unsaturated aikyi, or cycloalkyl, or Cs-7aryl or heteroaryl.
  • each X independently C, CH, CH2, N , NH, NCi-esaturated, unsaturated alkyl, or
  • the method employs a compound of formula (XXXVI II):
  • each X independently S, SO, SO2, NH, NCi-esaturated, unsaturated alkyl, or cycloalkyl, or O.
  • the method employs a compound of formula (XXXIX):
  • each X independently C, CH2, N, NH, O, S, SO, or S02.
  • the method employs a compound of formula (XXXX):
  • heterocycioalkyl NHCi-ssaturated or unsaturated alkyl, N(Ci-esaturated or unsaturated alky) 2 , or Cs-7aryl or heteroaryl.
  • the method employs a compound of formula (XXXXI):
  • the method employs a compound of formula (XXXXI I):
  • each X independently C or N.
  • each R independently H, Ci, Br, F, i, OH, OAc, CF 3 , NH 2 , CN, OC1-6 saturated, unsaturated alkyi, cycioaikyi, cycioheteroalkyi, or aryi, SCi-e saturated, unsaturated alkyi, cycioaikyi, cycioheteroalkyi, or aryi, C1-6 saturated alkyi, unsaturated alkyi, cycioaikyi, cycioheteroalkyi, CO2H, CO2C1-6 saturated or unsaturated aikyl, NHC1-6 saturated, unsaturated aikyl, or cycioaikyi, N(Ci-e saturated, unsaturated alkyi, or cycioaikyi, or Cs-raryi or heteroary
  • the method employs a compound of formula (XXXXI 11):
  • formula (XXXXI Ii) is nitrofural, nifurtomix, or furazolidone.
  • the method emplo compound of formula (XXXXIV):
  • n 0-6.
  • the method emplo compound of formula (XXXXV):
  • n 0-6.
  • formula (XXXXV) is D,L-mevalonic acid lactone.
  • the method employs a compound of formula (XXXXVI):
  • R 2 CI, Br, F, I, OH, CO2H, CN, NH2, CON e2, C02Ci-4alkyl, OCi-asatu rated, unsaturated alkyi, cycioaikyi, heterocycloalkyl, NHCi-3saturated or unsaiuraied alkyi, N(Ci-ssaturated or unsaturated alky)2, or Cs-yaryi or heteroaryi.
  • each X independently C, CH, CH2, S, S(O), S(02), N, NH, NCi-ssaturated, unsaturated aikyl, or cycioaikyi, orO.
  • each n independently 0-6.
  • the method employs a compound of formula (XXXXVI I):
  • R 2 H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, or aryi, SC1-6 saturated , unsaturated alkyl, cycloalkyi, cycloheteroalkyl, or aryi, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyi, cycloheteroalkyl, CO2H, CO2C1-6 saturated or unsaturated aikyi, NHC1-6 saturated, unsaturated alkyl, or cycloalkyi, N(Ci-e saturated , unsaturated alkyl, or cycloalkyi, or Canary!
  • each X independently C, CH , CH2, S, NH, N , NCi-esaturated , unsaturated alkyl, or cycloalkyi, or O.
  • each n independently 0-6.
  • formula (XXXXVH) is ezetimibe.
  • the method employs a compound of formula (XXXXVI II):
  • each X independently C, CH, CH2, S, SO, S02,N, NH, NCi-esaturated , unsaturated aikyi, or cycloalkyi, or O.
  • each R 1 independently H, CI, Br, F, i , OH , OAc, CF3, NH2, CN, OCi-e saturated, unsaturated aikyi, cycloalkyi, cycloheteroalkyl, or aryi, SC1-6 saturated, unsaturated aikyi, cycloalkyi, cycloheteroalkyl, o aryi, Ci-e saturated aikyi, unsaturated aikyi, cycloalkyi, cycloheteroalkyl, CO2H , CO2C1- e saturated or unsaturated aikyi, NHC i-s saturated, unsaturated alkyl, or cycloalkyi, N(Ci)
  • the method employs a compound of formula (XXXXIX):
  • each X independently C, CH, CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated alkyi, or cydoalkyi, or O.
  • n 0-6.
  • the method employs a compound of formula (L):
  • each X independently C, CH, CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated aikyl, or cydoalkyi, or O.
  • each n independently 0-8.
  • formula (L) is bromhexine.
  • the method employs a compound of formula (LI):
  • each X independently C, CH, CH2, S, SO, SO2, NH2, N, NH, NCi-8saturated, unsaturated alkyl, or cycioaikyl, o O.
  • each n independently 0-6,
  • each R 1 independently H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated alkyl, cycioaikyl, cycloheteroaikyl, or aryi, SCi-e saturated, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, or aryi, C1-6 saturated alkyi, unsaturated alkyl, cycioaikyl, cycloheteroaikyl, CO2H, CO2C1-6 saturated or unsaturated aikyi, NHC1-6 saturated, unsaturated alkyl, or c
  • the method employs a compound of formula (Lll):
  • each R 1 H, Ci, Br, F, I, OH, OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated alkyl, cycioaikyl, cycloheteroaikyl, or aryi, SC1-6 saturated, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, or aryi, C1-6 saturated alkyl, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, CO2H, CO2C1-6 saturated or unsaturated aikyi, NHC1-6 saturated, unsaturated alkyi, or cycioaikyl, N(Ci-e saturated, unsaturated alkyl, or cycioaikyl, or Cs-yaryi or heteroaryi.
  • each X independently C, CH, CH2, S, SO, SO2, NH, N, NCi-ssaturated, unsaturated alkyl, or cycioaikyl, or O.
  • each n independently 0-6.
  • the method employs a compound of formula (LIH):
  • each X independently C, CH, CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated aikyl, or cycioalkyi, or O.
  • each n independently 0-6.
  • formula (LIU) is oxandrolone.
  • the method employs a compound of formula (LIV):
  • each X independently C, CH, CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated alkyl, or cycioalkyi, or O.
  • each n independently 0-6.
  • the method employs a compound of formula (LV):
  • each X independently C, CH, CH2, S, SO, SO2, N, NH, NC i-ssaturated, unsaturated alkyl, or cycloalkyl, or O.
  • each n independently 0-6.
  • formula (LV) is ganaxolone.
  • the method employs a compound of formula (LVI):
  • each X independently C, CH, CH2, S, SO, SO2, N, NH, NC i-ssaturated, unsaturated aikyi, or cycloalkyl, or O.
  • each n independently 0-6.
  • formula (LVi) is toiperisone.
  • the method employs a compound of formula (LVi l):
  • the method employs a compound of formula (LVIII):
  • n 0-6.
  • the method employs a compound of formula (LIX):
  • each R 1 H, Ci, Br, F, I, OH, OAc, CFs, Nh , CN, OCi-e saturated, unsaturated alkyi, cycioalkyi, cycloheferoaikyl, or aryl, SCi-e saturated, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, o aryl, Ci-6 saturated alkyl, unsaturated alkyl, cycioalkyi, cycloheteroalkyl, CO2H, COC 1-8 alkyl unsaturated alkyi, or aryl, CO2C1-6 saturated, unsaturated alkyl, o aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyl or ary!, C02 (Ci-6 saturated, unsaturated alkyl or aryi)2, NHC1-8 saturated, unsaturated alkyi, or cycioai
  • each X CH, CH2, S, N, NH, NCi-esaturated, unsaturated alkyi, or cycioaikyl, or O.
  • each R H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated alkyl, cycioalkyi, cycloheteroalkyl, or aryi, SCi-e saturated, unsaturated aikyi, cycioaikyl, cycloheteroalkyl, or aryl, C1-6 saturated alkyl, unsaturated aikyi, cycioalkyi, cycloheteroalkyl, CO2H, COCi-s alkyi unsaturated alkyi, or aryl, CO2C1-6 saturated, unsaturated alkyl, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyl
  • the method empl nd of formula (LX):
  • each X independently CH, CH2, S, SO, SO2, N, NH, NCi-oSaturated, unsaturated aikyi, or cycioaikyl, or O.
  • each R independently H, CI, Br, F, i, OH, OAc, CF3, NH2, CN, OCi-e saturated, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, or aryi, SC1-3 saturated, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, or aryi, C1-6 saturated alkyl, unsaturated alkyl, cycioalkyi, cycloheteroalkyl, CO2H, COC i-s aikyi unsaturated alkyl, or aryi, CO2C1-6 saturated, unsaturated alkyi, or aryl, CONH2, CO2NHC
  • the method employs a compound of formula (LXI): X
  • each X independently CH, CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated alkyl, or cycioalkyi, or O.
  • each n independently 0-6.
  • the method employs a compound of formula (LXI I):
  • each X independently C, CH, CH2, S, SO, SO2, N, NH , NCi-ssaturated , unsaturated alkyi, or cycioalkyi, or O.
  • each n independently 0-6.
  • the method employs a compound of formula (LXI 11):
  • n 0-6.
  • formula (LXI II) is adiphenine.
  • the method employs a compound of formula (LXIV):
  • each R 1 independently H, CI, Br, F, I , OH, OAc, CFs, NH2, CN, OC1-6 saturated, unsaturated alky!, cycioaikyl, cycloheteroalkyl, or aryi, SC1-6 saturated , unsaturated aikyi, cycioaikyl, cycloheteroalkyl, or aryl, C1-6 saturated alkyl, unsaturated aikyi, cycioaikyl, cycloheteroalkyl, CO2H, COCi-s aikyi unsaturated aikyi, or aryl, CO2C1-6 saturated , unsaturated
  • the method employs a compound of formula (LXV):
  • each R 1 H , Ci, Br, F, I, OH , OAc, CF3, NH2, CN, OCi-e saturated, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, or aryl, SC1-6 saturated, unsaturated aikyi, cycioaikyl, cycloheteroalkyl, o aryl, C1-6 saturated aikyi, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, CO2H, COCi-s alkyl unsaturated aikyi, or aryl, CO2C1-6 saturated, unsaturated alkyl, o aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyl or aryi, C02 (Ci-6 saturated, unsaturated alkyl or aryl)2, NHCi-s saturated, unsaturated alkyl, or
  • each R 1 H, CI, Br, F, i , OH , OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated aikyi, cycioaikyl, cycloheteroalkyl, or aryl, SC1-6 saturated, unsaturated aikyi, cycioaikyl, cycloheteroalkyl, or aryi, C1-6 saturated aikyi, unsaturated alkyl, cycioaikyl, cycloheteroalkyl, CO2H, COC1 alkyl unsaturated alkyl, or aryl, CO2C 1-6 saturated , unsaturated aikyi, or
  • the method employs a compound of formula (LXVI):
  • each X independently C, CH2, S, SO, SO2, N , NH, NCi-ssaturated, unsaturated aikyi, or cycioaikyl, or O.
  • n 0-8.
  • formula (LXVI) is betazole.
  • the method employs a compound of formula (LXVI I):
  • each R 1 independently ⁇ H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated alkyi, cydoalkyl, cycloheteroalkyl, or aryl, SCi-e saturated, unsaturated aikyl, cydoalkyl, cycloheteroalkyl, or aryi, C1-6 saturated alkyi, unsaturated aikyl, cydoalkyl, cycloheteroalkyl, CO2H, COC i-s alkyi unsaturated alkyi, or aryl, CO2C1-6 saturated, unsaturated aikyl, or aryl, CONH2, C02NHCi-e saturated, unsaturated alkyi or aryl, C02N(Ci-8 saturated, unsaturated alkyi or aryi)2, NHC1-8 saturated, unsaturated alkyi, or cydoal
  • each X independently C, CH, CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated aikyl, or cydoalkyl, or O.
  • n 0-8.
  • each R 1 independently ⁇ H, Ci, Br, F, I, OH, OAc, CF 3 , NH 2 , CN, OCi-e saturated, unsaturated alkyl, cydoalkyl, cycloheteroalkyl, o aryi, SC1 -5 saturated, unsaturated alkyi, cydoalkyl, cycloheteroalkyl, or aryi, C1-6 saturated alkyl, unsaturated alkyi, cydoalkyl, cycloheteroalkyl, CO2H, COC1-8 alkyl unsaturated aikyl, or aryl, CO2C1-6 saturated, unsaturated alkyl, or aryi, CONH2, C02NHCi-e saturated, unsaturated alkyl or aryl, C02N(Ci-e saturated, unsaturated alkyl or aryl)2, NHC1-8 saturated, unsaturated alkyl, or cydo
  • the method employs a compound of formula (LXVI 11):
  • R each 1 H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OC1-5 saturated, unsaturated alkyi, cydoalkyl, cycloheteroalkyl, o aryi, SC1 -5 saturated, unsaturated alkyi, cydoalkyl, cycloheteroalkyl, or aryl, C1-6 saturated alkyl, unsaturated aikyl, cydoalkyl, cycloheteroalkyl, CO2H, COC1-8 alkyi unsaturated alkyi, or aryi, CO2C1-B saturated, unsaturated alkyi, or aryi, CONH2, CO2NHC1-S saturated, unsaturated alkyi or aryl, C02 (Ci-6 saturated, unsaturated alkyi or aryfb, NHCI-B saturated, unsaturated alkyi, or cydoalkyl,
  • R each 1 H, CI, Br, F, I, OH, OAc, CF3, NH2, CN, OC1-6 saturated, unsaturated alky!, cycloalkyl, cycloheteroalkyl, or aryi, SC1-6 saturated, unsaturated aikyi, cycloalkyl, cycloheteroalkyl, or aryi, C1-6 saturated aikyi, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, CO2H, COC1-8 alkyl unsaturated aikyi, or aryi, CO2C1-6 saturated, unsaturated alkyl, or aryl, CONH2, CO2NHC1-6 saturated, unsatur
  • the method employs a compound of formula (LXIX):
  • each X independently C, CH, CH2, S, N, NH , NCi-esaturated, unsaturated alkyi, or cycloalkyl, or O.
  • each n independently 0-8.
  • the method employs a compound of formula (LXX):
  • the method employs a compound of formula (LXXI):
  • each X independently C, CH, CH2, S, SO, SO2, N, NH, NCi- esaturated, unsaturated aikyl, or cycioalkyi, or O.
  • each R 1 independently H, CI, Br, F, i, OH, OAc, CF3, NH 2 , CN, NO2, OC1-6 saturated, unsaturated aikyl, cycioalkyi, cycioheteroalkyi, or aryi, SC1-6 saturated, unsaturated aikyl, cycioalkyi, cycioheteroalkyi, or aryi, Ci-e saturated aikyl, unsaturated alkyi, cycioalkyi, cycioheteroalkyi, CO2H, COC1-8 aikyl unsaturated aikyl, or aryi, CO2
  • method employs a compound of formula (LXXIi):
  • formula (LXXII) is molindone.
  • the method employs a compound of formula (LXXII I).
  • each X independently C, CH, CH2, S, SO, SO2, N, NH, NCi- esaturated, unsaturated alkyi, or cydoaikyi, o O.
  • n 0-6.
  • the method employs a compound of formula (LXXIV):
  • each X independentiy C, CH, CH2, S, SO, SO2, N, NH, NCi-esaturated, unsaturated alkyi, or cycioaikyl, o O.
  • the method employs a compound of formula (LXXV):
  • the method employs a compound of formula (LXXVI):
  • each R 1 H, Ci, Br, F, I, OH, ONa, OAc, CF 3 , NH 2 , CN, NO2, OCi-e saturated, unsaturated aikyl, cycloalkyl, cycloheieroalkyl, or aryl, SC1-6 saturated, unsaturated aikyl, cycloalkyl, cycloheteroaikyl, or aryl, Ci-e saturated alkyi, unsaturated aikyl, cycloalkyl, cycloheieroalkyl, CO2H, COC1-8 alkyl unsaturated aikyl, or aryl, CO2C1-6 saturated, unsaturated aikyl, or aryl, CONH2, CO2NHC1-5 saturated, unsaturated a!kyl or aryl, CG2 (Ci-s saturated, unsaturated a!kyl or aryl)2, NHCi-s saturated, unsaturated al
  • each R 1 H, CI, Br, F, I, OH, ONa, OAc, CF 3 , NH2, CN, NO2, OC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, SC1-6 saturated, unsaturated alkyl, cycloalkyl, cycioheteroalkyi, or aryl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycioheteroalkyi, CO2H, COC1 -8 alkyl unsaturated alkyl, or aryl, CO2C1-6 saturated, unsaiuraied alkyl, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyl or aryl, C02 (Ci-6 saturated, unsaturated alkyl or aryl)2, NHC1-6 saturated, unsaturated alkyl, or cycloalkyl, N(Ci
  • the method employs a compound of formula (LXXVIi):
  • each X independently CH, CH2, S, N, NH, NCi-esaturated, unsaturated alkyl, or cycloalkyl, or O.
  • each R independently H, CI, Br, F, i, OH, ONa, OAc, CFs, NH2, CN, NO2, OC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyl, or aryl, SCi-e saturated, unsaiuraied alkyl, cycloalkyl, cycloheteroalkyl, or aryl, C1-6 saturated alkyl, unsaturated alkyl, cycloalkyl, cycioheteroalkyi, CO2H, COC1-8 alkyl unsaturated alkyl, or aryl, CO2G1-6 saturated, unsaturated alkyl, or aryl, CONH2, C02 HCi-s saturated, unsaturated alkyl, or aryl, CONH2, C
  • the method employs a compound of formula (LXXVI 11):
  • each X independently C, CH, CH2, S, SO, SO2, N, NH, NCi- ssaturated, unsaturated alkyi, or cycloaikyi, or O.
  • each R independently H, Ci, Br, F, i, OH, ONa, OAc, CF3, NH2, CN, NO2, OC1-6 saturated, unsaturated alkyi, cycloaikyi, cycioheteroa!kyi, or aryl, SCi-e saturated, unsaturated aikyi, cycloaikyi, cycloheteroalkyi, or aryi, C1-6 saturated alkyi, unsaturated alkyi, cycloaikyi, cycloheteroalkyi, CO2H, COCi-s alkyi unsaturated alkyi, or aryl, CO2C1-6 saturated, unsaiuraied alkyi, or aryl, CONH2,
  • the method employs a compound of formula (LXXIX):
  • each X independently C, CH, CH2, S, SO, SO2, N, NH, NCi- esaturated , unsaturated alkyi, or cycioaikyl, or O.
  • each R independently H, CI, Br, F, I, OH, ONa, OAc, CF3, NH 2 , CN, NO2, OC1 -5 saturated, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, or aryl, SC1 -6 saturated, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, or aryl, C1-6 saturated alkyi, unsaturated aikyl, cycioaikyl, cycloheteroalkyl, CO2H, COC 1-8 alkyi unsaturated alkyi, or aryl, CO2C1-6 saturated, unsaturated alkyi, or ary
  • the method employs a compound of formula (LXXXI):
  • each X independently C, CH, CH2, S, SO, SO2, N, NH, NCi- esaturated , unsaturated alkyi, or cycioaikyl, or O.
  • each R 3 ⁇ 4 independently H, CI, Br, F, i, OH, ONa, OAc, CF 3 , NH 2 , CN, NO2, OCi-e saturated, unsaturated aikyl, cycioaikyl, cycloheteroalkyl, or aryl, SC i-s saturated, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, or aryl, C1-6 saturated aikyl, unsaturated alkyi, cycioaikyl, cycloheteroalkyl, CO2H, COCi-e alkyi unsaturated alkyi, or aryl, CO2C1-6 saturated,
  • the method employs a compound of formula (LXXXH):
  • each X independently C, CH, CH2, S, SO, SO2, N, NH , NCi- esaturated , unsaturated alkyi, or cycioaikyl, or O.
  • each R 1 independently H, CI, Br, F, i , OH, ONa, OAc, CF3, NH2, CN, NO2, OC1-6 saturated, unsaturated alkyi, cycloalkyi, cycioheteroalkyl, or aryl, SC1-6 saturated, unsaturated alkyi, cycloalkyi, cycioheteroalkyl, or aryl, C1-6 saturated alkyi, unsaturated alkyi, cycloalkyi, cycioheteroalkyl, CO2H, COCi-s alkyl unsaturated alkyi, or aryl, CO2C1-6 saturated , unsaturated alkyl, or aryl, CONH2,
  • the method employs a compound of formula (LXXXIl l):
  • each X independently C, CH , CH2, S, SO, SO2, N , NH, NCi- esaturated, unsaturated alkyl, or cycloalkyi, or O.
  • each R 3 ⁇ 4 independently H, CI, Br, F, i , OH, ONa, OAc, CF 3 , NH 2 , CN, NO2, OCi-e saturated, unsaturated alkyl, cycloalkyi, cycioheteroalkyl, or aryl, SC i-s saturated, unsaturated alkyl, cycloalkyi, cycioheteroalkyl, or aryl, C1-6 saturated alkyl, unsaturated alkyi, cycloalkyi, cycioheteroalkyl, CO2H, COCi-e alkyl unsaturated alkyl, or aryl, CO2C1-6 saturated , unsaturated
  • each X independently C, CH, CH2, S, SO, SO2, N, NH, NCi- esaturated, unsaturated alkyl, or cycloalkyl, or O.
  • each R independently H, CI, Br, F, I, OH, ONa, OAc, CF3, NH2, CN, NO2, OC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyi, or aryl, SC1-6 saturated, unsaturated alkyl, cycloalkyl, cycloheteroalkyi, or aryl, Ci-e saturated alkyl, unsaturated alkyl, cycloalkyl, cycloheteroalkyi, CO2H, COC1-8 alkyl unsaturated alkyl, or aryl, CO2C1-6 saturated, unsaturated alkyl, or aryl, CONH2, CO2NHC1-6 saturated, unsaturated alkyl or aryl, C
  • the method employs a compound of formula (LXXXV):
  • the method employs a compound of formula (LXXXVi):
  • the method employs a compound of formula (LXXXVl l):
  • the method employs a compound of formula (LXXXVI 11):
  • the method employs a compound of formula (LXXXIX):
  • the method employs a compound of formula (LXXXX):
  • the method employs a compound of formula (LXXXXI):
  • the method employs a compound of formula (LXXXXIi):
  • the method employs a compound of formula (LXXXXil I):
  • the compounds described above may thus be employed in one embodiment to prevent, inhibit or treat one or more symptoms associated with epileptic encephalopathies.
  • Epileptic encephalopathies are a group of rare, severe neurological disorders manifesting in childhood that may be strongly associated with de novo mutations.
  • a simple rapidly generated, cellular assay was developed to model an individual's rare-genetic disorder and this model was applied to high throughput screening methods to identify patient specific indications for approved drugs, in various embodiments, compositions and methods are provided for mitigating in a mammal one or more symptoms associated with a disease characterized by seizures, or delaying or preventing the onset of symptoms thereof.
  • compositions and methods are provided for reducing the risk, lessening the severity, or delaying the progression or onset of a disease characterized by dysfunction of a potassium channel in a mammal, in certain embodiments, methods are provided for preventing or delaying the onset of a seizure activity in a mammal.
  • compositions and methods are provided for modulating, e.g., voltage-gated, potassium channel activity in a mammal, in certain embodiments, compositions and methods are provided for altering function of voltage-gated potassium channels in a mammal.
  • the methods described herein are based, in part, on the discovery that certain compounds, including those with other different activities/targets, were effective to decrease the activity of a potassium channel, e.g., by decreasing potassium ion flow through the channel.
  • one or more of the compounds described herein or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, ester, amide, solvate, hydrate, or prodrug thereof or derivatives thereof, as well as one or more compounds of formulas (l)-(LXXXill), a compound in Table 1 , 2, 3, 4, or 5, or a combination thereof may be useful to modulate, in one embodiment, the activity of potassium channels.
  • a compound of formula (l)-(LXXXXIil), a compound in Table 1 , 2, 3, 4 or 5, or formulations thereof and/or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, ester, amide, solvate, hydrate, or prodrug thereof, or a derivative inhibits or treats epilepsy or cardiac dysfunction.
  • 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.
  • the compound or formulations thereof are used in a method of mitigating in a mammal, one or more symptoms associated with a by seizures, developmental delay or cognitive impairment, or slow after hyperpo!arizing activity pathological condition characterized of a mammal are also provided.
  • methods of directly or indirectly impacting potassium channels, in a mammal are provided.
  • each of these methods involve administering one or more compounds or formulations thereof and/or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, ester, amide, solvate, hydrate, or prodrug thereof, or a derivative thereof, in an amount sufficient to produce the desired activity, e.g., mitigating one or more symptoms associated with epilepsy or epileptic encephalopathies, or cardiac arrhythmias or delaying or preventing the onset of said symptoms, and/or reducing the risk, lessening the severity, or delaying the progression or onset of a disease characterized by altered potassium channel activity.
  • compositions having one or more of the compounds described herein suitable for administration, e.g., nasal, parenteral or oral administration, such as by intravenous, intramuscular, topical or subcutaneous routes, or by any other route of administration that allows drug to be delivered to the body or specific organs and tissues of the body, such as intrathecal, intracerebroventricular or intraparenchymal delivery to the central nervous system, optionally further comprising sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • the compositions can further comprise auxiliary agents or excipients, as known in the art.
  • the composition having one or more of the compounds described herein is generally presented in the form of individual doses (unit doses).
  • Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and/or emulsions, which may contain auxiliary agents or excipients known in the art.
  • Non-aqueous solvents examples include 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.
  • compositions having one or more of the compounds described herein can further comprise salts, buffers, adjuvants, or other substances which are desirable for improving the efficacy of the composition .
  • 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 Beauty (eds.), Wiley, New York (1984); Ranger & Peppas, J,.
  • a controlled release system e.g., one having a pump, or formed of polymeric materials
  • compositions having one or more of the compounds described herein comprise a therapeutically effective amount of compounds, for instance, those identified by the screening methods, and a pharmaceutically acceptable carrier, in a specific embodiment, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeiaes for use in animals, and more particularly in humans.
  • 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
  • compositions include starch, glucose, lactose, sucrose, gelatin , malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monosfearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, efhanoi and the like.
  • compositions can take the form of solutions, suspensions, emulsion , tablets, pills, capsules, powders, sustained-release formulations and the like.
  • 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.
  • 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.
  • suitable amount of carrier so as to provide the form for proper administration to the patient.
  • the formulation should suit the mode of administration.
  • compositions may be systemically administered, e.g. , orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent.
  • a pharmaceutically acceptable vehicle such as an inert diluent.
  • the compound(s) may be combined with one or more excipients and used in the form of ingesiible capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Such compositions should contain at least 0.1 % of active compound.
  • the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form.
  • the amount of active compound in such useful compositions is such that an effective dosage level will be obtained.
  • compositions may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like ; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
  • binders such as gum tragacanth, acacia, corn starch or gelatin
  • excipients such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil
  • 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.
  • sucrose or fructose as a sweetening agent
  • methyl and propylparabens as preservatives
  • a dye and flavoring such as cherry or orange flavor.
  • 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.
  • compositions can also be delivered by intravenous, intraperitoneal, intra-arterial, intrathecal, intraparenchymal or intracerebroventricular infusion or injection, or any other route of administration where delivery of a liquid formulation is suitable or appropriate for drug delivery.
  • Solutions of the compound(s) can be prepared in water or a suitable buffer, optionally mixed with a nontoxic surfactant.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of undesirable microorganisms.
  • the pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes, in ail cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyoi (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
  • the prevention of the action of undesirable microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chiorobutanol, phenol, sorbic acid, thimerosal, and the like, in many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride.
  • Sterile injectable solutions are prepared by incorporating the compound(s) in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by irradiation, steam (heat) or filter sterilization or any other preparatory method that results in a formulation thai is essentially free of bacterial and/or viral contamination.
  • Useful liquid carriers include water, alcohols or glycols or water-aicohol/giycol blends, in which the present compound(s) can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
  • Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
  • the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
  • Useful dosages of the compositions can be determined by comparing their in vitro activity and in vivo activity in animal models.
  • candidate drugs were identified for repurpose, focusing on gain of function mutations in KCNT1 .
  • a small molecule chemical library of 1 ,320 compounds including FDA approved drugs and drugs approved outside the United States (e.g., by E A and other foreign regulatory agencies) was tested for activity in a heterologous expression system expressing the mutated P924L KCNT1 channels. 41 candidate compounds were identified that significantly inhibited the gain of function associated with the respective pathogenic mutation, in one embodiment, certain compounds that produced greater than 10%, 20%, 30% or more inhibition (> 2 standard deviations away from the mean inhibition).
  • potassium channels the activity of which in a mammal may be altered by compounds, include those having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity to one of SEQ ID NOs:1 -2.
  • ion channel activity of which may be altered by compounds described herein include those having an amino acid residue other than proline at a residue corresponding to residue 924 in SEQ ID NO:1 or other than argsnsne at a residue corresponding to residue 398.
  • the compounds may have particular use for mammals with an amino acid residue in KCNT1 , other than P924, e.g., at position 924 in KCNT1 the mammal has L, S, A, i, V, G, or T, or other than R398, e.g., at position 398 in KCNT1 the mammal has Q, N, L, S, A, L V, G, or T.
  • the compounds disclosed herein alter the activity of other variants of KCNT1 , e.g., other gain-of-fu notion variants, e.g., KCNT1 proteins having 1 , 2, 3, 5 10 or up to 20 amino acid substitutions relative to one of SEQ ID Nos. 1 -2.
  • a cellular model of a patient's KCNT1 P924L mutation was generated in CHO cells.
  • the cellular model contains a replica of the KCNT1 P924L mutation identified in the patient's sequencing report. This was done by genetically altering a healthy KCNT1 DNA sequence to the mutant KCNT1 P924L sequence (C.27710T) and then inserting this mutant DNA sequence into cells in a controlled laboratory environment.
  • a rubidium efflux assay was used a proxy for potassium to measure ion flow through the Slack channel.
  • Rubidium (Rb) ions have the same charge as potassium ions, are nearly the same size, and move freely through many potassium channels, including Slack.
  • Cells loaded initially with radioactive rubidium ( 86 Rb) can subsequently be stimulated to open Slack channels and allow efflux of the 86 Rb to the outside of the ceil.
  • An 86 Rb efflux assay of this type was developed to characterize how the wild-type and mutant channels respond to added compounds.
  • the 86 Rb efflux assay was used to test both variant and wild-type cellular models with increasing concentrations of ioxapine, a known activator of Slack channels (Figure 2).
  • the mutant cellular model displayed stronger S6 Rb+ efflux in response to channel opening by Ioxapine than the wild-type cellular model: the EDso for the P924L cell model was 1 .7 ⁇ , which was six-fold lower than the wild-type cell model with an EDso of 10.5 ⁇ .
  • HTS was performed to search for compounds that might inhibit mutant Slack channel activity.
  • the KCNT1 P924L mutant cellular model was used to test for compounds that decrease potassium currents. These inhibitors of channel function could be useful therapeutic options for evaluation in patients with such KCNT1 mutations,
  • a library of about 1 ,290 compounds was screened in the P924L mutant cellular model to identify compounds that significantly inhibited 86 Rb efflux.
  • the inhibitory activities for all of the 1 ,290 compounds in the 8e Rb efflux assay are plotted by rank in order of activity in Figure 3. Each compound is represented by a blue dot. A total of 41 compounds had activity above 2 standard deviations (SD; orange line), and 20 of those were also above 3 SD (green line). Most compounds (>95%) had activity below the 2 SD line and were considered statistically insignificant.
  • Table 1 A shows results from the high-throughput screen listing the 41 compounds with inhibition that was greater than 2 standard deviations from the group mean (3.9% ⁇ 13.7%). Screening was based on incubation of ceils with 10 ⁇ of each compound. In follow-on testing the hit compounds from the screening study were evaluated across a series of concentration ranging from 0.03 ⁇ to 100 ⁇ . From this experiment, concentration-response curves (CRC) could be generated that served to confirm the inhibitory activity of the compound at the KCNT1 P924L channel and measure the EDso (concentration at which the compound yielded 50% of maximal inhibitory activity), an indicator of potency and maximal effectiveness (greatest level of inhibition).
  • CRC concentration-response curves
  • Table 1 B The results from CRC testing are shown in Table 1 B using the rubidium ion efflux assay as well as electrophysiology. The latter used patch clamp methodology across a series of concentrations ranging from 0.03 ⁇ to 300 ⁇ to derive a measure of ED50 and maximal effectiveness.
  • Table 1 A shows results from the high-throughput screen listing the 41 compounds with inhibition that was greater than 2 standard deviations from the group mean (3.9% ⁇ 13,7%). Screening was based on incubation of ceils with 10 ⁇ of each compound. In follow-on testing the hit compounds from the screening study were evaluated across a series of concentration ranging from 0,03 ⁇ to 100 ⁇ .
  • concentration-response curves could be generated that served to confirm the inhibitory activity of the compound at the KCNT1 P924L channel and measure the EDso (concentration at which the compound yielded 50% of maximal inhibitory activity), an indicator of potency and maximal effectiveness (greatest level of inhibition).
  • the results from CRC testing are shown in Table 1 B using the rubidium ion efflux assay as well as electrophysiology. The latter used patch clamp methodology across a series of concentrations ranging from 0.03 ⁇ to 300 ⁇ to derive a measure of EDso and maximal effectiveness.
  • a second model with a different KCNT1 mutation (R398Q) using different host cell (Xenopus oocytes) for electrophysiology was also tested (see Table 2), The R398Q mutation was shown previously to be a gain -of-f u n ctio n mutation (Milligan et ai, 2014). The R398Q mutation is in an entirely different region of the KNCT1 protein than the P924L mutation from Example 1 with a different structural alteration, but still results in a gain-of-function mutation.
  • the test system was Xenopus Oocyt.es that are a convenient model for transiently expressing a mutation and evaluating the effect with electrophysiology using methods standard to the field.
  • the drug library was also used to screen normal or wild-type KCNT1 wild-type for inhibitors using the same methods as described in Example 1 .
  • compounds with significant activity on the drug screen were then evaluated by CRC testing to confirm activity and derive an ED50 and maximal effectiveness. Results for CRC testing are shown in Tabie 5B based on the rubidium efflux assay and patch clamp electrophysiology.

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Abstract

L'invention concerne une méthode de prévention, d'inhibition ou de traitement d'un ou de plusieurs symptômes associés à l'épilepsie, aux encéphalopathies ou à un dysfonctionnement cardiaque chez un mammifère. La méthode consiste à administrer au mammifère une quantité efficace d'une composition comprenant un composé de formule (I) (LXXXXIII), ou un sel pharmaceutiquement acceptable de celui-ci, ou leur combinaison quelconque.
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