Pyrazolo[1,5-a]pyridin-2,3-ylamides as Kv7 channel activators

Abstract

Pyrazolo[1,5-a]pyridin-2,3-ylamide compounds, such as those represented by formula I, that function as Kv7.2 / 7.3 channel activators can be used to treat many diseases, disorders, and conditions associated with Kv7 potassium channels, such as, but not limited to, epilepsy, pain, migraine, and / or schizophrenia, and can be incorporated into dosage forms, pharmaceutical compositions, and / or medicaments for the treatment of Kv7 potassium channel-mediated diseases / disorders.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 297,295, filed January 7, 2022, the contents of which are incorporated herein by reference in their entirety.

[0002] (Government Interests) This invention was made with United States Government support under Grant No. U44NS093160 awarded by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health. The United States Government has certain rights in the invention. Summary of the Invention

[0003] Potassium (K + K channels are present on the plasma membrane of most cell types and are the most diverse class of all ion channels, being associated with a wide range of physiological functions including the regulation of electrical properties of excitable cells. The primary pore-forming (a) subunits of these highly selective cation channels are divided into three primary structural classes based on the number of transmembrane (TM) and pore (P) regions, currently classified as 6TM / 1P, 2TM / 1P and 4TM / 2P K + The Kv7 gene (originally designated KCNQ by the Human Genome Nomenclature Committee (HGNC)) is a voltage-gated K + The Kv7 subfamily is composed of five homologous pore-forming subunits (Kv7.1-7.5) and has a typical voltage-gated K channel structure with a 6TM transmembrane domain (S1-S6) flanked by intracellular N- and C-terminal domains, a typical voltage sensor domain located in S4 consisting of alternating positively charged residues, and a single P domain located between S5 and S6 of each subunit. +The structure of the channel. The channel is formed as a tetramer of primary subunits, either homotetramers or heterotetramers. Neurons are known to express Kv7 channels, which consist of Kv7.2-7.5 α subunits. Some of these gene products may be exclusively neuronal, while other products, such as Kv7.4 and Kv7.5, can be found in other tissues, such as smooth and skeletal muscles.

[0004] Native M channels, and the corresponding macroscopic M-currents, were first characterized in amphibian sympathetic neurons. M channels interact with G protein-coupled receptors (GPCRs) and physiological K currents by slowly activating and deactivating, by activating at or near the resting membrane potential of the neuron, and by reducing the M-current with muscarinic cholinergic agonists. + It was notable for demonstrating a direct, inhibitory link between Kv7.2 / 7.3 (and possibly Kv7.5 / 7.3) heteromultimers and the elusive M-channels that the pharmacological and biophysical identity was established only after this subfamily of genes was cloned, providing important new evidence for their importance in neuronal regulation.

[0005] The regional and developmental distribution of these channels, together with their biophysical properties, support their role in providing durable resistance to depolarizing excitatory influences. Under physiological conditions, as demonstrated for native M-channels, they are highly effective in regulating the subthreshold excitability of certain neuronal populations and have a key role in regulating the frequency, and thus the pattern, of action potential discharge in many types of neurons. Their importance in neuronal regulation was revealed by the discovery that neuronal Kv7 mutations lead to benign familial neonatal convulsions (BFNC), indicating that reduction or elimination of the influence of Kv7.2 and Kv7.3 channels can dramatically alter neuronal excitability. Mutational analysis demonstrated their involvement in BFNC and suggested their utility as targets for antiepileptic drugs (AEDs).

[0006] Unlike the established pharmacological terminology for GPCRs, K +The mechanism of action of channel modulators, especially channel-activating compounds, is still being refined. The application of voltage clamp techniques to ion channel pharmacology studies has enabled detailed biophysical studies of either whole cell currents or single channels, which has shed some light on the nature of compound-channel interactions, but continued confusion over terminology has been unavoidable. The terms opener or activator are commonly used throughout the literature, but do not adequately describe the mode of action of all these “positive modulator” compounds. In general, one would expect an opener or activator to increase the open probability of the channel or increase the macroscopic current amplitude, but this nomenclature is actually too simplistic. For example, retigabine, the first published Kv7 opener, has a complex and interesting profile in that it has inhibitory activity at higher membrane potentials. Neuronal Kv7 channel openers operate in concert with the activity of the channel over the “normal” activation voltage range, sometimes enhancing current without significantly affecting the activation threshold, and sometimes significantly shifting the activation threshold. Furthermore, there appear to be openers that completely remove the voltage dependence of activation. Whether these effects are sequential is currently unclear, since these effects are often concentration-dependent. Clearly, the interaction modes of compounds that can increase channel currents are complex and in most cases poorly understood, and the impact of these profiles on neuronal responsiveness and the physiology of the system is also unclear. Retigabine is a very effective opener of Kv7.2, Kv7.5, and heteromultimeric Kv7 channels, although it is mild in action and not highly specific. Its effect is characterized by a significant increase in channel current over a narrow voltage range. As mentioned above, at more positive voltages the opener is less effective, and under some conditions the channel current is significantly reduced at more positive voltages compared to the control current (the crossover voltage dependence of the opener action is a feature of many neuronal Kv7 channel openers). The effect is also concentration-dependent, more pronounced at higher concentrations.

[0007] Provided herein are compounds that are more potent than Kv7.4 homomultimers and / or exhibit at least a biased effect toward Kv7.2 / 7.3 heteromultimers, and may have reduced adverse side effects compared to retigabine. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] Before the compositions and methods are described, it should be understood that any invention is not limited to the specific processes, compositions, or methods described, which may vary. Furthermore, the processes, compositions, and methodologies described in a particular embodiment are interchangeable. Thus, for example, a composition, administration regimen, administration route, etc. described in a particular embodiment may be used in any of the methods described in other particular embodiments. It should also be understood that the terms used herein are for the purpose of describing a particular version or embodiment only, and are not intended to limit the scope of the invention, which is limited only by the appended claims. Unless expressly defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art. Although any method similar or equivalent to that described herein can be used to practice or test an embodiment of the invention, the preferred method is described herein. All publications and references mentioned herein are incorporated by reference. Nothing herein should be construed as an admission that the invention is not entitled to antedate such disclosure by prior invention. It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0009] As used herein, the term "about" means plus or minus 10% of the numerical value of the number with which it is used. Thus, about 50% means a range of 45% to 55%. Unless otherwise indicated, all numbers describing properties such as amounts of ingredients, molecular weights, reaction conditions, and the like used in the specification and claims should be understood in all cases as being modified by the term "about". Thus, unless indicated to the contrary, the numerical parameters set forth in the specification and the appended claims are approximations that may vary depending on the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of at least the number of digits following the reported significant number and by applying ordinary numerical rounding techniques.

[0010] When used in conjunction with a therapeutic agent, "administration" refers to administering a therapeutic agent directly into or onto a target tissue, or administering a therapeutic agent to a subject, thereby positively affecting the tissue to which the therapeutic agent is targeted. "Administration" of a composition may be accomplished by oral administration, injection, infusion, absorption, or any method in combination with other known techniques. "Administration" may include the act of self-administration or administration by another person, such as a medical professional or device.

[0011] As used herein, the terms "comprising," "comprise," "comprises," and "comprised" are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0012] As used herein, the terms "consists of" or "consisting of" mean that a composition or method includes only those elements, steps, or ingredients specifically recited in a particular embodiment or claim.

[0013] As used herein, the term "consisting essentially of" or "consists essentially of" means that a composition or method includes only the specified materials or steps, and those materials or steps that do not materially affect the basic and novel characteristics of the claimed invention.

[0014] In each of the embodiments disclosed herein, the compositions and methods may be utilized with or on a subject in need of such treatment, which may also be referred to as "in need of." As used herein, the phrase "in need of" means that the subject has been identified as having a need for a particular method or treatment, and the treatment has been given to the subject for that particular purpose.

[0015] As used herein, the terms "patient" and "subject" are used interchangeably to mean any organism that can be treated with the compounds of the present invention. Thus, the terms "patient" and "subject" can include, but are not limited to, any non-human mammal, primate, or human. In some embodiments, the "patient" or "subject" is an adult, child, infant, or fetus. In some embodiments, the "patient" or "subject" is a human. In some embodiments, the "patient" or "subject" is a mammal, such as a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, primate, or human.

[0016] As used herein, the terms "therapeutically effective amount" or "therapeutic dose" are used interchangeably and may refer to an amount of an active agent or pharmaceutical compound or composition that elicits a clinical, biological, or medicinal response in a tissue, system, animal, individual, or human that is being sought by a researcher, veterinarian, physician, or other clinical professional. The clinical, biological, or medical response may include, for example, one or more of: (1) preventing a disease, condition, or disorder in an individual who may be predisposed to the disease, condition, or disorder but has not yet experienced or manifested the pathology or symptoms of the disease, condition, or disorder; (2) inhibiting a disease, condition, or disorder or arresting further progression of the pathology and / or symptoms of the disease, condition, or disorder in an individual who is experiencing or manifesting the pathology or symptoms of the disease, condition, or disorder; and (3) ameliorating a disease, condition, or disorder in an individual experiencing or manifesting the pathology or symptoms of the disease, condition, or disorder, or reversing the pathology and / or symptoms experienced or manifested by the individual.

[0017] The term "treatment" may be used to mean prevention of a particular disorder, disease or condition, alleviation of symptoms associated with a particular disorder, disease or condition, and / or prevention of symptoms associated with a particular disorder, disease or condition. In some embodiments, the term refers to slowing the progression of a disorder, disease or condition, or alleviating symptoms associated with a particular disorder, disease or condition. In some embodiments, the term refers to alleviating symptoms associated with a particular disorder, disease or condition. In some embodiments, the term refers to alleviating symptoms associated with a particular disorder, disease or condition. In some embodiments, the term refers to restoring impaired or lost function due to a particular disorder, disorder, or condition.

[0018] "Pharmaceutically acceptable salt" is meant to refer to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of a patient without undue toxicity, irritation, allergic response, and the like, and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. (1977) J. Pharm. Sciences, Vol. 6, 1-19 describes pharma- ceutically acceptable salts in detail. A pharma- ceutically acceptable "salt" is any acid addition salt, preferably a halogen salt such as hydrobromide, hydrochloride, hydrofluoride and hydroiodide, an inorganic acid salt such as, for example, a nitrate, a perchlorate, a sulfate and a phosphate, for example, a sulfonate (methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate or p-toluenesulfonate), an acetate, a malate, a fumarate, a succinate, a citrate salt, a benzoate, a gluconate, a lactate, a mandelate, a mucate, a pamoate, an acetate, a malate, a fumarate, a succinate, a citrate ... mucate, a pamoate, an acetate, a malate The acid addition salts are pharma- ceutically acceptable acid addition salts, including, but not limited to, salts, organic acid salts such as pantothenate, oxalate and maleate, and amino acid salts such as aspartate or glutamate. The acid addition salts may be mono- or di-acid addition salts, such as dihydrogen halides, disulfates, diphosphates, or diorgano acid salts. In all cases, the acid addition salts used as achiral reagents are not selected based on any expected or known preference for interaction with or precipitation of a particular optical isomer of the product of the present disclosure.

[0019] Unless otherwise indicated, when a compound or chemical structural feature, such as pyrazolo[1,5-a]pyridin-2-ylcarbamoyl, is referred to as "optionally substituted," it includes features that have no substituents (i.e., unsubstituted) or features that are "substituted," meaning that the feature has one or more substituents. The term "substituent" has its broadest meaning known to those of skill in the art and includes one or more residues that are attached to the parent compound or structural feature and replace a hydrogen atom. In some embodiments, the substituent may be a conventional organic residue known in the art that may have a molecular weight (e.g., the sum of the atomic masses of the atoms of the substituent) of 15 Da to 50 Da, 15 Da to 100 Da, 15 Da to 150 Da, 15 Da to 200 Da, 15 Da to 300 Da, or 15 Da to 500 Da. In some embodiments, the substituent comprises or consists of 0-30, 0-20, 0-10, or 0-5 carbon atoms and 0-30, 0-20, 0-10, or 0-5 heteroatoms, each heteroatom being independently N, O, S, Si, F, Cl, Br, or I, with the proviso that the substituent contains one atom of C, N, O, S, Si, F, Cl, Br, or I. In some embodiments, the substituent has a molecular weight of 15 Da to 300 Da, 15 Da to 200 Da, 15 Da to 150 Da, or 15 Da to 100 Da and can be a moiety consisting of 1 to 5 chemical elements, where the chemical elements are independently C, H, O, N, S, F, Cl, or Br.

[0020] Examples of substituents include hydrocarbyls such as alkyl, alkenyl, and alkynyl; heteroalkyls including any alkyl in which one or more heteroatoms replace one or more carbon atoms and, optionally, some of the hydrogen atoms associated with said carbon atoms (e.g., N replaces CH, O replaces CH, Cl replaces CH), such as alkyl, acyloxy, thiocarbonyl, alkylcarboxylate, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, sulfinyl, isocyanato, isothiocyanato, and the like. Examples of heteroalkyl include, but are not limited to, heteroalkenyl, which includes any alkenyl in which one or more heteroatoms replace one or more carbon atoms and, optionally, some of the hydrogen atoms associated with said carbon atoms; heteroalkynyl, which includes any alkynyl in which one or more heteroatoms replace one or more carbon atoms and, optionally, some of the hydrogen atoms associated with said carbon atoms, such as cyano, thiocyanato, cyanato; aryl, heteroaryl, hydroxy, aryloxy, thiol, halo, S-sulfonamido, N-sulfonamido, nitro, silyl, sulfonyl, trihalomethanesulfonyl, trihalomethanesulfonamido, and the like.

[0021] For convenience, the term "molecular weight" is used in reference to a residue or portion of a molecule to indicate the sum of the atomic masses of the atoms in the residue or portion of a molecule, even if it is not a complete molecule.

[0022] Structures associated with some of the chemical names referred to herein are shown below. These structures may be unsubstituted, as shown below, and the substituents may independently be at any position normally occupied by a hydrogen atom when the structure is unsubstituted. Unless the point of attachment is indicated by |, the bond may be at any position normally occupied by a hydrogen atom. [ka]

[0023] As used herein, the term "alkyl" has the broadest meaning generally understood in the art and may include residues composed of carbon and hydrogen without double or triple bonds. Alkyl may be a straight chain alkyl, branched alkyl, cycloalkyl, or combinations thereof, and in some embodiments may contain 1 to 35 carbon atoms. In some embodiments, alkyl is a C alkyl group such as methyl (-CH3), methylene (-CH2-), ethyl (-CH2CH3), ethylene (-C2H4-), propylene (-C3CH6-), n-butyl (-CH2CH2CH2CH3), n-pentyl (-CH2CH2CH2CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), etc. 1~10 Straight chain alkyl, C3H7 (e.g. isopropyl), C4H9 (e.g. branched chain butyl isomers), C5H 11 (e.g., branched chain pentyl isomers), C6H 13 (e.g., branched-chain hexyl isomers), C7H 15 (e.g., heptyl isomers) 3~10 Cycloalkyl, C3H5 (e.g., cyclopropyl), C4H7 (e.g., cyclobutyl isomers such as cyclobutyl, methylcyclopropyl, etc.), C5H9 (e.g., cyclopentyl isomers such as cyclopentyl, methylcyclobutyl, dimethylcyclopropyl, etc.), C6H 11 (e.g., cyclohexyl isomers), C7H 13 (e.g., cycloheptyl isomers) 3~10 It may also include cycloalkyl.

[0024] With respect to an optionally substituted residue, such as an optionally substituted alkyl, the term "optionally substituted C 1~12 A term such as "alkyl" refers to a group that may be unsubstituted or may have one or more substituents and does not limit the number of carbon atoms in any substituent. 1~12 It refers to alkyl. So, for example, CH2(CH2) 11 OCH3 is an alkyl group with 12 carbon atoms, so it can be any substituted C 1~12"Optionally substituted C 1~12 "Alkyl" refers to unsubstituted C 1~12 "Alkyl" refers to an optionally substituted alkyl, or substituted alkyl, where the parent alkyl and all substituents have a total of 1 to 12 carbon atoms. For example, CH2CH2OCH3 represents an optionally substituted C 1~12 A similar convention may be applied to other optionally substituted moieties such as aryl and heterocyclyl.

[0025] The substituents on the alkyl may generally be the same as those described above, in some embodiments, the substituents on the alkyl are independently selected from F, Cl, Br, I, CN, CO2H, -O-alkyl, ester groups, acyl, amine groups, amide groups, phenyl (including fused phenyls resulting in an optionally substituted alkyl, such as indenyl, in which the phenyl substituent is fused to the parent alkyl moiety), and may have a molecular weight of from about 15 to about 100 or about 500.

[0026] As used herein, the term "aryl" has its broadest meaning as generally understood in the art and can include an aromatic ring or ring system, such as phenyl, naphthyl, etc. In some embodiments, an aryl can contain heteroatoms, such as S or N, for example, thiophenyl, pyridinyl, pyrimidinyl, etc.

[0027] The term "heterocyclyl" includes any ring or ring system containing a heteroatom, such as N, O, S, P. Heterocyclyl includes heteroaryl rings or ring systems (such as those listed below) and non-aromatic rings or ring systems. Examples of non-aromatic heterocyclyls include azetidinyl, oxatanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxalanyl, dithiolanyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholino, and the like.

[0028] The term "heteroaryl" also has the meaning understood by one of ordinary skill in the art and includes "aryls" having one or more heteroatoms in the ring or ring system, such as pyridinyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, oxadiazolyl, isoxazolyl, indolyl, quinolinyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, and the like.

[0029] As used herein, the term "carbocyclyl" has the broadest meaning generally understood in the art and includes rings that do not contain heteroatoms, such as cycloalkyls, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.; cycloalkenyls, e.g., cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, etc.; cycloalkynyls, e.g., cyclopropynyl, cyclobutynyl, cyclopentynyl, cyclohexynyl, etc.; bridged cycloalkyls, e.g., bicyclo[1.1.1]pentane, norborane, etc., as well as aryl rings that do not contain heteroatoms.

[0030] Unless otherwise indicated, all references to compounds herein by structure, name, or any other means include pharma- ceutically acceptable salts, prodrugs such as ester prodrugs, alternative solid forms such as polymorphs, solvates, hydrates, tautomers, or any other chemical species that may be rapidly converted to the compounds described herein under the conditions in which the compounds are used as described.

[0031] Prodrugs include compounds that are converted to a therapeutically active compound after administration, such as by hydrolysis of an ester group or some other biologically labile group.

[0032] Where stereochemistry is not indicated, the name or structural representation includes any stereoisomer or any mixture of stereoisomers.

[0033] Some embodiments include compounds represented by the formula: [ka] where Het is optionally substituted pyrazolo[1,5-a]pyridin-2-yl and R 1 is C 1~6 Linear or C 1~6 is a branched alkyl group, R 2 is H, OH, CF3, or C 3~6 -cycloalkyl-OH, R 3 is H, CF3, optionally substituted phenyl, optionally substituted pyridinyl, or optionally substituted C 3~6 It is cycloalkyl.

[0034] Some embodiments include compounds represented by the formula: [ka] In the formula, R 4 are H, F, Cl, Br, I, and C. 1~6 Alkyl, C 1~6 -Alkyl-OH, CF3, CN, C 1~6 -O-alkyl, optionally substituted C3~6 cycloalkyl, optionally substituted aryl, optionally substituted thiophenyl, or optionally substituted pyridinyl; R 5 , R 6 , R 7 , and R 8 are each independently H, F, Cl, Br, I, or C 1~6 Alkyl, C 1~6 -Alkyl-OH, CF3, CN, C 1~6 -O-alkyl, optionally substituted C 3~6 It is cycloalkyl, or optionally substituted aryl.

[0035] Some embodiments include compositions that include a compound described herein, eg, a compound of Formula 1 or Formula 2, wherein the composition is pharma- ceutically acceptable.

[0036] Some embodiments include a pharmaceutical dosage form comprising a compound described herein, such as a compound of Formula 1 or Formula 2.

[0037] Some embodiments include a method of activating Kv7 potassium comprising administering an effective amount of a compound described herein, for example a compound of Formula 1 or Formula 2, to a mammal in need thereof.

[0038] Some embodiments include a method of treating a disorder associated with the Kv7 potassium channel, comprising administering an effective amount of a compound described herein, e.g., a compound of Formula 1 or Formula 2, to a mammal in need thereof.

[0039] Some embodiments include the use of a compound of Formula 1 or Formula 2 in the manufacture of a medicament for treating a disorder associated with the Kv7 potassium channel.

[0040] With respect to any related structural representation, such as formula 1, Het is an optionally substituted pyrazolopyridinyl, such as, for example, an optionally substituted pyrazolo[1,5-a]pyridin-2-yl. When Het is substituted, it may have 1, 2, 3, 4, or 5 substituents. Any substituent may be included on the pyrazolopyridinyl. In some embodiments, some or all of the substituents on the pyrazolopyridinyl may have 0-10 carbon atoms and 0-10 heteroatoms, each heteroatom being independently O, N, S, F, Cl, Br, or I (provided that at least one non-hydrogen atom is present), and / or have a molecular weight of 15 Da to 500 Da. For example, the substituents may be C, CH3, C2H5, C3H7, cyclic C3H5, C4H9, cyclic C4H7, C5H n , cyclic C5H9, C6H 13 , cyclic CH n C etc. 1~6 Alkyl, C 1~20 Alkoxyl, C 1~20 Hydroxyalkyl, halo such as F, Cl, Br, or I, C such as OH, CN, NO2, CF3, CF2H, C2F5 1~6 fluoroalkyl, optionally substituted phenyl, such as methylphenyl, chlorophenyl, or fluorophenyl; optionally substituted heteroaryl, such as pyridinyl, thiophenyl; C, such as -OCCH, -COCH, -OCCH, -COC-phenyl, -CO-phenyl; 1~10 Esters, such as -COCH3, -COC2H5, -COC3H7, -CO-phenyl, etc. 1~10 Ketones, -OCH3, -OC2H5, -OC3H7, etc. 1~12 -O-alkyl or C such as NH2, NH(CH3), N(CH3)2, N(CH3)C2H5 1~10 In some embodiments, the substituent of Het is C 1~6 Alkyl, C 1~6 In some embodiments, Het is represented by the formula: [ka]

[0041] In some embodiments where thiophenyl is a substituent of Het, the bond may be, for example, at the 2-position of the thiophenyl residue in thiophen-2-yl, or any position normally occupied by a hydrogen atom.

[0042] For any relevant structural representation, such as Equation 1 and Equation 2, R 1 is -CH2-, [ka] [ka] Linear or branched chain -C4H8-, Linear or branched chain -C5H 11 C etc. 1~6 In some embodiments, R 1 is -CH2-, [ka] [ka] -C4H8-, or -C5H 11 In some embodiments, R 1 is -CH-. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 is -C4H8-. In some embodiments, R 1 is -CH 11 In some embodiments, R 1 teeth, [ka] [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] It is.

[0043] For any relevant structural representation, such as Equation 1 and Equation 2, R 2 is H, OH, CF3, or C such as -cyclopropyl-OH, -cyclobutyl-OH, -cyclopentyl-OH, -cyclohexyl-OH 3~6 -cycloalkyl-OH. In some embodiments, R 2 are H, OH, and CF 3、 [ka] or [ka] In some embodiments, R2 is H. In some embodiments, R 2 is CF3. In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] It is.

[0044] For any relevant structural representation, such as Equation 1 and Equation 2, R 3 is H, CF, optionally substituted phenyl, optionally substituted pyridinyl, or an optionally substituted C alkyl group such as optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl. 3~6 In some embodiments, R 3 is H, CF, phenyl, pyridinyl, optionally substituted cyclobutyl, or optionally substituted cyclopentyl. In some embodiments, R 3 is H. In some embodiments, R 3 is CF3. In some embodiments, R 3 is phenyl. In some embodiments, R 3 is pyridinyl. In some embodiments, R 3 is an optionally substituted cyclobutyl. In some embodiments, R 3 is optionally substituted cyclopentyl.

[0045] For any relevant structural representation, such as Equation 1 and Equation 2, R 4 , R 5 , R 6 , R 7 , and R 8may independently be H or any substituent, such as a substituent having 0-6 carbon atoms and 0-5 heteroatoms, each heteroatom independently having a molecular weight of O, N, S, F, Cl, Br, or I, and / or having a molecular weight of 15 Da to 300 Da, 15 Da to 200 Da, or 15 Da to 150 Da. 4 , R 5 , R 6 , R 7 , and R 8 are independent, R A , F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A , O.C.O.R. A , N.R. A COR B ,CONR A R B , optionally substituted aryl, such as optionally substituted phenyl, optionally substituted heteroaryl, such as thiophenyl, optionally substituted pyridinyl, etc. In some embodiments, R 5 , R 6 , R 7 , and R 8 are independently selected from H, F, Cl, CN, CF3, OH, NH2, methyl, ethyl, propyl isomers (e.g., n-propyl and isopropyl), cyclopropyl, butyl isomers, cyclobutyl isomers (e.g., cyclobutyl and methylcyclopropyl), pentyl isomers, cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, and the like. 1~6 Alkyl or C such as -O-methyl, -O-ethyl, -O-propyl, -O-cyclopropyl, the isomers of -O-butyl, the isomers of -O-cyclobutyl, the isomers of -O-pentyl, the isomers of -O-cyclopentyl, the isomers of -O-hexyl, the isomers of -O-cyclohexyl, etc. 1~6 It is alkoxy, optionally substituted phenyl, or optionally substituted pyridinyl. [ka]

[0046] Each R A are independently H, or a group of formula C a H a+1 or a linear or branched alkyl group having the formula C a H a-1 Cycloalkyl having C 1~12 alkyl, where a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, such as straight or branched chain alkyl of the following formulae: CH3, C2H5, C3H7, C4H9, C5H 11 , C6H 13 , C7H 15 , C8H 17 , C9H 19 , C 10 H 21 etc., or cycloalkyl of the following formulas: C3H5, C4H7, C5H9, C6H 11 , C7H 13 , C8H 15 , C9H 17 , C 10 H 19 In some embodiments, R A is H or C 1~6 In some embodiments, R A is H or C 1~3 In some embodiments, R A may be H or CH. In some embodiments, R A may be H.

[0047] Each R B are independently H, or a group of formula C a H a+1 or a linear or branched alkyl group having the formula C a H a Cycloalkyl having C 1~12 alkyl, where a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, such as straight or branched chain alkyl of the following formulae: CH3, C2H5, C3H7, C4H9, C5H 11 , C6H13 , C8H 17 , C7H 15 , C9H 19 , C 10 H 21 etc., or cycloalkyl of the following formulas: C3H5, C4H7, C5H9, C6H 11 , C7H 13 , C8H 15 , C9H 17 , C 10 H 19 In some embodiments, R B is H or C 1~3 In some embodiments, R B may be H or CH. In some embodiments, R B may be H.

[0048] For any relevant structural representation, such as Eq. 2, R 4 is H or any substituent, such as a substituent having a molecular weight of 15 Da to 50 Da, 75 Da, 100 Da, 150 Da, or 200 Da, and / or consists of 1, 2, 3, 4, or 5 chemical elements, the chemical elements being C, H, N, O, S, F, Cl, or Br. 4 are H, NO2, CN, F, Cl, Br, I, CO2H, OH, NH2, C 1~6 alkylamino, optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted thiophenyl, C 1~6 Alkyl, or C 1~6 In some embodiments, R 4 is cyclobutyl, optionally substituted phenyl, 4-fluorophenyl, 4-chlorophenyl, unsubstituted phenyl, 4-methylphenyl, 3-fluorophenyl, 5-chlorothiophen-2-yl, or 6-chloropyridin-3-yl. 4 is H. In some embodiments, R 4 is cyclobutyl. In some embodiments, R 4is an optionally substituted pyridinyl, such as an optionally substituted pyridin-3-yl (e.g., 6-chloropyridin-5-yl). In some embodiments, R 4 is an optionally substituted thiophenyl, such as an optionally substituted thiophen-2-yl (e.g., 5-chloro-thiophen-2-yl). In some embodiments, R 4 is an optionally substituted thiophen-2-yl. In some embodiments, R 4 is optionally substituted phenyl; R 4 is 4-fluorophenyl, and R 4 is 4-chlorophenyl, R 4 is unsubstituted phenyl, and R 4 is 4-methylphenyl, R 4 Further, for any of the above embodiments in this paragraph, R 5 , R 6 , R 7 , and R 8 are independent, R A F, Cl, CN, OR A CF3, NO2, NR A R B , C.O.R. A CO2R A O.C.O.R. A NR A COR B , or CONR A R B ; or H, F, Cl, CN, CF3, OH, NH2, C 1~6 Alkyl, or C 1~6 R may be alkoxy. 4 In some embodiments, where R is H, cyclobutyl, or optionally substituted phenyl, 6 , R 7 , and R 8 are independent of each other, H, C 1~4 Alkyl, OH, C 1~4 -O-alkyl, -CHO, C 2~4 -CO-alkyl, C 2~4 -CO-alkyl, COH, C 2~4It may be -CO2-alkyl, F, Cl, Br, I, NO2, CN, optionally substituted phenyl, optionally substituted pyridinyl, or optionally substituted thiophenyl.

[0049] For any relevant structural representation, such as Eq. 2, R 5 is H or any substituent, such as a substituent having a molecular weight of 15 Da to 50 Da, 75 Da, 100 Da, 150 Da, or 200 Da, and / or consists of 1, 2, 3, 4, or 5 chemical elements, the chemical elements being C, H, N, O, S, F, Cl, or Br. 5 are NO2, CN, H, F, Cl, Br, I, CO2H, OH, C 1~6 Alkylamino, C 1~6 Alkyl, or C 1~6 In some embodiments, R 5 is H, Cl, Br, CN, or -OCH. In some embodiments, R 5 is H. In addition, for any of the above embodiments in this paragraph, R 6 , R 7 , and R 8 are independent, R A F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A CO2R A O.C.O.R. A NR A COR B , or CONR A R B , or H, F, Cl, CN, CF3, OH, NH2, C 1~6 Alkyl, or C 1~6 R may be alkoxy. 5 In some embodiments where R is H, 6 , R 7 , and R 8 are independent of each other, H, C 1~4 Alkyl, OH, C 1~4It may be -O-alkyl, -CHO, C2.4-CO-alkyl, C2.4-CO-alkyl, CO2H, C2.4-CO2-alkyl, F, Cl, Br, I, NO2, CN, optionally substituted phenyl, optionally substituted pyridinyl, or optionally substituted thiophenyl.

[0050] For any relevant structural representation, such as Eq. 2, R 6 is H or any substituent, such as a substituent having a molecular weight of 15 Da to 50 Da, 75 Da, 100 Da, 150 Da, or 200 Da, and / or consists of 1, 2, 3, 4, or 5 chemical elements, the chemical elements being C, H, N, O, S, F, Cl, or Br. 6 are NO2, CN, H, F, Cl, Br, I, CO2H, OH, C 1~6 Alkylamino, C 1~6 Alkyl, or C 1~6 In some embodiments, R 6 is H, CF, CN, halo (such as F, Cl, or Br), or -OCH. In some embodiments, R 6 is H. In some embodiments, R 6 is CF3. In some embodiments, R 6 is CN. In some embodiments, R 6 is Cl. In some embodiments, R 6 is Br. In some embodiments, R 6 is -OCH3. Further, for any of the above embodiments in this paragraph, R 5 , R 7 , and R 8 are independent, R A F, Cl, CN, OR A CF3, NO2, NR A R B , C.O.R. A CO2R A , O.C.O.R. A NR A COR B , or CONR A R B, or H, F, Cl, CN, CF3, OH, NH2, C 1~6 Alkyl, or C 1~6 R may be alkoxy. 6 In some embodiments, where R is H, CF, CN, Cl, Br, or -OCH, 5 , R 7 , and R 8 are independent of each other, H, C 1~4 Alkyl, OH, C 1~4 -O-alkyl, -CHO, C 2~4 -CO-alkyl, C 2~4 -CO-alkyl, COH, C 2~4 It may be -CO2-alkyl, F, Cl, Br, I, NO2, CN, optionally substituted phenyl, optionally substituted pyridinyl, or optionally substituted thiophenyl.

[0051] For any relevant structural representation, such as Eq. 2, R 7 is H or any substituent, such as a substituent having a molecular weight of 15 Da to 50 Da, 75 Da, 100 Da, 150 Da, or 200 Da, and / or consists of 1, 2, 3, 4, or 5 chemical elements, the chemical elements being C, H, N, O, S, F, Cl, or Br. 7 are NO2, CN, H, F, Cl, Br, I, CO2H, OH, C 1-6 Alkylamino, C 1~6 Alkyl, or C 1~6 In some embodiments, R 7 is H, Cl, Br, CN, or -OCH. In some embodiments, R 7 is H. Further, for any of the above embodiments in this paragraph, R 5 , R 6 , and R 8 are independent, R A F, Cl, CN, OR A , CF3, NO2, NR A R B , C.O.R. A , CO2R A O.C.O.R. A , N.R.A COR B , or CONR A R B , or H, F, Cl, CN, CF3, OH, NH2, C 1~6 Alkyl or C 1~6 R may be alkoxy. 7 In some embodiments where R is H, 5 , R 6 and R 8 are independent of each other, H, C 1~4 Alkyl, OH, C 1~4 -O-alkyl, -CHO, C 2~4 -CO-alkyl, C 2~4 -CO-alkyl, COH, C 2~4 It may be -CO2-alkyl, F, Cl, Br, I, NO2, CN, optionally substituted phenyl, optionally substituted pyridinyl, or optionally substituted thiophenyl.

[0052] For any relevant structural representation, such as Eq. 2, R 8 is H or any substituent, such as a substituent having a molecular weight of 15 Da to 50 Da, 75 Da, 100 Da, 150 Da, or 200 Da, and / or consists of 1, 2, 3, 4, or 5 chemical elements, where the chemical elements are C, H, N, O, S, F, Cl, or Br. 8 are NO2, CN, H, F, Cl, Br, I, CO2H, OH, C 1~6 Alkylamino, C 1~6 Alkyl, or C 1~6 In some embodiments, R 8 is H, Cl, Br, CN, or -OCH. In some embodiments, R 8 is H or Br. In some embodiments, R 8 is H. In some embodiments, R 8 Further, for any of the above embodiments in this paragraph, R 5 , R 6 , and R 7 are independent, R A F, Cl, CN, ORA , CF3, NO2, NR A R B , C.O.R. A CO2R A , O.C.O.R. A , N.R. A COR B , or CONR A R B , or H, F, Cl, CN, CF3, OH, NH2, C 1~6 Alkyl, or C 1~6 R may be alkoxy. 8 In some embodiments, where R is H or Br, 5 , R 6 , and R 7 are independent of each other, H, C 1~4 Alkyl, OH, C 1~4 -O-alkyl, -CHO, C 2~4 -CO-alkyl, C 2~4 -CO-alkyl, COH, C 2~4 It may be -CO2-alkyl, F, Cl, Br, I, NO2, CN, optionally substituted phenyl, optionally substituted pyridinyl, or optionally substituted thiophenyl.

[0053] Table 1 shows the structures of various exemplary embodiments prepared by the methods disclosed herein and indicates the general coupling method used along with a summary of the LCMS analytical data. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

[0054] Medical ingredients The embodiments herein are directed to pharmaceutical compositions comprising a therapeutically effective amount of a compound described herein or an acceptable salt thereof, such as a compound of formula 1 or 2 or Table 1 or a pharma- ceutically acceptable salt thereof. Pharmaceutical formulations containing such compounds and suitable carriers can be in various forms, including but not limited to solids, solutions, powders, fluid emulsions, fluid suspensions, semi-solids, and dry powders, containing an effective amount of the compound of the present invention. It is also known in the art that the active ingredient can be contained in such formulations together with pharma- ceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water-soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, antioxidants, preservatives, and the like. Means and methods for administration are known in the art, and the skilled artisan can refer to various pharmacological texts for guidance. See, e.g., Modern Pharmaceutics, Banker & Rhodes, Marcel Dekker, Inc. (1979), and Goodman & Oilman's, The Pharmaceutical Basis of Therapeutics, 6th Edition, MacMillan Publishing Co., New York (1980), both of which are incorporated by reference in their entireties.

[0055] The subject compositions may be formulated for any desired route of delivery, including, but not limited to, parenteral, intravenous, intradermal, subcutaneous, oral, inhalation, transdermal, topical, transmucosal, rectal, intracisternal, intravaginal, intraperitoneal, buccal, and intraocular.

[0056] Parenteral, intradermal, or subcutaneous preparations may be sterile injectable aqueous or oily suspensions or solutions. Acceptable vehicles, solutions, suspensions, and solvents include, but are not limited to, water or other sterile diluents, saline, Ringer's solution, sodium chloride, fixed oils such as monoglycerides or diglycerides, fatty acids such as oleic acid, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents, antibacterial agents such as benzyl alcohol or methylparabens, antioxidants such as ascorbic acid or sodium bisulfate, chelating agents such as ethylenediaminetetraacetic acid, buffers such as acetates, citrates or phosphates, and agents for adjusting tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide. Parenteral preparations may be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass or plastic.

[0057] Pharmaceutical compositions suitable for injectable use may include sterile aqueous solutions or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include, but are not limited to, physiological saline, bacteriostatic water, CREMOPHOR EL® (BASF, Parsippany, NJ), or phosphate buffered saline (PBS). The solvent or dispersion medium may contain, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial growth can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. The composition may also include an isotonic agent, for example, sugar, polyalcohol such as mannitol, sorbitol, or sodium chloride. Prolonged absorption of the injectable compositions can be enhanced by the addition of agents which delay absorption, such as aluminum monostearate or gelatin.

[0058] Oral compositions may contain inert diluents or edible carriers. They may be enclosed in gelatin capsules or compressed into tablets. Tablets, pills, capsules, troches, etc. may contain ingredients such as binders such as microcrystalline cellulose, tragacanth gum or gelatin, excipients such as starch or lactose, disintegrants such as alginic acid, primogel or corn starch, lubricants such as magnesium stearate, lubricants such as colloidal silicon dioxide, sweeteners such as sucrose or saccharin, or flavorings such as peppermint, methyl salicylate, orange flavoring, or any of the compounds with similar properties.

[0059] In addition to oral administration or injection administration, systemic administration can be by transmucosal or transdermal means.For transmucosal or transdermal administration, a penetrant can be used.Such penetrants are generally known in the art, and include, for example, surfactants, bile salts, and fusidic acid derivatives.Transdermal administration can include a biologically active agent and can be formulated into ointments, salves, gels, or creams generally known in the art.Transmucosal administration can be achieved through the use of nasal sprays or suppositories.

[0060] The subject compounds may be administered in therapeutically effective amounts according to an appropriate dosing regimen. As will be appreciated by those skilled in the art, the exact amount required may vary from subject to subject, depending on the species, age and general condition of the subject, the severity of the infection, the particular drug, and the mode of administration. In some embodiments, about 0.001 mg / kg to about 50 mg / kg of the pharmaceutical composition based on the subject's body weight is administered one or more times per day to achieve the desired therapeutic effect. In other embodiments, about 0.01 mg / kg to about 25 mg / kg of the pharmaceutical composition based on the subject's body weight is administered one or more times per day to achieve the desired therapeutic effect.

[0061] The total daily dosage of the subject compound can be determined by the attending physician within the scope of sound medical judgment.The specific therapeutically effective dose level for any specific patient or subject depends on various factors, including the disorder being treated and the severity of the disorder, the activity of the specific compound used, the specific composition used, the age, weight, general health, sex and diet of the patient or subject, the administration time, route of administration and excretion rate of the specific compound used, duration of treatment, drugs used in combination with or simultaneously with the specific compound used, and other factors well known in the medical arts.

[0062] How to use Embodiments are directed to methods of treating a disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a subject compound of Formula 1 or Formula 2 or Table 1. In some embodiments, the disorder is selected from epilepsy, neonatal convulsions, pain, migraine headaches, disorders of neurotransmitter release, disorders of smooth muscle contraction, dyskinesia, dystonia, mania, hearing disorders, neuropathic pain, inflammatory pain, persistent pain, cancer pain, post-operative pain, anxiety, substance abuse, schizophrenia, bladder disorders, vascular disorders, tinnitus, benign familial neonatal seizures, epilepsy, neurological disorders mediated by reduced basal M-currents (and subsequent neuronal hyperexcitability), sensorineural hearing disorders, intellectual disability, epileptic encephalopathy, treatment-resistant epilepsy, cortical atrophy, neurological disorders, infantile convulsions with hyperarrhythmia, myoclonic tonic seizures, myoclonic seizures, tonic seizures, absence seizures and focal onset seizures with impaired consciousness, congenital neurological disorders with intellectual disability or epilepsy. epileptic encephalopathy, benign familial neonatal convulsions, severe epileptic encephalopathy, congenital neurodevelopmental disorder phenotyped as nonsyndromic intellectual disability or epileptic encephalopathy, neonatal convulsions, neonatal convulsions, epilepsy, benign familial neonatal epilepsy, epileptic encephalopathy, benign familial neonatal convulsions type 1, benign familial neonatal convulsions type 1, neonatal convulsions associated with hypoxic-ischemic injury, epileptic convulsions, epileptic encephalopathy, early infantile epileptic encephalopathy type 7, early infantile epileptic encephalopathy with psychomotor developmental delay, generalized tonic seizures, pallidum dysmorphology, apnea, cerebral edema, dystonia, facial erythema, hypotonia, febrile seizures, corpus callosum hypoplasia, arrhythmia, focal clonic seizures, generalized tonic-clonic seizures, myokymia, spastic quadriplegia, myokymia, and combinations thereof. In embodiments, such compounds may be administered in a pharmaceutical composition as described herein.

[0063] Without wishing to be bound by theory, it has been shown that various Kv7 channels are expressed in a variety of ways throughout the body. For example, Kv7.1 is highly expressed in the heart, cardiac myocytes, renal proximal tubules, digestive tract, colonic crypt cells, pancreatic acinar cells, thyroid cells, and airway epithelium. Kv7.2 and Kv7.3 are robustly expressed in central neurons, peripheral neurons, and sensory neurons. Kv7.4 is highly expressed in the cochlea of ​​the inner ear and cardiac mitochondria. Kv7.5 is expressed in neurons and skeletal muscles. The channel subunits Kv7.1, Kv7.4, and Kv7.5 are highly expressed in vascular smooth muscle and non-vascular smooth muscle. Therefore, activating or regulating specific Kv7 subunits is effective in treating various disorders related to the nervous system, cardiovascular system, urogenital system, digestive system, reproductive system, and respiratory system.

[0064] The KCNQ1-5 genes encode the five subunits 1 to 5 of the Kv7 potassium channel, respectively. Functional Kv7 potassium channels can be assembled using combinations of these five subunits arranged as homo- or heterotetramers. Mutations in the genes encoding each Kv7 channel have been associated with human disease. Thus, activators or modulators of the mutant channels may be effective in alleviating symptoms associated with disease.

[0065] In most neurons of the central nervous system (CNS) and peripheral nerves, the dominant Kv7 subunits are Kv7.2, Kv7.3, and Kv7.5. Kv7 activators can be used to treat stroke and neuropathic pain. Inhibition of Kv7 channels promotes synaptic plasticity and can be used as cognitive enhancers. Kv7 activators, but not blockers, may prevent cognitive impairment in Alzheimer's disease (AD). Kv7 modulators may also be used to treat schizophrenia, substance abuse, and anxiety. Kv7.2 / 7.3 in the nucleus accumbens is altered by chronic alcohol intake. Kv7 activators have antidepressant activity, possibly via enhancing resilience (ability to cope with stress) mechanisms.

[0066] Mutations in the KCNQ2 and KCNQ3 genes are associated with inherited benign forms of epilepsy in newborns. KCNQ2 gene variants are responsible for a wide range of phenotypes characterized by hyperexcitability, from mild and self-limiting epilepsy [benign familial neonatal epilepsy (BFNE)] to severe epileptic encephalopathy with cognitive impairment, neuroradiological changes, and drug-resistant seizures [neonatal epileptic encephalopathy (NEE)]. KCNQ3 variants have also been described, but are only associated with BFNE. Such heterogeneity is partly explained by different mutations affecting different domains of the Kv7.2 channel. Alterations in Kv7 channel activity are also involved in cerebral ischemic injury, age-related memory impairment, stress-related dysfunction of the neuroendocrine system, addiction, and neuronal differentiation. Therefore, Kv7 channel activators can be used to treat epilepsy, partial seizures, and drug-resistant seizures, i.e., NEE. Modulation of Kv7 channels can treat many other diseases caused by neuronal hyperexcitability, such as neuropathic pain, ischemia, and schizophrenia. More recently, dysfunction of Kv7.3 / 7.5 has been associated with autism.

[0067] An embodiment of the present invention relates to a method for treating a disorder associated with Kv7 potassium channel, comprising administering a therapeutically effective amount of a compound described herein, or a compound of Formula 1 or Formula 2 or Table 1 described herein, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. The disorder is associated with the nervous system, the cardiovascular system, the genitourinary system, the digestive system, or the respiratory system.

[0068] In some embodiments, the nervous system disorder is epilepsy, epileptic convulsions, neonatal convulsions, neonatal seizures, benign familial neonatal epilepsy (BFNE), neonatal epileptic encephalopathy (NEE), focal seizures, focal epilepsy, myoclonic seizures, tonic and clonic seizures, tonic-clonic seizures (grand mal), partial seizures, drug-resistant seizures, pain, migraine, disorders of neurotransmitter release, early infantile epileptic encephalopathy with psychomotor developmental delay (EIEE, Otahara syndrome), generalized tonic seizures, pallidal dysmorphism, apnea, cerebral edema, dyskinesia, dystonia, facial erythema, hypotonia, febrile convulsions, hypoplasia of the corpus callosum. The therapeutic agent is selected from arrhythmia, focal clonic seizures, generalized tonic-clonic seizures, infantile spasms (West syndrome), Dawes syndrome (myoclonic static epilepsy of childhood), benign rolandic epilepsy (BRE), Rasmussen syndrome, Lennox-Gastaut syndrome, electrical status epilepsy of sleep (ESES), Sturge-Weber syndrome, juvenile myoclonic epilepsy, Dravet syndrome, myokymia, spastic quadriplegia, myokymia, mania, hearing impairment, neuroradiological changes, hearing loss, neuropathic pain, inflammatory pain, persistent pain, cancer pain, postoperative pain, cerebral ischemic injury, age-related memory impairment, stress-related neuroendocrine dysfunction, anxiety, depression, substance abuse, addiction, chronic alcohol use, schizophrenia, autism, amyotrophic lateral sclerosis, Alzheimer's disease, tinnitus, and combinations thereof.

[0069] The compounds described herein have been shown to activate subtypes of the Kv7 potassium channel family. Mutations in the KCNQ2 or KCNQ3 genes, which code for the Kv7.2 and Kv7.3 potassium channel subunits, respectively, result in a range of epilepsy disorders. The embodiments herein are directed to a method of treating disorders associated with mutations in the KCNQ2 subunit, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, or a compound of formula 1 or formula 2 or table 1 described herein, or a pharmaceutically acceptable salt thereof. The embodiments herein are directed to a method of treating disorders associated with mutations in the KCNQ3 subunit, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described in formula 1 or formula 2 or table 1, or any other compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, disorders that may be treated by the compounds disclosed herein include epilepsy, epileptic convulsions, neonatal convulsions, neonatal seizures, benign familial neonatal epilepsy (BFNE), neonatal epileptic encephalopathy (NEE), focal seizures, focal epilepsy, myoclonic seizures, tonic and clonic seizures, tonic-clonic seizures (grand mal), partial seizures, drug-resistant seizures, pain, migraine, disorders of neurotransmitter release, early infantile epileptic encephalopathy with psychomotor developmental delay (EIEE, Otahara syndrome), generalized tonic seizures, pallidal dysmorphism, apnea, cerebral edema, dyskinesia, dystonia, facial erythema, hypotonia, febrile convulsions, hypoplasia of the corpus callosum.The conditions may include, but are not limited to, arrhythmias, focal clonic seizures, generalized tonic-clonic seizures, infantile spasms (West syndrome), Dawes syndrome (myoclonic static epilepsy of childhood), benign rolandic epilepsy (BRE), Rasmussen syndrome, Lennox-Gastaut syndrome, sleep epilepsy electrical status (ESES), Sturge-Weber syndrome, juvenile myoclonic epilepsy, Dravet syndrome, myokymia, spastic quadriplegia, myokymia, mania, hearing impairment, neuroradiological changes, hearing loss, neuropathic pain, inflammatory pain, persistent pain, cancer pain, postoperative pain, cerebral ischemic injury, age-related memory impairment, stress-related neuroendocrine dysfunction, anxiety, depression, substance abuse, addiction, chronic alcohol use, schizophrenia, autism, amyotrophic lateral sclerosis, Alzheimer's disease, tinnitus, and combinations thereof. In some embodiments, such compounds may be administered in a pharmaceutical composition as described herein.

[0070] The embodiments herein are directed to a method of treating a disorder associated with a KCNQ subunit, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described in formula 1 or formula 2 or table 1, or any other compound described herein, or a pharma- ceutically acceptable salt thereof. In some embodiments, the KCNQ gene and the encoded Kv7 subunit are not mutated, but activation of the subunit has a beneficial effect. The embodiments herein are directed to a method of treating a disorder associated with a KCNQ2 subunit, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described in formula 1 or formula 2 or table 1, or any other compound described herein, or a pharma-ceutically acceptable salt thereof. The embodiments herein are directed to a method of treating a disorder associated with a KCNQ3 subunit, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described in paragraphs 1 or formula 2 or table 1, or any other compound described herein, or a pharma-ceutically acceptable salt thereof.

[0071] In embodiments, such compounds may be administered in a pharmaceutical composition as described herein.

[0072] The therapeutically effective amount of the compounds disclosed herein ranges from about 0.1 mg to about 1000 mg. Such therapeutically effective amounts may be administered once a day, or in equally divided doses twice a day, three times a day, or four times a day.

[0073] Groupings of alternative elements or embodiments disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that for reasons of convenience and / or patentability, one or more members of a group may be included in or deleted from a group. When such inclusion or deletion occurs, the specification is deemed to include the modified group and thus fulfills all Markush group descriptions used in the appended claims.

[0074] Experimental Section [ka]

[0075] Scheme 1 shows a general method for the synthesis of pyrazolo[1,5-a]pyridin-2,3-ylamides 1.7. An appropriately substituted 2-halo-pyridine 1.1 is reacted with an appropriately substituted acetonitrile to give 2-(1-cyanomethyl)pyridine 1.2. Pyridine 1.2 can be reacted with a suitable nitrogen donor reagent, such as O-(mesitylsulfonyl)hydroxylamine 1.3, to generate pyrazolo[1,5-a]pyridin-2,3-ylamine 1.4. Amine 1.4 is coupled with a suitable carboxylic acid 1.5 under standard amide forming conditions or via reaction with an acyl halide (1.6, Y=Cl, F, Br) to give the target pyrazolo[1,5-a]pyridin-2,3-ylamide 1.7. [ka]

[0076] Scheme 2 shows a general method for the conversion of 5-halo-pyrazolo[1,5-a]pyridin-2,3-ylamines 2.1 (X=Cl, Br, I) to various 5-substituted pyrazolo[1,5-a]pyridin-2,3-ylamines 2.2 by palladium, copper, or other transition metal catalyzed cross-coupling reactions. Reactants 2.1 may also include 2-aminopyrazolo[1,5-a]pyridin-5-ylsulfonates (X=RSO3). For example, appropriately substituted halides or sulfonates 2.1 are treated with zinc(ll) cyanide and tetrakis(triphenylphosphine)palladium(0) to give nitriles 2.3. A wide range of other transformations of 2.1 can be achieved using conditions well known in the art, including coupling reactions of alkyl, aryl, or heteroaryl boronate reagents, alkenyl, aryl, or heteroaryl tin reagents, substituted or unsubstituted alkenes, alkynes, amines, alcohols, ketones, and the like (see Magano J, Dunetz JR, Chem Rev 2011, 111, 2177-2250, and references cited therein). [ka]

[0077] Scheme 3 shows a general method for converting pyrazolo[1,5-a]pyridin-2,3-ylamines 3.1 to 3-halo derivatives 3.2 (X=Cl, Br, I). The halides 3.2 can then be converted to a variety of 3-substituted pyrazolo[1,5-a]pyridin-2,3-ylamines 3.3 by palladium, copper, or other transition metal catalyzed cross-linking reactions. For example, appropriately substituted halides 3.2 are treated with aryl, heteroaryl, or alkylboronic acids or esters with dichloro-bis(triphenylphosphine)palladium(0) to give 3.3 (R=alkyl, aryl, heteroaryl). A wide range of other conversions of 3.2 to 3.3 can be achieved using conditions well known in the art, as described in Scheme 2 above. [ka]

[0078] Scheme 4 shows a general method for the preparation of optionally substituted 3-hydroxypropanoic acids 4.4. Zinc-catalyzed condensation of bromo esters 4.1 with ketones or aldehydes 4.2 provides 3-hydroxypropanoic acids 4.3. Standard hydrolysis conditions convert esters 4.3 to acids 4.4. Acids 4.4 are useful in amide bond forming reactions as outlined in Scheme 1, Step C. [ka]

[0079] Scheme 5 describes a general synthetic method for the synthesis of chiral alkyl carboxylic acids containing -silyloxy ether protected acids 5.4 or ent-5.4. These optically active acids are used as the acid component in the amide formation reaction (step C of Scheme 1) to give -tertiary alcohol amides. Using diastereoselective bond construction via titanium enolate chemistry described by Evans and co-workers, chiral imides 5.1 or ent-5.1 were condensed with ketones or other electrophiles to give diastereomerically pure aldol adducts 5.2 or ent-5.2, respectively (see Evans, DA, Urpi, F, Somers, TC, Clark, JS, Bilodeau, MT, J. Am. Chem. Soc. 1990, 112, 8215-8216). Appropriate selection of chiral imide 5.1 results in the desired absolute stereochemistry of the -stereocenter in carboxylic acid 5.4 or ent-5.4. Silyl ether protection of the aldol adducts 5.2 and ent-5.2 with tert-butyldimethylsilyl triflate and diisopropylethylamine affords the tert-butyldimethylsilyl ethers 5.3 and ent-5.3. Standard acyloxazolidinone hydrolysis conditions using lithium hydroxide and hydrogen peroxide in tetrahydrofuran and water provide the desired acids 5.4 or ent-5.4 (see Evans, DA, Britton, TC, Ellman, JA, Tetrahedron Lett. 1987, 28(49), 6141-6144). The appropriate choice of ketone or other electrophile in titanium enolate chemistry is determined by the R 12 Groups and R 13 The resulting aldol adducts are appropriately substituted, differing in the nature of the R groups of the starting imides 5.1 and ent-5.1. 11 Changing the group is R of acid 5.4 or ent-5.4 11 The size and nature of the groups can be used to vary. This methodology allows for the synthesis of a wide range of optically active acids with absolute stereocontrol of the chiral center relative to the carbonyl of the carboxylic acid. [ka]

[0080] A general synthetic method for the synthesis of enantiomerically pure 4-methyl-branched chiral carboxylic acids 6.4 or ent-6.4 is described in Scheme 6. Both enantiomerically pure oxazolidinones (S)-4-benzyloxazolidin-2-one 6.1 and (R)-4-benzyloxazolidin-2-one ent-6.1 are commercially available. These oxazolidinones are readily acylated by deprotonation with n-butyllithium followed by reaction with acid chloride 6.5 to give the chiral imides 6.2 and ent-6.2, respectively. The R of this starting material 21 Group, R 22 Group, and R 3 There are numerous commercially available acid chlorides 6.5 with a wide range of groups. This allows for the rapid synthesis of chiral imides 6.2 and ent-6.2 with different substituents at the exocyclic carbonyl group at the -position. The asymmetric alkylation reaction of the chiral imide sodium enolate developed by Evans can then be used to introduce the methyl group in a stereoselective manner (see Evans, DA, Ennis, MD, Mathre, DJ, J. Am. Chem. Soc. 1982, 104, 1737-1739). The sodium enolate of imide 6.2 can be generated by treatment of 6.2 with sodium hexamethyldisilazide in tetrahydrofuran. The resulting sodium enolate can then be stereoselectively methylated by the addition of methyl iodide. The pure and single diastereomers 6.3 and ent-6.3 can be isolated by silica gel column chromatography. Alternatively, the single diastereomers can be obtained by recrystallization of the crystalline products 6.3 and ent-6.3. The well-known chiral assisted hydrolysis conditions described above for Scheme 5 afford the optically active -methyl-branched chiral carboxylic acids 6.4 or ent-6.4, respectively. [ka]

[0081] Scheme 7 shows a general method for the synthesis of 3-hydroxypropanoic acids such as 7.3. An appropriately substituted 2-bromoethanoic acid ester 7.1 is reacted with a ketone or aldehyde to give the 3-hydroxypropanoic acid ester 7.2. The ester group can be hydrolyzed to the corresponding acid by saponification to provide the 3-hydroxypropanoic acid such as 7.3.

[0082] Scheme 7 shows a general method for the synthesis of 3-hydroxypropanoic acids such as 7.3. An appropriately substituted 2-bromoethanoic acid ester 7.1 is reacted with a ketone or aldehyde to give the 3-hydroxypropanoic acid ester 7.2. The ester group can be hydrolyzed to the corresponding acid by saponification to provide the 3-hydroxypropanoic acid such as 7.3. [ka]

[0083] Scheme 8 shows additional methods for the preparation of optionally substituted 3-hydroxypropanoic acids. Appropriately substituted 3-acetyloxazolidin-2-ones 8.1 are reacted with ketones or aldehydes to give 3-(3-hydroxypropanoyl)oxazolidin-2-ones 8.2. The hydroxyl groups are functionalized with protecting groups to give diastereomers 8.3, which are separable by silica gel chromatography. Each diastereomer 8.3 is then reacted in a two-step hydroxyl group deprotection and oxazolidinone cleavage sequence in either order to give 3-hydroxypropanoic acids such as 8.6. Additionally, acyl oxazolidinones 8.2 can be directly hydrolyzed to hydroxy acids 8.6 by standard conditions. [ka]

[0084] Scheme 9 describes methods that can be employed to prepare pyrazolo[1,5-a]pyridin-2,3-ylamides substituted with hydroxyl-containing acyl groups, such as 9.4. Appropriately substituted pyrazolo[1,5-a]pyridin-2,3-ylamines 9.1 can be coupled with protected alcohol derivatives, such as 9.2, to give the corresponding amides 9.3. The alcohol protecting groups can be removed by several methods, for example, via removal of the silyl group using tetrabutylammonium fluoride, to provide the alcohol-containing pyrazolo[1,5-a]pyridin-2,3-ylamides, such as 9.4.

[0085] Synthesis method

[0086] Section 1. Representative procedure for the preparation of pyrazolo[1,5-a]pyridin-2,3-ylamines (compound 1.4, Scheme 1). Method 1: [ka]

[0087] Step A. Preparation of 2-cyclobutyl-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile. To a 0 °C solution of 2-fluoro-4-(trifluoromethyl)pyridine (0.50 g, 3.02 mmol) and 2-cyclobutylacetonitrile (0.29 mL, 3.02 mmol) in toluene (3 mL) was added sodium hexamethyldisilazide solution (6.1 mL, 1 M in THF, 6.1 mmol) dropwise. The mixture was allowed to warm slowly to room temperature and stirred overnight. The mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. Column chromatography (0-50% EtOAc / hexanes) afforded 2-cyclobutyl-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (0.39 g, 1.62 mmol, 54% yield). MS (ESI) m / z 241.2 (MH + ). 1H NMR(CDCl3):δ8.78(d,J=4.8Hz,1H),7.57(s,1H),7.49(d,4.8Hz,1H),4.09 (d,J=7.6Hz,1H),2.99-2.93(m,1H),2.12-2.02(m,4H),1.97-1.88(m,2H).

[0088] The following 2-(pyridin-2-yl)acetonitriles were prepared using the general procedure described in Section 1, Method 1, Step A, with the appropriate starting materials. 2-Cyclobutyl-2-(pyridin-2-yl)acetonitrile 2-(4-Chloropyridin-2-yl)-2-cyclobutylacetonitrile 2-(4-Bromopyridin-2-yl)-2-cyclobutylacetonitrile 2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile 2-(4-Fluorophenyl)-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile 2-(6-Bromopyridin-2-yl)-2-cyclobutylacetonitrile 2-Cyclobutyl-2-(4-methoxypyridin-2-yl)acetonitrile [ka]

[0089] Step B. Preparation of 3-cyclobutyl-5-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-amine. To a solution of O-(mesitylsulfonyl)hydroxylamine (1.2 g, 5.8 mmol, prepared by the procedure described in Org. Proc. Res. Dev. 2009, 13, 263-267) in dichloromethane (30 mL) at 0° C. was added 2-cyclobutyl-2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (0.93 g, 3.9 mmol). After 10 min, the reaction mixture was allowed to warm to room temperature and stirred overnight. The solvent was removed in vacuo. The residue was dissolved in MeOH and K2CO3 was added. After 2 h, MeOH was removed in vacuo. The residue was taken up in EtOAc and H2O and the layers were separated. The aqueous phase was extracted with EtOAc and the combined organic layers were dried over Na2SO4 and concentrated. Column chromatography (0-50% EtOAc / hexanes) afforded 0.37 g (37% yield) of 3-cyclobutyl-5-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-amine. MS (ESI) m / z 256.0 (MH + ). 1 H NMR(CDCl3): δ8.18(d,J=7.2Hz,1H),7.54(s,1H),6.59(d,J=7.2Hz),3.97(s,2 H), 3.60-3.56 (m, 1H), 2.45-2.34 (m, 4H), 2.12-2.05 (m, 1H), 1.98-1.95 (m, 1H).

[0090] The following pyrazolo[1,5-a]pyridin-2-amines were prepared using the general procedure described in Section 1, Method 1, Step B, with the appropriate starting materials.

[0091] 3-Cyclobutylpyrazolo[1,5-a]pyridin-2-amine

[0092] 5-Chloro-3-cyclobutylpyrazolo[1,5-a]pyridin-2-amine

[0093] 5-Bromo-3-cyclobutylpyrazolo[1,5-a]pyridin-2-amine

[0094] 5-(Trifluoromethyl)pyrazolo[1,5-a]pyridin-2-amine

[0095] 7-Bromo-3-cyclobutylpyrazolo[1,5-a]pyridin-2-amine

[0096] 3-(4-Fluorophenyl)-5-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-amine: A modified procedure was used for the isolation of the title compound. After stirring a reaction mixture of starting material and MSH in dichloromethane overnight, a precipitate formed in the reaction mixture was removed by filtration. The filtrate was then concentrated in vacuo. The residue was taken up in ether and washed twice with 0.50 M KOH. The organic layer was dried (Na2SO4) and concentrated. Column chromatography (0-50% EtOAc / Hexanes) afforded 3-(4-fluorophenyl)-5-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-amine in 37% yield.

[0097] Method 2: Exemplary procedure for crosslinking of halo-substituted pyrazolo[1,5-a]pyridin-2-amines (Scheme 2). [ka]

[0098] Preparation of 2-amino-3-cyclobutylpyrazolo[1,5-a]pyridine-5-carbonitrile. Nitrogen gas was bubbled through a mixture of 5-bromo-3-cyclobutylpyrazolo[1,5-a]pyridin-2-amine (0.49 g, 1.8 mmol), zinc cyanide (0.21 g, 1.8 mmol), and tetrakis(triphenylphosphine)palladium[0] (0.43 g, 0.37 mmol) in N-methylpyrrolidinone (10 mL) for 10 min. The mixture was then heated to 110 °C in a sealed vial. After 5 h, the mixture was diluted with EtOAc and washed three times with water. The organic extract was dried over Na2SO4 and concentrated. Column chromatography (0-100% EtOAc / hexane) afforded 0.27 g (70% yield) of the title compound. MS (ESI) m / z 213.2 (MH + ). 1 H NMR(CDCI3):δ8.14(dd,J=0.8,7.2Hz,1H),7.65(dd,J=0.8,2.0Hz,1H),6.55(dd,J=2,7.2Hz, 1H),4.00(s,2H),3.60-3.53(m,1H),2.50-2.31(m,4H),2.20-2.05(m,1H),1.98-1.95(m,1H).

[0099] Method 3: An exemplary procedure for the iodination and subsequent cross-coupling of 3-unsubstituted pyrazolo[1,5-a]pyridin-2-amines (Scheme 3). [ka]

[0100] Step A. Preparation of 3-iodo-5-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-amine. 5-(Trifluoromethyl)pyrazolo[1,5-a]pyridin-2-amine (165 mg, 0.82 mmol) was dissolved in CH3CN (3.3 mL) and cooled to 0 °C. To this solution was added N-iodosuccinimide (146 mg, 0.82 mmol) and the solution was warmed to room temperature and stirred for 2 h. The reaction mixture was diluted with EtOAc, washed successively with H2O and brine, dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (0-40% EtOAc / hexanes) afforded the title compound (154 mg, 67%). MS (ESI) 280.0 / 282.0 (MH + ). [ka]

[0101] Step B. Preparation of 3-(p-tolyl)-5-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-amine. A pressure tube was combined with 3-iodo-5-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-amine (75 mg, 0.23 mmol), 4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2-dioxaborolane (100 mg, 0.46 mmol), 1:1 dioxane / HO (1.5 mL), solid NaCO (24 mg, 0.23 mmol), and dichloro-bis(triphenylphosphine)palladium[0] (3 mg, 0.005 mmol), the tube was sealed, and heated at 150° C. for 1 h. The mixture was cooled, the solution was diluted with EtOAc, washed with brine, and the organic layer was dried (NaSO), filtered, and concentrated in vacuo. Purification by column chromatography (0-30% EtOAc / hexanes) afforded the title compound (51 mg, 76%). NMR (CDCI3) δ 8.26 (d, J = 7.2 Hz, 1H), 7.66 (s, 1H), 7.40 (d, J = 7.6 Hz, 2H), 7.32 (d, J = 7.6 Hz, 2H), 6.71 (dd, J = 2.0, 8.0 Hz, 1H), 4.22 (s, 2H), 2.42 (s, 3H). MS (ESI) m / z 278.0 (MH +).

[0102] The following pyrazolo[1,5-a]pyridin-2-amines were prepared using the general procedure described in Section 1, Method 3, Step B, with the appropriate starting materials.

[0103] 3-(5-chlorothiophene-2-yl)-5-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-amine

[0104] 3-(6-chloropyridin-3-yl)-5-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-amine

[0105] Method 4: Exemplary procedure for the bromination of 3-unsubstituted pyrazolo[1,5-a]pyridin-2-amines and subsequent cross-coupling (Scheme 3). [ka]

[0106] Step A. Preparation of 3-bromo-5-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-amine. Following the procedure of Method 3, Step A, substituting N-iodosuccinimide for N-bromosuccinimide, the title compound was produced. NMR (CDCI3) δ 8.29 (d, J = 7.1 Hz, 1H), 7.68 (s, 1H), 7.53-7.43 (m, 1H), 7.33-7.28 (m, 1H), 7.25-7.20 (m, 1H), 7.07-7.00 (m, 1H), 6.76 (dd, J = 1.9, 7.2 Hz, 1H), 4.25 (s, 1H). MS (ESI) m / z 328.0 (MH + ) [ka]

[0107] Step B. Preparation of 3-(3-fluorophenyl)-5-(trifluoromethyl)-pyrazolo[1,5-a]pyridin-2-amine. Following the steps of Method 3, substituting 4,4,5,5-tetramethyl-2-(3-fluorophenyl)-1,3,2-dioxaborolane with 4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2-dioxaborolane, the title compound was produced. NMR(CDCl3)δ8.29(d,J=7.1Hz,1H)7.68(s,1H),7.53-7.43(m,1H),7.33-7.28(m,1H),7. 25-7.20(m,1H),7.07-7.00(m,1H)6.76(dd,J=1.9,7.2Hz,1H),4.25(s,2H).MS(ESI)m / z 296.0(MH + ).

[0108] The following pyrazolo[1,5-a]pyridin-2-amines were prepared using the general procedure described in Section 1, Method 4, Step B, with the appropriate starting materials.

[0109] 3-Phenyl-5-(trifluoromethyl)-pyrazolo[1,5-a]pyridin-2-amine

[0110] 3-(4-chlorophenyl)-5-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-amine

[0111] Section 2. Representative procedure for the preparation of pyrazolo[1,5-a]pyridin-2,3-ylamides (compound 1.6, Scheme 1). [ka]

[0112] Method 5: General procedure for amide formation using HATU (1-((dimethylamino)(dimethyliminio)methyl)-1H-benzo[d][1,2,3]triazole 3-oxide hexafluorophosphate (V)) and N,N-diisopropylethylamine.

[0113] To a solution of the appropriate carboxylic acid 1.5 (1.2-2.0 molar equivalents) in DMF, N-methylpyrrolidinone, or THF (0.1-1M) was added HATU (1.8 molar equivalents) and N,N-diisopropylethylamine (2.0 molar equivalents). The appropriate pyrazolo[1,5-a]pyridin-2-amine (1.0 molar equivalents) was added. The mixture was heated to 50-60 °C for 18-48 h. The mixture was then diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and water (4 times). The organic layer was dried over sodium sulfate and concentrated. Purification by column chromatography (0-100% EtOAc / Hexanes or 0-10% MeOH / CH2Cl2) afforded the amide compounds. [ka]

[0114] Method 6: Exemplary procedure for amide formation using HATU (1-((dimethylamino)(dimethyliminio)methyl)-1H-benzo[d][1,2,3]triazole 3-oxide hexafluorophosphate (V)) and pyridine. Preparation of N-(3-cyclobutyl-5-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl)-2-(1-hydroxycyclopentyl)acetamide.

[0115] To a solution of 2-(1-hydroxycyclopentyl)acetic acid (27 mg, 0.19 mmol) in DMF (0.3 mL) was added HATU (119 mg, 0.31 mmol) and pyridine (25 μL and 0.31 mmol) at room temperature. After 5 min, 3-cyclobutyl-5-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-amine (40 mg, 0.16 mmol) was added. The mixture was stirred at room temperature for 18 h. The crude reaction mixture was directly purified by reverse phase chromatography (10-100% acetonitrile / water). Further purification by column chromatography (0-100% EtOAc / DCM) afforded N-(3-cyclobutyl-5-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl)-2-(1-hydroxycyclopentyl)acetamide (13 mg, 0.034 mmol). (ESI) m / z 382.4 (M+H). [ka]

[0116] Method 7: Exemplary procedure for amide formation using HATU (1-((dimethylamino)(dimethyliminio)methyl)-1H-benzo[d][1,2,3]triazole 3-oxide hexafluorophosphate (V)) and pyridine, amide formation using a silyl-protected hydroxy acid, followed by deprotection of the silyl group. Preparation of (R)-N-(3-cyclobutyl-5-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl)-3-hydroxy-3-(pyridin-2-yl)butanamide. [ka]

[0117] Step A. Preparation of (R)-3-((tert-butyldimethylsilyl)oxy)-N-(3-cyclobutyl-5-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl)-3-(pyridin-2-yl)butanamide. To a solution of (R)-3-((tert-butyldimethylsilyl)oxy)-3-(pyridin-2-yl)butanoic acid (35 mg, 0.12 mmol) in DMF (0.3 mL) was added pyridine (19 μL, 0.24 mmol) and HATU (67 mg, 0.18 mmol) and the mixture was stirred at room temperature for 10 min. 3-Cyclobutyl-5-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-amine (30 mg, 0.12 mmol) was added and the mixture was stirred at 50° C. overnight. The solution was cooled to room temperature then diluted with EtOAc, washed successively with H.sub.2O and brine, dried (Na.sub.2SO.sub.4), filtered and concentrated to give the crude amide which was taken on to Step B without further purification. [ka]

[0118] Step B. Preparation of (R)-N-(3-cyclobutyl-5-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl)-3-hydroxy-3-(pyridin-2-yl)butanamide. The crude material from step A was dissolved in THF (0.35 mL) and a 1.0 M solution of tetra(n-butyl)ammonium fluoride in THF (1 mL) was added. The resulting mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo and the crude material was purified by column chromatography (gradient with 0-100% EtOAc / hexanes) followed by a second purification using HPLC (10-100% CH3CN / H2O) to give the title compound (29.4 mg, 59%). NMR(CDCl3)δ8.86(s,1H),8.54(d,J=4.4Hz,1H),8.38(d,J=8.4Hz,1H)7.82-7.71(m,2H),7.48(d,J=8.0Hz,1H),6.77(d,J=8.0Hz,1H) ,6.14(s,1H),3.58-3.44(m,1H),3.02(dd,J=14.8,28.4Hz,2H),2.40-2.17(m,4H),2.12-1.97(m,1H),1.97-1.83(m,1H).MS(ESI)m / z 419.2(MH + ). [ka]

[0119] Method 8: General procedure for amide formation using acyl chlorides.

[0120] To a solution of the appropriate pyrazolo[1,5-a]pyridin-2-amine (1 equiv.) in THF (0.1 M) was added triethylamine (2 equiv.) and acyl chloride (1.2 equiv.) at room temperature. The reaction mixture was stirred for 4 h. The mixture was partitioned between EtOAc and water. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by column chromatography (0-100% EtOAc / Hexanes or 0-10% MeOH / CH2Cl2) to give the amide compounds.

[0121] Section 3. Exemplary syntheses of carboxylic acids useful for coupling reactions with pyrazolo[1,5-a]pyridin-2,3-ylamines (1.7 in Scheme 1).

[0122] Method 9. Preparation of (S)-3-hydroxy-3-phenylbutanoic acid. [ka]

[0123] Step A. Preparation of (S)-4-benzyl-3-((S)-3-hydroxy-3-phenylbutanoyl)oxazolidin-2-one. A solution of LiN(TMS)2 (1.0 M in THF, 9.2 mL, 9.2 mmol) was added dropwise to a mixture of (S)-3-acetyl-4-benzyloxazolidin-2-one (2.0 g, 9.2 mmol) in THF (8 mL) at -78 °C. The mixture was stirred at -78 °C for 2 h, then acetophenone (0.5 g, 4.2 mmol) was added over 10 min. The mixture was stirred at -78 °C for 1 h, then quenched by the addition of 1.0 N HCl. The mixture was warmed to room temperature and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel chromatography (0-50% EtOAc / Hexanes) to give the product, which was further purified by recrystallization from hot MTBE to give the desired product (590 mg) as a single diastereomer by NMR. Stereochemical assignment derived from Theurer, et al, Tetrahedron, 2010, 66, 3814. [ka]

[0124] Step B. Preparation of (S)-3-hydroxy-3-phenylbutanoic acid. To a solution of (S)-4-benzyl-3-((S)-3-hydroxy-3-phenylbutanoyl)oxazolidin-2-one (590 mg, 1.7 mmol) in 1:1 THF:H2O (9 mL) was added 30% aqueous H2O2 (788 μL, 7.0 mmol) and LiOH (167 mg, 7.0 mmol). The mixture was stirred vigorously for 2 h, then the reaction was partitioned between water (50 mL) and EtOAc (25 mL). The aqueous layer was isolated and the pH was adjusted to pH=2 with 1.0 N HCl. The aqueous mixture was extracted three times with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to give the desired crude product, which was used directly in the following coupling reaction. (ESI) m / z 179.2 (MH).

[0125] Method 10. Preparation of (R)-3-((tert-butyldimethylsilyl)oxy)-3-(pyridin-2-yl)butanoic acid. [ka]

[0126] Step A: Preparation of (S)-4-benzyl-3-((R)-3-hydroxy-3-(pyridin-2-yl)butanoyl)oxazolidin-2-one. Lithium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 6.9 mL, 6.9 mmol) was added over 15 min to a suspension of (S)-3-acetyl-4-benzyloxazolidin-2-one (1.52 g, 6.9 mmol) in tetrahydrofuran (12 mL) at -78 °C. The mixture was stirred at -78 °C for 2 h. A solution of 2-acetylpyridine (800 mg, 6.6 mmol) in tetrahydrofuran (4 mL) was added over 35 min. The mixture was stirred at -78 °C for 1 h and then quenched by the addition of 0.5 M aqueous HCl. The mixture was allowed to warm to room temperature and then extracted with CHCl. The layers were separated and the aqueous phase was extracted two more times with CH2Cl2. The combined organics were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography (0-30% EtOAc / Hexanes) to give the desired compound in partially purified form (1.9 g), which was used as is. [ka]

[0127] Step B: Preparation of (S)-4-benzyl-3-((R)-3-((tert-butyldimethylsilyl)oxy)-3-(pyridin-2-yl)butanoyl)oxazolidin-2-one. tert-Butyldimethylsilyl trifluoromethanesulfonate (1.4 mL, 6.1 mmol) was added dropwise to a room temperature solution of the residue prepared as described in step A and Et3N (1.2 mL, 8.4 mmol) in CHCl2 (33 mL). The mixture was stirred overnight at room temperature and then partitioned between EtOAc and saturated aqueous NaHCO3. The phases were separated and the organics were washed with saturated aqueous NaCl. The two aqueous phases were then extracted twice successively with EtOAc. The combined organics were dried over anhydrous Na2SO4 and concentrated. The residue was purified twice by silica gel chromatography (0-15% EtOAc / Hexanes) to give the expected product (1.55 g, 61%). NMR (CDCl3) δ 8.47 (d, J = 5.4 Hz, 1H), 7.75-7.68 (m, 2H), 7.33-7.21 (m, 3H), 7.17-7.10 (m, 3H), 4.62-4.53 (m, 1H), 4.07 (d, J = 4.4 Hz, 2H), 3.87 (d, J = 15.6 Hz, 1H), 3.64 (d, J = 15.6 Hz, 1H), 3.18-3.11 (m, 1H), 2.69-2.59 (m, 1H), 0.94 (s, 9H), 0.14 (s, 3H), 0.09 (s, 3H). [ka]

[0128] Step C: Preparation of (R)-3-((tert-butyldimethylsilyl)oxy)-3-(pyridin-2-yl)butanoic acid. Lithium hydroxide (0.8 M in H2O, 21.3 mL, 17.0 mmol) and 30% aqueous hydrogen peroxide (1.74 mL, 17.0 mmol) were added to a mixture of (S)-4-benzyl-3-((R)-3-((tert-butyldimethylsilyl)oxy)-3-phenylbutanoyl)oxazolidin-2-one (1.55 g, 3.4 mmol) obtained from step B in tetrahydrofuran (20 mL) at 0°C. The mixture was stirred at 0°C to room temperature for 80 min. The mixture was adjusted to pH 2 by addition of 1 M aqueous HCl, then extracted with EtOAc. The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel chromatography (0-30% EtOAc / Hexanes) to give the expected product (0.70 g, 69%). NMR (CDCI3) δ 16.00 (s, 1H), 8.47 (d, J = 5.2 Hz, 1H), 7.89 (t, J = 7.4, 14.8 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.37 (t, J = 6.6, 13.2 Hz, 1H), 3.25 (d, J = 14.4 Hz, 1H), 2.99 (d, J = 13.2 Hz, 1H), 1.69 (s, 3H), 0.93 (s, 9H), 0.145 (s, 3H), 0.135 (s, 3H). [ka]

[0129] Method 11. Preparation of (S)-3-((tert-butyldimethylsilyl)oxy)-3-(pyridin-2-yl)butanoic acid.

[0130] The title compound was prepared in the same manner as in Step A above, except that (R)-3-acetyl-4-benzyloxazolidin-2-one was used instead of (S)-3-acetyl-4-benzyloxazolidin-2-one.

[0131] Method 12. Example of the synthesis of 3,3-dialkyl-3-hydroxypropanoic acids. Preparation of 2-(1-hydroxycyclopentyl)acetic acid. [ka]

[0132] Step A. Preparation of ethyl 2-(1-hydroxycyclopentyl)acetate. Chlorotrimethylsilane (181 μL, 1.4 mmol) was added to a suspension of zinc powder (1.2 g, 19 mmol) in Et2O (30 mL). The mixture was stirred at room temperature for 15 min and then refluxed for 15 min. The heat source was removed and ethyl bromoacetate (1.8 mL, 14 mmol) was added dropwise to the warm mixture. The mixture was then refluxed for 1 h and then stirred at room temperature for 1 h. Cyclopentanone (1.0 g, 12 mmol) was then added dropwise. The resulting mixture was stirred for 1 h and then poured into ice-cold concentrated aqueous ammonia (80 mL). The layers were separated and the aqueous phase was extracted with Et2O (3×40 mL). The combined organics were dried (K2CO3) and concentrated to give 1.7 g of a colorless oil. This material was used directly in the next step. [ka]

[0133] Step B. Preparation of 2-(1-hydroxycyclopentyl)acetic acid. Lithium hydroxide (1.4 g, 58 mmol) was added to a room temperature solution of the crude ester, prepared as described in the previous step (1.0 g, 5.8 mmol), in 1:1 EtOH:water (29 mL). After 2 h, the reaction was partitioned between water (100 mL) and MTBE (100 mL). The aqueous layer was isolated and the pH was adjusted to pH=2 with 1.0 N HCl. The aqueous mixture was extracted three times with EtOAc. The combined organics were dried (Na2SO4) and concentrated to give the desired product (500 mg, 60%). (ESI) m / z 143.2 (MH).

[0134] The following carboxylic acids were prepared using the general procedure described in Method 12 with the appropriate starting materials.

[0135] 2-(1-Hydroxycyclobutyl)acetic acid

[0136] 3-Cyclopropyl-3-hydroxybutanoic acid

[0137] 3-Cyclobutyl-3-hydroxybutanoic acid

[0138] 3-Cyclopentyl-3-hydroxybutanoic acid

[0139] Common analytical methods LCMS was performed on an Agilent 1100 MSD instrument equipped with an Ascentis Express C18, 10 cm x 4.6 mm x 2.7 mm column using the following method.

[0140] HPLC Method A Solvent A: 0.1% formic acid in water Solvent B: Acetonitrile Flow rate: 1.4mL / min method: Gradient from 0 to 6.0 min, B = 10% to B = 95% 6.0-8.0 min, B held at 95% 8.0–8.2 min, gradient from B=95% to B=10% 8.2-10.0 min, B held at 10%

[0141] HPLC method B: Solvent A: 0.1% formic acid in water Solvent B: Acetonitrile Flow rate: 1.4mL / min method: Gradient from 0 to 3.0 min, B = 10% to B = 95% 3.0-4.0 min, B held at 95% 4.0–4.2 min, gradient from B=95% to B=10% 4.2-6.0 min, B held at 10%

[0142] Biological Assay Methods Kv7.2 / 7.3 activation assay

[0143] The ability of compounds to enhance K currents in Kv7.2 / 7.3 containing HEK cells was assessed using planar patch clamp on the QPatch automated screening platform.

[0144] Cell Lines: The hKv7.2 / 7.3 cell line was obtained from Chantest (Cleveland, OH 44128) catalog number CT6147. These HEK cells express the Kv7.2 / 7.3 ion channel upon induction.

[0145] Cell culture: Cells were maintained in medium containing DMEM / F12; 50 / 50 (GIBCO catalog no. 11330), 10% fetal bovine serum (FBS) (GIBCO catalog no. 26140), 100 units / mL penicillin-streptomycin (GIBCO catalog no. 15140), 0.005 mg / mL blasticidin (INVIVOGEN catalog no. ant-bl-1), 0.5 mg / mL geneticin (GIBCO catalog no. 10131), 0.1 mg / mL zeocin (GIBCO catalog no. R25001). Cells used in electrophysiology assays were maintained in medium without blasticidin, geneticin, and zeocin for 2 days, and channel expression was induced by adding tetracycline (BIOKINE catalog no. BIO-87030) at a final concentration of 1 mg / mL. Cells were grown in T-175 flasks to approximately 75% confluency. Currents were recorded 24 hours after channel induction.

[0146] Compound Plate: Test compounds were plated on a Biomek NX P (BECKMAN COULTER). Final dilutions were made in external recording solution with a final DMSO concentration of 0.1% DMSO. For the single concentration screen, each plate had 10 μM retigabine as a positive control and 0.1% DMSO as a negative control.

[0147] Electrophysiology: On the day of the experiment, cells were washed with Hank's Balanced Salt Solution (HBBS) (GIBCO Catalog No. 14175) and harvested in a Tryple (GIBCO Catalog No. 12604). Cells were then centrifuged at 2000 rpm for 5 min and resuspended in CHO-S-SFM (GIBCO Catalog No. 12052) at ∼3 × 10 6 The cells were resuspended at 1000 cells / mL. The cells were stirred for 30 min before starting the experiment. The external recording solution contained (in mM) NaCl (145), KCl (4), CaCl2 (2), MgCl2 (1), HEPES (10), and glucose (10), pH adjusted to 7.4 with NaOH, and osmolality adjusted to 300–305 mOsM with sucrose, as needed. The internal solution contained (in mM) KCl (125), KF (10), EGTA (5), Na2ATP (5), MgCl2 (3.2), and HEPES (5), pH adjusted to 7.2 with KOH, and osmolality adjusted to 298–302 mOsM with sucrose.

[0148] Potassium channel activity was measured on a QPatch HTX (Sophion Bioscience) using QPIates with 48 wells / plate. Each cell was taken as an independent experiment and only one compound was tested per well. Potassium channel activity was induced by holding at -80 mV and stepping to -30 mV for 2 s followed by a 100 ms pulse to -120 mV.

[0149] Single concentration screen: Baseline conditions were obtained by recording five sweeps in external solution alone, which was repeated for three applications of external solution. The effect of test compounds on the evoked currents was then assessed by recording five sweeps in the presence of 3 μM compound solution. Steady-state currents at the end of a 2 s pulse to -30 mV were measured to determine the fold increase from baseline.

[0150] The data from the Kv7.2 / 7.3 activation assay are summarized in Table 2. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

[0151] The thallium flux assay is used as a surrogate indicator of potassium channel activity.

[0152] The experimental protocol was extracted from the FluxORTM II Green Potassium Ion Channel Assay User Guide (Pub. No. MAN0016084, Invitrogen). Conditions were optimized for the Kv7.2 / 7.3 cell line.

[0153] Cell lines: The hKv7.2 / 7.3 cell line was obtained from Chantest (Cleveland, OH 44128) catalog number CT6147.

[0154] Cell culture: Kv7.2 / 7.3 cells were maintained in medium containing DMEM / F12; 50 / 50 (GIBCO catalog no. 11330), 10% fetal bovine serum (FBS) (GIBCO catalog no. 26140), 100 units / mL penicillin-streptomycin (GIBCO catalog no. 15140), 0.005 mg / mL blasticidin (SIGMA 15205), 0.5 mg / mL genetics (GIBCO catalog no. 10131), and 0.1 mg / mL zeocin (GIBCO catalog no. R25001). The day before the experiment, cells were plated in 96-well clear bottom plates (Corning catalog no. 353219) in medium without blasticidin, geneticin, or zeocin. Channel expression was induced with a final concentration of 10 ng / mL tetracycline (Bioline catalog number BIO87030).

[0155] Compound plate: Test compounds are diluted in a mixture of 0.1% DMSO / extracellular solution in an 8-point concentration range from 0.014 μM to 30 μM. Serial dilutions were performed on a Biomek NXP (BECKMAN COULTER).

[0156] Measurement and Data Analysis: The ion channel modulating properties of novel compounds are evaluated using a plate reader (Enspire, Perkin Elmer) at an excitation wavelength of 475 nm and an emission wavelength of 530 nm. After a 15 second baseline measurement, a stimulation buffer containing thallium and potassium is injected. A final endpoint measurement is taken after 90 seconds. Responses are normalized to a positive control (retigabine, up to 30 μM). The average normalized responses at each concentration tested were fitted to the standard Hill equation to calculate the EC50 and maximum response.

[0157] The thallium flux assay data are summarized in Table 3. [Table 3]

[0158] Groupings of alternative elements or embodiments disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that for reasons of convenience and / or patentability, one or more members of a group may be included in or deleted from a group. When such inclusion or deletion occurs, the specification is deemed to include the modified group and thus fulfills all Markush group descriptions used in the appended claims.

[0159] Certain embodiments are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations of these described embodiments will become apparent to those skilled in the art upon reading the foregoing description. The inventors expect those skilled in the art to adopt such variations as necessary, and the inventors intend the invention to be carried out in ways not specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter recited in the claims that are permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is contemplated unless otherwise indicated herein or clearly contradicted by context.

[0160] In conclusion, it should be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be employed are within the scope of the claims. Thus, by way of example, and not of limitation, alternative embodiments may be utilized in accordance with the teachings of the present specification. Thus, the claims are not limited to the exact embodiments shown and described.

Claims

1. A compound represented by the formula: 【Chemistry 1】 wherein Het is optionally substituted pyrazolo[1,5-a]pyridin-2-yl; R １ But C １～６ Linear or C １～６ is a branched alkyl; R ２ But H, OH, CF ３ , or C ３～６ -cycloalkyl-OH, R ３ But H, CF ３ , optionally substituted phenyl, optionally substituted pyridinyl, or optionally substituted C ３～６ or a pharmaceutically acceptable salt thereof, provided that the compound 【change】 (Except).

2. R ２ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

3. R ２ But CF ３ 2. The compound of claim 1, wherein:

4. R ２ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: is OH.

5. R ２ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is cyclobutyl-OH, or -cyclopentyl-OH.

6. R ３ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 is CF 3 and R 3 is H.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 is OH and R 3 is H.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 is cyclobutyl-OH or -cyclopentyl-OH and R 3 is H.

10. R ３ But CF ３ 2. The compound of claim 1, wherein:

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 is CF 3 and R 3 is CF 3 .

12. R ３ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is optionally substituted phenyl.

13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 is H and R 3 is optionally substituted phenyl.

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 is OH and R 3 is optionally substituted phenyl.

15. R ３ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is optionally substituted pyridinyl.

16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 is H and R 3 is optionally substituted pyridinyl.

17. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 is OH and R 3 is optionally substituted pyridinyl.

18. R ３ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is optionally substituted cyclobutyl or optionally substituted cyclopentyl.

19. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 is H and R 3 is optionally substituted cyclobutyl or optionally substituted cyclopentyl.

20. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 is OH and R 3 is optionally substituted cyclobutyl or optionally substituted cyclopentyl.

21. Het, R １ , and R ３ or a pharmaceutically acceptable salt thereof, wherein any substituent independently has a molecular weight of 15 Da to 200 Da and consists of 1 to 5 chemical elements, said chemical elements being C, H, O, N, S, F, Cl, or Br.

22. Het, R １ , and R ３ any of the substituents independently selected from H, F, Cl, Br, I, C １～６ Alkyl, C １～６ Alkyl-OH, CF ３ , C.N., C. １～６ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is O-alkyl, or optionally substituted aryl.

23. A compound represented by the following formula: 【Chemistry 2】 In the formula, R ４ But H, F, Cl, Br, I, C １～６ Alkyl, C １～６ -Alkyl-OH, CF ３ , C.N., C. １～６ -O-alkyl, optionally substituted C ３～６ cycloalkyl, optionally substituted aryl, optionally substituted thiophenyl, or optionally substituted pyridinyl; R ５ , R ６ , R ７ , and R ８ are each independently H, F, Cl, Br, I, C １～６ Alkyl, C １～６ -Alkyl-OH, CF ３ , C.N., C. １～６ -O-alkyl, optionally substituted C ３～６ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is cycloalkyl, or optionally substituted aryl.

24. R ４ 24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein is cyclobutyl, optionally substituted phenyl, optionally substituted pyridinyl, or optionally substituted thiophenyl.

25. A compound of the formula: 【Transformation 3】 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 【Transformation 34】 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 【Transformation 38】 【Chemistry 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemistry 44】 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 【Chemistry 49】 [Transformation 50] 【Chemistry 51】 【Chemistry 52】 【Chemistry 53】 【Chemistry 54】 【Transformation 55】 【Transformation 56】 【Chemistry 57】 【Chemistry 58】 【Chemistry 59】 【Transformation 60】 【Chemistry 61】 【Transformation 62】 【Transformation 63】 【Chemistry 64】 【Transformation 65】 【Chemical Formula 66】 【Transformation 67】 【Transformation 68】 【Transformation 69】 【Transformation 70】 【Chemistry 71】 【Chemistry 72】 【Transformation 73】 【Chemistry 74】 【Chemistry 75】 【Transformation 76】 【Chemical 77】 【Transformation 78】 【Transformation 79】 【Chemistry 80】 【Chemistry 81】 【Chemistry 82】 【Chemistry 83】 【Chemical 84】 【Chemical 85】 【Chemical 86】 【Transformation 87】 【Chemical 88】 【Chemistry 89】 [Chemical 90] 【Chemistry 91】 【Chemistry 92】 【Chemistry 93】 【Chemical 94】 【Chemical 95】 【Chemistry 96】 【Chemistry 97】 【Chem.98】 or 【Chem.99】 2. The compound of claim 1, wherein:

26. A pharmaceutical composition comprising a compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof.

27. ​​A pharmaceutical composition as described in claim 26, comprising a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, for treating a disorder associated with the Kv7 potassium channel.

28. The disorder is epilepsy, epileptic convulsions, neonatal convulsions, neonatal seizures, benign familial neonatal epilepsy (BFNE), neonatal epileptic encephalopathy (NEE), focal seizures, focal epilepsy, myoclonic seizures, tonic and clonic seizures, tonic-clonic seizures (grand mal seizures), partial seizures, drug-resistant seizures, pain, migraine, disorders of neurotransmitter release, early infantile epileptic encephalopathy with psychomotor developmental delay (EIEE, Ohtahara syndrome), generalized tonic seizures, pallidal dysmorphism, apnea, cerebral edema, dyskinesia, dystonia, facial erythema, hypotonia, febrile convulsions, hypoplasia of the corpus callosum.

27. The pharmaceutical composition of claim 26, wherein the therapeutic agent is selected from arrhythmia, focal clonic seizures, generalized tonic-clonic seizures, infantile spasms (West syndrome), Dawes syndrome (myoclonic static epilepsy of childhood), benign rolandic epilepsy (BRE), Rasmussen syndrome, Lennox-Gastaut syndrome, electrical states of sleep epilepsy (ESES), Sturge-Weber syndrome, juvenile myoclonic epilepsy, Dravet syndrome, myokymia, spastic quadriplegia, myokymia, mania, hearing impairment, neuroradiological changes, hearing loss, neuropathic pain, inflammatory pain, persistent pain, cancer pain, post-operative pain, cerebral ischemic injury, age-related memory impairment, stress-related neuroendocrine dysfunction, anxiety, depression, substance abuse, addiction, chronic alcohol use, schizophrenia, autism, amyotrophic lateral sclerosis, Alzheimer's disease, tinnitus, and combinations thereof.

29. The pharmaceutical composition of claim 26, comprising a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, for treating a disorder associated with a mutation in KCNQ2 or KCNQ3.

30. The disorder is epilepsy, epileptic convulsions, neonatal convulsions, neonatal seizures, benign familial neonatal epilepsy (BFNE), neonatal epileptic encephalopathy (NEE), focal seizures, focal epilepsy, myoclonic seizures, tonic and clonic seizures, tonic-clonic seizures (grand mal seizures), partial seizures, drug-resistant seizures, pain, migraine, disorders of neurotransmitter release, early infantile epileptic encephalopathy with psychomotor developmental delay (EIEE, Ohtahara syndrome), generalized tonic seizures, pallidal dysmorphism, apnea, cerebral edema, dyskinesia, dystonia, facial erythema, hypotonia, febrile convulsions, hypoplasia of the corpus callosum.

30. The pharmaceutical composition of claim 29, wherein the therapeutic agent is selected from arrhythmia, focal clonic seizures, generalized tonic-clonic seizures, infantile spasms (West syndrome), Dawes syndrome (myoclonic static epilepsy of childhood), benign rolandic epilepsy (BRE), Rasmussen syndrome, Lennox-Gastaut syndrome, electrical states of sleep epilepsy (ESES), Sturge-Weber syndrome, juvenile myoclonic epilepsy, Dravet syndrome, myokymia, spastic quadriplegia, myokymia, mania, hearing impairment, neuroradiological changes, hearing loss, neuropathic pain, inflammatory pain, persistent pain, cancer pain, post-operative pain, cerebral ischemic injury, age-related memory impairment, stress-related neuroendocrine dysfunction, anxiety, depression, substance abuse, addiction, chronic alcohol use, schizophrenia, autism, amyotrophic lateral sclerosis, Alzheimer's disease, tinnitus, and combinations thereof.

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