Pyrazolyl compounds as KV7 channel activators

Abstract

Provided herein are optionally substituted pyrazolyl acetamides, pharmaceutical compositions comprising a therapeutically effective amount of such compounds and a pharma- ceutically acceptable excipient, and methods of treating diseases or disorders, such as epilepsy, amyotrophic lateral sclerosis, various types of pain, hyperexcitability, dyskinesia, dystonia, mania, tinnitus, neurodevelopmental diseases or disorders, disorders of smooth muscle contractility, Dravet syndrome, and post-traumatic stress disorder (PTSD), using such compounds and pharmaceutical compositions.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. § 119 to U.S. Provisional Patent Application No. 63 / 313,208, filed February 23, 2022, and any and all benefits arising therefrom, the contents of which are incorporated herein by reference in their entirety.

[0002] Statement on Federally Sponsored Research This invention was made with United States Government support under Grant No. U44NS115732 awarded by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health. The United States Government has certain rights in this invention. [Background technology]

[0003] Potassium (K + ) channels are the most diverse class of all ion channels and are associated with a wide range of physiological functions, including the regulation of electrical properties of excitable cells. The primary pore-forming (α) 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, the 6TM / 1P, 2TM / 1P and 4TM / 2P K + The Kv7 gene (originally called KCNQ, a name assigned by the HUGO Gene Nomenclature Committee (HGNC)) is designated by the International Union of Pharmacology (IUPHAR) as a voltage-gated K + The Kv7 subfamily is a voltage-gated K channel that has an intracellular N-terminal domain and a 6TM-spanning region (S1-S6) adjacent to the C-terminal domain. +It consists of five homologous pore-forming α subunits Kv7.1-7.5 with the typical structure of a channel, a typical voltage sensor domain located at S4 composed of alternating positively charged residues, and a single P region between S5 and S6 of each subunit. The channel is formed as a tetramer of primary α subunits, either as a homotetramer or heterotetramer. Neurons are known to express Kv7 channels composed of Kv7.2-7.5 α subunits. Some of these gene products may be exclusively neuronal, while others, such as Kv7.4 and Kv7.5, may 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 are slowly activated and deactivated, are active at or near the resting membrane potential of neurons, and muscarinic cholinergic agonists cause a decrease in the M-current, indicating that M-channels interact with G protein-coupled receptors (GPCRs) and physiological K-currents. + It was remarkable because it demonstrated a direct and inhibitory link between Kv7.2 / 7.3 (and possibly Kv7.5 / 7.3) heteromultimers and the elusive "M" channels until the cloning of this subfamily of genes, providing important new evidence for their importance in neuromodulation.

[0005] The regional and developmental distribution of these channels, as well as their biophysical properties, support their role in providing durable resistance to the excitatory effects of depolarization. Under physiological conditions, as shown for native M-channels, they can be highly effective in modulating the subthreshold excitability of specific neuronal populations, with a key role in regulating the frequency and ultimately the pattern of action potential discharge in many types of neurons. Their importance in neuronal regulation was interrupted by the discovery that neuronal Kv7 mutations cause 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, suggesting their usefulness as targets for antiepileptic drugs (AEDs).

[0006] Unlike established pharmacological terminology for GPCRs, K +The mode of action of channel modulators, especially compounds that activate channels, is still being refined. The application of voltage clamp techniques to the study of ion channel pharmacology allows detailed biophysical studies on either whole cell currents or single channels, allowing some characterization of the nature of compound-channel interactions, but does not prevent continued confusion regarding terminology. The terms opener or activator are commonly used throughout the literature, but do not fully describe the mode of action of all these "positive modulator" compounds. In general, openers or activators are expected to increase the open probability of the channel or increase the macroscopic current amplitude, but this nomenclature is really too simplistic. For example, ezogabine, 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 can work in concert with the activity of the channel over the "normal" activation voltage range, enhancing currents without significantly affecting the activation threshold, while others may significantly alter the activation threshold. In addition, some openers appear to completely remove the voltage dependence of activation. Whether these effects represent any continuum is unclear at this time, since the effects are often concentration-dependent. Clearly, the mode of interaction of compounds that can increase channel current is complex and in most cases not well understood, and the impact of these profiles on neuronal responsiveness and the physiology of the system is also unclear. Ezogabine is a moderately potent, not very specific, but very effective opener of Kv7.2, Kv7.5 and heteromultimeric Kv7 channels. 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 (this "crossover" voltage dependence of the opener action is a feature of many neuronal Kv7 channel openers). This effect is also concentration-dependent, being more pronounced at higher concentrations.

[0007] There remains a need for new selective Kv7 channel openers to effectively treat a variety of medical conditions. Summary of the Invention

[0008] Provided herein are genera and compounds that may be potent against Kv7.2 / 7.3 heteromultimers, which may have reduced undesirable side effects compared to ezogabine.

[0009] Mutations in Kv7.2, and less commonly in Kv7.3, have been reported to be the cause of autosomal dominant benign neonatal seizures (BFNS), mainly due to haploinsufficiency. BFNS is an idiopathic epilepsy with seizures occurring on the first postnatal day and is caused by mutations in both Kv7.2 and Kv7.3. Kv7.2 and Kv7.3 interact to give larger currents than the individual currents obtained as homomers. In situ hybridization shows that Kv7.2 is present mainly in the cerebellar cortex, including the dentate gyrus, the neocortex, and the hippocampal formation. These three structures show distinct epileptic seizure susceptibility. Kv7.3 is localized in the same regions of the mouse brain. However, Kv7.2 expression appears earlier than Kv7.3 expression and increases rapidly during the first postnatal week. At birth, Kv7.3 is expressed in very low amounts, whereas Kv7.2 is already expressed at significant levels. Thus, distinct profiles of Kv7.2 and Kv7.3 association occur during development.

[0010] BFNS usually shows an excellent long-term prognosis, but recurrence of seizures later in life has also been described. More recently, novel and maternally inherited mutations in Kv7.2 have been found to be involved in 5%–23% of cases of early infantile epileptic encephalopathy (EIEE). Kv7.2 encephalopathy is often present in the first week of life and has a distinct electroclinical pattern, characterized by frequent tonic seizures with or without autonomic features, and burst suppression or multifocal epileptiform abnormalities with attenuation on electroencephalography (EEG). Neuroimaging reveals in some cases frontal lobe hypoplasia or transient MRI signal abnormalities in the basal ganglia or thalamus. Even if seizure control with the use of AEDs is achieved in the first months of life, neurodevelopmental outcome is poor in all children. It has been proposed that clinical variability in Kv7.2-related epilepsy may be related to the functional consequences of mutations on M-currents and thus predict neurological prognosis. There is a striking disparity in the effects of known mutations on Kv7.2 function, which changes in association with the Kv7.3 subunit. Homomeric channel density may be the most reliable property linking Kv7.2 function to encephalopathy. It is hypothesized that homomeric Kv7.2 channels play an essential role in fine-tuning neural connections during early brain development and correlate with the severity of the dominant-negative effect of encephalopathy-causing Kv7.2 mutations.

[0011] The compounds of formula 1 or Table 1 provided herein, or pharma- ceutically acceptable salts thereof, are effective activators of Kv7.2 homotetramer, Kv7.3 homotetramer, Kv7.2 / 7.3 heterotetramer, and based on the above-mentioned expression of Kv7.2 and Kv7.3 channels, such compounds are effective in treating disorders of early infantile development, such as Angelman syndrome, neonatal abstinence syndrome, early myoclonic encephalopathy, Landau-Kleffner syndrome, electrical status epilepticus during sleep, Ohtahara syndrome, autism spectrum disorder, Dravet syndrome, Lennox-Gastaut syndrome, Rett syndrome, Hirschsprung's disease (HSCR), West syndrome, SCN8A-associated epilepsy with encephalopathy (EIEE13), infantile epilepsy with migrating focal seizures (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), Doose syndrome, and combinations thereof.

[0012] In certain embodiments, the compounds of Formula 1 or Table 1 described herein, or pharma- ceutically acceptable salts thereof, modulate Kv7.2 / 7.3 and GABA A In certain embodiments, the compounds of Formula 1 or Table 1 described herein, or pharma- ceutically acceptable salts thereof, do not modulate α1β3γ2 GABA A It is a selective activator of Kv7.2 / 7.3 with very low or no regulatory selectivity for the receptor.

[0013] In some embodiments, the compounds of Formula 1 or Table 1 described herein, or pharma- ceutically acceptable salts thereof, are superior to ezogabine due to the absence of undesirable off-target side effects, which are selected from the group consisting of dizziness, fatigue, drowsiness, confusion, vertigo, tremor, ataxia, double or blurred vision, attention deficit, memory impairment, muscle weakness, skin discoloration, withdrawal episodes, QT interval changes, suicidal behavior, urinary retention, drowsiness, hallucinations, confusion, and combinations thereof.

[0014] In certain embodiments, the compound of formula 1 or table 1 described herein, or a pharma- ceutically acceptable salt thereof, has increased stability against photo-oxidation compared to ezogabine.In certain embodiments, the compound of formula 1 or table 1 described herein, or a pharma- ceutically acceptable salt thereof, has higher potency in activating Kv7 channels compared to ezogabine.In certain embodiments, the compound of formula 1 or table 1 described herein, or a pharma- ceutically acceptable salt thereof, has higher subject tolerance compared to ezogabine. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] Before describing the compositions and methods, it should be understood that any invention is not limited to the specific process, composition, or methodology described, as this may vary. Moreover, the processes, compositions, and methodologies described in a particular embodiment are interchangeable. Thus, for example, a composition, dosing regimen, route of administration, 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 merely for the purpose of describing particular aspects or embodiments, and are not intended to limit the scope of the invention, which will be 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 one of ordinary skill in the art. Although any method similar or equivalent to those described herein may be used in the practice or testing of embodiments of the present invention, the preferred method is described below. 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.

[0016] Please note that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0017] 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 within the range of 45% to 55%. Unless otherwise indicated, all numbers expressing the amounts of ingredients, properties such as molecular weight, 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 otherwise indicated to the contrary, the numerical parameters set forth in the following specification and the appended claims are approximations that may vary depending on the desired properties sought to be obtained. At the very least, and without any intention to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed at least in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0018] "Administering," when used in conjunction with a therapeutic agent, means administering the therapeutic agent directly into or onto a target tissue, or administering the therapeutic agent to a subject, thereby positively affecting the tissue to which the therapeutic agent is targeted. "Administering" a composition may be accomplished by oral administration, injection, infusion, absorption, or by any method in combination with other known techniques. "Administering" may include the act of self-administration, or administration by other people or devices, such as a health care provider.

[0019] 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.

[0020] 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.

[0021] As used herein, the terms "consisting essentially of" or "consists essentially of" mean a composition or method that includes only the recited materials or steps, as well as those that do not materially affect the basic and novel characteristics of the claimed invention.

[0022] The term "improve" is used to convey that the present invention refers to the overall physical condition of an individual to whom an active agent is administered. For example, an individual's overall physical condition can be "improved" if one or more symptoms of a condition, disease or disorder, such as a neurodegenerative disorder, are alleviated by administration of an active agent. "Improving" can also refer to a change in the appearance, morphology, characteristics, and / or physical attributes, or any combination thereof, of the tissue to which it is provided, applied, or administered.

[0023] The terms "inhibit," "suppress," "reduce," "interfere," and / or "reduce" (and similar terms) generally refer to the act of directly or indirectly decreasing a function, activity, or behavior compared to natural, expected, average, or current conditions.

[0024] As used herein, the phrase "Kv7-related disease" refers to a disease, disorder, or condition, or combination thereof, associated with a mutation in the KCNQ2 gene, associated with a mutation in the KCNQ3 gene, associated with a mutation in the KCNQ4 gene, associated with a mutation in the KCNQ5 gene, associated with a gene encoding the Kv7 potassium channel, associated with a non-mutated Kv7 potassium channel, but associated with a dysfunctional Kv7 potassium channel, associated with cellular hyperexcitability that is believed to cause the disease, disorder, or condition. Regardless of causation, these Kv7-related diseases, disorders, or conditions can be treated by activating the Kv7 potassium channel, even if the Kv7 potassium channel may not be the direct or indirect cause of the disease, disorder, or condition.

[0025] Examples of Kv7-related disorders associated with mutations in the KCNQ2 gene include, but are not limited to, benign familial neonatal seizures (BFNS) or KCNQ2 encephalopathy (also known as KCNQ2 neonatal epileptic encephalopathy). Examples of Kv7-related disorders associated with mutations in the KCNQ3 gene include, but are not limited to, BFNS or KCNQ3-related developmental disorders. Examples of Kv7-related disorders associated with mutations in the KCNQ4 gene include, but are not limited to, autosomal dominant nonsyndromic hearing loss. Examples of Kv7-related disorders associated with mutations in the KCNQ5 gene include, but are not limited to, nonsyndromic intellectual disability or epileptic encephalopathy. Examples of disorders associated with cellular hyperexcitability that are believed to cause a disease, disorder, or condition include, but are not limited to, focal clonic seizures, generalized tonic-clonic seizures, neuropathic pain, overactive bladder, or smooth muscle disorder, or a combination thereof.

[0026] In each embodiment 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 is given to the subject for that particular purpose.

[0027] As used herein, the term "therapeutic agent" means an agent utilized to treat, combat, alleviate, or prevent an unwanted condition, disorder, or disease in a subject, or side effects thereof, or any combination thereof.

[0028] As used herein, the terms "patient" and "subject" are interchangeable and may be construed to mean any living organism that may be treated with a compound of the invention. Thus, the terms "patient" and "subject" may include, but are not limited to, any non-human mammal or human. In some embodiments, a "patient" or "subject" is an adult, child, infant, or fetus. In some embodiments, a "patient" or "subject" is a human. In some embodiments, a "patient" or "subject" is a mammal, such as a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, non-human primate, or human.

[0029] The terms "therapeutically effective amount" or "therapeutic dose" as used herein are interchangeable 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 medicinal response may include, for example, one or more of the following: (1) preventing a disease, condition, or disorder in an individual who is susceptible to the disease, condition, or disorder but has not yet experienced or exhibited the pathology or symptoms of the disease, condition, or disorder; (2) inhibiting a disease, condition, or disorder in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder, or halting further progression of the pathology and / or symptoms of the disease, condition, or disorder; and (3) ameliorating a disease, condition, or disorder in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder, or reversing the pathology and / or symptoms experienced or exhibited by the individual.

[0030] The terms "treat," "treated," or "treating" may be interpreted 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 reducing symptoms associated with a particular disorder, disease, or condition. In some embodiments, the term refers to reducing symptoms associated with a particular disorder, disease, or condition. In some embodiments, the term refers to reducing 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.

[0031] "Pharmaceutically acceptable salts" is meant to refer to those salts that, within the scope of sound medical judgment, are suitable for use in contact with patient tissues without undue toxicity, irritation, allergic response, and the like, and are 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 pharmaceutically acceptable salts in detail. A pharma- ceutically acceptable "salt" is any acid addition salt, preferably a pharma- ceutically acceptable acid addition salt, including, but not limited to, halogen salts, such as hydrobromide, hydrochloride, hydrofluoride, and hydroiodide; inorganic acid salts, such as, for example, nitrate, perchlorate, sulfate, and phosphate; sulfonate (methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate or p-toluenesulfonate), acetate, malate, fumarate, succinate, citrate, benzoate, gluconate, These include organic acid salts such as lactate, mandelate, mucate, pamoate, pantothenate, oxalate, and maleate; and amino acid salts such as aspartate or glutamate. The acid addition salt may be a monovalent or divalent acid addition salt, such as a dihalate, disulfate, diphosphate, or diorgano acid salt. In all cases, the acid addition salt is used as an achiral reagent that is not selected based on any expected or known preference for interaction with or precipitation by a particular optical isomer of the product of the present disclosure.

[0032] Unless otherwise indicated, when a compound or chemical structural feature, such as aryl, is referred to as "optionally substituted," it includes a feature that does not have a substituent (i.e., unsubstituted) or a feature that is "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 a moiety that replaces one or more hydrogen atoms bonded to a parent compound or structural feature. In some embodiments, the substituent may be a conventional organic moiety 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 g / mol to 50 g / mol, 15 g / mol to 100 g / mol, 15 g / mol to 150 g / mol, 15 g / mol to 200 g / mol, 15 g / mol to 300 g / mol, or 15 g / mol to 500 g / mol. In some embodiments, a 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 of which may independently be N, O, S, Si, F, Cl, Br, or I, with the proviso that the substituent contains one C, N, O, S, Si, F, Cl, Br, or I atom. Examples of substituents include, but are not limited to, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, acyl, acyloxy, alkylcarboxylate, thiol, alkylthio, cyano, halo, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxyl, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, etc. The prefix "halo" in the name of any substituent means that one or more halogen atoms may be present in the substituent.

[0033] For convenience, the term "molecular weight" is used in reference to a part or portion of a molecule, which may not be a complete molecule, to indicate the sum of the atomic masses of the atoms in the part or portion of the molecule.

[0034] Below are structures associated with some of the chemical names mentioned herein. These structures may be substituted or unsubstituted. [ka] Unless indicated by, bonding may occur at any position normally occupied by a hydrogen atom.

[0035] As used herein, the term "alkyl" has the broadest meaning generally understood in the art and may include moieties composed of carbon and hydrogen that do not contain double or triple bonds. Alkyl may be a straight chain alkyl, branched chain alkyl, cycloalkyl, or combinations thereof, and in some embodiments, may contain 1 to 35 carbon atoms. In some embodiments, alkyl includes C 1~10 Straight chain alkyls, such as methyl (-CH3), methylene (-CH2-), ethyl (-CH2CH3), ethylene (-C2H4-), n-propyl (-CH2CH2CH3), propylene (-C3H6-), n-butyl (-CH2CH2CH2CH3), n-pentyl (-CH2CH2CH2CH2CH3), pentylene (-CH2CH2CH2CH2CH2CH2-), n-hexyl (-CH2CH2CH2CH2CH2CH3), hexylene (-CH2CH2CH2CH2CH2CH2-), etc.; C 3~10 Branched alkyl, e.g., C3H7 (e.g., iso-propyl), C4H9 (e.g., branched butyl isomers), C5H 11 (e.g., branched pentyl isomers), C6H 13 (e.g., branched-chain hexyl isomers), C7H 15 (e.g., branched-chain heptyl isomers), etc.; C 3~10Cycloalkyl, for example, C3H5 (e.g., cyclopropyl), C4H7 (e.g., cyclobutyl isomers, for example, cyclobutyl, methylcyclopropyl, etc.), C5H9 (e.g., cyclopentyl isomers, for example, cyclopentyl, methylcyclobutyl, dimethylcyclopropyl, etc.), C6H 11 (e.g., cyclohexyl isomers), C7H 13 (e.g., cycloheptyl isomers), bicyclo[1.1.1]pentane, norborane, and the like.

[0036] With respect to an optionally substituted moiety, such as an optionally substituted alkyl, the term "optionally substituted C 1~12 Terms such as "alkyl" and "alkyl-1,1-C alkyl" include C alkyl groups that may be unsubstituted or may have one or more substituents and do 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 optionally substituted C 1~12 It is an alkyl group. 1~12 "Optionally substituted alkyl of" refers to unsubstituted C 1~12 Refers to an alkyl or substituted alkyl group in which the alkyl parent and all of the substituents both contain 1 to 12 carbon atoms. For example, CH2CH2OCH3 is a C 1~12 and optionally substituted alkyl of the formula: Similar rules can be applied to other optionally substituted moieties such as aryl and heterocyclyl.

[0037] The substituents on the alkyl may be the same as those generally 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 optionally substituted alkyls such as indenyl, where the phenyl substituent is fused to a parent alkyl moiety), and may have a molecular weight of from about 15 to about 100 or about 500.

[0038] As used herein, the term "haloalkyl" has the broadest meaning understood in the art and may include the above-defined alkyl group in which at least one hydrogen is replaced with a halogen selected from fluorine, chlorine, bromine, and iodine. Examples of "haloalkyl" may include fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, etc.

[0039] As used herein, the term "hydroxyalkyl" has the broadest meaning understood in the art and may include alkyl groups as defined above, in which at least one hydrogen is replaced with hydroxyl (-OH). Examples of "hydroxyalkyl" may include hydroxymethyl, hydroxyethyl, hydroxypropyl, and the like.

[0040] As used herein, the term "cycloalkyl" has its broadest meaning as understood in the art and can include groups having one or more saturated rings in which all of the ring members are carbon, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0041] As used herein, the term "halocycloalkyl" has the broadest meaning understood in the art and may include a cycloalkyl group as defined above in which at least one hydrogen is replaced with a halogen selected from fluorine, chlorine, bromine, and iodine. Examples of "halocycloalkyl" may include fluorocyclopropyl, difluorocyclopropyl, fluorocyclobutyl, difluorocyclobutyl, and the like.

[0042] As used herein, the term "alkanoyl" has the broadest meaning understood in the art and may include groups having the formula "alkyl-C(=O)-", where "alkyl" is an alkyl group as defined above. Examples of "alkanoyl" may include methylcarbonyl, ethylcarbonyl, propylcarbonyl, and the like.

[0043] As used herein, the term "alkenyl" has the broadest meaning understood in the art and may include straight or branched chain monovalent hydrocarbon radicals having at least one carbon-carbon double bond. Examples of "alkenyl" may include ethenyl, propenyl, butenyl, butadienyl, and the like.

[0044] As used herein, the term "aryl" shall have its broadest meaning as generally understood in the art and may include aromatic rings or ring systems such as phenyl, naphthyl, dihydroindene, and the like.

[0045] As used herein, the term "haloaryl" has the broadest meaning generally understood in the art and may include an aryl group as defined above in which at least one hydrogen is replaced with a halogen selected from fluorine, chlorine, bromine, and iodine. Examples of "haloaryl" may include fluorophenyl, chlorophenyl, iodophenyl, and the like.

[0046] 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.

[0047] 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, thiophenyl, pyrazolyl, triazolyl, oxadiazolyl, isoxazolyl, indolyl, indazolyl, indenyl, thiodiazolyl, quinolinyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzisoxazolyl, pyridinyl, methylpyridinone, and the like.

[0048] 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, cycloalkynyls, e.g., cyclopropynyl, cyclobutynyl, cyclopentynyl, cyclohexynyl, bridged cycloalkyls, e.g., bicyclo[1.1.1]pentane, norborane, etc., as well as aryl rings that do not contain heteroatoms.

[0049] The ranges of groups listed include all groups contained therein having the specified number of carbon atoms. For example, "C 1~4 The term "alkyl" includes C1 alkyl, C2 alkyl, C3 alkyl, and C4 alkyl groups, and is used interchangeably with "C 3~8 The term "cycloalkyl" includes C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, C7 cycloalkyl, and C8 cycloalkyl groups, and is intended to include "C 2~8 The term "heterocyclyl" includes C2 heterocyclyl, C3 heterocyclyl, C4 heterocyclyl, C5 heterocyclyl, C6 heterocyclyl, C7 heterocyclyl, and C8 heterocyclyl groups. 1~4 The statement "alkyl" is equivalent to the statement "C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl" and "C 3~8A statement such as "C cycloalkyl" is equivalent to a statement such as "C cycloalkyl, C cycloalkyl, C 5 cycloalkyl, C 6 cycloalkyl, C 7 cycloalkyl, C 8 cycloalkyl" and "C 2~8 It is understood that the description "heterocyclyl" is equivalent to the descriptions "C2 heterocyclyl, C3 heterocyclyl, C4 heterocyclyl, C5 heterocyclyl, C6 heterocyclyl, C7 heterocyclyl, C8 heterocyclyl."

[0050] Where stereochemistry is not indicated, the name or structural representation includes any stereoisomer or any mixture of stereoisomers, and applicants reserve the right to specifically identify and claim compounds as single stereoisomers or any particular mixture of stereoisomers.

[0051] The compounds described herein may contain asymmetric centers and therefore may exist as enantiomers. When compounds according to embodiments herein have two or more asymmetric centers, they may further exist as diastereomers. The embodiments herein include all such possible stereoisomers as substantially pure resolved enantiomers, their racemic mixtures, as well as mixtures of diastereomers. In some embodiments, the formulas are shown without definitive stereochemistry at specific positions. The embodiments herein include all stereoisomers of such formulas and pharma-ceutically acceptable salts thereof. Diastereomeric pairs of enantiomers may be separated, for example, by fractional crystallization from a suitable solvent, and the enantiomeric pairs thus obtained may be separated into individual stereoisomers by conventional means, for example, by using an optically active acid or base as a resolving agent, or on a chiral HPLC column. Additionally, any enantiomer or diastereomer of a compound of the general formula may be obtained by stereospecific or stereoselective synthesis using optically pure or enantioenriched starting materials or reagents of known configuration. The scope of the embodiments described and claimed herein encompasses racemic forms of the compounds, as well as individual enantiomers, diastereomers, and stereoisomer-enriched mixtures, and applicants reserve the right to specifically identify and claim any such forms of the compounds.

[0052] The compounds disclosed herein can exist as all stereoisomers, conformational isomers, and mixtures thereof in all proportions, as well as isotopic forms such as deuterated compounds, and therefore applicants reserve the right to specifically identify and claim any such form of the compound.

[0053] In some embodiments of the present invention, one or more hydrogen atoms are replaced with deuterium.It is well established that deuteration of physiologically active compounds provides the advantage of retaining the pharmacological profile of their hydrogen counterparts while positively affecting their metabolic results.Selectively replacing one or more hydrogen atoms with deuterium in the compounds of the present invention can improve the safety, tolerability and efficacy of the compound compared to its all hydrogen counterparts.

[0054] Methods for incorporating deuterium into compounds are well established. Using metabolic studies established in the art, compounds of the present invention can be tested to identify sites for selective placement of deuterium isotopes, where the isotope is not metabolized. Furthermore, these studies identify sites of metabolism as the locations where the deuterium atoms are placed.

[0055] compound Some embodiments of the present invention include a compound represented by formula 1, [ka] During the ceremony, R1 is optionally substituted C 1~4 Alkyl, optionally substituted C 3~8 Cycloalkyl, optionally substituted C 5~10 Aryl, optionally substituted C 2~8 Heteroaryl, optionally substituted C 2~8 Heterocyclyl or optionally substituted -C(O)NHC 1~4 alkyl, each optional substituent is independently halogen, OH, CN, -C(O)NH2, -N(C 1~4 Alkyl)2, C 1~4 Alkyl, C 5~10 Aryl and C 5~10 haloaryl; R2 is H, halogen, optionally substituted C 1~8 Alkyl, optionally substituted C 1~8Haloalkyl, optionally substituted -OC 1~8 Alkyl, optionally substituted C 2~8 Alkanoyl, optionally substituted C 3~10 Cycloalkyl, optionally substituted benzo(C 3~8 cycloalkyl), optionally substituted C 5~10 Aryl, optionally substituted benzoyl, optionally substituted -OC 5~10 Aryl, optionally substituted C 2~8 Heteroaryl or optionally substituted -OC 2~8 heteroaryl, each optional substituent independently being halogen, OH, CN, COH, C 1~4 Alkyl, C 1~4 Hydroxyalkyl, C 1~4 Haloalkyl, -OC 1~4 Alkyl, -OC 1~4 Haloalkyl, C 3~8 Cycloalkyl, C 3~8 Halocycloalkyl, -CO2H, -SO2C 1~4 Alkyl, -SO2C 1~4 Haloalkyl, C 5~10 Aryl and C 5~10 Haloaryl, -N(C 1~4 Alkyl)2, -NC 1~4 Alkyl 、 or optionally substituted C 2~8 heterocyclyl; R3 is H, halogen, optionally substituted C 1~6 Alkyl, optionally substituted C 3~8 Cycloalkyl, optionally substituted C 2~8 Heterocyclyl or optionally substituted C 5~10 aryl, each optional substituent is independently selected from the group consisting of halogen, OH, N(R7)(R8), and R7 and R8 are independently H or C 1~4 alkyl, and R7 and R8 are optionally connected to form a ring, CN, C 1~4 Alkyl, C 1~4 Hydroxyalkyl and C1~4 Forming a haloalkyl R4 is H, C 1~3 Alkyl, C 3~6 Cycloalkyl, or C 1~4 is hydroxyalkyl, R5, [ka] and A is C 1~8 Alkyl, C 2~8 Alkenyl, C 3~8 Cycloalkyl, C 5~10 Bicycloalkyl, C 2~5 Heterocyclyl, C 5~10 Aryl or C 2~8 is heteroaryl, X is H, F, Cl, optionally substituted C 1~6 Alkyl, optionally substituted C 3~8 Cycloalkyl, optionally substituted -OC 1~6 Alkyl, optionally substituted C 2~5 Heterocyclyl or optionally substituted C 5~10 aryl, each optional substituent independently being halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl, -OC 1~3 Alkyl, C 3~8 Cycloalkyl, C 3~8 halocycloalkyl, and CN; Y is H, halogen, OH, optionally substituted C 1~3 Alkyl, optionally substituted C 3~6 Cycloalkyl, optionally substituted -OC 1~3 Alkyl, optionally substituted C 1~3 Haloalkyl, or optionally substituted -OC 1~3 haloalkyl, each optional substituent is independently halogen, OH, C 1~3 Alkyl, C 1~3 Haloalkyl, -OC 1~3 Alkyl, C 3~8Cycloalkyl, C 3~8 halocycloalkyl, and CN; Z is a bond, C(R6)2, NR6, O, C(R6)2NR6, C(R6)2O, NR6C(R6)2, or OC(R6)2; R6 is H, C 1~3 Alkyl or C 1~4 a compound which is a hydroxyalkyl or a pharma- ceutically acceptable salt thereof.

[0056] In some embodiments of Formula 1, R is C 1~4 Alkyl or C 3~8 and cycloalkyl, each of which is optionally substituted as described above.

[0057] In some embodiments, R2 is optionally substituted C 3~10 It may also be cycloalkyl.

[0058] In some embodiments, R3 is C 1~6 Alkyl or C 3~8 and cycloalkyl, each of which is optionally substituted as described above.

[0059] In some embodiments, R4 can be H.

[0060] In some embodiments, R5 is [ka] A may be C 1~8 Alkyl or C 3~8 It may also be cycloalkyl.

[0061] In some embodiments of Formula 1, R1 is optionally substituted C 1~4 Alkyl or optionally substituted C 3~8 may be cycloalkyl, R2 is optionally substituted C3~6 may be cycloalkyl, R3 is optionally substituted C 1~4 Alkyl or optionally substituted C 3~6 may be cycloalkyl, R4 may be H; R5, [ka] may be A is C 1~4 Alkyl or C 3~6 may be cycloalkyl, X is H, F, optionally substituted C 1~6 Alkyl or optionally substituted C 3~8 may be cycloalkyl, Y may be H or halogen; Z may be a bond, C(R6)2, NR6, or O, where R6 is as defined above.

[0062] In some of these embodiments of formula 1, R is an optionally substituted C 1~4 In some other embodiments, R1 is optionally substituted C 3~8 R2 may be a C substituted with at least one F. 3~6 R3 may be C 1~4 Alkyl or C 3~6 It may also be cycloalkyl.

[0063] With respect to the scope of formula 1, each chemical group listed in any of the definitions of the substituents R1, R2, R3, R4, R5, R6, R7, R8, A, X, Y, and Z may be combined with any chemical group listed for any other substituent selected from R1, R2, R3, R4, R5, R6, R7, R8, A, X, Y, and Z. Thus, any group selected from each of R1, R2, R3, R4, R5, R6, R7, R8, A, X, Y, and Z based on those definitions may form a subgenus of formula 1 that falls within the concept of the present invention. For practical reasons, all such combination possibilities are not explicitly described herein, but based on the description of formula 1, a person skilled in the art will easily understand that any subgenus of formula 1 including any possible combination of the substituents R1, R2, R3, R4, R5, R6, R7, R8, A, X, Y, and Z is within the scope of formula 1 and is therefore part of the concept of the present invention.

[0064] Some embodiments of Formula 1 are further illustrated by compounds 1-574, as shown in Table 1, or a pharma- ceutically acceptable salt thereof.

[0065] In some embodiments, provided herein is any one of compounds 1-574 shown in Table 1, or a pharma- ceutically acceptable salt thereof.

[0066] Pharmaceutical Compositions 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 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 included in such formulations with pharma- ceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water-soluble vehicles, emulsifiers, buffers, humectants, wetting agents, 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 references for guidance. See, for example, Modern Pharmaceutics, Banker & Rhodes, Marcel Dekker, Inc. (1979), and Goodman & Gilman's, The Pharmaceutical Basis of Therapeutics, 6th Edition, MacMillan Publishing Co., New York (1980), both of which are incorporated herein by reference in their entireties.

[0067] In some embodiments, a single unit dose of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, is from about 0.1 mg to about 1,500 mg, from about 1 mg to about 1,500 mg, from about 10 mg to about 1,500 mg, from about 50 mg to about 1,500 mg, from about 75 mg to about 1,500 mg, from about 100 mg to about 1,500 mg, from about 125 mg to about 1,500 mg, from about 150 mg to about 1,500 mg, from about 175 mg to about 1,500 mg, from about 200 mg to about 1,500 mg, from about 22 The amount is selected from the group consisting of 5 mg to about 1,500 mg, about 250 mg to about 1,500 mg, about 275 mg to about 1,500 mg, about 300 mg to about 1,500 mg, about 400 mg to about 1,500 mg, about 450 mg to about 1,500 mg, about 500 mg to about 1,500 mg, about 600 mg to about 1,500 mg, about 700 mg to about 1,500 mg, about 800 mg to about 1,500 mg, about 1,000 mg to about 1,500 mg, and about 1,200 mg to about 1,500 mg.

[0068] In some embodiments, a single unit dose of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, is about 25 mg to about 5,000 mg, about 50 mg to about 5,000 mg, about 100 mg to about 5,000 mg, about 150 mg to about 5,000 mg, about 200 mg to about 5,000 mg, about 250 mg to about 5,000 mg, about 300 mg to about 5,000 mg, about 400 mg to about 5,000 mg, about 450 mg to about 5,000 mg, about 100 mg to about 3,000 mg, about 150 mg to about 3,000 mg, about 20 ...500 mg to about 5,000 mg, about 500 mg to about 5,000 mg, about 600 mg to about 5,000 mg, about 700 mg to about 5,000 mg, about 800 mg to about 5,000 mg, about 900 mg to about 5,000 mg, about 100 mg to about 3,000 mg, about 200 mg to about 5,000 mg, about 300 mg to about 5,000 mg, about 400 mg to about 5,000 mg, about 500 mg to about 5,000 mg, about 500 mg to about 5,000 Selected from the group consisting of about 3,000 mg, about 250 mg to about 3,000 mg, about 300 mg to about 3,000 mg, about 400 mg to about 3,000 mg, 450 mg to about 3,000 mg, about 100 mg to about 1,000 mg, about 150 mg to about 1,000 mg, about 200 mg to about 1,000 mg, about 250 mg to about 1,000 mg, about 300 mg to about 1,000 mg, about 400 mg to about 1,000 mg, about 450 mg to about 1,000 mg, about 500 mg to about 1000 mg, and about 600 mg to about 1,000 mg. In some embodiments, the amount of a single unit dose may be 10 mg / day to 1,500 mg / day, or about 100 mg / day to 600 mg / day. In some embodiments, such single unit doses may be administered once per day, or multiple times per day, for example, two times per day, or three times per day.

[0069] In some embodiments, the single unit dose further comprises a pharma- ceutically acceptable carrier.

[0070] The compound can be formulated for parenteral or intravenous administration by injection, for example, bolus injection or continuous infusion.The preparation for injection can be provided in unit dosage form, for example, in ampoules or multi-dose containers, with added preservatives.The composition can take the form of a suspension, solution or emulsion in an oily or aqueous vehicle, and can contain formulating agents such as suspending agents, stabilizing agents, and / or dispersing agents.

[0071] Injectable preparations can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents.Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol.Acceptable vehicles and solvents that can be used are, in particular, water, Ringer's solution, and isotonic sodium chloride solution.

[0072] Other embodiments include the compound prepared as described above, which is formulated as solid dosage form for oral administration, including capsules, tablets, pills, powders and granules.In such embodiments, active compound can be mixed with one or more inert diluents, such as sucrose, lactose or starch.Such dosage forms can also contain additional substances other than inert diluents, such as magnesium stearate, as is common practice.In the case of capsules, tablets and pills, dosage forms can also contain buffers and can further be prepared with enteric coating.

[0073] The preparation of the composition of the present invention in solid dosage form may be various.For example, in one embodiment, liquid or gelatin preparations can be prepared by combining the compounds as described above and adding a thickening agent to the liquid mixture to form gelatin.The gelatin can then be encapsulated into a unit dosage form to form a capsule.In another exemplary embodiment, the oily preparation of the compound prepared as described above can be lyophilized for a solid that can be mixed with one or more pharma-ceutically acceptable excipients, carriers or diluents to form a tablet.

[0074] Further embodiments that may be useful for oral administration of the compounds of the present invention include liquid dosage forms.In such embodiments, liquid dosages may include pharma-ceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs that contain inert diluents commonly used in the art, such as water.Such compositions may also include adjuvants, such as wetting agents, emulsifying and suspending agents, as well as sweeteners, flavoring agents, and aromatic agents.

[0075] In still further embodiments, the compounds described herein may be formulated as depot preparations. Such long-acting formulations may be administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Depot injections may be administered at intervals of about 1 to about 6 months, or at longer intervals. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as, for example, sparingly soluble derivatives, e.g., as a sparingly soluble salt.

[0076] How to use Some embodiments of the invention relate to a method of treating a disease or disorder, comprising administering a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof, wherein the disease or disorder is selected from a Kv7-associated disorder, a disorder associated with a KCNQ subunit, a disorder associated with a mutation in a KCNQ subunit, a neurodegenerative disorder, a disease or disorder that may benefit from activation of Kv7.2 homomers, a neurodevelopmental disease or disorder, or a CA group disease or disorder.

[0077] Some embodiments of the present invention relate to a method of treating a Kv7-associated disorder, comprising administering a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Kv7-related disorders include epilepsy, neonatal spasms, pain, migraine, disorders of neurotransmitter release, disorders of smooth muscle elasticity, dyskinesia, dystonia, mania, hearing loss, neuropathic pain, inflammatory pain, persistent pain, cancer pain, postoperative 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 loss, intellectual disability, epileptic encephalopathy, treatment-resistant epilepsy, cortical atrophy, neurological disorders, infantile spasms with hypsarrhythmia, myoclonic-tonic seizures, myoclonic seizures, tonic seizures, absence and focal onset seizures with impaired consciousness, congenital neurological disorders with intellectual disability or epileptic encephalopathy. In one embodiment, the present invention relates to a neurological disorder, autism spectrum disorder, congenital neurological disorder with a phenotype of epileptic encephalopathy, benign familial neonatal convulsions, severe epileptic encephalopathy, nonsyndromic intellectual disability or epileptic encephalopathy, neonatal spasms, neonatal seizures, epileptic encephalopathy, benign familial neonatal convulsions type 1, benign familial neonatal seizures 1, neonatal seizures associated with hypoxic-ischemic injury, epileptic spasms, epileptic encephalopathy, early infantile epileptic encephalopathy 7, early infantile epileptic encephalopathy with delayed psychomotor development, generalized tonic seizures, abnormal globus pallidus morphology, apnea, cerebral edema, dystonia, facial erythema, hypotonia, febrile seizures, hypoplasia of the corpus callosum, hypsarrhythmia, focal clonic seizures, generalized tonic-clonic seizures, myokymia, spastic quadriplegia, gynecological disorders, and combinations thereof. In some embodiments, the Kv7-associated disorder is selected from epilepsy, neonatal spasms, pain, migraine, disorders of neurotransmitter release, disorders of smooth muscle contractility, dyskinesia, dystonia, mania, hearing loss, neuropathic pain, inflammatory pain, persistent pain, cancer pain, post-operative pain, anxiety, substance abuse, schizophrenia, bladder disorders, vascular disorders, tinnitus, frontotemporal dementia (FTD), familial FTD, or amyotrophic lateral sclerosis. In some embodiments, such compounds may be administered in a pharmaceutical composition described herein.

[0078] In some embodiments, the gynecological disorder is selected from the group consisting of premature labor, postpartum hemorrhage, uterine atony, uterine perforation, uterine hyperstimulation, menorrhagia, uterine bleeding, dysfunctional uterine bleeding, dysmenorrhea, and endometriosis.

[0079] The KCNQ genes encode five Kv7 potassium channel subunits (1-5). Functional Kv7 potassium channels can be assembled using combinations of these five subunits arranged as homo- or heterotetramers. KCNQ2, KCNQ3, KCNQ4, and KCNQ5 are expressed in the nervous system and have been linked to a range of disorders involving neuronal excitability.

[0080] Embodiments herein are directed to a method of treating a disorder associated with a KCNQ subunit, comprising administering a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof.Embodiments herein are directed to a method of treating a disorder associated with a KCNQ2 subunit, comprising administering a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof.Embodiments herein are directed to a method of treating a disorder associated with a KCNQ3 subunit, comprising administering a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof.Embodiments herein are directed to a method of treating a disorder associated with a KCNQ4 subunit, comprising administering a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Embodiments herein are directed to a method of treating a disorder associated with the KCNQ5 subunit, comprising administering a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof.

[0081] Embodiments herein are directed to a method of treating a disorder associated with a mutation in a KCNQ subunit, comprising administering a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, the disorder associated with a mutation in a KCNQ subunit is a disorder associated with a KCNQ2 mutation. In some embodiments, the disorder associated with a mutation in a KCNQ subunit is a disorder associated with a KCNQ3 mutation. In some embodiments, the disorder associated with a mutation in a KCNQ subunit is a disorder associated with a KCNQ4 mutation. In some embodiments, the disorder associated with a mutation in a KCNQ subunit is a disorder associated with a KCNQ5 mutation. In some embodiments, the disorder associated with a mutation in a KCNQ subunit is selected from the group consisting of a disorder associated with a KCNQ2 mutation, a disorder associated with a KCNQ3 mutation, a disorder associated with a KCNQ4 mutation, or a disorder associated with a KCNQ5 mutation, and combinations thereof.

[0082] Embodiments herein are directed to a method of treating a disorder associated with a mutation in the KCNQ2 subunit, comprising administering a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Embodiments herein are directed to a method of treating a disorder associated with a mutation in the KCNQ3 subunit, comprising administering a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Embodiments herein are directed to a method of treating a disorder associated with a mutation in the KCNQ4 subunit, comprising administering a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Embodiments herein are directed to a method of treating a disorder associated with a mutation in the KCNQ5 subunit, comprising administering a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof.

[0083] The compounds described herein have been shown to activate Kv7 potassium channels. Mutations in KCNQ3, the gene encoding the Kv7 potassium channel, cause a wide range of disorders. The embodiments herein are directed to a method of treating a disorder associated with a KCNQ3 mutation, comprising administering a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. The disorder associated with a KCNQ3 mutation is selected from the group consisting of benign familial neonatal seizures, epilepsy, neurological diseases mediated by reduced basal M-current (and subsequent neuronal hyperexcitability), and any combination thereof.

[0084] The compounds described herein have been shown to activate Kv7 potassium channels. Mutations in KCNQ4, the gene that codes for Kv7 potassium channels, cause a wide range of disorders. The embodiments herein are directed to a method for treating disorders associated with KCNQ4 mutations, comprising administering a therapeutically effective amount of a compound of formula 1 or table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. The disorder associated with KCNQ4 mutations is sensorineural hearing disorder.

[0085] The compounds described herein have been shown to activate Kv7 potassium channels. Mutations in KCNQ5, the gene encoding the Kv7 potassium channel, cause a wide range of disorders. The embodiments herein are directed to a method of treating a disorder associated with a KCNQ5 mutation, comprising administering a therapeutically effective amount of a compound of formula 1 or table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. The disorder associated with a KCNQ5 mutation is selected from the group consisting of intellectual disability, epileptic encephalopathy, treatment-resistant epilepsy, cortical atrophy, neurological disorder, infantile spasms with hypsarrhythmia, myoclonic-tonic seizures, myoclonic seizures, tonic seizures, absence and focal onset seizures with impaired consciousness, congenital neurological disorders with intellectual disability or epileptic encephalopathy, benign familial neonatal convulsions, severe epileptic encephalopathy, congenital neurological disorders with nonsyndromic intellectual disability or epileptic encephalopathy phenotype, and any combination thereof.

[0086] The compounds described herein have been shown to activate Kv7 potassium channels. Mutations in KCNQ2, the gene that codes for Kv7 potassium channels, cause a wide range of disorders. The embodiments herein are directed to a method for treating disorders associated with KCNQ2 mutations, comprising administering a therapeutically effective amount of a compound of formula 1 or table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Disorders associated with KCNQ2 mutations are selected from neonatal spasms, neonatal seizures, epilepsy, benign familial neonatal epilepsy (KCNQ2-BFNE), epileptic encephalopathy (KCNQ2-NEE), benign familial neonatal convulsions type 1 (BFNC), benign familial neonatal seizures 1 (BFNS1), neonatal seizures associated with hypoxic-ischemic injury, epileptic spasms, epileptic encephalopathy, early infantile epileptic encephalopathy 7 (EIEE7), early infantile epileptic encephalopathy with delayed psychomotor development, generalized tonic seizures, abnormal globus pallidus morphology, apnea, cerebral edema, dystonia, facial erythema, hypotonia, febrile seizures, hypoplasia of the corpus callosum, hypsarrhythmia, focal clonic seizures, generalized tonic-clonic seizures, myokymia, spastic tetraplegia, and combinations thereof. In some embodiments, such compounds may be administered in a pharmaceutical composition as described herein.

[0087] Embodiments are directed to a method for treating a condition associated with cellular hyperexcitability in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, wherein the hyperexcitability is treated.

[0088] Embodiments are directed to a method for treating a Kv7-associated disorder in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, wherein a symptom of the disorder is alleviated or ameliorated due to activation of the Kv7 potassium channel.

[0089] An embodiment is directed to a method for treating a neurodegenerative disease in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, whereby the neurodegenerative disease is treated. The compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, may be administered to any individual exhibiting symptoms of a neurodegenerative disease or an individual predisposed to a neurodegenerative disease. Non-limiting examples of neurodegenerative diseases that may be treated using a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, include amyotrophic lateral sclerosis (ALS), Huntington's disease, metabolically induced neurological damage, Alzheimer's disease, Pick's disease, senile dementia, age-related cognitive impairment, vascular dementia, multi-infarct dementia, dementia with Lewy bodies, neurodegenerative dementia, frontotemporal dementia (FTD), familial FTD, neurodegenerative movement disorder, ataxia, Friedreich's ataxia, multiple sclerosis, spinal muscular atrophy, primary lateral sclerosis, seizure disorders, motor neuron disorders or diseases, inflammatory demyelinating disorders, Parkinson's disease, hepatic encephalopathy, chronic encephalopathy, chronic encephalitis, or any combination thereof.

[0090] Embodiments are directed to a method for treating a neurodegenerative disease, e.g., amyotrophic lateral sclerosis, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, whereby the neurodegenerative disease is treated. In embodiments, the subject has well-defined ALS, with a duration of amyotrophic lateral sclerosis symptoms of less than about 18 months, a plasma creatinine level of about 72 μM / L or greater, co-administration of riluzole, co-administration of dexpramipexole, and combinations thereof.

[0091] An embodiment is directed to a method for treating amyotrophic lateral sclerosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, whereby amyotrophic lateral sclerosis is treated.

[0092] Embodiments are directed to a method for treating amyotrophic lateral sclerosis in a subject diagnosed with definite amyotrophic lateral sclerosis, comprising administering to the subject a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, whereby amyotrophic lateral sclerosis is treated. In some embodiments, definite amyotrophic lateral sclerosis is as defined by the El Escorial diagnostic criteria. In some embodiments, the subject has definite ALS, a duration of amyotrophic lateral sclerosis symptoms of less than about 18 months, a plasma creatinine level of about 72 μM / L or greater, co-administration of riluzole, co-administration of dexpramipexole, and combinations thereof.

[0093] An embodiment is directed to a method for treating amyotrophic lateral sclerosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula 1 or table 1, or a pharma- ceutically acceptable salt thereof, wherein the subject is selected from subjects with well-defined amyotrophic lateral sclerosis, subjects with limb-onset amyotrophic lateral sclerosis, subjects with bulbar amyotrophic lateral sclerosis, subjects with amyotrophic lateral sclerosis symptom duration of less than about 18 months, subjects with high levels of plasma creatinine, subjects with low bicarbonate levels, subjects with concomitant administration of riluzole, subjects with concomitant administration of dexpramipexole, and combinations thereof, wherein amyotrophic lateral sclerosis is treated. In certain embodiments, the method further comprises monitoring the subject for any clinical features associated with amyotrophic lateral sclerosis. In certain embodiments, the method further comprises initiating therapy with a therapeutically effective amount of a compound of formula 1 or table 1, or a pharma- ceutically acceptable salt thereof upon diagnosis of amyotrophic lateral sclerosis. In certain embodiments, the subject exhibits symptoms of amyotrophic lateral sclerosis, hi certain embodiments, the subject has definite, probable, possible, or suspected amyotrophic lateral sclerosis.

[0094] Embodiments are directed to methods for treating amyotrophic lateral sclerosis in a subject diagnosed with definite amyotrophic lateral sclerosis, comprising administering to the subject a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, whereby amyotrophic lateral sclerosis is treated. In some embodiments, definite amyotrophic lateral sclerosis is characterized by the presence of El Escorial diagnostic criteria, duration of amyotrophic lateral sclerosis symptoms of less than about 18 months, limb-onset amyotrophic lateral sclerosis, plasma creatinine levels of about 72 μM / L or greater, concomitant administration of riluzole, concomitant administration of dexpramipexole, an ALSFRS-R score of greater than 36.0, a pre-test progression rate of 0.8 points or greater per month, a predicted relaxed (slow) vital capacity of 102.0 or less, or a mean of 100.0 or less. Abnormal neurological examination of the tongue; abnormal neurological examination of the pharynx, larynx, and swallowing; abnormal neurological examination of the lower limbs; abnormal neurological examination of the upper limbs; abnormal neurological examination of the triceps; abnormal neurological examination of muscle mass and bulk; abnormal neurological examination of the biceps; abnormal neurological examination; pulse rate greater than 81.0 beats / min; diastolic blood pressure greater than 82.0 mmHg; systolic blood pressure less than or equal to 117.0 mmHg; creatinine greater than 72.0 μmol / L; phosphorus less than or equal to 1.090 μmol / L; and 248.0 × 10 9 These include a platelet count of less than or equal to 100 cells / L, a cholesterol level of less than 5.3 mmol / L, a lactate dehydrogenase level of less than 161.0 U / L, a creatine phosphokinase level of less than 184.0 U / L, a bicarbonate level of less than 21.6 mmol / L, a triglyceride level of less than 1.4 mmol / L, a uric acid level of more than 320.0 μmol / L, a gamma-glutamyltransferase (GGT) level of more than 37.0 U / L, a total bilirubin level of less than 6.0 μmol / L, a urine pH of less than 5.5, or any combination thereof.

[0095] An embodiment is directed to a method for treating amyotrophic lateral sclerosis in a subject exhibiting symptoms of amyotrophic lateral sclerosis, comprising administering to the subject a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, whereby the symptoms of amyotrophic lateral sclerosis are treated. In some embodiments, the subject has definite amyotrophic lateral sclerosis, duration of amyotrophic lateral sclerosis symptoms of less than about 18 months, limb-onset amyotrophic lateral sclerosis, plasma creatinine level of about 72 μM / L or greater, concomitant administration of riluzole, concomitant administration of dexpramipexole, an ALSFRS-R score of greater than 36.0, a pre-study progression rate of 0.8 points per month or greater or a predicted resting vital capacity (SVC) percentage of 102.0 or less, an ALSFRS-R fine motor domain score of greater than 10.0 points, an ALSFRS-R swallowing domain score of greater than 9.0 points, an ALSFRS-R gross motor domain score of greater than 8.0 points, an abnormal neurological examination of the tongue, an abnormal neurological examination of the pharynx, larynx, and swallowing, an abnormal neurological examination of the lower extremities, an abnormal neurological examination of the upper extremities, an abnormal neurological examination of the triceps, an abnormal neurological examination of muscle mass and bulk. , an abnormal neurological exam of the biceps, an abnormal neurological exam, a pulse rate greater than 81.0 beats per minute, a diastolic blood pressure greater than 82.0 mmHg, a systolic blood pressure equal to or less than 117.0 mmHg, a creatinine level greater than 72.0 μmol / L, a phosphorus level equal to or less than 1.090 μmol / L, a platelet count equal to or less than 248.0 x 109 cells / L, a cholesterol level equal to or less than 5.3 mmol / L, a lactate dehydrogenase level equal to or less than 161.0 U / L, a creatine phosphokinase level equal to or less than 184.0 U / L, a bicarbonate level equal to or less than 21.6 mmol / L, a triglyceride level equal to or less than 1.4 mmol / L, a uric acid level equal to or greater than 320.0 μmol / L, a gamma-glutamyltransferase (GGT) level equal to or greater than 37.0 U / L, a total bilirubin level equal to or less than 6.0 μmol / L, a urine pH equal to or less than 5.5, or any combination thereof.

[0096] The embodiments described herein are directed to a method of treating a disease or disorder that may benefit from activation of Kv7.2 homomers, comprising administering a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, the disease or disorder is a developmental disease or disorder and is diagnosed prenatally, neonatally, in infancy, early childhood, adolescence, and early adulthood. In certain embodiments, the human subject is diagnosed prenatally. In certain embodiments, the neonate is diagnosed at about birth to about 1 week, or at about 1 week to about 1 month. In certain embodiments, the infant is diagnosed at about birth to about 1 week, about 1 week to about 1 month, or about 1 month to about 12 months. In certain embodiments, the subject is an infant from about birth to about 12 months. In certain embodiments, the subject is a fetus and is treated in utero. In certain embodiments, the subject is a child from about 1 year to about 12 years of age.

[0097] Embodiments described herein are directed to methods of treating a neurodevelopmental disease or disorder, comprising administering a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, the disease or disorder occurs early in life, between about 0 days and about 1 year. The neonatal brain undergoes changes early in development, making it susceptible to changes during this sensitive period. Studies in rodents show that KCNQ2 expression predominates over KCNQ3 early in the disorder. Delayed expression of KCNQ3 results in greater formation of KCNQ2 homomers compared to KCNQ2 / KCNQ3 heteromers. In embodiments described herein, the methods of treating a developmental disease or disorder are effective in restoring cellular electrical balance or normalizing hyperexcitability caused by genes or mechanisms unrelated to KCNQ2. In certain embodiments, the neurodevelopmental disease or disorder is selected from the group consisting of Angelman syndrome, neonatal abstinence syndrome, early myoclonic encephalopathy, Landau-Kleffner syndrome, electrical status epilepticus during sleep, Ohtahara syndrome, autism spectrum disorder, Dravet syndrome, Lennox-Gastaut syndrome, Rett syndrome, Hirschsprung's disease (HSCR), West syndrome, SCN8A-associated epilepsy with encephalopathy (EIEE13), infantile epilepsy with migratory focal seizures (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), Douce syndrome, and combinations thereof.

[0098] The embodiments described herein are directed to a method of treating Angelman syndrome, comprising administering a therapeutically effective amount of a compound of formula 1 or table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Angelman syndrome is caused by loss of function of the UBE3A gene, which plays a role in the normal development of the nervous system. Patients exhibit mental retardation, abnormal gait, speech disorder, seizures, and an inappropriate happy attitude, including frequent laughter, smiling, and excitability. They are typically treated with anticonvulsants. The compounds described herein are effective in treating seizures associated with Angelman syndrome.

[0099] The embodiments described herein are directed to a method of treating neonatal abstinence syndrome, comprising administering a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Neonatal abstinence syndrome is seen in infants born with drug dependence due to exposure in utero. At birth, infants may experience withdrawal symptoms, including seizures. Withdrawal from opiates can cause changes in excitatory transmission. The compounds described herein reverse excitability and ameliorate withdrawal symptoms.

[0100] Embodiments described herein are directed to methods of treating early myoclonic encephalopathy, Landau-Kleffner syndrome, and sleep electrical status epilepticus, comprising administering a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Early myoclonic encephalopathy is diagnosed in infants who present with early attacks of a disorder with multiple contributing factors. The attacks are refractory to standard therapy and have a poor prognosis. The compounds described herein are effective in treating early myoclonic encephalopathy.

[0101] The embodiments described herein are directed to a method of treating Otahara syndrome, comprising administering a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Otahara syndrome (OS) or early infantile epileptic encephalopathy (EIEE) is a rare type of epilepsy that typically becomes evident between 1 and 3 months of age. OS can be caused by brain malformations, metabolic disorders, and genetic mutations, including KCNQ2. Infants have primarily tonic seizures, but may also experience partial seizures and, rarely, myoclonic seizures. Most infants with this disorder show significant underdevelopment of some or all of the cerebral hemispheres. EEGs of infants with Otahara syndrome reveal a characteristic pattern of high-voltage spike-wave discharges followed by less activity. This pattern is known as "burst suppression." The course of Otahara syndrome is severe and progressive. Seizures become more frequent and are accompanied by delayed physical and cognitive development. Some children die in infancy, while others survive but are severely disabled. As they grow older, some children progress to other epileptic disorders such as West syndrome or Lennox-Gastaut syndrome. Due to the early onset of the disease, Kv7 channel activators are an effective treatment option for this disease.

[0102] The embodiments described herein are directed to a method of treating autism spectrum disorder, comprising administering a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Several voltage-gated potassium channels have been implicated in autistic patients, including mutations and truncations of the KCNQ3 gene. Dysregulation of Kv7 function promotes seizures and impairs normal development, which can lead to the autistic phenotype. Autism spectrum disorder (ASD) is a developmental disorder that affects communication and behavior. Autism can be diagnosed at any age, but symptoms generally appear within the first two years of life, which is why it is referred to as a "developmental disorder." According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), a guide created by the American Psychiatric Association used to diagnose mental disorders, people with ASD have 1) difficulty communicating and interacting with others, 2) restricted interests and repetitive behaviors, and 3) symptoms that impair people's ability to function properly in school, work, and other areas of life. Autism is known as a "spectrum" disorder because there is wide variation in the type and severity of symptoms people experience. The compounds described herein restore synaptic transmission necessary for normal development.

[0103] The embodiments described herein are directed to a method of treating Dravet syndrome, comprising administering a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Mutations in the SCN1A gene, which encodes a voltage-gated sodium channel, are common in Dravet syndrome. The mutations cause reduced sodium currents, leading to hyperexcitability of GABAergic inhibitory neurons, resulting in epilepsy. More recently, KCNQ2 mutations have been found to contribute to the clinical picture of Dravet syndrome. Dravet syndrome, formerly known as severe myoclonic epilepsy of infancy (SMEI), is a rare, treatment-resistant developmental epileptic encephalopathy with significant neurodevelopmental, motor, cognitive, and behavioral consequences that begin in infancy and persist into adulthood. Dravet syndrome is characterized by prolonged febrile and non-febrile seizures within the first year of life in children. The disease progresses to other seizure types, such as myoclonic and partial seizures, psychomotor retardation, and ataxia. This disease is characterized by cognitive impairment, behavioral disorder, and motor disorder. Behavioral disorder often includes hyperactivity and impulsivity, and in rare cases, includes autistic behavior. Seizures experienced by people with Dravet syndrome worsen as patients age. Compounds described herein are effective in Dravet syndrome by restoring the balance of excitation and inhibition in these neurons.

[0104] The embodiments described herein are directed to a method of treating Lennox-Gastaut syndrome, comprising administering a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Lennox-Gastaut syndrome (LGS) is a severe, complex, and rare childhood-onset epilepsy with multifactorial causes. Evidence suggests that cortical excitability during development contributes to the disease. Changes in excitability may be secondary to brain injury. Symptoms of Lennox-Gastaut syndrome usually begin in infancy or childhood, most often between the ages of 3-5 years. Affected children experience several different types of seizures, most commonly atonic, tonic, and atypical absence seizures. Tonic seizures cause increased muscle tone and muscle stiffness. They are characterized by sustained muscle contractions that may cause mild abnormalities (e.g., slight bending of the body, brief interruptions in breathing, or muscle spasms in the face) as well as more significant problems such as flexion or extension of the arms and legs. Tonic seizures are usually brief (lasting a few seconds to a minute) and are especially common at night during sleep, but can also occur during the day. Cataplexy causes a sudden loss of muscle tone and limping. It can cause a drooping or nodding head, postural problems, and sudden falls. Cataplexy is also known as a drop attack. Cataplexy may only partially affect consciousness and usually lasts only a few seconds. Atypical absence seizures are associated with periods of unconsciousness that are usually characterized by a nonresponsive stare. Absence seizures usually begin and end suddenly, and the affected individual usually resumes activity with no memory of the episode. Absence seizures do not cause convulsions and may be mild enough to go unnoticed. They usually last only a few seconds. Children with Lennox-Gastaut syndrome may also develop cognitive impairment, delayed achievement of developmental milestones, and behavioral problems ranging from hyperactivity and irritability to autistic symptoms and psychosis. The prognosis for LGS is poor, with a 5% mortality rate in childhood and 80%-90% with persistent seizures into adulthood. In general, three findings are required for diagnosis: multiple generalized seizure patterns, a slow spike-and-wave pattern on EEG (<2.5 Hz), and cognitive impairment.The compounds described herein may normalize brain excitability, reduce seizures, improve developmental outcomes, and reduce behavioral problems.

[0105] The embodiments described herein are directed to a method of treating Rett Syndrome, comprising administering a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Rett Syndrome is a rare genetic neurological disorder that occurs primarily in girls. Patients appear normal early in life, but then experience slowed growth and development, with the emergence of problems with walking, seizures, and intellectual disability. Many cases involve mutations in the MECP2 gene, which is believed to control the function of many other genes and disrupt the normal function of nerve cells. At the time of clinical diagnosis, patients were found to have mutations in other genes, including KCNQ2. The compounds described herein are effective treatments for Rett Syndrome.

[0106] The embodiments described herein are directed to a method of treating Hirschsprung's disease (HSCR), comprising administering a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Hirschsprung's disease is a condition that affects a newborn's ability to perform intestinal motility. The cause is unknown, but it is thought to be related to a genetic mutation that causes nerve cells in the colon to not form properly, thus resulting in poor contractility and fewer intestinal motility. Kv7 channels are expressed in smooth muscle and contribute to controlling the excitability of these cells. More recently, it has been observed that Kv7 expression is reduced in HSCR patients. The compounds described herein activate these cells and restore nerve function allowing for normal contractility.

[0107] The embodiments described herein are directed to a method of treating West Syndrome, comprising administering a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. West Syndrome is characterized by epileptic spasms and intellectual disability that occur early in life. In many cases, infantile spam also includes arrhythmias, chaotic and disorganized brain activity. Diagnosis is clinical, a combination of myoclonic reflexes, developmental regression, and characteristic EEG patterns. There are many underlying causes, including structural, metabolic, and genetic causes, all of which lead to seizure disorders. Due to the early onset of the disease, the compounds described herein are effective treatment options for this disease.

[0108] The embodiments described herein are directed to a method of treating SCN8A-associated epilepsy with encephalopathy (EIEE13), comprising administering a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. EIEE13 is characterized by recurrent seizures, abnormal brain function, and intellectual disability, with symptoms beginning in infancy. Seizure frequency can be as high as hundreds of seizures per day, and is unresponsive to current anti-epileptic drugs. EIEE13 is caused by mutations in the SCN8A gene, resulting in increased Nav1.6 function. Increased Nav1.6 activity causes excitation of neurons in the brain. The compounds described herein reduce excitability in the brain and restore normal brain function during a critical neurodevelopmental period.

[0109] The embodiments described herein are directed to a method of treating infantile epilepsy with migratory focal seizures (EIMFS), comprising administering a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Infantile epilepsy with migratory focal seizures (EIMFS) is also referred to as migratory partial epilepsy of infancy, migratory partial epilepsy of infancy, and malignant migratory partial epilepsy of infancy. EIMFS is a rare epilepsy syndrome in which seizures begin within a few weeks of birth. Seizures are localized but migrate to different parts of the brain. During seizures, autonomic changes (respiratory arrest, bluish discoloration, sweating, hiccups) are frequently observed. EIMFS is associated with mutations in several genes, including the KCNT1 potassium channel, which accounts for 40% of EIMFS cases. The KCNT1 channel contributes to resting membrane potential and neuronal firing. The compounds described herein are effective in treating EIMFS.

[0110] The embodiments described herein are directed to a method of treating autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), comprising administering a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. ADNFLE is a rare form of epilepsy that begins early in childhood. Seizures typically occur at night during sleep. Seizures tend to come in clusters and may present with sudden repetitive movements and vocalizations. ADNFLE is caused by mutations in the gene encoding the nicotinic acetylcholine receptor, which plays a key role in signaling between nerve cells and the brain. Disruption of neuronal networks is associated with seizures. Kv7 activation can restore normal brain function and prevent seizures during this critical developmental period. The compounds described herein are effective in treating ADNFLE.

[0111] The embodiments described herein are directed to a method of treating Douce Syndrome, comprising administering a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Douce Syndrome, also known as myoclonic atonic seizures (MAE), is a childhood epilepsy syndrome that affects boys more often than girls, with onset typically occurring between ages 2-6. Children with Douce Syndrome develop multiple seizure types, including drop attacks. Approximately one-third of children may have episodes of nonconvulsive status epilepticus. Childhood development prior to the onset of seizures is usually normal. Along with frequent seizures, development may slow and regress. The compounds described herein are effective in treating Douce Syndrome.

[0112] Some embodiments of the present invention relate to a method of treating a CA group disease or disorder, comprising administering a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. The diseases or disorders of the CA group are selected from the group consisting of alcohol use disorder, Dravet syndrome, traumatic brain injury, cerebral vasospasm following subarachnoid hemorrhage, stroke, gout pain, temporomandibular joint (TMJ) pain, chronic cough, asthma or chronic obstructive pulmonary disease, trigeminal neuralgia (TN), atypical facial pain, cluster headache, chemotherapy-induced neuropathic pain, orofacial cold-warm hyperalgesia, depression, major depressive disorder, peripheral nerve hyperexcitability (PNH) syndrome, neuromyotonia, fasciculations syndrome (CFS), Morvan's syndrome, disorders involving hypoxic pulmonary vasoconstriction (HPV), hypoxia-induced pulmonary hypertension and high altitude pulmonary edema, preeclampsia, paroxysmal dystonia, psychostimulant addiction, bipolar disorder, post-traumatic stress disorder (PTSD), noise-induced tinnitus, salicylate-induced hearing loss and tinnitus, and combinations thereof. In embodiments, such compounds may be administered in a pharmaceutical composition as described herein.

[0113] Some embodiments of the present invention relate to a method for treating alcohol use disorder, comprising administering a therapeutically effective amount of a compound of formula 1 or table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Ethanol has been shown to reduce M-currents in hippocampal neurons, which increases their excitability, ultimately contributing to the reinforcing effects of ethanol. The compounds described herein are effective by reversing ethanol-induced excitability and reducing ethanol consumption.

[0114] Some embodiments of the present invention relate to a method of treating Dravet syndrome, comprising administering a therapeutically effective amount of a compound of formula 1 or table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Mutations cause a decrease in sodium current, leading to hyperexcitability of GABAergic inhibitory neurons, resulting in epilepsy. More recently, KCNQ2 mutations have been found to contribute to the clinical picture of Dravet syndrome. Dravet syndrome, formerly known as severe myoclonic epilepsy of infancy (SMEI), is a rare, treatment-resistant developmental epileptic encephalopathy with significant neurodevelopmental, motor, cognitive, and behavioral consequences that begin in infancy and persist into adulthood. Dravet syndrome is characterized by prolonged febrile and non-febrile seizures within the first year of life in children. The disease progresses to other seizure types, such as myoclonic and partial seizures, psychomotor retardation, and ataxia. The disease is characterized by cognitive, behavioral, and motor disorders. Behavioral disorders often include hyperactivity and impulsivity, and in rare cases, autistic behavior.The seizures experienced by people with Dravet syndrome worsen as patients age.The compounds described herein are effective in Dravet syndrome by restoring the balance of excitation and inhibition in these neurons.

[0115] Some embodiments of the present invention relate to a method of treating traumatic brain injury, comprising administering a therapeutically effective amount of a compound of formula 1 or table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Seizures are very common in traumatic brain injury (TBI) patients due to TBI-induced hyperexcitability, which ultimately leads to cell death. This hyperexcitability is due to impaired activity of the GABAergic inhibitory network. The compounds described herein can reverse neuronal excitability and reverse or prevent brain injury following TBI.

[0116] Some embodiments of the present invention relate to a method for treating cerebral vasospasm after subarachnoid hemorrhage, comprising administering a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Cerebral vasospasm after subarachnoid hemorrhage (SAH) is typically the result of head injury or cerebral aneurysm. Cerebral vasospasm is the constriction and narrowing of arteries and is the leading cause of death after the initial injury. Compounds described herein can dilate arteries and reduce ischemia.

[0117] Some embodiments of the present invention relate to a method for treating stroke, comprising administering a therapeutically effective amount of a compound of formula 1 or table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Acute ischemic stroke causes damage to surrounding tissues, including blood vessels and neurons, due to low blood supply. In addition, post-ischemic hyperexcitability contributes to inflammatory responses and behavioral disorders. Since KCNQ channels are expressed in CNS neurons and cerebral vascular smooth muscle, administration of a compound described herein after stroke reduces stroke-induced damage and dysfunction.

[0118] Some embodiments of the present invention relate to a method for treating gout pain, comprising administering a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Gout pain is an inflammatory pain caused by the accumulation of urate / uric acid crystals in the joints. Peripheral inflammation increases the sensitivity of receptors at the site of inflammation, increasing the excitability of spinal neurons. KCNQ channels are expressed in both the CNS and PNS, and the compounds described herein reverse this excitability and pain response.

[0119] Some embodiments of the present invention relate to a method of treating temporomandibular joint (TMJ) pain, comprising administering a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. TMJ pain is an inflammatory pain that can evolve into central sensitization causing nerve excitability and spontaneous pain. The compounds described herein inhibit abnormal firing and control nerve excitability to reduce pain.

[0120] Some embodiments of the present invention relate to a method for treating trigeminal neuralgia (TN), atypical facial pain, cluster headache, chemotherapy-induced neuropathic pain, orofacial cold hyperalgesia, comprising administering a therapeutically effective amount of a compound of formula 1 or table 1, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. Some embodiments of the present invention relate to a method for treating trigeminal neuralgia (TN), atypical facial pain, or chemotherapy-induced neuropathic pain, comprising administering a therapeutically effective amount of a compound of formula 1 or table 1, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. These are types of neuropathic pain that can be caused by many factors, including compression of the trigeminal nerve caused by tumors, damage to the nerve itself, or damage to the myelin sheath, such as multiple sclerosis. Damage to trigeminal afferent neurons results in cellular hyperexcitability. The trigeminal nerve transmits thermal, mechanical, and nociceptive signals from the periphery to the central nervous system. Kv7 channels play an important role in regulating neuronal excitability and are expressed in the trigeminal ganglion. The compounds described herein are useful in treating these types of pain.

[0121] Some embodiments of the present invention relate to a method for treating chronic cough, asthma or chronic obstructive pulmonary disease, comprising administering a therapeutically effective amount of a compound of formula 1 or table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Chronic cough is a pulmonary inflammatory disease associated with increased excitability of vagus sensory C-fibers. KCNQ is expressed in mouse nodose ganglion neurons and can thus regulate the activity of fibers that innervate the lungs. Expression of KCNQ in airway smooth muscle cells can relax the airway in the case of histamine-induced contraction. The compounds described herein are effective in treating chronic cough and other inflammatory airway diseases, including asthma and chronic obstructive pulmonary disease (COPD).

[0122] Some embodiments of the present invention relate to a method for treating depression and major depressive disorder, comprising administering a therapeutically effective amount of a compound of formula 1 or table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Upregulated K+ channels stabilize ventral tegmental area (VTA) dopaminergic (DA) neurons by counteracting the pathological overactivity of these neurons. The firing rate of dopaminergic neurons in the VTA is important for regulating dopamine levels in the brain. Compounds described herein produce baseline changes in connectivity to the ventral striatum, the brain's "reward center," effectively treating major depressive disorder and associated eating and sleep disorders.

[0123] Some embodiments of the present invention relate to a method for treating peripheral nerve hyperexcitability (PNH) syndrome, neuromyotonia, cramp fasciculations syndrome (CFS), and Morvan's syndrome, comprising administering a therapeutically effective amount of a compound of formula 1 or table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. PNH is caused by spontaneous muscle fiber spasms and contractility due to overactive motor neurons. Mutations in KNCQ2 that result in reduced potassium currents have been described in patients with PNH. The compounds described herein effectively treat these diseases due to their generalized increase in nerve fiber excitability.

[0124] Some embodiments of the present invention relate to a method for treating diseases involving hypoxic pulmonary vasoconstriction (HPV), hypoxia-induced pulmonary hypertension and high altitude pulmonary edema, comprising administering a therapeutically effective amount of a compound of formula 1 or table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. HPV is a mechanism that diverts blood to more ventilated areas by restricting blood flow. Hypoxic smooth muscle cells have reduced Kv7 mRNA, which contributes to cell depolarization and the development of hypoxia-induced pulmonary hypertension. The compounds described herein are protective in pulmonary vascular diseases by relaxing vascular smooth muscle cells.

[0125] Some embodiments of the present invention relate to a method for treating preeclampsia, comprising administering a therapeutically effective amount of a compound of formula 1 or table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Preeclampsia contributes to pregnancy complications by reducing placental blood flow, which causes hypoxia and inflammation. Decreased KCNQ protein expression has been observed in arteries from women with preeclampsia. In smooth muscle, the compounds described herein effectively regulate contractility to promote blood flow.

[0126] Some embodiments of the present invention relate to a method for treating paroxysmal dystonia, comprising administering a therapeutically effective amount of a compound of formula 1 or table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Paroxysmal dystonia is a movement disorder in which patients suffer from periods of dystonic movements and muscle spasms. Clinical diagnosis distinguishes it from epilepsy, but treatment involves the use of anticonvulsants. Channelopathies are believed to play a causative role in paroxysmal dystonia. The compounds described herein are effective in treating paroxysmal dystonia.

[0127] Some embodiments of the present invention relate to a method for treating psychostimulant addiction, comprising administering a therapeutically effective amount of a compound of formula 1 or table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Drugs such as cocaine, methylphenidate, and phencyclidine act by stimulating brain regions containing dopaminergic (DA) neurons, which enhance the effects of these drugs to promote addiction. Kv7 channels expressed in these brain regions can directly reduce the activity of these neurons. In addition, Kv7 channels have been shown to reduce cortical excitability, which indirectly inhibits the release of dopamine. The compounds described herein are effective in treating addiction.

[0128] Some embodiments of the present invention relate to a method for treating bipolar disorder (BD), comprising administering a therapeutically effective amount of a compound of formula 1 or table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Bipolar disorder is a brain disorder characterized by abnormal energy shifts. Ion channel dysregulation is involved in the abnormal excitability and altered dopaminergic activity of the brain associated with mania and depression. In addition, accumulating evidence suggests that variants of KCNQ may also be associated with BD, and thus the compounds described herein are useful for treating BD by reducing hyperexcitability.

[0129] Some embodiments of the present invention relate to a method for treating post-traumatic stress disorder (PTSD), comprising administering a therapeutically effective amount of a compound of formula 1 or table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. The body responds to stress by altering synaptic input and neuroendocrine function through changes in ion channel activity. Kv7 channel expression is decreased in response to acute stress, which increases the activity of the hypothalamic-pituitary-adrenal (HPA) axis. Chronic stress is also associated with overactivity of the HPA axis. The compounds described herein effectively enhance M-current and reduce HPA axis activity.

[0130] Some embodiments of the present invention relate to a method for treating noise-induced tinnitus, comprising administering a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. Excessive exposure to noise can cause damage and lead to changes in cochlear neurons. These changes lead to abnormal hyperactive firing patterns and phantom perception of sound, i.e., tinnitus. This hyperactivity is caused, in part, by a decrease in Kv7 currents in cochlear neurons. The compounds described herein can restore normal function of these neurons, resulting in relief of tinnitus.

[0131] Some embodiments of the present invention relate to a method for treating salicylic acid-induced hearing loss and tinnitus, comprising administering a therapeutically effective amount of a compound of formula 1 or table 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. High doses of salicylic acid, the active ingredient of aspirin, are known to induce hearing loss and tinnitus. Outer hair cell (OHC) conductivity is driven by membrane potential and is essential for controlling hearing sensitivity. Salicylic acid-induced reduction in Kv7.4 current contributes to the disrupted electromotor response of outer hair cells (OHC). In addition, salicylic acid increases spontaneous activity of the auditory nerve. Compounds described herein improve conductivity in OHCs and reverse salicylic acid-induced changes by reducing auditory nerve activity.

[0132] In some embodiments, the compound of formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, is superior to ezogabine. In some embodiments, the compound of formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, has higher potency than ezogabine.

[0133] In certain embodiments, the compounds of formula 1 or table 1 described herein, or pharma- ceutically acceptable salts thereof, have increased stability against photo-oxidation compared to ezogabine.In certain embodiments, the compounds of formula 1 or table 1 described herein, or pharma-ceutically acceptable salts thereof, have higher potency in activating Kv7 channels compared to ezogabine.In certain embodiments, the compounds of formula 1 or table 1 described herein, or pharma-ceutically acceptable salts thereof, have higher subject tolerance compared to ezogabine.

[0134] In certain embodiments, the compounds of Formula 1 or Table 1 described herein, or pharma- ceutically acceptable salts thereof, modulate Kv7.2 / 7.3 and GABA A In certain embodiments, the compounds of Formula 1 or Table 1 described herein, or pharma- ceutically acceptable salts thereof, do not modulate α1β3γ2 GABA AIt has very low or no activity at the receptor and is selective for regulating Kv7.2 / 7.3.

[0135] In some embodiments, the therapeutically effective amount of the compound of formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, has a reduction in undesirable side effects. Undesirable side effects are selected from the group consisting of dizziness, fatigue, drowsiness, confusion, vertigo, tremor, ataxia, double or blurred vision, attention deficit, memory impairment, muscle weakness, skin discoloration, withdrawal attacks, QT interval changes, suicidal behavior, urinary retention, drowsiness, hallucinations, confusion, and combinations thereof. In some embodiments, the therapeutically effective amount of the compound of formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, is better tolerated by subjects due to its selectivity, with little or no side effects.

[0136] In some embodiments, administering a therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof, can provide a therapeutically effective amount of about 0.1 mg to about 1,500 mg, about 1 mg to about 1,500 mg, about 10 mg to about 1,500 mg, about 50 mg to about 1,500 mg, about 75 mg to about 1,500 mg, about 100 mg to about 1,500 mg, about 125 mg to about 1,500 mg, about 150 mg to about 1,500 mg, about 175 mg to about 1,500 mg, about 200 mg to about 1,500 mg, about 22 This may include administering a daily dose of 5 mg to about 1,500 mg, about 250 mg to about 1,500 mg, about 275 mg to about 1,500 mg, about 300 mg to about 1,500 mg, about 400 mg to about 1,500 mg, about 450 mg to about 1,500 mg, about 500 mg to about 1,500 mg, about 600 mg to about 1,500 mg, about 700 mg to about 1,500 mg, about 800 mg to about 1,500 mg, about 1,000 mg to about 1,500 mg, and about 1,200 mg to about 1,500 mg.

[0137] In some embodiments, the therapeutically effective amount of a compound of Formula 1 or Table 1, or a pharma- ceutically acceptable salt thereof is selected from the group consisting of about 0.1 mg to about 1,000 mg per day, about 50 mg to about 1,000 mg, about 100 mg to about 1,000 mg per day, about 150 mg to about 1,000 mg per day, about 300 mg to about 1,000 mg per day, about 50 mg to about 300 mg per day, and about 150 mg to about 300 mg per day.

[0138] 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. In some embodiments, administering a therapeutically effective amount comprises administering a dose equal to about half the daily dose twice a day. In some embodiments, the doses are administered about every 12 hours. In some embodiments, administering a therapeutically effective amount comprises administering about 25 mg twice a day, about 75 mg twice a day, about 150 mg twice a day, or about 300 mg twice a day.

[0139] The present invention is further illustrated by the following non-limiting examples.

[0140] Experimental Section and Examples The following schemes show general methodologies for the synthesis of compounds of the invention.

[0141] As shown in Scheme 1, appropriately substituted ester 1.1 is reacted with an alkylcyano and a base such as LDA, LiHMDS, NaH, or NaOMe to give the β-ketonitrile 1.2, which is reacted with an appropriately substituted alkylhydrazine or alkylhydrazine hydrochloride in the presence or absence of an acid such as acetic acid or hydrochloric acid or a base such as NaOH or triethylamine to give the N-alkylpyrazole 1.3 as the major product and N-alkylpyrazole 1.4 as the by-product. [ka]

[0142] An alternative method for preparing N-alkylpyrazoles 1.3 is described in Scheme 2.

[0143] Reaction of the β-ketonitrile 1.2 with hydrazine in a solvent such as EtOH gives the pyrazole 2.1. Reaction of this compound with phthalic anhydride and acetic acid gives the phthalimide 2.2. Alkylation in the presence of an alkyl halide and a base such as potassium carbonate or sodium hydride gives the regioisomeric N-2 alkylated pyrazole as the major product with the N-1 alkylated pyrazole 2.3 as a by-product. Treatment of 2.3 with hydrazine hydrate gives the aminopyrazole 1.3. [ka]

[0144] An alternative method for preparing pyrazole 1.3 is described in Scheme 3. Aminopyrazole 2.1 is reacted with an alkyl halide in the presence of a base such as sodium hydride to give N-alkylpyrazole 1.3. Typically, the major regioisomer formed is pyrazole 1.4. These regioisomers can be separated by chromatography. [ka]

[0145] As shown in Scheme 4, reaction of 1.3 with an appropriate carboxylic acid in the presence of an amino acid coupling reagent such as HATU, BTFFH (1-(fluoro(pyrrolidin-1-yl)methylene)pyrrolidin-1-ium hexafluorophosphate (V)) or T3P (propylphosphonic anhydride) and a base such as Hunig's base or pyridine provides the N-alkylpyrazole amide 4.1. Alternatively, the amide formation is prepared from 1.3 by reacting 1.3 with an appropriate acyl chloride in the presence of a base such as triethylamine or Hunig's base. [ka]

[0146] As shown in Scheme 5, reaction of 1.3 with phenyl chloroformate forms phenyl carbamate 5.1, followed by reaction with an appropriate alcohol or amine and an appropriate base such as Hunig's base, potassium carbonate, or potassium tert-butoxide to give N-alkylpyrazole carbamate 5.2 or N-alkylpyrazole urea 5.3, respectively. Alternatively, carbamate 5.2 can be prepared by reacting aminopyrazole 1.3 with an appropriate substituted chloroformate 5.4. Alternatively, urea 5.2 can be prepared by reacting 1.3 with a substituted isocyanate in the presence of a base such as triethylamine. Alternatively, urea 5.3 is prepared by reacting aminopyrazole 1.3 with a substituted isocyanate such as 5.6. [ka]

[0147] As shown in Scheme 6, the silyloxyl 6.1 (prepared as described in the methods above) is treated with TBAF to give the alcohol 6.2. [ka]

[0148] As shown in Scheme 7, pyrazole amines 7.5 are prepared by reacting diethyl oxalate 7.1 with alkyl nitrile 7.2 in the presence of a base such as potassium tert-butoxide, with or without 18-crown-6, in a suitable solvent to provide hydroxyacrylate 7.3, which is then treated with an appropriately substituted hydrazine to form the aminoester pyrazole 7.4, which is treated with an alkyl or aryl magnesium halide to give pyrazole amine 7.5. [ka]

[0149] As shown in Scheme 8, alcohols 8.2 are prepared by lithiation of aryl halides 8.1 with t-BuLi or n-BuLi in the presence or absence of i-PrMgCl, followed by quenching with a ketone. [ka]

[0150] As shown in Scheme 9, carbamate 5.2 can be alkylated in the presence of an alkyl halide and a base such as sodium hydride to give the alkylated carbamate 9.1. [ka]

[0151] As shown in Scheme 10, ketal 10.1 can be treated with an acid such as p-toluenesulfonic acid or hydrochloric acid to form ketone 10.2. Ketone 10.2 can then be reacted with an alkyl magnesium halide to form alkyl hydroxycyclobutyl 10.3. Alternatively, ketone 10.2 can be treated with a reducing agent such as sodium borohydride to give cyclobutyl alcohol 10.4. [ka]

[0152] As shown in Scheme 11, aryloxypyrazoles 11.2 can be prepared from the appropriate hydroxypyrazole in the presence of an arylboronic acid, copper acetate, a base such as pyridine, in a suitable solvent such as dichloroethane with or without molecular sieves. Starting materials 11.1 are prepared by the methods described in Table 1. [ka]

[0153] As shown in Scheme 12, ester 12.1 can be treated with an alkyl or aryl substituted magnesium halide in a suitable solvent such as THF to form alcohol 12.2. [ka]

[0154] LC-MS method: LC-MS method A Instrument: Shimadzu LCMS 2020 equipped with LC-40D and SPD-M30A diode array detectors Column: Shimadzu Nexcol C18, 50 x 3.0 mm, 5 mm Solvent A: 0.1% formic acid in water Solvent B: Acetonitrile Flow rate: 0.4mL / min 0–3 min, gradient from B=5% to B=95% Hold at B=95% for 3-4 minutes 4–4.2 min, gradient from B = 95% to B = 10% 4. Hold at B=10% for 2-5 min.

[0155] LC-MS method B: Column: X Bridge C18 3.5um 4.6×50mm, Mobile phase A: 10mm ammonium acetate B: 100% ACN, gradient 0 / 10, 0.5 / 10, 4 / 90, 8 / 90, 8.10 / 10, 10 / 10, flux: 0.6mL / min.

[0156] Synthetic Methods: The methods listed below are representative of methods that can be used with the appropriate starting materials to synthesize the compounds set forth in Table 1 in the manner specified in the table.

[0157] 1. Synthesis method: β-ketonitrile Method A: [ka] To a stirred solution of N,N-diisopropylamine (4.9 mL, 34.7 mmol) in THF (0.5 M, 63.0 mL) at -78°C was added n-BuLi solution (13.2 mL, 33.1 mmol, 2.5 M in hexanes). The mixture was stirred at 0°C for 30 min, then cooled to -78°C, and then cyclobutylacetonitrile (3.0 g, 31.5 mmol) was added slowly. The reaction mixture was warmed to 0°C, stirred for 30 min, and then cooled to -78°C. Methyl 3,3-difluorocyclobutane-1-carboxylate (5.7 g, 37.8 mmol) was added slowly, and the reaction mixture was stirred at -78°C for 2.5 h. The mixture was then quenched with saturated aqueous NH4Cl, warmed to room temperature, and extracted with ethyl acetate (2 times). The combined organic layers were washed with brine (1x) and water (1x), then dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by chromatography (silica gel, 0-50% ethyl acetate / hexanes) to give 2-cyclobutyl-3-(3,3-difluorocyclobutyl)-3-oxopropanenitrile as a colorless liquid (4.0 g, 60%). LC-MS (Method A, ESI): m / z, 212 (MH). - , t R =3.8 minutes.

[0158] Method B: [ka] To a solution of 3,3-dimethylbutanenitrile (1.0 g, 10.3 mmol) in THF (0.4 M, 26 mL) at -78 °C, LiHMDS (15.4 mL, 15.5 mmol, 1.0 M in THF) was slowly added and the reaction mixture was stirred for 30 min. Then, methyl 3,3-difluorocyclobutane-1-carboxylate (1.85 g, 12.4 mmol) was added to the reaction mixture and stirred for 2 h, then warmed to room temperature and stirred overnight. The reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with ethyl acetate (2 times). The combined organic layers were washed with brine (1 time), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (silica gel, 0-30% ethyl acetate / hexanes) to give 2-(3,3-difluorocyclobutane-1-carbonyl)-3,3-dimethylbutanenitrile as a pale yellow thick liquid (780 mg, 35%). LC-MS (Method A, ESI): m / z, 214 (MH). - , t R =3.9 minutes.

[0159] Method C: [ka] To a slurry of sodium hydride (1.10 g, 26.7 mmol) in THF (0.2 M, 67 mL) at 0° C., acetonitrile (1.4 mL, 26.7 mmol) was added, followed by dropwise addition of methyl 3,3-difluorocyclobutane-1-carboxylate (2.0 g, 13.2 mmol). The reaction mixture was stirred at 65° C. for 12 h. The reaction mixture was then quenched by dropwise addition of saturated aqueous NH4Cl until hydrogen evolution ceased. The reaction mixture was extracted with ethyl acetate (2 times). The combined organic layers were washed with brine (1×), dried over Na2SO4, filtered, and concentrated under reduced pressure at 25° C. The resulting residue was purified by chromatography (silica gel, 0-50% ethyl acetate / hexanes) to give 3-(3,3-difluorocyclobutyl)-3-oxopropanenitrile as a colorless dark liquid (1.4 g, 67%). LC-MS (Method A, ESI): m / z,159(MH) - , t R =3.2 minutes.

[0160] Method D [ka] To a sealed tube was added ethyl cyclobutanecarboxylate (431 μL, 3.1 mmol), 3-cyclobutyl-2-(4-fluorophenyl)-3-oxopropanenitrile (468 μL, 3.9 mmol), and 25% sodium methoxide solution (714 μL, 3.1 mmol). The tube was sealed and stirred at 85 °C overnight. The cooled mixture was diluted with H2O and concentrated hydrochloric acid was added to adjust the pH to 6. The mixture was extracted with EtOAc (3 times) and the extracts were combined, washed with brine, dried (Na2SO4), filtered, and concentrated. The crude material was purified on a 40 g silica gel column eluting with 0-30% EtOAc / hexane to give the desired product (367.9 mg, 54%). LC-MS (Method A, ESI): m / z, 216 (MH). - , t R =4.0 minutes.

[0161] 2. Synthesis method of N-alkylpyrazole Method E: [ka] To a solution of 2-cyclobutyl-3-(3,3-difluorocyclobutyl)-3-oxopropanenitrile (1.5 g, 7.0 mmol) in toluene (0.4 M, 18 mL) in a pressure tube was added methylhydrazine (740 μL, 7.04 mmol) and heated to 110 °C overnight. Volatiles were removed under reduced pressure and the resulting residue was purified by silica gel chromatography to give 4-cyclobutyl-3-(3,3-difluorocyclobutyl)-1-methyl-1H-pyrazol-5-amine (eluted with 0-100% ethyl acetate / hexanes, isolated as a pale yellow solid, 1.2 g, 85% yield, LC-MS (ESI): m / z, 242 (M+H). + , t R=3.0), and 4-cyclobutyl-5-(3,3-difluorocyclobutyl)-1-methyl-1H-pyrazol-3-amine (eluted with 0-15% methanol / dichloromethane, isolated as a light brown solid, 0.2 g, 15% yield, LC-MS (Method A, ESI): m / z, 242 (M+H) + , t R =3.2).

[0162] Method F: [ka] To a solution of methylhydrazine (200 μL, 3.83 mmol) and 2-(3,3-difluorocyclobutane-1-carbonyl)-3,3-dimethylbutanenitrile (412 mg, 1.91 mmol) in ethanol (6.4 mL) in a 15 mL pressure tube, acetic acid (162 μL, 2.87 mmol) was added. The mixture was heated to reflux overnight. After complete consumption of the starting compound (LC-MS), the volatiles were removed under reduced pressure. The resulting residue was diluted with cold water, the pH was adjusted to 10 with aqueous ammonium hydroxide (25-30% in H2O), and then extracted with ethyl acetate (2 times). The combined organic layers were washed with saturated aqueous NaHCO3 (1 time), brine (1 time), and water (1 time), then dried over anhydrous Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by chromatography (silica gel, 0-100% ethyl acetate / hexanes) to give 4-(tert-butyl)-3-(3,3-difluorocyclobutyl)-1-methyl-1H-pyrazol-5-amine as a beige solid (80 mg, 17%). LC-MS (Method A, ESI): m / z, 244 (M+H). + , t R =3.2 minutes.

[0163] Method G [ka] A solution of tert-butylhydrazine hydrochloride (2.88 g, 23.1 mmol) and NaOH (920 mg, 23.1 mmol) in EtOH (20 mL) was stirred at room temperature for 10 min. To this mixture, a solution of 3-(3,3-difluorocyclobutyl)-2-methyl-3-oxopropanenitrile (2.00 g, 11.6 mmol) in EtOH (5 mL) was added dropwise and the mixture was stirred in a sealed tube at 120° C. for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the volatiles were removed under reduced pressure and the resulting residue was diluted with water (100 mL) and then extracted with EtOAc (2×100 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. Silica gel column chromatography eluting with a 15% to 20% EtOAc / hexane gradient afforded 1-(tert-butyl)-3-(3,3-difluorocyclobutyl)-4-methyl-1H-pyrazol-5-amine (1.20 g, 43%) as a light brown solid. LC-MS (Method B, + ve mode): m / z, 244.1 (M+H) + , t R =4.99 minutes.

[0164] Method H [ka] Step 1. 2-Cyclobutyl-3-oxo-3-(2-(trifluoromethyl)thiazol-5-yl)propanenitrile (0.700 g, 2.55 mmol) and hydrazine hydrate (0.149 mL, 3.06 mmol) were combined in EtOH (5 mL) and refluxed overnight. Volatiles were removed and the crude material was purified by chromatography (silica gel, 0-10% MeOH / DCM) to give 620 mg (84%) of 4-cyclobutyl-3-(2-(trifluoromethyl)thiazol-5-yl)-1H-pyrazol-5-amine. Confirmed by LC-MS (Method A, ESI): m / z, 289 (M+H). + , t R =3.6 minutes.

[0165] Step 2. 4-Cyclobutyl-3-(2-(trifluoromethyl)thiazol-5-yl)-1H-pyrazol-5-amine (0.620 g, 2.15 mmol) and phthalic anhydride (0.478 g, 3.23 mmol) were refluxed in acetic acid (4.0 mL) for 1 h. Most of the acetic acid was removed in vacuo and the remaining residue was taken up in EtOAc and washed several times with saturated aqueous NaHCO3 until gas evolution ceased. The organic portion was dried (Na2SO4) and the volatiles removed to give the crude material, which was purified via chromatography (silica gel, 0-100% EtOAc / hexanes) to give 410 mg (46%) of 2-(4-cyclobutyl-3-(2-(trifluoromethyl)thiazol-5-yl)-1H-pyrazol-5-yl)isoindoline-1,3-dione. Confirmed by LC-MS (Method A, ESI): m / z, 419 (M+H). + , t R =4.2 minutes.

[0166] Step 3. Potassium carbonate (0.406 g, 2.94 mmol) followed by iodomethane (0.122 mL, 1.96 mmol) were added to a solution of 2-(4-cyclobutyl-3-(2-(trifluoromethyl)thiazol-5-yl)-1H-pyrazol-5-yl)isoindoline-1,3-dione (0.410, 0.980 mmol) in NMP (1.4 mL) and the resulting reaction mixture was stirred overnight at 60 °C. Complete conversion of starting material to product was confirmed by LC-MS. The reaction mixture was diluted in EtOAc, and the organic portion was washed (3x with HO, 1x with brine), dried (NaSO) and concentrated to give a crude residue which was purified by chromatography (silica gel, 0-100% EtO / hexanes) to give 2-(4-cyclobutyl-1-methyl-3-(2-(trifluoromethyl)thiazol-5-yl)-1H-pyrazol-5-yl)isoindoline-1,3-dione (0.150 g, LC-MS (Method A, ESI): m / z, 433 (M+H). + , t R= 4.7), 2-(4-cyclobutyl-1-methyl-5-(2-(trifluoromethyl)thiazol-5-yl)-1H-pyrazol-3-yl)isoindoline-1,3-dione (0.070 g, LC-MS (Method A, ESI): m / z, 433 (M+H) + , t R = 4.2), and 0.040 g of a mixture of N-Me regioisomers (61% combined yield).

[0167] Step 4. 2-(4-Cyclobutyl-1-methyl-3-(2-(trifluoromethyl)thiazol-5-yl)-1H-pyrazol-5-yl)isoindoline-1,3-dione (0.100 g, 0.231 mmol) and hydrazine hydrate (0.056 mL, 1.16 mmol) were combined in EtOH (1.2 mL) and refluxed overnight. After cooling to ambient temperature, the white solid was removed by filtration, washed with EtOH, and discarded. The filtrate was stripped of volatiles and the crude residue obtained was loaded directly onto a silica gel column and eluted (0-10% MeOH / DCM) to give 0.040 mg (57%) of 4-cyclobutyl-1-methyl-3-(2-(trifluoromethyl)thiazol-5-yl)-1H-pyrazol-5-amine. Confirmed by LC-MS (Method A, ESI): m / z, 303 (M+H). + , t R =3.9 minutes.

[0168] Method I [ka] Step 1. To a round bottom flask containing anhydrous THF (3.4 mL) was added 18-crown-6 (72 mg, 0.27 mmol). The mixture was cooled to 0 °C and potassium tert-butoxide (383 mg, 3.41 mmol) was added. To the mixture at 0 °C was added diethyl oxalate (465 μL, 3.4 mmol) dropwise. Upon completion of the addition, the mixture was heated to 60 °C. To the mixture was added cyclobutylacetonitrile (409 μL, 3.4 mmol) dropwise and heating was continued for 30 min. The mixture was added to 1N aqueous HCl, then the mixture was extracted with EtOAc (3 times). The combined extracts were dried (Na2SO4), filtered, and concentrated to a pale yellow oil to give ethyl (E)-3-cyano-3-cyclobutyl-2-hydroxyacrylate (741.0 mg, 93%). LC-MS (Method A, ESI): m / z,194(MH) - , t R =3.5 minutes.

[0169] Step 2. To ethyl (E)-3-cyano-3-cyclobutyl-2-hydroxyacrylate (455 mg, 2.3 mmol) in EtOH (5.0 mL) was added methylhydrazine (123 μL, 2.3 mmol), followed by concentrated hydrochloric acid (180 μL). The mixture was refluxed for 6 h, at which point LCMS indicated the reaction was complete. The mixture was cooled and diluted with H2O. The mixture was extracted with EtOAc (3 times) and the combined extracts were washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated. The crude residue was purified on a 24 g silica gel column eluting with 0-100% EtOAc / hexanes to give ethyl 5-amino-4-cyclobutyl-1-methyl-1H-pyrazole-3-carboxylate (41.1 mg, 8%). LC-MS (Method A, ESI): m / z, 224 (M+H) + , t R =3.1 minutes.

[0170] Step 3. To ethyl 5-amino-4-cyclobutyl-1-methyl-1H-pyrazole-3-carboxylate (100 mg, 0.45 mmol) in THF (2.2 mL) at 0° C. was added a solution of methylmagnesium bromide (746 μL, 2.2 mmol, 3M in THF) dropwise. The mixture was stirred at 0° C. for 10 min and then warmed to room temperature over 1 h. LCMS showed the reaction was complete. The reaction was quenched with saturated aqueous NH4Cl, diluted with H2O, and extracted with EtOAc (3 times). The extracts were combined, dried (Na2SO4), filtered, and concentrated. Purification (12 g silica gel column eluted with 0-10% CH3OH / DCM) gave 2-(5-amino-4-cyclobutyl-1-methyl-1H-pyrazol-3-yl)propan-2-ol (65 mg, 70%). LC-MS (Method A, ESI): m / z,210(M+H) + , t R =2.4 minutes.

[0171] Method J [ka] To 2-cyclobutyl-4-(3,3-difluorocyclobutyl)-3-oxobutanenitrile (500 mg, 2.2 mmol) in EtOH (4.4 mL) was added triethylamine (1.2 mL, 8.8 mmol) and methylhydrazine (232 μL, 4.4 mmol). The mixture was heated to reflux for 3 h, cooled to room temperature, and concentrated. The resulting residue was dissolved in EtOAc. The mixture was washed with H2O and brine, dried (Na2SO4), filtered, and concentrated. The crude material was purified on a 24 g silica gel column eluted with 0-30% EtOAc / hexane to give 4-cyclobutyl-3-((3,3-difluorocyclobutyl)methyl)-1-methyl-1H-pyrazol-5-amine (195.8 mg, 35%). LC-MS (Method A, ESI): m / z, 256 (M+H). + , t R =2.9 minutes.

[0172] Method T [ka] Sodium hydride (0.108 g, 2.70 mmol, 60 wt%) was added to a solution of 4-cyclobutyl-3-(4,4-difluorocyclohexyl)-1H-pyrazol-5-amine (0.420 g, 1.50 mmol) in DMF (1.5 mL) at 0° C. and the resulting reaction mixture was stirred at that temperature for 30 min. Iodomethane (0.103 mL, 1.65 mmol) was added and the reaction mixture was removed from the ice bath and stirred at ambient temperature for 2 h. LC-MS shows consumption of starting material and two main products with the desired mass (m / z+1=270). The reaction mixture was treated with EtOAc, washed (3x with HO, 1x with brine), the organic portion dried (NaSO) and the volatiles removed to give the crude material which was purified via chromatography (silica gel, 0-100% EtOAc / hexanes) to give 4-cyclobutyl-3-(4,4-difluorocyclohexyl)-1-methyl-1H-pyrazol-5-amine (160 mg, 40%, confirmed by LC-MS (Method A, ESI): m / z, 270 (M+H). + , t R = 2.8) and 4-cyclobutyl-5-(4,4-difluorocyclohexyl)-1-methyl-1H-pyrazol-3-amine (140 mg, 35%, confirmed by LC-MS (Method A, ESI): m / z, 270 (M+H) + , t R = 3.2 min).

[0173] Method V Method V is similar to Method A with the addition of 1.2 equivalents of diisopropylethylamine to the reaction mixture.

[0174] Method DD [ka] A mixture of 5-amino-4-cyclobutyl-1-methyl-1H-pyrazol-3-ol (155 mg, 0.927 mmol), phenylboronic acid (283 mg, 2.32 mol), Cu(OAc)2 (253 mg, 1.39 mmol), pyridine (229 μL, 2.78 mmol), and molecular sieves (4 Å, 150 mg) in dichloroethane (9 mL) was stirred at room temperature for 2 days. The mixture was diluted with EtOAc and washed with H2O. The organic layer was dried (Na2SO4), concentrated, and chromatographed (silica column, 0-10% MeOH / DCM) to give 4-cyclobutyl-1-methyl-3-phenoxy-1H-pyrazol-5-amine (75.5 mg, 33%).

[0175] 3. Synthetic method: amine functionalization / final step. Method K: [ka] To a solution of 3,3-difluorocyclobutane-1-carboxylic acid (40 mg, 0.16 mmol) in NMP (0.6 mL) was added HATU (113 mg, 0.30 mmol) and N,N-diisopropylethylamine (58 μL, 0.33 mmol), the resulting reaction mixture was stirred for 5 min, and then 4-cyclobutyl-3-(3,3-difluorocyclobutyl)-1-methyl-1H-pyrazol-5-amine (27 mg, 0.19 mmol) was added. The reaction mixture was heated to 55° C. and stirred at that temperature overnight. The resulting reaction mixture was injected directly onto a reverse phase HPLC column (C18, 10-100% acetonitrile / water and monitoring at 220 nm wavelength) to give N-(4-cyclobutyl-3-(3,3-difluorocyclobutyl)-1-methyl-1H-pyrazol-5-yl)-3,3-difluorocyclobutane-1-carboxamide (31 mg, 52%) as a white solid. 1H-NMR(400MHz, CDCl3):δ 6.75(s,1H),3.63(s,3H),3.20-3.6(m,2H),2.94-3.05(m,2H),2.78-2.91(m,6H),2.43-2.72(m ,1H),2.17-2.27(m,2H),1.98-2.08(m,3H),1.76-1.88(m,1H),LC-MS(Method A, ESI):m / z,360(M+H) + , t R =3.8 minutes.

[0176] Method L: Example 243: 3,3-Difluorocyclobutyl (4-cyclobutyl-3-(3,3-difluorocyclobutyl)-1-methyl-1H-pyrazol-5-yl)carbamate Step 1, Option 1: [ka] To a stirred solution of 4-cyclobutyl-3-(3,3-difluorocyclobutyl)-1-methyl-1H-pyrazol-5-amine (50 mg, 0.21 mmol) in acetone (3 mL) at 0° C., K2CO3 (43 mg, 0.32 mmol) and phenyl chloroformate (29 μL, 0.23 mmol) were added, and the reaction mixture was stirred at room temperature overnight. LC-MS showed that the starting material was consumed and the desired product was formed. The solvent was removed under reduced pressure, and the resulting residue was diluted with water, sonicated for 2 min, and extracted with ethyl acetate (2 times). The combined organic layers were washed with saturated aqueous NaHCO3 (1 time), brine (1 time), and water (1 time), then dried over Na2SO4 and concentrated. The resulting residue was purified by chromatography (silica gel, 0-100% ethyl acetate / hexanes) to give phenyl (4-cyclobutyl-3-(3,3-difluorocyclobutyl)-1-methyl-1H-pyrazol-5-yl)carbamate as a white solid (61 mg, 82%). LC-MS (Method A, ESI): m / z, 362 (M+H). + , t R =4.1 minutes.

[0177] Step 1, Option 2: [ka] To a stirred THF solution of 4-cyclobutyl-3-(3,3-difluorocyclobutyl)-1-methyl-1H-pyrazol-5-amine (520 mg, 2.15 mmol) at 0° C., N,N-diisopropylethylamine (0.75 mL, 4.3 mmol) and phenyl chloroformate (332 μL, 2.59 mmol) were added, and the reaction mixture was stirred at room temperature for 2 h. LC-MS showed that the starting material was consumed. The reaction mixture was then quenched with saturated aqueous NH4Cl and extracted with ethyl acetate (2 times). The combined organic layers were washed with brine (1 time), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by chromatography (silica gel, 0-100% ethyl acetate / hexanes) to give (4-cyclobutyl-3-(3,3-difluorocyclobutyl)-1-methyl-1H-pyrazol-5-yl)phenylcarbamate as a white solid (613 mg, 79%). LC-MS (Method A, ESI): m / z,362(M+H) + , t R =4.1 minutes.

[0178] Step 2: [ka] To a solution of (4-cyclobutyl-3-(3,3-difluorocyclobutyl)-1-methyl-1H-pyrazol-5-yl)phenylcarbamate (100 mg, 0.28 mmol) and 3,3-difluorocyclobutanol (36 mg, 0.33 mmol) in dry N,N-dimethylformamide / dioxane (0.1 M, 2.8 mL) in a microwave tube (2.0-5.0 mL) was added N,N-diisopropylethylamine (96 μL, 0.55 mmol). The reaction mixture was irradiated under microwave conditions at 120 °C for 45 min. The resulting reaction mixture was injected directly onto a reverse phase HPLC column (C18, 10-100% acetonitrile / water and monitoring at 220 nm wavelength) to give 3,3-difluorocyclobutyl (4-cyclobutyl-3-(3,3-difluorocyclobutyl)-1-methyl-1H-pyrazol-5-yl)carbamate (Example 243, 35 mg, 34%). 1 H-NMR(400MHz, CDCl3):δ 6.05(s,1H),5.0(s,1H),3.66(s,3H),3.20-3.36(m,2H),2.98-3.16(m,2H),2.54-2.96(m,6 H),2.18-2.31(m,2H),1.93-2.17(m,3H),1.77-1.89(m,1H), LC-MS (Method A, ESI): m / z,376(M+H) + , t R =4.0 minutes.

[0179] Method M: Example 374: 1-(4-cyclobutyl-3-(3,3-difluorocyclobutyl)-1-methyl-1H-pyrazol-5-yl)-3-(2,2-difluoroethyl)urea [ka] To a solution of (4-cyclobutyl-3-(3,3-difluorocyclobutyl)-1-methyl-1H-pyrazol-5-yl)phenylcarbamate (40 mg, 0.11 mmol) and 2,2-difluoroethylamine (11 mg, 0.13 mmol) in dry N,N-dimethylformamide / dioxane (0.2 M, 0.6 mL) in a microwave tube (2.0-5.0 mL), N,N-diisopropylethylamine (38 μL, 0.22 mmol) was added. The reaction mixture was irradiated under microwave conditions at 120 °C for 45 min. The resulting reaction mixture was injected onto a reverse phase HPLC column (C18, 10-100% acetonitrile / water and monitoring at 220 nm wavelength) to give 1-(4-cyclobutyl-3-(3,3-difluorocyclobutyl)-1-methyl-1H-pyrazol-5-yl)-3-(2,2-difluoroethyl)urea (Example 374, 22 mg, 57%). 1 H-NMR (400MHz, CDCl3):δ 5.98(s,1H),5.70-6.05(m,1H),4.70(bs,1H),3.69(s,3H),3.37-3.50(m,2H),3.25-3.37(m,2H),2.80-2.99(m, 4H),2.19-2.29(m,2H),2.07-2.17(m,2H),1.93-2.06(m,1H),1.77-1.88(m,1H), LC-MS (Method A, ESI): m / z,349(M+H) + , t R =3.5 minutes.

[0180] Method N: Example 483: N-(1-cyclobutyl-3-(cyclobutylmethyl)-4-methyl-1H-pyrazol-5-yl)-3,3-difluorocyclobutane-1-carboxamide [ka] To a solution of 1-cyclobutyl-3-(cyclobutylmethyl)-4-methyl-1H-pyrazol-5-amine (0.030 g, 0.118 mmol) in EtOAc was added 3,3-difluorocyclobutane-1-carboxylic acid (0.026 g, 0.176 mmol), pyridine (0.019 g, 0.019 mL, 0.235 mmol) and anhydrous propylphosphonic acid solution (50% by weight or more in ethyl acetate, 0.070 mL, 0.235 mmol). The mixture was stirred at 60° C. overnight, then diluted with DCM, washed with 0.5 M HCl, H2O, saturated aqueous NaHCO3, and brine, then dried (Na2SO4), filtered and concentrated. The crude material was purified on a 12 g silica gel column eluting with 0-40% EtOAc / Hexanes to give N-(1-cyclobutyl-3-(cyclobutylmethyl)-4-methyl-1H-pyrazol-5-yl)-3,3-difluorocyclobutane-1-carboxamide (Example 483, 23 mg, 50% yield). LC-MS (Method A, ESI): m / z, 388 (M+H). + , t R =3.9 minutes.

[0181] Method O Example 372: N-(4-cyclobutyl-3-((3,3-difluorocyclobutyl)methyl)-1-methyl-1H-pyrazol-5-yl)-3,3-dimethylbutanamide [ka] To 4-cyclobutyl-3-((3,3-difluorocyclobutyl)methyl)-1-methyl-1H-pyrazol-5-amine (25 mg, 0.10 mmol) in DCM (0.39 mL) was added pyridine (40 μL, 0.49 mmol) and 3,3-dimethylbutanoyl chloride (41 μL, 0.29 mmol). The mixture was stirred at room temperature for 3 h. The solvent was removed and the residue was dissolved in 3M ammonia in CH3OH (1 mL). The mixture was stirred at 50 °C for 1 h and concentrated. To the crude material was added saturated aqueous NH4Cl and the mixture was extracted with EtOAc. The extracts were combined and concentrated. The crude material was purified on a 4 g silica gel column eluting with 0-100% EtOAc / Hexanes. The product was repurified by HPLC (C18 column, eluting with 10-100% CH3CN / HO) to give N-(4-cyclobutyl-3-((3,3-difluorocyclobutyl)methyl)-1-methyl-1H-pyrazol-5-yl)-3,3-dimethylbutanamide (Example 372, 9.3 mg, 27%).

[0182] Method P Example 127: (4-cyclobutyl-3-cyclohexyl-1-methyl-1H-pyrazol-5-yl)carbamate ethyl [ka] To 4-cyclobutyl-3-cyclohexyl-1-methyl-1H-pyrazol-5-amine (10.5 mg, 0.045 mmol) in THF was added triethylamine (19 μL, 0.14 mmol) and ethyl chloroformate (10 μL, 0.11 mmol). The mixture was stirred overnight and the reaction was determined to be incomplete by LCMS. Additional triethylamine (40 μL, 0.29 mmol) and ethyl chloroformate (20 μL, 0.21 mmol) were added to the mixture and it was stirred overnight. The mixture was diluted with EtOAc, then washed with saturated aqueous NaHCO3, dried over Na2SO4, and then concentrated. Purification by column chromatography (0-100% EtOAc / hexanes) afforded ethyl (4-cyclobutyl-3-cyclohexyl-1-methyl-1H-pyrazol-5-yl)carbamate (Example 127, 4.7 mg, 35%).

[0183] Method Q Example 542: (1-(tert-butyl)-3-(3,3-difluorocyclobutyl)-4-methyl-1H-pyrazol-5-yl)carbamic acid phenyl (1s,3s)-3-fluorocyclobutyl [ka] Step 1. To a solution of 1-(tert-butyl)-3-(3,3-difluorocyclobutyl)-4-methyl-1H-pyrazol-5-amine (500 mg, 2.06 mmol) and N,N-diisopropylethylamine (1.79 mL, 10.3 mmol) in CHCl (20 mL) was added phenyl chloroformate (0.5 mL, 4.1 mmol) dropwise over 5 min at 0 °C and the solution was stirred at room temperature for 48 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the volatiles were removed under reduced pressure and the resulting residue was purified by silica gel column chromatography eluting with a 15% to 20% EtOAc / Hexane gradient to give (1-(tert-butyl)-3-(3,3-difluorocyclobutyl)-4-methyl-1H-pyrazol-5-yl)carbamate (600 mg, 81%) as an off-white solid. LC-MS (Method B, -ve mode): m / z, 364 (M+H) + , t R =5.4 minutes.

[0184] Step 2. To a mixture of potassium tert-butoxide (155 mg, 1.39 mmol) in THF (3 mL), a solution of (1s,3s)-3-fluorocyclobutan-1-ol (93.8 mg, 1.04 mmol) in dry THF was added dropwise at 0° C. and the mixture was stirred for 30 min. (1-(tert-butyl)-3-(3,3-difluorocyclobutyl)-4-methyl-1H-pyrazol-5-yl)carbamate (250 mg, 0.694 mmol) in THF (3 mL) was added dropwise to the above reaction mixture at 0° C. and then stirred for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the volatiles were removed under reduced pressure and the resulting residue was purified by silica gel column chromatography eluting with 15% EtOAc / hexane to afford (1s,3s)-3-fluorocyclobutyl (1-(tert-butyl)-3-(3,3-difluorocyclobutyl)-4-methyl-1H-pyrazol-5-yl)carbamate (85 mg, 34%) as an off-white solid.

[0185] 1H NMR (300MHz, DMSO-D6):δ 8.80-9.04(m,1H),4.70-4.97(m,1H),4.50-4.56(m,1H),3.23-3.29(m,1H),2.67-2.96 (m,6H),1.92-2.27(m,2H),1.70(s,3H),1.48(s,9H), LC-MS (Method B, -ve mode): m / z,358(MH) - , t R =4.9 minutes.

[0186] Method R: Example 180: N-(4-cyclobutyl-1-methyl-3-(2-(trifluoromethyl)thiazol-5-yl)-1H-pyrazol-5-yl)-1-(trifluoromethyl)cyclopropane-1-carboxamide [ka] 1-(Trifluoromethyl)cyclopropane-1-carboxylic acid (0.027 g, 0.172 mmol), 1-(fluoro(pyrrolidin-1-yl)methylene)pyrrolidin-1-ium hexafluorophosphate (V) (0.063 g, 0.198 mmol), and diisopropylethylamine (0.104 mL, 0.595 mmol) were stirred in DCM (0.5 mL) in a vial at ambient temperature for 30 minutes followed by the addition of 4-cyclobutyl-1-methyl-3-(2-(trifluoromethyl)thiazol-5-yl)-1H-pyrazol-5-amine (0.040 g, 0.132 mmol). The vial was capped and sealed with parafilm and electrical tape and the reaction mixture was heated at reflux overnight. LCMS indicates complete consumption of the desired product and amine. The DCM was removed under high vacuum and the reaction mixture was diluted with MeOH and loaded onto a C18 HPLC column and eluted with 10-100% MeCN / HO. 1H-NMR(400MHz,CDCl3)δ 7.90(s,1H),7.47(s,1H),3.70(s,3H),3.60-3.64(m,1H),2.29-2.33(m,2H),2.08-2.17(m ,2H),2.00-2.05(m,1H),1.81-2.00(m,1H),1.43(bs,2H),LC-MS(Method A, ESI):m / z,439(M+H) + , t R = 4.2 min, yielding 8 mg (14%) of N-(4-cyclobutyl-1-methyl-3-(2-(trifluoromethyl)thiazol-5-yl)-1H-pyrazol-5-yl)-1-(trifluoromethyl)cyclopropane-1-carboxamide.

[0187] Method S: Example 217: 1-(4-cyclobutyl-3-(3,3-difluorocyclobutyl)-1-methyl-1H-pyrazol-5-yl)-3-phenylurea [ka] To a solution of 4-cyclobutyl-3-(3,3-difluorocyclobutyl)-1-methyl-1H-pyrazol-5-amine (30 mg, 0.12 mmol) in dichloromethane (2.0 mL) at 0° C. was added phenyl isocyanate (20 μL, 0.18 mmol) and triethylamine (35 μL, 0.24 mmol). The reaction mixture was then stirred overnight at room temperature. The volatiles were removed under reduced pressure and the resulting residue was dissolved in acetonitrile and purified by reverse phase HPLC column (C18, 10-100% acetonitrile / water and monitoring at 220 nm wavelength) to give 1-(4-cyclobutyl-3-(3,3-difluorocyclobutyl)-1-methyl-1H-pyrazol-5-yl)-3-phenylurea as a white solid (Example 217, 14 mg, 32%). 1H-NMR(400MHz, CDCl3):δ 7.29-7.37(m,4H),7.08-7.15(m,1H),6.30(s,1H),6.0(s,1H),3.74(s,3H),3.28-3.40(m,2H),2.80- 3.01(m,4H),2.10-2.30(m,4H),1.91-2.05(m,1H),1.77-1.88(m,1H), LC-MS (Method A, ESI): m / z,361(M+H) + , t R =3.9 minutes.

[0188] Method W Example 102: (R)-N-(4-cyclobutyl-3-(4-fluorophenyl)-1-(2-hydroxyethyl)-1H-pyrazol-5-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide [ka] To (R)-N-(1-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-cyclobutyl-3-(4-fluorophenyl)-1H-pyrazol-5-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide (17 mg, 0.025 mmol) in THF (1 mL) was added TBAF solution (50 μL, 0.05 mmol, 1 M in THF). After 2 h, TLC indicated consumption of starting material. The mixture was purified by direct application to a reverse-phase HPLC column (10-100% ACN / HO) to give (R)-N-(4-cyclobutyl-3-(4-fluorophenyl)-1-(2-hydroxyethyl)-1H-pyrazol-5-yl)-2-(2,2,3,3-tetrafluorocyclobutyl)acetamide (Example 102, 8.3 mg, 75%).

[0189] Method X Example 294: 3,3-difluorocyclobutyl (4-cyclobutyl-3-(3,3-difluorocyclobutyl)-1-methyl-1H-pyrazol-5-yl)(methyl)carbamate [ka] To a slurry of sodium hydride (4 mg, 0.16 mmol) in DMF (0.3 mL) at 0° C. was added a solution of 3,3-difluorocyclobutyl (4-cyclobutyl-3-(3,3-difluorocyclobutyl)-1-methyl-1H-pyrazol-5-yl)carbamate (20 mg, 0.053 mmol, in 0.6 mL DMF). The mixture was stirred for 30 minutes, and then iodomethane (4 μL, 0.069 mmol) was added. The reaction mixture was allowed to warm to ambient temperature and stirred for 2 hours, at which point the reaction mixture was cooled to 0° C. and quenched by carefully adding saturated aqueous NH4Cl solution dropwise thereto until hydrogen evolution ceased. The reaction mixture was diluted with ethyl acetate and the organic portion was washed with cold water (4 times) and brine (1 time), then dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (silica gel, 0-100% ethyl acetate / hexanes) to give 3,3-difluorocyclobutyl (4-cyclobutyl-3-(3,3-difluorocyclobutyl)-1-methyl-1H-pyrazol-5-yl)(methyl)carbamate as an oil (11 mg, 53%). 1 H-NMR(400MHz, CDCl3):δ 5.04(bs,1H),3.60(s,3H),3.19-3.35(m,2H),3.15(s,3H),2.93-3.05(m,2H),2.76-2.91(m,4H),2.45 -2.60(m,1H),2.11-2.26(m,2H),1.92-2.10(m,3H),1.75-1.88(m,1H), LC-MS(Method A, ESI): m / z,390(M+H) + , t R =4.3 minutes.

[0190] Method Y Example 77: N-(4-cyclobutyl-3-(4-(2-hydroxypropan-2-yl)phenyl)-1-methyl-1H-pyrazol-5-yl)-3,3-dimethylbutanamide [ka] N-(3-(4-bromophenyl)-4-cyclobutyl-1-methyl-1H-pyrazol-5-yl)-3,3-dimethylbutanamide (20 mg, 0.05 mmol) was dissolved in THF (1.6 mL) and cooled to 0° C. in an ice bath. To this solution was added i-PrMgCl (42 μL, 0.08 mmol, 2M in THF) dropwise. The solution was stirred at 0° C. for 10 min, then cooled to −78° C., and t-BuLi (125 μL, 0.21 mmol, 1M in hexanes) was added dropwise. The solution was stirred at −78° C. for 15 min, then acetone (36 μL, 0.50 mmol) was added, and the solution was allowed to warm to room temperature over 1 h. The mixture was quenched with saturated aqueous NH4Cl and then extracted with EtOAc. The extracts were combined, washed with brine, dried (MgSO4), filtered, and concentrated. The residue was dissolved in 0.5 mL of ACN and purified by reverse-phase HPLC (C18 column, eluted with 10-100% CH3CN / HO) to give N-(4-cyclobutyl-3-(4-(2-hydroxypropan-2-yl)phenyl)-1-methyl-1H-pyrazol-5-yl)-3,3-dimethylbutanamide (Example 77, 3.1 mg, 16%).

[0191] Method Z Example 442: 1-(4-(azetidin-3-yl)-3-(3,3-difluorocyclobutyl)-1-methyl-1H-pyrazol-5-yl)-3-(2,2,2-trifluoroethyl)urea hydrochloride [ka] To a solution of tert-butyl 3-(3-(3,3-difluorocyclobutyl)-1-methyl-5-(3-(2,2,2-trifluoroethyl)ureido)-1H-pyrazol-4-yl)azetidine-1-carboxylate (50 mg, 0.11 mmol) in dichloromethane (2 mL) was added 4N HCl / dioxane (654 μL) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 2.5 h. LC-MS showed that the starting compound was consumed. The volatiles were removed under reduced pressure and the resulting residue was triturated with methanol / diethyl ether (1:9). The precipitate was collected by filtration and dried under high vacuum to give 1-(4-(azetidin-3-yl)-3-(3,3-difluorocyclobutyl)-1-methyl-1H-pyrazol-5-yl)-3-(2,2,2-trifluoroethyl)urea hydrochloride as a white solid (38 mg, 88%). 1 H-NMR(400MHz,DMSO-d6):δ 9.14(bs,1H),8.60-8.85(m,2H),7.38(s,1H),3.98-4.12(m,4H),3.79-3.95(m,3H),3.55(s,3H),2.70-3.01(m,5H),LC-MS(ESI):m / z,368(M+H) + , t R =2.3 minutes.

[0192] Method AA Example 251: 5-amino-4-cyclobutyl-N-(3,3-difluorocyclobutyl)-3-(4-fluorophenyl)-1H-pyrazole-1-carboxamide [ka] To a solution of 4-cyclobutyl-5-(4-fluorophenyl)-1H-pyrazol-3-amine (30 mg, 0.13 mmol) and phenyl (3,3-difluorocyclobutyl)carbamate (44 mg, 0.19 mmol) in DMF / dioxane (0.7 mL, 1:9) in a microwave tube (2.0-5.0 mL) was added N,N-diisopropylethylamine (45 μL, 0.26 mmol). The reaction mixture was irradiated at 120° C. under microwave conditions for 45 min. The resulting reaction mixture was injected directly onto a reverse phase HPLC column (C18, 10-100% acetonitrile / water, and monitored at 220 nm wavelength) to give 5-amino-4-cyclobutyl-N-(3,3-difluorocyclobutyl)-3-(4-fluorophenyl)-1H-pyrazole-1-carboxamide as a white solid (Example 251, 12 mg, 25%). 1 H-NMR(400MHz, CDCl3):δ 7.40-7.51(m,2H),7.30-7.37(m,1H),7.04-7.18(m,2H),5.39(s,2H),4.21-4.37(m,1H),3.39-3.54(m,1H),2.95-3 .14(m,2H),2.55-2.75(m,2H),2.03-2.22(m,4H),1.84-1.99(m,1H),1.77-1.83(m,1H),LC-MS(ESI):m / z,365(M+H) + , t R =4.5 minutes.

[0193] Method BB: Example 555: 2-(3,3-difluorocyclobutyl)-N-(3-(3,3-difluorocyclobutyl)-1-(2-hydroxy-2-methylpropyl)-4-methyl-1H-pyrazol-5-yl)acetamide [ka] Methylmagnesium bromide (0.658, 1.97 mmol, 3.0 M in Et2O) was added to a solution of ethyl 2-(3-(3,3-difluorocyclobutyl)-5-(2-(3,3-difluorocyclobutyl)acetamido)-4-methyl-1H-pyrazol-1-yl)acetate (0.080 g, 0.197 mmol) in 1.0 mL of THF and the reaction mixture was stirred overnight. The reaction was quenched with 1N HCl, extracted (2x with EtOAc), the combined organics were dried (Na2SO4) and the volatiles were removed to give a crude residue that was purified by preparative HPLC (C18 column, 10-100% MeCN / H2O) to give 1 H-NMR(400MHz,CDCl3)δ 8.03(s,1H),3.92(s,2H),3.25-3.30(m,1H),2.78-2.91(m,6H),2.61(bs,3H),2.4 6(s,1H),2.22-2.39(m,2H),1.92(s,3H),1.22(s,6H),LC-MS(ESI):m / z,392(M+H) + , t R = 3.6 min, 12 mg (16%) of 2-(3,3-difluorocyclobutyl)-N-(3-(3,3-difluorocyclobutyl)-1-(2-hydroxy-2-methylpropyl)-4-methyl-1H-pyrazol-5-yl)acetamide was obtained.

[0194] Method CC Example 238: N-(4-cyclobutyl-3-(3-hydroxy-3-phenylcyclobutyl)-1-methyl-1H-pyrazol-5-yl)-3,3-difluorocyclobutane-1-carboxamide [ka] Step 1. N-(4-cyclobutyl-3-(3,3-dimethoxycyclobutyl)-1-methyl-1H-pyrazol-5-yl)-3,3-difluorocyclobutane-1-carboxamide (0.097 g, 0.253 mmol) was dissolved in acetone / water (4 mL, 3:1) and p-toluenesulfonic acid monohydrate (0.048 g, 0.253 mmol) was added. The mixture was stirred at 75° C. for 1 h. The mixture was cooled to room temperature and concentrated. The resulting solid was taken up in DCM, washed with saturated aqueous NaHCO3 and dried over MgSO4. The organics were then concentrated to give N-(4-cyclobutyl-1-methyl-3-(3-oxocyclobutyl)-1H-pyrazol-5-yl)-3,3-difluorocyclobutane-1-carboxamide as a white solid (73.9 mg, 87% yield), which was used in the next step without further purification. LC-MS (ESI): m / z, 338 (M+H). + , t R =3.4 minutes.

[0195] Step 2. N-(4-cyclobutyl-1-methyl-3-(3-oxocyclobutyl)-1H-pyrazol-5-yl)-3,3-difluorocyclobutane-1-carboxamide (0.097 g, 0.147 mmol) was dissolved in THF (0.500 mL) and phenylmagnesium bromide solution (0.134 mL, 0.741 mmol) was added. The mixture was stirred at 0° C. for 1 h. The reaction was quenched with saturated NH4Cl and allowed to warm to room temperature. The mixture was extracted with EtOAc (2×10 mL), dried over Na2SO4, and concentrated. The crude material was purified on a 12 g silica gel column eluted with MeOH / DCM (0-10%) to give N-(4-cyclobutyl-3-(3-hydroxy-3-phenylcyclobutyl)-1-methyl-1H-pyrazol-5-yl)-3,3-difluorocyclobutane-1-carboxamide (30 mg, 62% yield). LC-MS (ESI): m / z, 416 (M+H). + , t R =3.7 minutes. 1H NMR(400MHz,MeOH-D4):δ 7.60-7.62(m,2H),7.37-7.41(m,2H),7.28-7.30(m,1H),3.59(s,3H),3.01-3.18(m,2H),2. 81-2.98(m,6H),2.60-2.66(m,2H),2.12-2.18(m,4H),2.0-2.09(m,1H),1.96-1.98(m,1H).

[0196] Method DD Example 332: 1-(4-cyclobutyl-3-(3-hydroxycyclobutyl)-1-methyl-1H-pyrazol-5-yl)-3-(3,3-difluorocyclobutyl)urea [ka] 1-(4-Cyclobutyl-1-methyl-3-(3-oxocyclobutyl)-1H-pyrazol-5-yl)-3-(3,3-difluorocyclobutyl)urea (0.016 g, 0.045 mmol) was dissolved in anhydrous methanol (2 mL) at 0 °C, NaBH4 (0.003 g, 0.091 mmol) was added under N2, and the reaction mixture was stirred for 1 h. LCMS confirmed the formation of the product. The mixture was allowed to warm to room temperature and concentrated. The resulting solid was taken up in DCM, washed with aqueous NaHCO3, and dried over Na2SO4. The organics were concentrated and the crude material was purified on a 12 g silica gel column eluting with MeOH / DCM (0-10%) to give 1-(4-cyclobutyl-3-(3-hydroxycyclobutyl)-1-methyl-1H-pyrazol-5-yl)-3-(3,3-difluorocyclobutyl)urea as a white solid. (9mg, 56%). LC-MS(ESI):m / z,355(M+H) + , t R =2.9 minutes.

[0197] Compounds made by these methods are shown in Table 1. [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

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

Table 1-50

Table 1-51

Table 1-52

Table 1-53

[0198] Biological Assay Methods Kv7.2 / 7.3 activation assay The thallium flux assay is used as a surrogate indicator of potassium channel activity.

[0199] The experimental protocol was adapted from the FluxOR™ II Green Potassium Ion Channel Assay User Guide (Pub. No. MAN0016084, Invitrogen). Conditions were optimized for the Kv7.2 / 7.3 cell line.

[0200] Cell lines: The hKV7.2 / 7.3 cell line was obtained from Chantest (Cleveland, Ohio 44128) catalog number CT6147.

[0201] Cell culture: Kv7.2 / 7.3 cells were maintained in medium containing DMEM / F12; 50 / 50 (Fisher 11-330), 10% fetal bovine serum (FBS) (Fisher 26-140), 100 units / mL penicillin-streptomycin (Fisher 15-140), 0.005 mg / mL blasticidin (InvivoGen ant-bl-1), 0.5 mg / mL Geneticin (InvivoGen ant-gn-5), and 0.1 mg / mL Zeocin (Fisher R25001). One day before the experiment, cells were seeded in 96-well clear bottom plates (Corning Cat. No. 353219) in medium without blasticidin, geneticin, and zeocin. Channel expression was induced by adding tetracycline (Sigma T7660) at a final concentration of 10 ng / mL.

[0202] Compound plate: Test compounds are diluted in a mixture of 0.1% DMSO / extracellular solution at a single concentration of 10 μM. The dilutions were performed in a Biomek NXP (BECKMAN COULTER).

[0203] Measurement and Data Analysis: A plate reader (Enspire, Perkin Elmer) is used to characterize the ion channel modulating properties of the novel compounds using 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, 30 μM).

[0204] Data from the 7.2 / 7.3 thallium flux assay are summarized in Table 2. [Table 3-1] [Table 3-2]

Table 3-3

Table 3-4

Table 3-5

Table 3-6

Table 3-7

Table 3-8

Table 3-9

Table 3-10

Table 3-11

Table 3-12

Table 3-13

Table 3-14

Table 3-15

Table 3-16

[0205] Groupings of alternative elements or embodiments disclosed herein should not be construed as limitations. Each group member may be referenced 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 group as modified to satisfy the written description of all Markush groups used in the appended claims.

[0206] 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 of ordinary skill in the art upon reading the foregoing description. The inventors expect such variations to be adopted by those of ordinary skill in the art as appropriate, and the inventors do not intend to practice the invention otherwise than as specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter recited in the claims as 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.

[0207] Finally, it is to 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 configurations may be utilized in accordance with the teachings herein. Accordingly, the claims are not limited to the embodiments precisely as shown and described.

Claims

1. A compound represented by formula 1, 【Chemistry 1】 During the ceremony, R １ is optionally substituted C １～４ Alkyl, optionally substituted C ３～８ Cycloalkyl, optionally substituted C ５～１０ Aryl, optionally substituted C ２～８ Heteroaryl, optionally substituted C ２～８ Heterocyclyl or optionally substituted -C(O)NHC １～４ alkyl, each optional substituent is independently halogen, OH, CN, -C(O)NH ２ , -N(C １～４ Alkyl) ２ , C １～４ Alkyl, C ５～１０ Aryl, and C ５～１０ haloaryl; R ２ is H, halogen, optionally substituted C １～８ Alkyl, optionally substituted C １～８ Haloalkyl, optionally substituted -OC １～８ Alkyl, optionally substituted C ２～８ Alkanoyl, optionally substituted C ３～１０ Cycloalkyl, optionally substituted benzo(C ３～８ cycloalkyl), optionally substituted C ５～１０ Aryl, optionally substituted benzoyl, optionally substituted —OC ５～１０ Aryl, optionally substituted C ２～８ Heteroaryl or optionally substituted —OC ２～８ heteroaryl, each optional substituent independently being halogen, OH, CN, CO ２ H.C. １～４ Alkyl, C １～４ Hydroxyalkyl, C １～４ Haloalkyl, -OC １～４ Alkyl, -OC １～４ Haloalkyl, C ３～８ Cycloalkyl, C ３～８ Halocycloalkyl, —CO ２ H, -SO ２ C １～４ Alkyl, -SO ２ C １～４ Haloalkyl, C ５～１０ Aryl, and C ５～１０ Haloaryl, -N(C １～４ Alkyl) ２ , -NC １～４ Alkyl 、 or optionally substituted C ２～８ heterocyclyl; R ３ is H, halogen, optionally substituted C １～６ Alkyl, optionally substituted C ３～８ Cycloalkyl, optionally substituted C ２～８ heterocyclyl, or optionally substituted C ５～１０ aryl, each optional substituent independently being halogen, OH, N(R ７ ) (R ８ ) selected from the group consisting of R ７ and R ８ are independently H or C １～４ alkyl, R ７ and R ８ is optionally connected to a ring, CN, C １～４ Alkyl, C １～４ Hydroxyalkyl, and C １～４ Forming a haloalkyl R ４ But, H, C １～３ Alkyl, C ３～８ Cycloalkyl, or C １～４ is hydroxyalkyl, R ５ but, 【Chemistry 2】 and A is C １～８ Alkyl, C ２～８ Alkenyl, C ３～８ Cycloalkyl, C ５～１０ Bicycloalkyl, C ２～５ Heterocyclyl, C ５～１０ Aryl, or C ２～８ is heteroaryl, X is H, F, Cl, optionally substituted C １～６ Alkyl, optionally substituted C ３～８ Cycloalkyl, optionally substituted -OC １～６ Alkyl, optionally substituted C ２～５ Heterocyclyl, or optionally substituted C ５～１０ aryl, each optional substituent independently being halogen, OH, C １～３ Alkyl, C １～３ Haloalkyl, -OC １～３ Alkyl, C ３～８ Cycloalkyl, C ３～８ halocycloalkyl, and CN; Y is H, halogen, OH, optionally substituted C １～３ Alkyl, optionally substituted C ３～６ Cycloalkyl, optionally substituted -OC １～３ Alkyl, optionally substituted C １～３ haloalkyl, or optionally substituted —OC １～３ haloalkyl, each optional substituent is independently halogen, OH, C １～３ Alkyl, C １～３ Haloalkyl, -OC １～３ Alkyl, C ３～８ Cycloalkyl, C ３～８ halocycloalkyl, and CN; Z is a bond, C(R ６ ) ２ , N.R. ６ , O, C(R ６ ) ２ N.R. ６ , C(R ６ ) ２ O, N.R. ６ C(R ６ ) ２ , or OC(R ６ ) ２ and R ６ But, H, C １～３ Alkyl, or C １～４ a compound which is a hydroxyalkyl or a pharma- ceutically acceptable salt thereof.

2. R １ is optionally substituted C １～４ Alkyl or optionally substituted C ３～８ The compound of claim 1 which is cycloalkyl.

3. R ２ is optionally substituted C ３～１０ The compound of claim 1 which is cycloalkyl.

4. R ３ is optionally substituted C １～６ Alkyl or optionally substituted C ３～８ The compound of claim 1 which is cycloalkyl.

5. R ４ The compound of claim 1 , wherein

6. A is C １～８ Alkyl or C ３～８ The compound of claim 1 which is cycloalkyl.

7. R １ is optionally substituted C １～４ Alkyl or optionally substituted C ３～８ is cycloalkyl, R ２ is optionally substituted C ３～６ is cycloalkyl, R ３ is optionally substituted C １～４ Alkyl or optionally substituted C ３～６ is cycloalkyl, R ４ is H, R ５ but, 【Chemistry 3】 and A is C １～４ Alkyl or C ３～６ is cycloalkyl, X is H, F, optionally substituted C １～６ Alkyl or optionally substituted C ３～８ is cycloalkyl, Y is H or halogen; Z is a bond, C(R ６ ) ２ , N.R. ６ and O.

8. R １ is optionally substituted C １～４ The compound of claim 7, which is alkyl.

9. R １ is optionally substituted C ３～８ The compound of claim 7 which is cycloalkyl.

10. R ２ is substituted with at least one F ３～６ The compound of claim 7 which is cycloalkyl.

11. R ３ But, C １～４ Alkyl or C ３～６ The compound of claim 7 which is cycloalkyl.

12. The compound of claim 1, wherein the compound is selected from compounds 1-574 in Table 1, or a pharma- ceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, or a pharma- ceutically acceptable salt thereof.

14. A method for treating a disease or disorder, comprising administering a therapeutically effective amount of a compound of claim 1, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof, wherein the disease or disorder is selected from a Kv7-associated disorder, a disorder associated with a KCNQ subunit, a disorder associated with a mutation in a KCNQ subunit, a neurodegenerative disease, a disease or disorder that may benefit from activation of a Kv7.2 homomer, a neurodevelopmental disease or disorder, or a disease or disorder of the CA group.

15. The method of claim 14, wherein the disease or disorder is a Kv7-associated disorder.

16. The method of claim 15, wherein the Kv7-related disorder is selected from epilepsy, neonatal spasms, pain, migraine, disorders of neurotransmitter release, disorders of smooth muscle contractility, dyskinesia, dystonia, mania, hearing loss, neuropathic pain, inflammatory pain, persistent pain, cancer pain, post-operative pain, anxiety, substance abuse, schizophrenia, bladder disorders, vascular disorders, tinnitus, frontotemporal dementia (FTD), familial FTD, or amyotrophic lateral sclerosis.

17. 15. The method of claim 14, wherein the disease or disorder is a disorder associated with a mutation in a KCNQ subunit.

18. 18. The method of claim 17, wherein the disorder associated with a mutation in a KCNQ subunit is a disorder associated with a KCNQ2 mutation.

19. 19. The method of claim 18, wherein the disorder associated with a KCNQ2 mutation is selected from neonatal spasms, neonatal seizures, epilepsy, benign familial neonatal epilepsy (KCNQ2-BFNE), epileptic encephalopathy (KCNQ2-NEE), benign familial neonatal convulsions type 1 (BFNC), benign familial neonatal seizures 1 (BFNS1), neonatal seizures associated with hypoxic-ischemic injury, epileptic spasms, epileptic encephalopathy, early infantile epileptic encephalopathy 7 (EIEE7), early infantile epileptic encephalopathy with delayed psychomotor development, generalized tonic seizures, abnormal globus pallidus morphology, apnea, cerebral edema, dystonia, facial erythema, hypotonia, febrile seizures, hypoplasia of the corpus callosum, hypsarrhythmia, focal clonic seizures, generalized tonic-clonic seizures, myokymia, spastic tetraplegia, and combinations thereof.

20. 15. The method of claim 14, wherein the disease or disorder is a neurodevelopmental disease or disorder.

21. 21. The method of claim 20, wherein the subject is a fetus, an infant from about birth to about 12 months, or a child from about 1 year to about 12 years of age.

22. 21. The method of claim 20, wherein the neurodevelopmental disease or disorder is selected from the group consisting of Angelman syndrome, neonatal abstinence syndrome, early myoclonic encephalopathy, Landau-Kleffner syndrome, electrical status epilepticus during sleep, Ohtahara syndrome, autism spectrum disorder, Dravet syndrome, Lennox-Gastaut syndrome, Rett syndrome, Hirschsprung's disease (HSCR), West syndrome, SCN8A-associated epilepsy with encephalopathy (EIEE13), infantile epilepsy with migrating focal seizures (EIMFS), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), Doose syndrome, and combinations thereof.

23. The compound regulates Kv7.2 / 7.3 and GABA Ａ The method of claim 14, wherein the

24. 15. The method of claim 14, wherein the therapeutically effective amount does not cause undesirable side effects.

25. 25. The method of claim 24, wherein the undesirable side effect is selected from the group consisting of dizziness, fatigue, drowsiness, confusion, vertigo, tremors, ataxia, double or blurred vision, lack of attention, memory impairment, muscle weakness, skin discoloration, withdrawal episodes, QT interval changes, suicidal behavior, urinary retention, drowsiness, hallucinations, confusion, and combinations thereof.

26. 15. The method of claim 14, wherein the compound is more potent than ezogabine.

27. 15. The method of claim 14, wherein the therapeutically effective amount is better tolerated than ezogabine.

28. 15. The method of claim 14, wherein the disease or disorder is a CA group disease or disorder.

29. 29. The method of claim 28, wherein the disease or disorder of the CA group is selected from the group consisting of alcohol use disorder, Dravet syndrome, traumatic brain injury, cerebral vasospasm after subarachnoid hemorrhage, stroke, gout pain, temporomandibular joint (TMJ) pain, chronic cough, asthma or chronic obstructive pulmonary disease, trigeminal neuralgia (TN), atypical facial pain, cluster headache, chemotherapy-induced neuropathic pain, orofacial cold-warm hyperalgesia, depression, major depressive disorder, peripheral nerve hyperexcitability (PNH) syndrome, neuromyotonia, fasciculations syndrome (CFS), Morvan's syndrome, diseases involving hypoxic pulmonary vasoconstriction (HPV), hypoxia-induced pulmonary hypertension and high altitude pulmonary edema, preeclampsia, paroxysmal dystonia, psychostimulant addiction, bipolar disorder, post-traumatic stress disorder (PTSD), noise-induced tinnitus, salicylate-induced hearing loss and tinnitus, and combinations thereof.

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