Prodrugs of Kv7 channel openers

Abstract

A prodrug of a pharmacologically active 1,2,4-triaminobenzene derivative of general formula (I) or a pharma- ceutically acceptable salt thereof, represented by the symbol R 1 , R 2 , R 3 , R 4 , R 5 And R 6a , R 6b , and R 6c and the symbol Z is defined. Methods are provided for the synthesis, purification, testing, and use as prodrugs of pharmacologically active agents at Kv7 ion channels. TIFF2024511057000047.tif5267

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 163,470, filed March 19, 2021, the contents of which are incorporated herein by reference.

[0002] The present disclosure relates to the field of prodrugs of pharmacologically active drugs, and in particular to the field of prodrugs of drugs active at Kv7 potassium ion channels. The prodrugs of the present disclosure contain one or more hydrolyzable bonds between a pharmacologically active drug or compound, such as ezogabine, flupirtine, or other chemicals that are active at Kv7 potassium ion channels, and a carbonyl-containing prodrug side group, for example from an amino acid, or from a carbonyl-containing side group found in various acetal diester or ketal diester derivatives, such as the prodrug side group exemplified by gabapentin enacarbil, that is not active on the Kv7 potassium ion channel itself. The hydrolyzable bonds of the prodrugs of the present disclosure are cleaved in the mammalian body to generate the pharmacologically active drug. [Background technology]

[0003] Prodrugs: Prodrugs are bioreversible derivatives of drug molecules that must undergo enzymatic and / or chemical transformation in vivo to release the active parent drug, which can then exert its desired pharmacological effect.

[0004] Generally, prodrugs are biologically inactive compounds that are activated after administration to their pharmacologically active forms. In many cases, prodrugs are formulated to overcome physicochemical barriers such as poor solubility and absorption, extensive first-pass metabolism, lack of brain penetration, or rapid excretion, as well as impurities and pharmacokinetic barriers such as instability, undesirable degradation products, or toxicity, tolerability, side effects, and poor efficacy. Activation of prodrugs is usually carried out either through enzymatic processes such as cytochrome enzymes, esterases, and amidases, or chemical processes (inter- or intra-molecular) such as hydrolysis and oxidation.

[0005] Prodrug development is now well established as a strategy to improve the physicochemical, biopharmaceutical or pharmacokinetic properties of pharmacologically potent compounds, thereby overcoming barriers to drug developability and utility.

[0006] Compounds active at Kv7 potassium ion channels: Voltage-gated Kv7 (or KCNQ) channels play a key role in controlling membrane excitability. The Kv7 subfamily of voltage-gated potassium channels consists of five members (Kv7.1-5), each of which exhibits a characteristic tissue distribution and physiological role. Given their functional heterogeneity, Kv7 channels represent important pharmacological targets for the development of new drugs for neurological, neuromuscular, cardiovascular and metabolic diseases. Similar to typical voltage-gated ion channels, Kv7 channels undergo a closed-to-open transition by sensing changes in transmembrane potential, thereby mediating an inhibitory K(+) current to reduce membrane excitability. Reduced Kv7 channel activity as a result of genetic mutations is a contributing factor in a variety of human diseases resulting from membrane hyperexcitation, including epilepsy, arrhythmias and hearing loss. As a result, the discovery of small compounds that activate voltage-gated ion channels is an important strategy for clinical intervention in such disorders. Because ligand binding can induce conformational changes that lead to subthreshold channel opening, there is great interest in understanding these "gain-of-function" molecules on a molecular basis. Although small molecule activators of cation channels are rare, several novel compounds have been identified that activate Kv7 voltage-gated channels.

[0007] Ezogabine (USAN, or retigabine [INN]) and flupirtine inhibit Kv7K + These are two examples of compounds that are active at the channel and have been developed into drugs but are no longer on the market as therapeutic agents.

[0008] Ezogabine is used with other drugs to control partial-onset seizures (seizures involving only part of the brain) and focal seizures in adults, and works by reducing neuronal hyperexcitability in the peripheral and central nervous systems. Overall, the most frequently reported adverse reactions (occurring in 4% or more, approximately twice the placebo rate) in patients receiving ezogabine, offered under the brand name POTIGA®, a registered trademark of Valeant Pharmaceuticals North America, were dizziness (23%), somnolence (22%), fatigue (15%), confusion (9%), spatial disorientation (8%), tremor (8%), abnormal coordination (7%), diplopia (7%), attention disorder (6%), memory impairment (6%), asthenia (5%), blurred vision (5%), gait disturbance (4%), aphasia (4%), dysarthria (4%), and balance disorder (4%). In most cases, reactions were mild or moderate in intensity (Potiga label, updated May 2016).

[0009] Ezogabine has demonstrated efficacy in a variety of cells, tissues, animal models, and clinical trials relevant to the location of these targets. In addition to blocking seizures, ezogabine has demonstrated pharmacological properties consistent with its use as an analgesic, neuroprotective agent in the treatment of hearing loss, in the treatment of status epilepticus associated with organophosphate poisoning (Barker 2021, Neuroscience), and in the treatment of demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis. Ezogabine has provided important information and clues regarding novel mechanistic approaches to the treatment of a range of clinical conditions involving neuronal hyperexcitability.

[0010] Flupirtine is used as a centrally acting analgesic in patients with a range of acute and persistent pain conditions without the adverse effects characteristic of opioids and nonsteroidal anti-inflammatory drugs, and is well tolerated by the majority of the patient population. The pharmacological profile exhibited by flupirtine involves actions on several cellular targets, including Kv7 channels, G protein-regulated inwardly rectifying K channels, and γ-aminobutyric acid type A receptors, although there is also evidence of additional unidentified mechanisms of action involved in the effects of flupirtine.

[0011] Flupirtine has demonstrated effects on various cells and tissues related to the location of these targets. In addition to analgesia, flupirtine has demonstrated pharmacological properties consistent with its use as an anticonvulsant, neuroprotectant, skeletal and smooth muscle relaxant in the treatment of hearing and visual disorders, as well as memory and cognitive disorders. Flupirtine has provided important information and clues regarding novel mechanistic approaches to the treatment of a range of clinical conditions involving cellular hyperexcitability. However, flupirtine has several undesirable side effects, including nausea, vomiting, dizziness, pruritus, rash formation, abdominal pain, bloating, tremors, dry mouth, idiopathic hepatotoxicity, and fatigue.

[0012] More specifically, pharmacologically active compounds that interact with the Kv7.2 channel subtype are also being investigated (https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC2932606 / ) and may be useful as potential future drug compounds, although only two drugs, ezogabine and flupirtine, have been administered to humans as approved pharmaceuticals to date.

[0013] Kv7 channels present an interesting target for new therapeutic approaches to diseases caused by neural hyperexcitability, such as epilepsy, neuropathic pain, and migraine. The molecular mechanism of Kv7 activation by retigabine has been elucidated as stabilization of the open conformation by binding to the pore region of the Kv7 channel (J Physiol, Maljevic. 2008).

[0014] Literature studies have demonstrated that Kv7 channel openers such as retigabine, or pharmacological actions that enhance the open state of Kv72-5 subtypes, are potentially effective in treating, ameliorating, or preventing the progression of diseases or disorders selected from the group of diseases related to neurological indications and pain. In one example, it has been demonstrated that channel opening is influenced by the basal channel current that sets the resting membrane threshold. Enhancement of membrane threshold consisting of seizure neurons from Kv7.2(S559A) knock-in mice showed normal basal M-currents. Knock-in mice showed reduced M-current suppression when challenged by muscarinic agonists, and oxotremorine-M. Kv7.2(S559A) mice were resistant to chemoconvulsant-induced seizures and there was no mortality. Administration of XE991, a Kv7.2 blocker, transiently exacerbated seizures in knock-in mice comparable to wild-type mice. After experiencing an epileptic condition, Kv7.2(S559A) knock-in mice showed neither seizure-induced cell death nor spontaneous recurrent seizures. (L Greene, Epilepsia 2018) This example shows how channel opening blocks seizures and neuroprotects. ICA-105665, a Kv7.2 channel opener, reduced SPR in patients at single doses of 100 (1 out of 4), 400 (2 out of 4), and 500 mg (4 out of 6). This is the first evaluation of the effect of Kv7 potassium channel activation in a light-sensitive proof of concept model. The reduction in SPR in this patient population provides evidence of central nervous system (CNS) penetration of ICA-105665, and preliminary evidence that engagement with neuronal Kv7 potassium channels has an anti-seizure effect. (Epilepsia, Trenite, 2013).

[0015] In models of pain, more specifically neuropathic pain, and chronic headache, paclitaxel-induced peripheral neuropathy and associated neuropathic pain are severe and resistant to intervention. Results from rodent models demonstrated that retigabine / ezogabine can be used to inhibit the development of paclitaxel-induced peripheral neuropathy. (J Pain, Li. 2019).

[0016] Several drugs, including flupirtine and retigabine, enhance neuronal Kv7 / M channel activity, primarily through a hyperpolarizing shift in their voltage gating. As a result, they can reduce neuronal excitability and inhibit nociceptive stimulation and transmission. Flupirtine is one of the best-selling nonopioid analgesics in Europe and served as a central analgesic before being removed from the market, and retigabine, an analog of flupirtine, was approved as an adjunctive treatment for partial onset seizures, is a broad-spectrum anticonvulsant in animals, and is an effective analgesic in animal models of chronic inflammatory and neuropathic pain, central pain, pain associated with diabetic neuropathy, postherpetic neuralgia, and peripheral nerve injury (Brown Br J Pharmacology, 2009).

[0017] Czuzcwar additionally summarizes preclinical data showing that retigabine / ezogabine may be applied to patients with neuropathic pain and affective disorders, such as drug addiction and affective disorders. Early clinical data suggests that retigabine may also be effective in Alzheimer's disease or stroke. (Czuzcwar, Pharmacological Reports 2010)

[0018] There are numerous papers showing that Kv7 channel opening may be effective for many neurological therapeutic targets, including but not limited to anxiety, CNS damage caused by neurodegenerative illnesses or diseases or injuries, cognitive impairment, obsessive behavior, dementia, depression, Huntington's disease, dystonia, mania, etc. As retigabine / ezogaibin and flupirtine are well tolerated in humans, the current findings of significant anti-dystonic efficacy in dtsz mutant mice suggest that neuronal Kv7 channel activators are interesting candidates for the treatment of dystonia-associated dyskinesias and possibly other types of dystonia. The established analgesic effect of Kv7 channel openers may contribute to the improvement of these disorders, which are often accompanied by painful muscle spasms (Richter, Br J Pharmacology 2006).

[0019] A recent paper showed that retigabine could delay the spread of depolarization signs after submaximal OGD stimulation. (Aiba, Brain 2021). Interestingly, Kv7.2 activators are neuroprotective in experimental ischemia and brain trauma studies, and the anti-spreading depolarizing properties of the activators may contribute to these neuroprotective effects. Further review of recent studies supports the emerging role of Kv7 channels in intrinsic and synaptic plasticity, as well as their contribution to cognition and behavior. The KV7 family of voltage-gated potassium channels (KV7.2-5) play a key role in controlling neuronal excitability and are therefore attractive targets for the treatment of CNS disorders associated with hyperexcitability, and such diseases associated with hyperexcitability, such as cognitive impairment, memory impairment, memory disorder, and memory failure. (For example, Boehm,Pain 2019, Maghera,Epilepsia 2020, De Jong,Physiological Reports 2018, Jakubowski,Epilepsy Behav 2013, Zizhen Wu,J Pharmacol Exp Ther 2020, JE Larsson,In Physiology 2020, Yadav,Saudi J Anaesth 2017, Garakani,Front Psychiatry 2020, Maljevic,J Physiol 2008, R.Brant,Gastroenterology 2017, Hui Sun,JCI Insight 2019, R Brant,Gastroenterology 2017, Ravi Misra,Gastroenterology 2017, Parreno,Front Physiol 2020, Blom,PLoS One.2014)(Feng neuroscience 2019) (E Redford, Physiol Biochem 2021) (J Gunthrope, Epilepsia 2012, Epilepsia, Villalba. 2018) (Frontal Physiol, Baculis. 2020, Frontal Physoil, Vigil. 2020).

[0020] Considering that Kv7 channels are important for neonatal brain development and inhibition (Peters et al., 2005; Soh et al., 2014), memory impairments in these genetic models may result from abnormal hippocampal morphology and / or hyperexcitability (Peters et al., 2005; Milh et al., 2020). Kv7 channels also regulate multiple behaviors. Behavioral phenotyping of global or conditional homozygous KCNQ2 knockout mice was not possible due to early postnatal lethality or early death, respectively (Watanabe et al., 2000; Soh et al., 2014). However, heterozygous KCNQ2 knockout mice are viable and exhibit increased locomotor activity and exploratory behavior (Kim et al., 2020), consistent with behavioral hyperactivity induced by transgenic inhibition of Kv7 currents (Peters et al., 2005) and amphetamine and XE991 (Sotty et al., 2009). These mice also exhibit reduced sociality and increased repetitive and compulsive behaviors (Kim et al., 2020), reminiscent of the autism seen in some EE patients with dominant KCNQ2 mutations (Weckhuysen et al., 2012, 2013; Milh et al., 2013).

[0021] Recent animal studies have shown that enhancing M currents (Kv7 opening) can be a therapeutic target for multiple brain disorders, including those for which there are currently no treatments, such as TBI and psychostimulant addiction and movement disorders (Lee, J Neurophysio 2017), movement disorders, neurodegenerative diseases, Parkinson's disease, Parkinson-like movement disorders (Jama Neurol, Wainger. 2021; Neurosci Bull, chen. 2017; Neural Plast, Ramirez. 2015), phobia, Pick's disease, psychosis, and bipolar disorder (Frontal Physoil, Vigil. 2020).

[0022] Spinal cord injury may be treated by reducing neuronal activity by opening KCNQ / Kv7 channels to protect spinal neurons and axons from degeneration after spinal cord injury, thereby promoting recovery of motor and sensory function. A study by We et al. demonstrated that repeated application of retigabine to open these channels during the acute phase of injury promotes neurobehavioral recovery after spinal cord injury (Wu, J Pharmacol 2020).

[0023] Due to their important physiological roles, dysfunctional Kv7 channels are often associated with disorders characterized by abnormal potassium ion conductance, including cardiac arrhythmias, hearing loss, epilepsy, pain, and hypertension (Front Physiol, Larsson. 2020, J Physoil, Maljevic. 2008).

[0024] The study by Lee et al. provides evidence that mouse Kv7 channels may contribute differently to regulating the functional properties of cerebral and coronary arteries. Such heterogeneity has important implications for developing new therapeutic agents for cardiovascular dysfunction. (Lee, Microcirculation, 2015).

[0025] Finally, Kv7 channels present an interesting target for new therapeutic approaches against diseases caused by neuronal hyperexcitability, such as epilepsy, neuropathic pain, and migraine. The molecular mechanism of Kv7 activation by retigabine has recently been elucidated as stabilization of the open conformation by binding to the pore region, which may be important in the treatment of migraine and tension headaches. (J Physoil,Maljevic.2008).

[0026] Further experiments demonstrated that M-current inhibition simultaneously required an increase in cytoplasmic Ca2+ concentration and depletion of membrane phosphatidylinositol 4,5-bisphosphate (PIP2). PLC- and Ca2 / PIP2-mediated inhibition of M-current in sensory neurons may represent one of the common mechanisms underlying pain generated by inflammatory mediators and thus open a new therapeutic window for the treatment of this major clinical problem in intestinal diseases, inflammatory disorders such as ulcerative colitis, Crohn's disease, and Creutzfeldt-Jakob disease (J Neurosci, Linley. 2008).

[0027] Additional Kv7 channel openers, such as QO58, can specifically agonize Kv7.2 / 7.3 / M channels. Oral or intraperitoneal administration of QO58 can reverse inflammatory pain in rodent models (Acta Pharmacol Sin, Teng. 2016) and may be effective in peripheral hypertension.

[0028] Published data suggests that by stabilizing KCNQ4-mediated conductance (Kv7.4) in cells related to hearing, chemical channel openers can protect against degeneration and progression of hearing loss in the DFNA2 mouse model, which may be useful for progressive hearing loss or tinnitus (J Physoil, Maljevic. 2008).

[0029] Behavioral studies demonstrated that SF0034 is a more potent and less toxic anticonvulsant than retigabine in rodents. Moreover, SF0034 prevented the development of tinnitus in mice. We propose that SF0034 not only provides a powerful tool to study ion channel properties, but most importantly, a clinical candidate for the treatment of epilepsy and prevention of tinnitus (Br J Pharmacol, Leithner. 2014, J Neurosci, Kalappa. 2015).

[0030] The functional role of Kv7 channels may vary depending on the cell type. Several studies have demonstrated that impairment of Kv7 channels has a strong impact on lung physiology contributing to the pathophysiology of various respiratory diseases such as cystic fibrosis, asthma, chronic obstructive pulmonary disease, chronic cough, lung cancer, and pulmonary hypertension. Kv7 channels are now recognized to play a relevant physiological role in many tissues, which has prompted the search for Kv7 channel modulators with potential therapeutic applications in many diseases, including those affecting the lungs. Modulation of Kv7 channels has been proposed to provide beneficial effects in many pulmonary conditions. Thus, Kv7 channel openers / enhancers or drugs acting in part through these channels have been proposed as bronchodilators, expectorants, antitussives, chemotherapeutic agents and pulmonary vasodilators (Front Physiol, Mondejar-Parreno.2020), and as agents for obesity and disease-related hypertension (Front Cardivasc Med, Fosmo.2017).

[0031] Further research on autism and autism spectrum disorders may suggest that administering compounds that have the potential to positively regulate Kv7 channels may be effective in these neurological disorders. Data suggests that dysfunction of heteromeric KV7.3 / 5 channels is involved in the pathogenesis of some forms of autism spectrum disorders, epilepsy, and possibly other psychiatric disorders, and thus KCNQ3 and KCNQ5 are suggested as candidate genes for these disorders (Gilling, Front Genet. 2013; Guglielmi, Front Cell Neurosci. 2015).

[0032] Several background documents are incorporated herein by reference for such teachings. There is a need to more effectively deliver these compounds capable of interacting with Kv7.2 channel subtypes, particularly pharmacologically potent compounds, as prodrugs with improved physicochemical, biopharmaceutical, or pharmacokinetic properties.

Prior Art Documents

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Summary of the Invention

[0034] The present disclosure provides compounds useful for treating diseases via, among other things, the regulation of potassium ion flux through voltage-dependent potassium channels. More specifically, the present disclosure provides prodrugs, compositions, and methods of compounds useful for treating central or peripheral nervous system disorders (e.g., migraine, ataxia, Parkinson's disease, bipolar disorder, trigeminal neuralgia, convulsions, mood disorders, brain tumors, psychiatric disorders, myokymia, seizures, epilepsy, hearing and vision loss, dysmenorrhea, vulvodynia, dyspareunia, pain associated with endometriosis, multiple sclerosis, amyotrophic lateral sclerosis, spasticity, spasm, autism, Alzheimer's disease, age-related memory loss, learning disabilities, anxiety and motor neuron diseases, organophosphate exposure, central and peripheral neuropathic pain conditions), and as neuroprotectants (e.g., to prevent stroke, spinal cord and brain injury, retinal degeneration, etc.). The compounds of the present disclosure are used as prodrug agents to treat convulsive conditions, such as those following grand mal seizures, petit mal seizures, psychomotor epilepsy or focal seizures. The prodrug compounds of the present disclosure, when metabolized or converted to active compounds, are also useful in treating disease conditions such as restless legs syndrome, post-herpetic neuralgia, and the like.

[0035] In addition, the compounds of the present disclosure are useful as prodrugs in the treatment of pain, such as neuropathic pain, diabetic pain, inflammatory pain, cancer pain, migraine headache, vulvar pain, abdominal pain, and musculoskeletal pain.The compounds are also prodrugs that are metabolized in vivo to produce active compounds useful for treating conditions that may be the origin of pain, such as arthritic conditions (e.g., rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, and gouty arthritis) and non-articular inflammatory conditions (e.g., herniated, ruptured, and prolapsed disc syndromes, bursitis, tendinitis, tendonitis, fibromyalgia syndromes, and other conditions associated with ligament sprains and localized musculoskeletal strains) and inflammatory conditions, including pain associated with nerve demyelinating diseases.Particularly preferred compounds of the present disclosure may exhibit lower central nervous system side effects, such as dizziness and somnolence, due to the more controlled release of active drug.In addition, the compounds of the present disclosure are prodrugs that are metabolized in vivo to compounds useful for treating conditions and pain associated with abnormally elevated skeletal muscle strain.

[0036] The compounds of the present disclosure are also prodrugs of compounds used to treat anxiety (e.g., anxiety disorders) and depression, including separation anxiety disorder, selective mutism, specific phobias, social anxiety disorder (social phobia), panic disorder, agoraphobia, generalized anxiety disorder, substance / medication-induced anxiety disorder, and anxiety disorder due to another medical condition.

[0037] Anxiety also occurs as a symptom associated with other psychiatric disorders, such as obsessive-compulsive disorder, post-traumatic stress disorder, schizophrenia, mood disorders and major depressive disorder, as well as organic clinical conditions including, but not limited to, Parkinson's disease, multiple sclerosis, and other physically disabling disorders.

[0038] In view of the above discoveries, the present disclosure provides prodrugs of compounds, as well as compositions comprising these prodrugs of compounds, and methods for increasing ionic flux through voltage-gated potassium channels, particularly channels responsible for the M-current. As used herein, the terms "M-current," "channels responsible for the M-current," and the like refer to slowly activated, slowly deactivated, voltage-gated K-current channels. + M-currents are active at voltages near the threshold for action potential generation in a wide variety of neuronal cells and are therefore important modulators of neuronal excitability.

[0039] Members of the voltage-gated potassium channel family have been shown to be directly involved in diseases of the central or peripheral nervous system. Here, prodrugs of the compounds provided herein have been shown to metabolize and release compounds that act as potassium channel regulators, particularly openers, for heteromultimeric channels such as KCNQ2 and KCNQ3, KCNQ4 and KCNQ5, and KCNQ2 / 3, KCNQ3 / 5, or M-current.

[0040] One embodiment of the present disclosure is a compound of formula I: [ka] (In the formula, R 1 But, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkyl-C 3~6 is cycloalkyl, R 2 But, H, C 1~3 Alkyl, C 1~3 Alkoxy, halogen, C 1~3 is haloalkoxy; Z is N or CH; R 3 is "Pro" and "Pro" is C(O)R 10 is selected from the group consisting of R 10 But the structure C(O)OL 1 O.C.(O)R 11 is a hydrolyzable prodrug moiety of R 11 is unsubstituted or substituted C1-C 10 Alkyl, aryl, C1-C 10 It is aralkyl, L 1 But, C1~C 10 alkylene, L 1 The two oxygen atoms shown bonded to L 1 on the same carbon atom in R 4 and R 5 each is independently H; or R 4 and R 5 together with the atoms to which they are attached form a 5- to 6-membered ring, optionally containing one or more degrees of unsaturation; R 6a , R 6b , and R 6c each independently is H or halogen; 6a , R 6b , and R 6c at least one of is H; or a pharma- ceutically acceptable salt thereof.

[0041] One embodiment of the present disclosure is a compound of formula II: [ka] (In the formula, R 1 But, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkyl-C 3~6 is cycloalkyl, R 2 But, H, C 1~3 Alkyl, C 1~3 Alkoxy, halogen, C 1~3 is haloalkoxy; R 3 is "Pro" and "Pro" is C(O)R 10 is selected from the group consisting of R 10 But the structure C(O)OL 1 O.C.(O)R 11 is a hydrolyzable prodrug moiety of R 11 is unsubstituted or substituted C1-C 10 Alkyl, aryl, C1-C 10 It is aralkyl, L 1 But, C1~C 10 alkylene, L 1 The two oxygen atoms shown bonded to L 1 on the same carbon atom in R 4 and R 5 each is independently H; or R 4 and R 5 together with the atoms to which they are attached form a 5- to 6-membered ring, optionally containing one or more degrees of unsaturation; R 6a , R 6b , and R 6c each independently is H or halogen; 6a , R 6b , and R 6c at least one of is H; or a pharma- ceutically acceptable salt thereof.

[0042] One embodiment of the present disclosure is a compound of formula III: [ka] (In the formula, R 1 But, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkyl-C 3~6 is cycloalkyl, R 2 But, H, C 1~3 Alkyl, C 1~3 Alkoxy, halogen, C 1~3 is haloalkoxy; Z is N or CH; R 4 and R 5 each is independently H; or R 4 and R 5 together with the atoms to which they are attached form a 5- to 6-membered ring, optionally containing one or more degrees of unsaturation; R 6a , R 6b , and R 6c each independently is H or halogen; 6a , R 6b , and R 6c at least one of is H; R 7 But, C 1~6 Alkyl, phenyl, or C 1~2 alkyl-phenyl), or a pharma- ceutically acceptable salt thereof.

[0043] An embodiment of the present disclosure includes a compound according to claim 3, wherein the compound has the formula III-A: [ka] (In the formula, L 1But, C1~C 10 alkylene, L 1 The two oxygen atoms depicted above are L 1 on the same carbon atom within the group consisting of aryl, aryl, aryl and aryl groups, or a pharma- ceutically acceptable salt thereof.

[0044] One embodiment of the disclosure includes the following compound or a pharma- ceutically acceptable salt thereof: [ka]

[0045] One embodiment of the present disclosure is a compound of formula IV: [ka] (In the formula, R 1 But, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkyl-C 3~6 is cycloalkyl, R 2 But, H, C 1~3 Alkyl, C 1~3 Alkoxy, halogen, C 1~3 is haloalkoxy; Z is N or CH; R 10 But the structure C(O)OL 1 O.C.(O)R 11 is a hydrolyzable prodrug moiety of R 11 is unsubstituted or substituted C1-C 10 Alkyl, aryl, C1-C 10 It is aralkyl, L 1 But, C1~C 10 alkylene, L 1 The two oxygen atoms shown bonded to L 1 on the same carbon atom in R 4 and R 5 each is independently H; or R4 and R 5 together with the atoms to which they are attached form a 5- to 6-membered ring, optionally containing one or more degrees of unsaturation; R 6a , R 6b , and R 6c each independently is H or halogen; 6a , R 6b , and R 6c at least one of is H; or a pharma- ceutically acceptable salt thereof.

[0046] One embodiment of the present disclosure includes a pharmaceutical composition comprising a compound of the present disclosure and one or more pharma- ceutically acceptable excipients.

[0047] One embodiment of the present disclosure includes a method of eliciting one or more of an antiepileptic, muscle relaxant, fever reducing, peripheral analgesic, or anticonvulsant effect in a patient in need thereof comprising administering an effective amount of a compound of the present disclosure.

[0048] In one embodiment of the present disclosure, the present invention relates to a method for treating depression in patients with cancer, depression in patients with Parkinson's disease, post-myocardial infarction depression, depression in patients with human immunodeficiency virus (HIV), subsyndromal symptomatic depression, depression in infertile women, childhood depression, major depression, single episode depression, recurrent depression, child abuse induced depression, postpartum depression, DSM-IV major depression, treatment refractory major depression, severe depression, psychotic depression, post-stroke depression, neuropathic pain, manic-depressive disorders including manic-depressive disorders with mixed episodes and manic-depressive disorders with depressive episodes, seasonal affective disorder, bipolar depression BP I, bipolar depression BP depression, including major depression with dysthymia II, or dysthymia; dysthymia; phobias, including agoraphobia, social phobia or simple phobias; eating disorders, including anorexia nervosa or bulimia nervosa; drug dependence, including dependence on alcohol, cocaine, amphetamines and other psychostimulants, morphine, heroin and other opioid agonists, phenobarbital and other barbiturates, nicotine, diazepam, benzodiazepines and other psychoactive substances; Parkinson's disease, including Parkinson's dementia, neuroleptic-induced parkinsonism or tardive dyskinesia; headache, including headache associated with vascular disorders; withdrawal syndromes; age-related learning and psychiatric disorders; apathy; bipolar disorder, chronic fatigue syndrome; chronic or acute stress; behavioural disorders; cyclothymic disorder; somatoform disorders, such as somatisation disorder, conversion disorder, pain disorder, hypochondriasis, body dysmorphic disorder, undifferentiated disorder and somatoform NOS; incontinence; inhalation disorders; intoxication disorders disorder); mania; oppositional defiant disorder; peripheral neuropathy; post-traumatic stress disorder; late luteal phase dysphoric disorder; certain developmental disorders; SSRI "POOP OUT" syndrome, or the failure of a patient to maintain a satisfactory response to SSRI therapy after an initial period of satisfactory response; and tic disorders, including Tourette's disease.

[0049] One embodiment of the disclosure is a method for treating stroke, pain, neuropathic pain, chronic headache, central pain, diabetic neuropathy, post-herpetic neuralgia and pain associated with peripheral nerve injury; drug addiction, affective disorders, Alzheimer's disease, anxiety, neurodegenerative illness or CNS damage caused by disease or injury, cognitive impairment, obsessive-compulsive behavior, dementia, depression, Huntington's disease, dystonia, mania, cognitive impairment, memory ... disorder), memory failure, movement disorder, movement disorder, neurodegenerative disease, Parkinson's disease, Parkinson-like movement disorder, phobia, Pick's disease, psychosis, bipolar disorder, schizophrenia (schizophrenia subtypes are catatonic subtype, paranoid subtype, disorganized subtype or residual subtype), spinal cord injury, cardiomyopathia, cardiac arrhythmia, long QT syndrome, movement disorder or motility disorder, myasthenia gravis, migraine, tension headache, intestinal disease, inflammation The present invention includes a method for treating, ameliorating, or preventing the progression of a disease or disorder selected from the group consisting of chronic obstructive pulmonary disease, ulcerative colitis, Crohn's disease, Creutzfeldt-Jakob disease, eye conditions, progressive hearing loss or tinnitus, fever, multiple sclerosis, diabetes, or metastatic tumor growth, aluminosis, anthraxia, asbestosis, lithiasis, lash loss, siderosis, silicosis, pneumoconiosis such as tobacco disease and sinusitis, and chronic obstructive pulmonary disease (COPD), and hypertension associated with obesity and disease.

[0050] An embodiment of the present disclosure is directed to treating primary dystonia, paroxysmal dystonia, secondary dystonia, drug-induced dystonia / dyskinesia, tardive dystonia, neuroleptic-induced dystonia, treatment-induced dystonia / dyskinesia in Parkinson's disease patients, genetically degenerative dystonia, dystonia in Huntington's disease patients, dystonia in Tourette's syndrome patients, dystonia in restless legs syndrome patients, dystonia-like symptoms in tic patients, dystonia-associated Methods for treating one or more movement disorders selected from dyskinesia, paroxysmal dyskinesia, paroxysmal non-kinesigenic dyskinesia, paroxysmal dystonic choleoathetosis, paroxysmal kinetic dyskinesia, paroxysmal kinesigenic choleoathetosis, kinesigenic dyskinesia, paroxysmal sleep-induced dyskinesia, drug-induced dyskinesia, myokymia, neuromyotonia, autism, and autism spectrum disorder, comprising administration of a compound of the present disclosure.

[0051] One embodiment of the present disclosure includes a method of delivering a broad spectrum Kv7.2-7.5 active molecule to the systemic circulation, comprising administering a compound of the present disclosure, and releasing the active Kv channel opener at an effective therapeutic concentration to treat one or more susceptible diseases or disorders. In one aspect, the release of the active molecule is Enhanced by increased absorption via the clinical route of administration; Delayed time to onset to ameliorate treatment-emergent adverse events; and Increase half-life or residence time by slowing circulation and release; This provides under one or more of the following: obviating the need for development of modified, sustained, delayed, or extended release formulations.

[0052] One embodiment of the present disclosure includes a method for enhancing chemical stability and reduction of impurities and degradants in the manufacture of drug substances and drug products, thereby improving drug use and tolerability.

[0053] One embodiment of the present disclosure includes the use of a compound of the present disclosure for the manufacture of a medicament for eliciting one or more of an antiepileptic, muscle relaxant, fever reducing, peripheral analgesic, or anticonvulsant effect in a patient in need thereof.

[0054] In one embodiment of the present disclosure, the present invention relates to a method for treating depression in patients with cancer, depression in patients with Parkinson's disease, post-myocardial infarction depression, depression in patients with human immunodeficiency virus (HIV), subsyndromal symptomatic depression, depression in infertile women, childhood depression, major depression, single episode depression, recurrent depression, child abuse induced depression, postpartum depression, DSM-IV major depression, treatment refractory major depression, severe depression, psychotic depression, post-stroke depression, neuropathic pain, manic-depressive disorders including manic-depressive disorders with mixed episodes and manic-depressive disorders with depressive episodes, seasonal affective disorder, bipolar depression BP I, bipolar depression BP depression, including major depression with dysthymia II, or dysthymia; dysthymia; phobias, including agoraphobia, social phobia or simple phobias; eating disorders, including anorexia nervosa or bulimia nervosa; drug dependence, including dependence on alcohol, cocaine, amphetamines and other psychostimulants, morphine, heroin and other opioid agonists, phenobarbital and other barbiturates, nicotine, diazepam, benzodiazepines and other psychoactive substances; Parkinson's disease, including Parkinson's dementia, neuroleptic-induced parkinsonism or tardive dyskinesia; headache, including headache associated with vascular disorders; withdrawal syndromes; age-related learning and psychiatric disorders; apathy; bipolar disorder, chronic fatigue syndrome; chronic or acute stress; behavioural disorders; cyclothymic disorder; somatoform disorders, such as somatisation disorder, conversion disorder, pain disorder, hypochondriasis, body dysmorphic disorder, undifferentiated disorder and somatoform NOS; incontinence; inhalation disorders; intoxication disorders and tic disorders, including Tourette's disease.

[0055] One embodiment of the present disclosure is directed to treating stroke, pain, neuropathic pain, chronic headache, central pain, diabetic neuropathy, post-herpetic neuralgia and pain associated with peripheral nerve injury; drug addiction, affective disorders, Alzheimer's disease, anxiety, neurodegenerative illness or CNS damage caused by disease or injury, cognitive impairment, obsessive-compulsive behavior, dementia, depression, Huntington's disease, dystonia, mania, cognitive impairment, memory impairment, memory impairment disorder), memory failure, movement disorder, motility disorder, neurodegenerative disease, Parkinson's disease, Parkinson-like movement disorder, phobia, Pick's disease, psychosis, bipolar disorder, schizophrenia (schizophrenia subtypes are catatonic subtype, paranoid subtype, disorganized subtype or residual subtype), spinal cord injury, cardiomyopathia, cardiac arrhythmia, long QT syndrome, movement disorder or motility disorder, myasthenia gravis, migraine, tension headache, intestinal disease, inflammatory disease, ulcerative colitis and the like. In one embodiment, the present invention relates to a method for treating, ameliorating, or preventing the progression of a disease or disorder selected from the group consisting of: rheumatoid arthritis, Crohn's disease, Creutzfeldt-Jakob disease, eye conditions, progressive hearing loss or tinnitus, fever, multiple sclerosis, diabetes, or metastatic tumor growth, aluminosis, anthraxia, asbestosis, lithiasis, lash loss, siderosis, silicosis, pneumoconiosis such as tobacco disease and sinusitis, and chronic obstructive pulmonary disease (COPD), and hypertension associated with obesity and disease.

[0056] One embodiment of the present disclosure includes the use of a compound of the present disclosure for the manufacture of a medicament for treating one or more movement disorders selected from: primary dystonia, paroxysmal dystonia, secondary dystonia, drug-induced dystonia / dyskinesia, tardive dystonia, neuroleptic-induced dystonia, treatment-induced dystonia / dyskinesia in Parkinson's disease patients, genetic degenerative dystonia, dystonia in Huntington's disease patients, dystonia in Tourette's syndrome patients, dystonia in restless legs syndrome patients, dystonia-like symptoms in tic patients, dystonia-associated dyskinesia, paroxysmal dyskinesia, paroxysmal non-kinesiogenic dyskinesia, paroxysmal dystonic choleoathetosis, paroxysmal kinetic-induced dyskinesia, paroxysmal kinesiogenic choleoathetosis, kinesiogenic dyskinesia, paroxysmal sleep-induced dyskinesia, drug-induced dyskinesia, myokymia, neuromyotonia, autism, autism spectrum disorder.

[0057] One embodiment of the present disclosure includes the use of a compound of the present disclosure for the manufacture of a medicament for the treatment of one or more susceptible diseases or disorders by delivering a broad spectrum Kv7.2-7.5 active molecule to the systemic circulation and releasing said active Kv channel opener at an effective therapeutic concentration. In one aspect, the release of the active molecule is Enhanced by increased absorption, Delayed time to onset to ameliorate treatment-emergent adverse events; and Increase half-life or residence time by slowing circulation and release; This provides under one or more of the following: obviating the need for development of modified, sustained, delayed, or extended release formulations.

[0058] One embodiment of the disclosure includes a compound of the disclosure for use in eliciting one or more of an antiepileptic, muscle relaxant, fever reducing, peripheral analgesic, or anticonvulsant effect in a patient in need thereof.

[0059] In one embodiment of the present disclosure, the present invention relates to a method for treating depression in patients with cancer, depression in patients with Parkinson's disease, post-myocardial infarction depression, depression in patients with human immunodeficiency virus (HIV), subsyndromal symptomatic depression, depression in infertile women, childhood depression, major depression, single episode depression, recurrent depression, child abuse induced depression, postpartum depression, DSM-IV major depression, treatment refractory major depression, severe depression, psychotic depression, post-stroke depression, neuropathic pain, manic-depressive disorders including manic-depressive disorders with mixed episodes and manic-depressive disorders with depressive episodes, seasonal affective disorder, bipolar depression BP I, bipolar depression BP depression, including major depression with dysthymia II, or dysthymia; dysthymia; phobias, including agoraphobia, social phobia or simple phobias; eating disorders, including anorexia nervosa or bulimia nervosa; drug dependence, including dependence on alcohol, cocaine, amphetamines and other psychostimulants, morphine, heroin and other opioid agonists, phenobarbital and other barbiturates, nicotine, diazepam, benzodiazepines and other psychoactive substances; Parkinson's disease, including Parkinson's dementia, neuroleptic-induced parkinsonism or tardive dyskinesia; headache, including headache associated with vascular disorders; withdrawal syndromes; age-related learning and psychiatric disorders; apathy; bipolar disorder, chronic fatigue syndrome; chronic or acute stress; behavioural disorders; cyclothymic disorder; somatoform disorders, such as somatisation disorder, conversion disorder, pain disorder, hypochondriasis, body dysmorphic disorder, undifferentiated disorder and somatoform NOS; incontinence; inhalation disorders; intoxication disorders and tic disorders, including Tourette's disease.

[0060] One embodiment of the present disclosure is directed to treating stroke, pain, neuropathic pain, chronic headache, central pain, diabetic neuropathy, post-herpetic neuralgia and pain associated with peripheral nerve injury; drug addiction, affective disorders, Alzheimer's disease, anxiety, neurodegenerative illness or CNS injury caused by disease or injury, cognitive impairment, obsessive-compulsive behavior, dementia, depression, Huntington's disease, dystonia, mania, cognitive impairment, memory impairment, memory disorder, memory failure, movement disorder, motility disorder, neurodegenerative disease, Parkinson's disease, Parkinson-like movement disorder, phobia, Pick's disease, psychosis, bipolar disorder, schizophrenia (wherein the schizophrenia subtype is catatonic subtype, paranoid subtype, disorganized subtype or residual subtype), spinal cord injury, cardiomyopathia, cardiac arrhythmia, long QT syndrome, movement disorder or motility disorder, myasthenia gravis, migraine, tension headache, bowel disease, inflammatory disease. , ulcerative colitis, Crohn's disease, Creutzfeldt-Jakob disease, eye conditions, progressive hearing loss or tinnitus, fever, multiple sclerosis, diabetes, or metastatic tumor growth, aluminosis, anthraxia, asbestosis, lithiasis, lash loss, iron deposition, silicosis, pneumoconiosis such as tobacco disease and sinusitis, and chronic obstructive pulmonary disease (COPD), and hypertension associated with obesity and disease.

[0061] One embodiment of the present disclosure comprises a compound of the present disclosure for use in the treatment of one or more movement abnormalities selected from primary dystonia, paroxysmal dystonia, secondary dystonia, drug-induced dystonia / dyskinesia, tardive dystonia, neuroleptic-induced dystonia, treatment-induced dystonia / dyskinesia in Parkinson's disease patients, genetic degenerative dystonia, dystonia in Huntington's disease patients, dystonia in Tourette's syndrome patients, dystonia in restless legs syndrome patients, dystonia-like symptoms in tic patients, dystonia-associated dyskinesia, paroxysmal dyskinesia, paroxysmal non-kinesiogenic dyskinesia, paroxysmal dystonic choleoathetosis, paroxysmal kinetic-induced dyskinesia, paroxysmal kinesiogenic choleoathetosis, kinesiogenic dyskinesia, paroxysmal sleep-induced dyskinesia, drug-induced dyskinesia, myokymia, neuromyotonia, autism, autism spectrum disorder.

[0062] One embodiment of the present disclosure includes compounds of the present disclosure for use in delivering broad spectrum Kv7.2-7.5 active molecules to the systemic circulation and releasing the active Kv channel openers at effective therapeutic concentrations to treat one or more susceptible diseases or disorders. In one aspect, the release of the active molecules comprises: Enhanced by increased absorption, Delayed time to onset to ameliorate treatment-emergent adverse events; and Increase half-life or residence time by slowing circulation and release; This provides under one or more of the following: obviating the need for development of modified, sustained, delayed, or extended release formulations.

[0063] One or more aspects and embodiments may be combined in different embodiments, even if not specifically described, i.e. all aspects and embodiments may be combined in any way or combination. [Brief description of the drawings]

[0064] [Figure 1] 1 is a graphical representation of the stability and solubility study of Compound 3 over a period of 3-7 days. [Diagram 2] 1 is a graphical representation of the testing of Compound 4 for stability over a four day period. [Diagram 3] 1 is a graphical representation of in vitro mouse and rat plasma stability testing of Compound 3 at 37° C. [Figure 4] 1 is a graphical representation of in vitro mouse and rat plasma stability studies of Compound 4 at 37° C. [Figure 5A] FIG. 1 is a graphical representation of the linear plots of Compound 1 and Compound 4 following administration of Compound 4 SC at 100 mg / kg in male mice. [Figure 5B] FIG. 1 is a graphical representation of semi-log plots of Compound 1 and Compound 4 following administration of Compound 4 SC at 100 mg / kg in male mice. [Figure 6] FIG. 1 is a graphical representation of a semi-log plot of Compound 1 following administration of either 20 mg / kg Compound 1, 30 mg / kg Compound 3, or 30 mg / kg Compound 4 by oral route to male mice. [Figure 7] FIG. 1 is a graphical representation of semi-log plots of N-acetyl metabolites following administration of either 20 mg / kg of Compound 1, 30 mg / kg of Compound 3, or 30 mg / kg of Compound 4 by oral route to male mice. [Figure 8] FIG. 1 is a graphical representation of semi-log plots of Compound 1 and Compound 4 following administration of Compound 4 IM at 75 mg / kg in male rats. [Figure 9] FIG. 1 is a graphical representation of a semi-log plot of Compound 1 following administration of either 20 mg / kg Compound 1, 30 mg / kg Compound 3, or 30 mg / kg Compound 4 via the oral route to male Sprague Dawley rats. [Figure 10] FIG. 1 is a graphical representation of semi-log plots of N-acetyl metabolites following administration of either 20 mg / kg of Compound 1, 30 mg / kg of Compound 3, or 30 mg / kg of Compound 4 by oral route to male mice. [Figure 11] 1 is a graphical representation of an in vitro screen of Kv7.2 / 7.3 voltage-gated potassium channels. [Figure 12] 1 is a graphical representation of trials within the CF-1 mouse maximal electric shock (MES) test. [Figure 13] 1 is a graphical representation of Compound 1 concentrations in CF-1 mice. [Figure 14] 1 is a graphic representation of Compound 4 protection of SD rats against MES-induced seizures following IM administration. [Figure 15] 1 is a table showing dose-related responses to XYZ-203 / Compound 3 from the CCI model of neuropathic pain. [Figure 16] FIG. 1 is a graphic representation of the results of XYZ-203 (Compound 3) from the CCI model of neuropathic pain. [Figure 17] 1 is a graphical representation of the results of XYZ-203 (Compound 3) from the CCI model of neuropathic pain. [Figure 18] 1 is a graphical representation of mouse hind paw flicks or licks following plantar injection of 5% formalin. [Figure 19] FIG. 1 is a graphic representation of compounds 4, 6 and 2 dosed at equimolar doses to ezogabine (20 mg / kg) using the same formulation (0.5% methylcellulose in water) in male jugular vein cannulated rats. [Figure 20] 1 is a graphical depiction of compound 28 and ezogabine concentrations (ng / mL) per dose group and MES protection. [Figure 21] 1 is a graphic representation of compound 28, ezogabine and pregabalin concentrations (ng / mL) at 0.5 hours following a 24 mg / kg dose. [Figure 22] 1 is a graphical depiction of compound 28 and ezogabine concentrations (ng / mL) over 24 hours. [Diagram 23] 1 is a graphical representation of mouse MES assay, brain and plasma concentrations of ezogabine following administration of Compound 29. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0065] As used herein, "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, and preferably 1 to 6 carbon atoms. The hydrocarbon chain can be either straight or branched. Exemplary alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. Similarly, an "alkenyl" group refers to an alkyl group having one or more double bonds in the chain, and an "alkynyl" group refers to an alkyl group having one or more triple bonds in the chain.

[0066] As used herein, "halogen" or "halo" refers to a halogen. In some embodiments, the halogen is preferably Br, Cl, or F.

[0067] As used herein, "haloalkyl" refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, in which at least one hydrogen atom is replaced by a halogen, including, but not limited to, perhalo groups in which all hydrogen atoms are replaced by halogen atoms. The haloalkyl chain can be either straight or branched. Exemplary alkyl groups include trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluorobutyl, and pentafluoroethyl. Similarly, a "haloalkenyl" group refers to a haloalkyl group having one or more double bonds in the chain, and a "haloalkynyl" group refers to a haloalkyl group having one or more triple bonds in the chain. Additionally, an "alkylene" linking group refers to a divalent alkyl group, i.e., (CH2) x Refers to 、 x is 1 to 20, preferably 1 to 8, preferably 1 to 6, and more preferably 1 to 3.

[0068] The term "haloalkyloxy" refers to an O-haloalkyl.

[0069] As used herein, "alkoxy" refers to an O-alkyl group having the specified number of carbon atoms.

[0070] An "alkylene" group is an alkyl group, as defined above, that is positioned between and serves to connect two other chemical groups. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0071] The term "heteroalkyl" refers to an alkyl group as defined above, wherein one or more carbon atoms in the chain is replaced by a heteroatom selected from the group consisting of O, S, and N, such as NH or NR', where R' is a general indicator of a non-hydrogen group.

[0072] As used herein, "hydroxyalkyl" refers to an alkyl group, as defined herein, substituted with one or more -OH groups. Similarly, a "hydroxyalkenyl" group refers to a hydroxyalkyl group having one or more double bonds in the chain, and a "hydroxyalkynyl" group refers to a hydroxyalkyl group having one or more triple bonds in the chain. Similarly, a "dihydroxyalkyl" group provides two -OH substituents.

[0073] The term "alkylaminyl" means NR x -alkyl, R x is hydrogen.

[0074] The term "dialkylaminyl" refers to N(R y )2, each R y is independently C1 to C3 alkyl.

[0075] The term "alkylaminylalkyl" means alkyl-NR x -alkyl, R x is hydrogen.

[0076] The term “dialkylaminylalkyl” refers to alkyl-N(R y )2, each Ry are independently C1-C4 alkyl, and alkyl-N(R y )2 alkyl is an alkyl group as defined above, which may be optionally substituted with hydroxy or hydroxyalkyl.

[0077] As used herein, "aryl" refers to either pendant or fused, substituted or unsubstituted carbocyclic aromatic ring systems such as phenyl, naphthyl, anthracenyl, phenanthryl, tetrahydronaphthyl, indane, or biphenyl. A preferred aryl group is phenyl.

[0078] An "aralkyl" or "arylalkyl" group comprises an aryl group covalently linked to an alkyl group, as defined above, either of which independently may be optionally substituted or unsubstituted. Examples of aralkyl groups include (C1-C6)alkyl(C6-C 10 ) aryl, including, but not limited to, benzyl, phenethyl, and naphthylmethyl. Examples of substituted aralkyls are those in which an alkyl group is substituted with a hydroxyalkyl.

[0079] As used herein, "cycloalkyl" refers to an unsaturated or partially saturated hydrocarbon ring containing 3 to 15 ring atoms. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and partially saturated versions thereof, such as cyclohexenyl, and cyclohexadienyl. Additionally, bridged rings such as adamantane are included in the definition of "cycloalkyl."

[0080] As used herein, the term "heterocyclyl" refers to an unsaturated or partially saturated hydrocarbon ring containing 3 to 15 ring atoms, in which one or more carbon atoms are replaced with a heteroatom selected from O, N, or S, and each N, S, or Si may be optionally oxidized and each N may be optionally quaternized. A heterocyclyl group may be attached to the remainder of the molecule through a heteroatom. Heterocyclyl does not include heteroaryl.

[0081] The term "heterocyclylalkyl" refers to a heterocyclyl group, as defined herein, covalently attached to an alkyl group, as defined herein, where the radical is present on the alkyl group, and the alkyl group of the heterocyclylalkyl can be optionally substituted with hydroxy or hydroxyalkyl.

[0082] As used herein, the term "heteroaryl" or "heteroaromatic" refers to an aromatic ring group having 5 to 14 ring atoms selected from carbon and at least one (typically 1 to 4, more typically 1 or 2) heteroatoms (e.g., oxygen, nitrogen, sulfur, or silicon). They include monocyclic rings and polycyclic rings in which a monocyclic heteroaromatic ring is fused to one or more other carbocyclic aromatic or heteroaromatic rings. Examples of monocyclic heteroaryl groups include furanyl (e.g., 2-furanyl, 3-furanyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 2-oxadiazolyl, 5-oxadiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), Examples of monocyclic 6-membered nitrogen-containing heteroaryl groups include pyrimidinyl, pyridinyl, and pyridazinyl. Examples of polycyclic aromatic heteroaryl groups include carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, or benzisoxazolyl.

[0083] The terms "arylalkyl", "heteroarylalkyl", and "heterocyclylalkyl" refer to radicals in which an aryl, heteroaryl, or heterocyclyl group is linked via an alkyl group. Examples include benzyl, phenethyl, pyridylmethyl, and the like. The term also includes alkyl-linked groups in which a carbon atom, e.g., a methylene group, is replaced by, e.g., an oxygen atom. Examples include phenoxymethyl, pyrid-2-yloxymethyl, 3-(naphth-1-yloxy)propyl, and the like. Similarly, as used herein, the term "benzyl" is a radical in which a phenyl group is linked to a CH2 group, thus CH2Ph. Heteroaryl groups can be substituted or unsubstituted. The term substituted benzyl refers to radicals in which the phenyl group or CH2 contains one or more substituents. In one embodiment, the phenyl group may have 1-5 substituents, or in another embodiment, 2-3 substituents.

[0084] A "heteroarylalkyl" group includes a heteroaryl group covalently bonded to an alkyl group, where the radical is on the alkyl group, and the alkyl group is independently optionally substituted or unsubstituted. Examples of heteroarylalkyl groups include heteroaryl groups having 5, 6, 9, or 10 ring atoms bonded to a C1-C6 alkyl group. Examples of heteroaralkyl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolylethyl, benzimidazolylmethyl, benzimidazolylethylquinazolinylmethyl, quinolinylmethyl, quinolinylethyl, benzofuranylmethyl, indolinylethylisoquinolinylmethyl, isoinodylmethyl, cinnolinylmethyl, and benzothiophenylethyl. Specifically excluded from the scope of this term are compounds having adjacent ring O and / or S atoms.

[0085] As used herein, "optionally substituted" refers to the replacement of a hydrogen atom that would otherwise be present on a substituent. When discussing ring systems, optional substitutions are typically 1, 2, or 3 substituents that replace hydrogens that are normally present. However, when referring to straight-chain and branched moieties, the number of substitutions may be more, provided that hydrogens are present. The substitutions may be the same or different.

[0086] Exemplary substituents having multiple substituents may be the same or different and include halogen, haloalkyl, R', OR', OH, SH, SR', NO2, CN, C(O)R', C(O)(alkyl substituted with one or more of halogen, haloalkyl, NH2, OH, SH, CN, and NO2), C(O)OR', OC(O)R', CON(R'), OC(O)N(R'), NH2, NHR', N(R'), NHCOR', NHCOH, NHCONH2, NHCONHR', NHCON(R'). 2, NRCOR', NRCOH, NHCOH, NHCOR', NHC(S)NH, NHC(S)NHR', NHC(S)N(R'), COR', COH, CHO, CONH, CONHR', CON(R'), S(O)H, S(O)R', SONH, S(O)H, S(O)R', SONHR', SON(R'), NHS(O)H, NR'S(O)H, NHS(O)R', NR'S(O)R', and Si(R'), each of the foregoing being a divalent alkylene linking group (CH) x (x is 1, 2, or 3). In embodiments in which the saturated carbon atom is optionally substituted with one or more substituents, the substituents may be the same or different and include =O, =S, =NNHR', =NNH2, =NN(R')2, =N-OR', =N-OH, =NNHCOR', =NNHCOH, =NNHCO2R', =NNHCO2H, =NNHSO2R', =NNHSO2H, =N-CN, =NH, or =NR'. For each of the foregoing, each may be an alkylene linking group ((CH2) x, x is 1, 2, or 3), and each occurrence of R' is the same or different and represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, or when two R' are each attached to a nitrogen atom, they may form a saturated or unsaturated heterocycle containing 4 to 6 ring atoms.

[0087] As used herein, an "effective amount" of a compound is an amount sufficient to negatively modulate or inhibit the activity of a target. Such an amount can be administered as a single dose or according to a regimen, thereby being effective.

[0088] As used herein, a "therapeutically effective amount" of a compound is an amount sufficient to ameliorate a condition, or in some manner reduce or stop or reverse the progression of symptoms, or negatively regulate or inhibit the activity of a target. Such an amount may be administered as a single dose or may be administered according to a regimen, thereby being effective.

[0089] As used herein, treatment refers to any manner in which the symptoms or pathology of a condition, disorder, or disease are ameliorated or otherwise beneficially altered. Treatment also includes any pharmaceutical use of the compositions herein.

[0090] As used herein, amelioration of symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any relief, whether permanent or temporary, persistent or transient, that can be attributed to or associated with administration of the composition.

[0091] As used herein, the term "about," when used to modify a parameter defined by a numerical value (e.g., a dose of an inhibitor or a pharma- ceutically acceptable salt thereof detailed herein, or a length of treatment time described herein), means that the parameter may vary 25%, 20%, 15%, 10%, or 5% below or above the numerical value stated for that parameter. For example, a dose of about 5 mg / kg may vary between 3.75 mg / kg and 6.25 mg / kg. "About" used at the beginning of a list of parameters is meant to modify the respective parameter. For example, about 0.5 mg, 0.75 mg, or 1.0 mg means about 0.5 mg, about 0.75 mg, or about 1.0 mg. Similarly, about 5% or more, 10% or more, 15% or more, 20% or more, and 25% or more means about 5% or more, about 10% or more, about 15% or more, about 20% or more, and about 25% or more.

[0092] As used herein, salt refers to any salt of a compound disclosed herein that retains its biological properties and is not toxic or otherwise undesirable for pharmaceutical use.

[0093] Such salts may be derived from a variety of organic and inorganic counterions known in the art, including hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, sulfamic, acetic, trifluoroacetic, trichloroacetic, propionic, hexanoic, cyclopentylpropionic, glycolic, glutaric, pyruvic, lactic, malonic, succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, picric, cinnamic, mandelic, phthalic, lauric, methanesulfonic, ethanesulfonic, 1,2-ethane-disulfonic, 2-hydroxyethanesulfonic, 2-hydroxyethanesulfonic, 1 ... Acid addition salts formed with organic or inorganic acids such as sulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylsulfamic acid, quinic acid, muconic acid, and similar acids.

[0094] Salts may further include, by way of example only, halides, such as chlorides and bromides, sulfates, phosphates, sulfamates, nitrates, acetates, trifluoroacetates, trichloroacetates, propionates, hexanoates, cyclopentylpropionates, glycolates, glutarates, pyruvates, lactates, malonates, succinates, sorbates, ascorbates, malates, maleates, fumarates, tartrates, citrates, benzoates, 3-(4-hydroxybenzoyl)benzoates, picrates, cinnamates, mandelates, phthalates, laurates, methanesulfonates (mesylates), ethanesulfonates, 1,2-ethanediamines ... and non-toxic salts of organic or inorganic acids such as sulfonates, 2-hydroxyethanesulfonates, benzenesulfonates (besylates), 4-chlorobenzenesulfonates, 2-naphthalenesulfonates, 4-toluenesulfonates, camphorates, camphorsulfonates, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylates, glucoheptonates, 3-phenylpropionates, trimethylacetates, tert-butylacetates, lauryl sulfates, gluconates, benzoates, glutamates, hydroxynaphthoates, salicylates, stearates, cyclohexylsulfamates, quinates, muconates, and similar salts.

[0095] Examples of inorganic bases which can be used to form base addition salts include, but are not limited to, metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; metal amides such as lithium amide and sodium amide; metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate; and ammonium bases such as ammonium hydroxide and ammonium carbonate.

[0096] Examples of organic bases which can be used to form base addition salts include metal alkoxides such as lithium, sodium, and potassium alkoxides, including, for example, lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, and potassium tert-butoxide, quaternary ammonium hydroxides, such as choline hydroxide, and aliphatic amines (i.e., alkylamines, alkenylamines, alkynylamines, and alicyclic amines), heterocyclic amines, arylamines, heteroarylamines, basic amino acids, amino sugars, and polyamines, but are not limited to these.

[0097] The base may be a quaternary ammonium hydroxide, with one or more of the alkyl groups of the quaternary ammonium ion optionally substituted with one or more suitable substituents. Preferably, at least one alkyl group is substituted with one or more hydroxyl groups. Non-limiting examples of quaternary ammonium hydroxides that may be used in accordance with the present disclosure include choline hydroxide, trimethylethylammonium hydroxide, tetramethylammonium hydroxide, preferably choline hydroxide. The alkylamine base may be substituted or unsubstituted. Non-limiting examples of unsubstituted alkylamine bases that may be used in accordance with the present disclosure include methylamine, ethylamine, diethylamine, and triethylamine. The substituted alkylamine base may be substituted with one or more hydroxyl groups, preferably one to three hydroxyl groups. Non-limiting examples of substituted alkylamine bases that may be used in accordance with the present disclosure include 2-(diethylamino)ethanol, N,N-dimethylethanolamine (deanol), tromethamine, ethanolamine, and diolamine.

[0098] In certain cases, the depicted substituents may contribute to optical isomers and / or stereoisomers. Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are called "isomers". Isomers that differ in the arrangement of their atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereomers" and stereoisomers that are not superimposable with each other are called "enantiomers". When a compound has an asymmetric center, for example when it is bonded to four different groups, a pair of enantiomers is possible. Molecules having at least one stereocenter may be characterized by the absolute configuration of that asymmetric center, designated as (R) or (S) according to the rules of Cahn and Prelog (Cahn et al., 1966, Angew. Chem. 78:413-447, Angew. Chem., Int. Ed. Engl. 5:385-414 (errata: Angew. Chem., Int. Ed. Engl. 5:511); Prelog and Helmchen, 1982, Angew. Chem. 94:614-631, Angew. Chem. Internat. Ed. Eng. 21:567-583; Mata and Lobo, 1993, Tetrahedron: Asymmetry 4:657-668) or by the way in which the molecule rotates the plane of polarized light, designated as dextrorotatory or levorotatory (i.e., as (+)- or (-)-isomers, respectively). Chiral compounds can exist as either individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0099] In certain embodiments, the compounds disclosed herein may have one or more asymmetric centers, and therefore such compounds may be produced as racemic mixtures, enantiomerically enriched mixtures, or individual enantiomers.Unless otherwise indicated, for example by designating the stereochemistry at any position in the formula, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures thereof, racemic or otherwise.Methods for determining stereochemistry and separating stereoisomers are well known in the art.

[0100] In certain embodiments, the compounds disclosed herein are "stereochemically pure". A stereochemically pure compound has a level of stereochemical purity that would be recognized as "pure" by those skilled in the art. Of course, this level of purity may be less than 100%. In certain embodiments, "stereochemically pure" refers to a compound that is substantially free of alternative isomers, i.e., at least about 85% or more. In certain embodiments, the compound is at least about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or about 99.9% free of other isomers.

[0101] As used herein, the terms "subject" and "patient" are used interchangeably. In one embodiment, the subject is a human. In one embodiment, the subject is a companion animal, such as a dog or cat. In a further embodiment, the subject is an animal, such as a sheep, cow, horse, goat, fish, pig, or poultry (e.g., chicken, turkey, duck, or goose). In another embodiment, the subject is a primate, such as a monkey, such as a cynomolgus monkey or a chimpanzee.

[0102] I. Modulators of voltage-gated potassium channels Compound 1 is a potassium ion channel modulator [ka]

[0103] The present disclosure provides novel prodrugs that are metabolized in vitro to release potassium ion channel modulators, such as those presented as Compound 1, and in particular novel prodrugs that release compounds effective in modulating KCNQ according to the formula of the present disclosure.

[0104] An embodiment of the present disclosure comprises: [ka] [ka] (R 1 But, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkyl-C 3~6 is cycloalkyl, R 2 But, H, C 1~3 Alkyl, C 1~3 Alkoxy, halogen, C 1~3 is haloalkoxy; R 3 is "Pro", a prodrug moiety as described herein; R 4 and R 5 each is independently H; or R 4 and R 5 together with the atoms to which they are attached form a 5- to 6-membered ring, optionally containing one or more degrees of unsaturation; R 6a、 R 6b , and R 6c each independently is H or halogen; 6a , R 6b , and R 6c at least one of is H; or a pharma- ceutically acceptable salt thereof, C 1~3Haloalkoxy is -OCF3, -OCF2H, -OCFH2, -OC2F5, -OC2F4H, -OC2F3H2, -OC2F2H3, -OC2FH4, -OC3F7, -OC3F6H, -OC3F5H2, -OC3F4H3, -OC3F3H4, -OC3F2H5 or -OC3FH6.

[0105] In one embodiment, the variable “Pro” is C(O)R 10 R 10 teeth, an alkylamine-containing residue, such as the alkylamine-containing moiety of a naturally occurring L- or D-amino acid; or Glycine, or theanine or the alkylamine-containing moiety of gabapentin or pregabalin, or R 10 is -C(O)OL 1 O.C.(O)R 11 wherein the prodrug moiety is selected from hydrolyzable prodrug moieties such as those found in groups having the structure R 11 is C1~C 10 Alkyl, Bn, t-Bu, other substituted or unsubstituted C3-C 10 a secondary or tertiary alkyl group, or Ar; and L 1 is C1~C 10 is a branched or chain alkylene; L 1 The top two oxygen atoms are L 1 on the same carbon atom within the alkyl group (i.e., a divalent alkyl forming a ketal or acetal-like moiety).

[0106] One embodiment of the present disclosure is a compound of formula I: [ka] (In the formula, R 1 But, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkyl-C 3~6 is cycloalkyl, R 2But, H, C 1~3 Alkyl, C 1~3 Alkoxy, halogen, C 1~3 is haloalkoxy; Z is N or CH; R 3 is "Pro" and "Pro" is C(O)R 10 is selected from the group consisting of R 10 but, a) an alkylamine-containing residue, such as an alkylamine-containing moiety of a naturally occurring L- or D-amino acid, or b) a glycine residue, c) theanine residue, d) gabapentin residue, e) pregabalin residue, and f) Structure C(O)OL 1 O.C.(O)R 11 a hydrolyzable prodrug moiety selected from R 11 is unsubstituted or substituted C1-C 10 Alkyl, aryl, C1-C 10 It is aralkyl, L 1 But, C1~C 10 alkylene, L 1 The two oxygen atoms depicted as bonded to L 1 (i.e., are divalent alkyls forming a ketal or acetal-like moiety), R as alkylamines from naturally occurring amino acids 10 Examples of (CH2)-NH2 from glycine, CH(CH3)-NH2 from alanine, CH(CH(CH3)2)-NH2 from valine, CH(CHCH(CH))-NH from leucine, CH(CH(CH3)CH2CH3)-NH2 from isoleucine, CH(CH2Ph)-NH2 from phenylalanine, Cyclo-CHCH2CH2CH2NH- from proline, CH(CHOH)-NH from serine, CH(CH(OH)CH3)-NH2 from threonine, CH(CH2(PhOH))-NH2 from tyrosine, CH(CHSH)-NH from cysteine, CH(CH2CH2SCH3)-NH2 from methionine, CH(CH2CH2CH2CH2NH2)-NH2 from lysine, CH(CH2CH2CH2NHC(NH)NH2)-NH2 from arginine, CH(CH2(C3N2H3))NH2 from histidine, CH(CH2-indol-3-yl)NH2 from tryptophan, CH(CH2CO2H)-NH2 from aspartic acid, CH(CH2CH2CO2H)-NH2 from glutamic acid, CH(CH2CONH2)-NH2 from asparagine, and CH(CH2CH2CONH2)-NH2 from glutamine, or CH(CH2CH2CONHCH2CH3)-NH2 from theanine or CH2C(-CH2CH2CH2CH2CH2-)CH2NH2 from gabapentin, or CH2CH(CH2CH(CH3)2)CH2NH2 from pregabalin, Alkylamine moieties from the D- or S-isomers of the above amino acids are also examples of alkylamine moieties from amino acids contemplated by the present disclosure. R 4 and R 5 each is independently H; or R 4 and R 5 together with the atoms to which they are attached form a 5- to 6-membered ring, optionally containing one or more degrees of unsaturation; R 6a、 R 6b , and R 6c each independently is H or halogen; 6a , R6b , and R 6c at least one of is H; or a pharma- ceutically acceptable salt thereof.

[0107] In a further exemplary embodiment, the present disclosure provides a compound of formula III, more specifically, formula III-A, and specifically, compound 3: [ka] (R 1 But, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkyl-C 3~6 is cycloalkyl, R 2 But, H, C 1~3 Alkyl, C 1~3 Alkoxy, halogen, C 1~3 is haloalkoxy; Z is N or CH; R 3 is a prodrug moiety, Pro, as defined herein; R 4 and R 5 each is independently H; or R 4 and R 5 together with the atoms to which they are attached form a 5- to 6-membered ring, optionally containing one or more degrees of unsaturation; R 6a , R 6b , and R 6c each independently is H or halogen; 6a , R 6b , and R 6c at least one of is H; R 7 But, C 1~6 Alkyl (including branched or straight chain as described herein), phenyl, or C 1~2 alkyl-phenyl), or a pharma- ceutically acceptable salt thereof.

[0108] The embodiments of the present disclosure are [ka] (L 1 is C1~C 10 is a branched or chain alkylene; L 1 The top two oxygen atoms are L 1 on the same carbon atom within the alkyl group (i.e., a divalent alkyl forming a ketal or acetal-like moiety).

[0109] An embodiment of the present disclosure comprises: [ka] Includes.

[0110] In a further exemplary embodiment, the present disclosure provides a compound of formula IV, more specifically formula IV-A, and specifically compound 4: [ka] (R 1 But, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkyl-C 3~6 is cycloalkyl, R 2 But, H, C 1~3 Alkyl, C 1~3 Alkoxy, halogen, C 1~3 is haloalkoxy; Z is N or CH; R 3 is "Pro", a prodrug moiety as described herein; R 4 and R 5 each is independently H; or R 4 and R 5 together with the atoms to which they are attached form a 5- to 6-membered ring, optionally containing one or more degrees of unsaturation; R 6a、R 6b , and R 6c each independently is H or halogen; 6a , R 6b , and R 6c at least one of is H; R 10 However, alkylamines from naturally occurring amino acids include -(CH2)-NH2) from glycine, -CH(CH3)-NH2 from alanine, -CH(CH(CH3)2)-NH2 from valine, -CH(CH2CH(CH3)2)-NH2 from leucine, -CH(CH(CH3)CH2CH3)-NH2 from isoleucine, -CH(CH(CH3)CH2CH3)-NH2 from phenylalanine, -CH(CH2Ph)-NH2 from proline, -CH(CH2OH)-NH2 from serine, -CH(CH(OH)CH3)-NH2 from threonine, -CH(CH2(PhOH))-NH2 from tyrosine, -CH(CH2SH)-NH2 from cysteine, -CH(CH2CH2SCH3)-NH2 from methionine, -CH(CH2CH2CH2CH2NH2)-NH2 from lysine, -CH(CH2CH2CH -CH(CHCH(CHH)NH2)-NH2 from histidine, -CH(CH2(C3N2H3))NH2 from histidine, -CH(CH2-indol-3-yl)NH2 from tryptophan, -CH(CH2CO2H)-NH2 from aspartic acid, -CH(CH2CH2CO2H)-NH2 from glutamic acid, -CH(CH2CONH2)-NH2 from asparagine, -CH(CH2CH2CONH2)-NH2 from glutamine, or -CH(CH2CH2CONHCH2CH3)-NH2 from theanine, or -CH2C(-CH2CH2CH2CH2CH2-)CH2NH2 from gabapentin, or -CH2CH(CH2CH(CH3)2)CH2NH2 from pregabalin, wherein alkylamine moieties from the D-isomers of the above amino acids are also examples of alkylamine moieties from amino acids contemplated in the present disclosure; or a pharma- ceutically acceptable salt thereof.

[0111] An embodiment of the present disclosure comprises: [ka] (wherein the dashed bonds depicted are either enantiomers).

[0112] One embodiment of the disclosure includes a compound or a pharma- ceutically acceptable salt thereof: [ka]

[0113] One embodiment of the disclosure includes a compound or a pharma- ceutically acceptable salt thereof: [ka]

[0114] One embodiment of the disclosure includes a compound or a pharma- ceutically acceptable salt thereof: [ka]

[0115] One embodiment of the present disclosure is 10 is CH2C(-CH2CH2CH2CH2CH2-)CH2NH2 from gabapentin, or CH2CH(CH2CH(CH3)2)CH2NH2 from pregabalin.

[0116] One embodiment of the disclosure includes a compound or a pharma- ceutically acceptable salt thereof: [ka]

[0117] II. Assays for Modulators of Kv7 Channels Kv7 channel was previously identified as KCNQ channel, and is one of the same channel. The assay for determining the ability of active molecules, i.e., positive allosteric modulators, to maintain Kv7 channel in the open position with a higher probability is generally known in the art. Those skilled in the art can determine the appropriate assay for investigating the activity of selected compounds of the present disclosure against a particular ion channel. For the sake of brevity, some of the following discussion focuses on Kv7.2 (KCNQ2) as a representative example, but the discussion is equally applicable to other Kv7 subtype potassium ion channels.

[0118] KCNQ (Kv7) monomers, as well as KCNQ alleles and polymorphic variants, are subunits of potassium channels. The activity of potassium channels containing KCNQ subunits can be assessed using a variety of in vitro and in vivo assays, such as measuring currents, measuring membrane potentials, measuring ion fluxes, such as potassium or rubidium ion fluxes, measuring potassium concentrations, measuring second messenger and transcript levels using potassium-dependent yeast growth assays, and using, for example, voltage-sensitive dyes, radioactive tracers, and patch clamp electrophysiology.

[0119] Furthermore, such assays can be used to test inhibitors and activators of channels comprising KCNQ. Such modulators of potassium channels are useful for treating a variety of disorders involving potassium channels, including, for example, central and peripheral nervous system disorders (e.g., migraine, ataxia, Parkinson's disease, bipolar disorder, trigeminal neuralgia, convulsions, mood disorders, brain tumors, psychiatric disorders, myokymia, seizures, epilepsy, hearing and vision loss, Alzheimer's disease, age-related memory loss, learning disabilities, anxiety, and motor neuron diseases, and can also be used as neuroprotective agents (e.g., to prevent stroke, etc.). Such modulators can be used to investigate the channel diversity offered by KCNQ and They are also useful for regulating / modulating potassium channel activity provided by KCNQ. Prodrugs that are metabolized by amidases, esterases, and other metabolic or hydrolytic mechanisms in mammals or cells can produce active modulators of channels that contain KCNQ. Some prodrugs themselves may also have weak activity as KCNQ channel modulators. However, any activity may result from degradation to active drug in the test system, and in most of these cases, the metabolized prodrug produces a more active KCNQ modulator than the prodrug itself.

[0120] Modulators of potassium channels are tested using recombinant or naturally occurring biologically active KCNQ, or using native cells, such as cells from the nervous system, that express M-currents. KCNQ may be isolated, co-expressed or expressed in cells, or expressed in membranes derived from cells. In such assays, KCNQ2 is expressed alone to form homomeric potassium channels, or co-expressed with a second subunit (e.g., another KCNQ family member, preferably KCNQ3) to form heteromeric potassium channels. Modulation is tested using one of the in vitro or in vivo assays described above. Samples or assays treated with potential potassium channel inhibitors or activators are compared to control samples that do not contain the test compound to determine the degree of modulation. Control samples (not treated with activators or inhibitors) are assigned a relative potassium channel activity value of 100. Activation of channels containing KCNQ2 is achieved when the potassium channel activity value is 130%, more preferably 150%, more preferably 170% higher than the control. Compounds that increase the flux of ions increase the probability that channels containing KCNQ2 are open, decrease the probability that the channels are closed, increase the conductance through the channels, and increase the number or expression of channels, thereby causing an increase in the detectable ion current density. In these experiments, it is important to have materials present in each experiment that are known to metabolize the prodrugs of the present disclosure to compounds that are active at the receptor site of interest. Alternatively, these experiments can be performed using the actual drug compounds themselves, and the assumption can be made that the metabolized prodrugs will have similar activity at the desired ion channel site once in the mammalian body.

[0121] The activity of the metabolites of these prodrug compounds of the present disclosure is 50 Preferred compounds of the present disclosure release active molecules upon hydrolysis or metabolism, which have an EC in the potassium ion channel assay of about 0.1 nM to about 1 mM, preferably about 1 nM to about 10 μM, and more preferably about 10 nM to about 2 μM. 50 has.

[0122] Changes in ion flux can be assessed by determining changes in polarization (i.e., electrical potential) of cells or membranes expressing exemplary potassium channels such as KCNQ2, KCNQ2 / 3, or M-currents. A preferred means for assessing changes in cell polarization is to measure changes in current or voltage using voltage clamp and patch clamp techniques using the "cell attached" mode, "inside out" mode, "outside out" mode, "through-the-cell" mode, "one or two electrode" mode, or "whole cell" mode (see, e.g., Ackerman et al., New Engl. J. Med. 336:1575-1595 (1997)). Whole cell currents are conveniently determined using standard methodology (see, e.g., Hamil et al., Pflugers. Archiv. 391:85 (1981). Other known assays include radiolabeled rubidium flux assays and fluorescent assays using voltage-sensitive dyes (see, e.g., Vestergarrd-Bogind et al., J. Membrane Biol. 88:67-75 (1988); Daniel et al., J. Pharmacol. Meth. 25:185-193 (1991); Holevinsky et al. J. Membrane Biology 137:59-70 (1994)). Assays for compounds capable of inhibiting or increasing potassium flux through channel proteins comprising KCNQ2 or heteromultimers of KCNQ subunits can be performed by applying the compounds to a bath solution containing cells in contact with the channels of the present disclosure (see, e.g., Blatz et al., Nature 137:59-70 (1994)). 323:718-720 (1986); Park, J. Physiol. 481:555-570 (1994). Generally, the compounds to be tested are present in the range of about 1 pM to about 1 mM, preferably about 10 pM to about 100 μM.

[0123] The effect of the test compound on the function of the channel can be measured by the change in current or ion flux, or the result of the change in current and flux. The change in current or ion flux is measured by either the increase or decrease in the flux of ions, such as potassium or rubidium ions. The cations can be measured in a variety of standard ways. They can be measured directly by the change in concentration of the ion, or indirectly by the membrane potential or radiolabeling of the ion. The effect of the test compound on the ion flux can be very diverse. Thus, any suitable physiological change can be used to evaluate the effect of the test compound on the channel of the present disclosure.

[0124] III. Pharmaceutical Compositions of Potassium Channel Modulators In another aspect, the present disclosure provides a pharmaceutical composition comprising a pharma- ceutically acceptable excipient and a compound of formula I above.

[0125] Formulation of Compounds (Compositions) The compounds of the present disclosure can be prepared and administered in a wide variety of oral, parenteral and topical dosage forms.Thus, the compounds of the present disclosure can be administered by injection, i.e., intravenously, intramuscularly, intradermally, subcutaneously, intraduodenal or intraperitoneally.The compounds described herein can also be administered by inhalation, for example, intranasally.In addition, the compounds of the present disclosure can be administered transdermally, ocularly, intracochlearly or intrarectally.Thus, the present disclosure also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and a compound of formula I, or any of its pharmaceutically acceptable salts.

[0126] For preparing pharmaceutical compositions from the compounds of the present disclosure, pharma-ceutically acceptable carriers can be either solid or liquid.Solid form preparations include powder, tablets, pills, capsules, cachets, suppositories, and dispersible granules.Solid form can be either immediate release, sustained release, slow release, or delayed release.Solid carriers can be one or more substances that can also act as diluents, flavorings, binders, preservatives, tablet disintegrating agents, or encapsulating materials.

[0127] In powders, the carrier may be a finely divided solid that is a mixture of finely divided active compound. In tablets, the active compound is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.

[0128] Powders and tablets preferably contain 5% or 10% to 85% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter, and the like. The term "preparation" is intended to include formulations of the active compound with encapsulating material as a carrier to provide a capsule in which the active ingredient is surrounded by, and thus associated with, the carrier, with or without other carriers. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0129] In one method of preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active ingredient is dispersed homogeneously therein, for example by stirring. The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and solidify.

[0130] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions.For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

[0131] Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickening agents, as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active ingredient in water with viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

[0132] Also included are solid form preparations that are intended to be converted immediately prior to use into liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

[0133] Pharmaceutical preparations are preferably in unit dosage form.In such dosage form, the preparation is subdivided into unit doses containing appropriate amounts of active ingredients.The unit dosage form can be a packaged preparation, the package containing discrete amounts of the preparation, such as packeted tablets, capsules, and powders in vials or ampoules.The unit dosage form can also be a capsule, tablet, pill, cachet, sachet, or lozenge itself, or the appropriate number of any of these packaged.

[0134] The quantity of active ingredient in a unit dose preparation may be varied or adjusted from 0.1 mg to 10,000 mg, more typically from 1.0 mg to 5,000 mg, most typically from 20 mg to 1,000 mg, depending on the particular application and the potency of the active ingredient. The composition may, if desired, also contain other compatible therapeutic agents.

[0135] IV. Effective Dosage The pharmaceutical compositions provided by the present disclosure include compositions in which the active ingredient is contained in a therapeutically effective amount, i.e., an amount effective to achieve its intended purpose. The actual amount effective for a particular application depends, inter alia, on the condition being treated. For example, when administered in a method for treating pain, epilepsy, depression, or anxiety, such compositions contain an amount of active ingredient effective to achieve a clinically relevant degree of reduction in the condition being treated. Similarly, when a pharmaceutical composition is used to treat or prevent central or peripheral nervous system disorders, such as Parkinson's disease, a therapeutically effective amount reduces one or more symptoms characteristic of the disease (e.g., tremor) below a predetermined pressure threshold. Determining the therapeutically effective amount of a compound of the present disclosure is well within the capabilities of one of ordinary skill in the art, especially in light of the detailed disclosure herein.

[0136] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. Target plasma concentration is the concentration of active compound that can modulate, e.g., activate or open, KCNQ channel. In a preferred embodiment, KCNQ channel activity is changed by at least 5% at clinically effective free drug concentration for certain diseases or treatments, and at least 10% in other diseases or treatments. The rate of change of KCNQ channel in patients with prodrugs of Kv7 positive allosteric modulators can be adjusted based on the plasma drug concentration of the active agent, and dosage can be adjusted upward or downward to achieve the desired therapeutic effect.

[0137] As is well known in the art, therapeutically effective amounts for human use can also be determined from animal models.For example, the dose for humans can be formulated to achieve the circulating concentration found to be effective in animals.A particularly useful animal model for predicting anticonvulsant dosage is the maximum electroshock assay (Fischer RS, Brain Res.Rev.14:245-278(1989)).Dosage in humans can be adjusted by monitoring the activation of KCNQ channels as described above, and adjusting dosage upwards or downwards as described above.

[0138] Therapeutically effective doses can also be determined from human data for compounds known to exhibit similar pharmacological activity, such as ezogabine (Rudnfeldt et al., Neuroscience Lett. 282:73-76 (2000)).

[0139] Adjusting dosages to achieve maximal efficacy in humans based on these and other methods is well known in the art and well within the capabilities of one of ordinary skill in the art.

[0140] By way of example, when compounds of the present disclosure are used for the prevention and / or treatment of exemplary disorders such as epilepsy and pain, circulating concentrations of the administered compound of about 0.001 μM to 1 mM are believed to be effective, with about 0.01 μM to 100 μM being preferred.

[0141] Patient doses for oral administration of the compounds described herein, which is the preferred mode of administration for the prevention and treatment of exemplary disorders such as epilepsy, typically range from about 1 mg / day to about 10,000 mg / day, more typically from about 10 mg / day to about 3,000 mg / day, and most typically from about 1 mg / day to about 1000 mg / day. In terms of patient weight, typical dosages range from about 0.01 to about 150 mg / kg / day, more typically from about 0.1 to about 50 mg / kg / day, and most typically from about 0.5 to about 25 mg / kg / day.

[0142] For other modes of administration, dosage and intervals can be tailored to provide effective plasma levels of the administered compound for the particular clinical indication being treated. For example, if acute epileptic seizures are the most prevalent clinical symptom, in one embodiment, the compound according to the present disclosure can be administered at relatively high concentrations multiple times a day. Alternatively, if a patient only exhibits periodic epileptic seizures, migraines, or other acute onset clinical signs or symptoms from a chronic or acute disease state infrequently, periodically, or irregularly, in one embodiment, it may be more desirable to administer the compound of the present disclosure at the lowest effective concentration and use a less frequent administration regimen. This provides a treatment regimen that is commensurate with the severity of the individual's disease state.

[0143] Utilizing the teachings provided herein, one can design effective prophylactic or therapeutic treatment regimens that do not cause substantial toxicity, yet are entirely effective in treating the clinical symptoms exhibited by a particular patient.

[0144] This plan should involve careful selection of active compounds by considering factors such as compound potency, relative bioavailability, patient weight, presence and severity of adverse side effects, preferred administration method, and toxicity profile of selected agent.By way of example and without limitation, intranasal administration route may be useful for treating migraine headaches, and ocular administration route may be useful for treating one or more diseases of the eye.Therefore, a particular administration route may be selected based on the intended therapeutic application of the compound of the present disclosure.

[0145] V. Compound Toxicity The ratio between the toxicity and therapeutic effect of a particular compound is its therapeutic index, LD 50 (lethal dose of compound in 50% of the population) and ED 50(the amount of compound effective in 50% of the population). Compounds that exhibit high therapeutic indices are preferred. Therapeutic index data obtained from cell culture assays and / or animal studies can be used in formulating a range of doses for use in humans. The dosage of such compounds can be determined to be within the ED50 range with little or no toxicity. 50 It is preferred that the plasma concentration range includes the range of 0.1 to 0.5% by weight of the compound. The dosage may vary within this range depending on the dosage form used and the route of administration utilized. See, for example, Fingl et al., In: THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, Ch. 1, p. 1, 1975. The exact formulation, route of administration and dosage can be selected by the individual physician in view of the patient's condition and the particular method in which the compound is used.

[0146] VII. METHODS FOR TREATING CONDITIONS MEDIATED BY VOLTAGE-GATED POTASSIUM CHANNELS In yet another aspect, the disclosure provides a method for treating a disorder or condition of the central or peripheral nervous system through modulation of voltage-gated potassium channels, comprising administering to a subject in need of such treatment an effective amount of a compound having the formula above.

[0147] The compounds provided herein are useful prodrugs of potassium channel modulators and find therapeutic utility through modulation through improved pharmacokinetics, solubility, and stability of molecules active at voltage-dependent potassium channels in the treatment of diseases or conditions. The potassium channel targets of the compounds of the present disclosure are described herein as voltage-dependent potassium channels, such as KCNQ potassium channels. As mentioned above, these channels may include homomultimers and heteromultimers of KCNQ2, KCNQ3, KCNQ4, and KCNQ5. Heteromultimers of two proteins, e.g., KCNQ2 and KCNQ3, are referred to, for example, as KCNQ2 / 3, KCNQ3 / 5, etc. Conditions that can be treated with the compounds and compositions of the present disclosure may include, but are not limited to, central or peripheral nervous system disorders (e.g., migraine, ataxia, Parkinson's disease, bipolar disorder, trigeminal neuralgia, convulsions, mood disorders, brain tumors, psychiatric disorders, myokymia, seizures, epilepsy, hearing and vision loss, Alzheimer's disease, age-related memory loss, learning disabilities, anxiety, and motor neuron diseases). The compounds and compositions of the present disclosure may also function as neuroprotective agents (e.g., to prevent stroke, retinal degeneration, demyelinating diseases, etc.). In a preferred embodiment, the condition or disorder to be treated is epilepsy or seizures, central or peripheral neuropathic pain, chronic pain, inflammatory pain. In another preferred embodiment, the condition or disorder is the treatment of hearing loss or diseases associated with neuronal demyelination or neuronal hyperexcitability.

[0148] Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.

[0149] One embodiment of the present disclosure is directed to treating stroke, pain, neuropathic pain, chronic headache, central pain, diabetic neuropathy, post-herpetic neuralgia and pain associated with peripheral nerve injury, drug addiction, affective disorders, Alzheimer's disease, anxiety, neurodegenerative disease or CNS injury caused by disease or injury, cognitive impairment, obsessive-compulsive behavior, dementia, depression, Huntington's disease, dystonia, mania, cognitive impairment, memory impairment, memory disorder, memory failure, movement disorder, movement disorder, neurodegenerative disease, Parkinson's disease, Parkinson-like movement disorder, phobia, Pick's disease, psychosis, bipolar disorder, schizophrenia, (wherein schizophrenia subtype is catatonic subtype, paranoid subtype, disorganized subtype or residual subtype), spinal cord injury, cardiomyopathia, cardiac arrhythmia, long QT syndrome, movement disorder or movement disorder, myasthenia gravis, migraine, tension headache, intestinal disease The present invention also includes a method of treating, ameliorating, or preventing the progression of a disease or disorder selected from the group consisting of: inflammatory diseases, ulcerative colitis, Crohn's disease, Creutzfeldt-Jakob disease, eye conditions, progressive hearing loss or tinnitus, fever, multiple sclerosis, diabetes, or metastatic tumor growth, aluminosis, anthraxia, asbestosis, lithiasis, lash loss, siderosis, silicosis, pneumoconiosis such as tobacco disease and sinusitis, and chronic obstructive pulmonary disease (COPD), obesity, and hypertension associated with the disease.

[0150] An embodiment of the present disclosure includes a method of treating one or more movement disorders selected from primary dystonia, paroxysmal dystonia, secondary dystonia, drug-induced dystonia / dyskinesia, tardive dystonia, neuroleptic-induced dystonia, treatment-induced dystonia / dyskinesia in Parkinson's disease patients, genetically degenerative dystonia, dystonia in Huntington's disease patients, dystonia in Tourette's syndrome patients, dystonia in restless legs syndrome patients, dystonia-like symptoms in tic patients, dystonia-associated dyskinesia, paroxysmal dyskinesia, paroxysmal non-kinesiogenic dyskinesia, paroxysmal dystonic choleoathetosis, paroxysmal kinetic-induced dyskinesia, paroxysmal kinesiogenic choleoathetosis, kinesiogenic dyskinesia, paroxysmal sleep-induced dyskinesia, drug-induced dyskinesia, myokymia, neuromyotonia, autism, autism spectrum disorder. The following citations may be incorporated by reference for their teachings regarding the relevance of mechanisms to the disease or disorder of interest.

[0151] a. Seizures (L Greene,Epilepsia 2018, J Neurosci,Qiu.2008). Neurons from Kv7.2(S559A) knock-in mice showed normal basal M-currents. Knock-in mice showed reduced M-current suppression when challenged by muscarinic agonists, and oxotremorine-M. Kv7.2(S559A) mice were resistant to chemoconvulsant-induced seizures and did not die. Administration of XE991 transiently exacerbated seizures in knock-in mice comparable to wild-type mice. After experiencing a state of epilepsy, Kv7.2(S559A) knock-in mice did not exhibit seizure-induced cell death or spontaneous recurrent seizures.

[0152] Using M channel blockers, we found that SST4 coupling to M channels was important for inhibiting epileptiform activity. This is the first demonstration of an endogenous enhancer of IMs that is important in controlling seizure activity. Thus, the SST4 receptor may be an important novel target for developing new antiepileptic and anticonvulsant drugs.

[0153] b. Pain, neuropathic pain, chronic headache (J Pain, Li.2019). Paclitaxel-induced peripheral neuropathy and associated neuropathic pain are severe and resistant to intervention. The results of our study demonstrated that retigabine, a clinically available drug, can be used to inhibit the development of paclitaxel-induced peripheral neuropathy.

[0154] c. Central pain, diabetic neuropathy, post-herpetic neuralgia and pain associated with peripheral nerve injury (Brown Br J Pharmacology, 2009, Epilepsia, Trenite. 2013). Several drugs, including flupirtine and retigabine, enhance neuronal Kv7 / M channel activity, primarily through a hyperpolarizing shift in their voltage gating. As a result, they can reduce neuronal excitability and inhibit nociceptive stimulation and transmission. Flupirtine is used as a central analgesic, and retigabine is in clinical trials as a broad-spectrum anticonvulsant and is an effective analgesic in animal models of chronic inflammatory and neuropathic pain.

[0155] ICA-105665 reduced SPR in patients at single doses of 100 (1 of 4), 400 (2 of 4), and 500 mg (4 of 6). This is the first evaluation of the effect of Kv7 potassium channel activation in a light-sensitive proof of concept model. The reduction in SPR in this patient population provides evidence of central nervous system (CNS) penetration of ICA-105665 and preliminary evidence that engagement with neuronal Kv7 potassium channels has an anti-seizure effect.

[0156] d. Alzheimer's disease, (Czuzcwar, Pharmacological Reports 2010). The most significant adverse effects of retigabine in combination with existing antiepileptic treatments are dizziness, somnolence, and fatigue.Preclinical data indicates that this antiepileptic drug can be applied to patients with neuropathic pain and emotional disorders.Early clinical data suggests that retigabine may also be effective in Alzheimer's disease or stroke.

[0157] e. Anxiety, neurodegenerative diseases or CNS damage caused by disease or injury, cognitive impairment, obsessive-compulsive behavior, dementia, depression, Huntington's disease, dystonia, mania, (Richter, Br J Pharmacology 2006; Aiba, Brain 2021; Boehm, Pain 2019; Maghera, Epilepsy 2020; De Jong, Physiological Reports 2018; Jakubowski, Epilepsy Behav 2013; Zizhen Wu, J Pharmacol Exp Ther 2020; JE Larsson, In Physiology 2020; Yadav, Saudi J Anaesth 2017; Garakani, Front Psychiatry 2020; Maljevic, J Physiol 2008; R. Brant, Gastroenterology 2017; Hui Sun, JCI Insight 2019;R Brant,Gastroenterology 2017;Ravi Misra,Gastroenterology 2017;Parreno,Front Physiol 2020;Blom,PLoS One.2014)(Feng Neuroscience 2019)(E Redford,Physiol Biochem 2021)(J Gunthrope,Epilepsia 2012; Epilepsia, Villalba. 2018). Because retigabine and flupirtine are well tolerated in humans, the current findings of pronounced antidystonic efficacy in dtsz mutants suggest that neuronal Kv7 channel activators are interesting candidates for the treatment of dystonia-associated dyskinesias and possibly other types of dystonia. The established analgesic effects of Kv7 channel openers may contribute to the amelioration of these disorders, which are often accompanied by painful muscle spasms.

[0158] Retigabine has been shown to delay the onset of spreading depolarization following submaximal OGD stimulation. Interestingly, Kv7.2 activators are neuroprotective in experimental ischemia and brain trauma studies, and the anti-spreading depolarizing properties of the activators may contribute to these neuroprotective effects.

[0159] Studies support novel roles for Kv7 channels in intrinsic and synaptic plasticity and their contribution to cognition and behavior

[0160] Voltage-gated potassium channels of the KV7 family (KV7.1-5) play a key role in controlling neuronal excitability and are therefore attractive targets for the treatment of CNS disorders associated with hyperexcitability.

[0161] f. Cognitive impairment, memory impairment, memory disorder, memory failure (Frontal Physiol, Baculis. 2020, Frontal Physoil, Vigil. 2020). Considering that Kv7 channels are important for neonatal brain development and inhibition (Peters et al., 2005; Soh et al., 2014), memory impairments in these genetic models may result from abnormal hippocampal morphology and / or hyperexcitability (Peters et al., 2005; Milh et al., 2020). Kv7 channels also regulate multiple behaviors. Behavioral phenotyping of global or conditional homozygous KCNQ2 knockout mice was not possible due to early postnatal lethality or early death, respectively (Watanabe et al., 2000; Soh et al., 2014).

[0162] However, heterozygous KCNQ2 knockout mice are viable and show increased locomotor activity and exploratory behavior (Kim et al., 2020), consistent with behavioral hyperactivity induced by transgenic inhibition of Kv7 currents (Peters et al., 2005) and amphetamine and XE991 (Sotty et al., 2009). These mice also show reduced sociality and increased repetitive and compulsive behaviors (Kim et al., 2020), reminiscent of the autism seen in some EE patients with dominant KCNQ2 mutations (Weckhuysen et al., 2012, 2013; Milh et al., 2013). The International Kv7 Symposium held in Naples, Italy in 2019 shows great translational potential. Animal studies indicate that M currents are a therapeutic target for multiple brain disorders, including those that currently have no treatment, such as TBI and psychostimulant addiction.

[0163] g. Schizophrenia, (Transl Psychiatry, Nielsen.2017, Br J Pharmacol, Wang.2020). Genetic or pharmacological inhibition of neuronal Kv7 channels can alleviate NMDA antagonist-induced PPI and cognitive impairment, thus suggesting the therapeutic potential of such inhibition of Kv7 channels in the treatment of schizophrenia or cognitive disorders.

[0164] h. Spinal cord injury (J Pharmacol, Wu.2020). Reducing neuronal activity by opening KCNQ / Kv7 channels can protect spinal neurons and axons from degeneration after SCI, thereby promoting the recovery of motor and sensory function. Repeated application of retigabine to open these channels during the acute phase promotes neurobehavioral recovery after SCI.

[0165] i. Cardiomyopathy, cardiac arrhythmias (Front Physiol, Larsson. 2020; J Physoil, Maljevic. 2008; Lee, Microcirculation. 2015). Due to their important role in physiology, dysfunctional KV7 channels are frequently associated with disorders characterized by abnormal potassium ion conductance, including cardiac arrhythmias, hearing loss, epilepsy, pain, and hypertension.

[0166] Mouse Kv7 channels may contribute differently to regulating the functional properties of cerebral and coronary arteries. Such heterogeneity has important implications for developing new therapeutic agents for cardiovascular dysfunction.

[0167] h. Long QT syndrome, (J Physoil,Maljevic.2008, Acta Pyhsoil.Skarsfeldt.2020:Acta Physoil,Bahannon.2019). Polyunsaturated fatty acids with double bonds closer to the head group had higher apparent affinity for the IK channel and increased IK currents more, whereas moving the bond further away from the head group decreased apparent binding affinity and effect on IK currents. Interestingly, we found that ω-6 and ω-9 PUFAs had the most left-shifted voltage dependence of activation because their first double bond is closer to the head group. These results may enable informed design of new therapeutics targeting IK channels in long QT syndrome.

[0168] KV7 channels present an interesting target for new therapeutic approaches against diseases caused by neuronal hyperexcitability, such as epilepsy, neuropathic pain, and migraine. The molecular mechanism of KV7 activation by retigabine, which is in phase III clinical trials to treat drug-resistant focal epilepsy, has recently been elucidated as stabilization of an open conformation by binding to the pore region.

[0169] i. Bowel diseases, inflammatory diseases, ulcerative colitis, Crohn's disease, (J Neurosci, Linley. 2008). Further experiments demonstrated that M-current inhibition required a concomitant increase in cytoplasmic Ca2 concentration and depletion of membrane phosphatidylinositol 4,5-bisphosphate (PIP2). We propose that PLC- and Ca2 / PIP2-mediated inhibition of M-currents in sensory neurons may represent one of the common mechanisms underlying pain generated by inflammatory mediators, and thus may open a new therapeutic window for the treatment of this major clinical problem.

[0170] j.Creutzfeldt-Jakob disease, (Acta Pharmacol Sin, Teng. 2016). The modified QO58 compound (QO58-lysine) can specifically activate Kv7.2 / 7.3 / M channels. Oral or intraperitoneal administration of QO58-lysine, which has improved bioavailability and a half-life of about 3 hours in plasma, can reverse inflammatory pain in rodent models.

[0171] k. Progressive hearing loss or tinnitus (J Physoil,Maljevic.2008, Br J Pharmacol,Leithner.2014, J Neurosci,Kalappa.2015). By stabilizing KCNQ4-mediated conductance in OHCs, chemical channel openers can protect against OHC degeneration and the progression of hearing loss in DFNA2.

[0172] Behavioral studies demonstrated that SF0034 is a more potent and less toxic anticonvulsant than retigabine in rodents. Furthermore, SF0034 prevented the development of tinnitus in mice. We propose that SF0034 not only provides a powerful tool to study ion channel properties, but most importantly, offers a clinical candidate for the treatment of epilepsy and prevention of tinnitus.

[0173] l. Diabetes, (Front Cardiovasc Med, Fosmo.2017). Kv7 channel activity may contribute to the development of cardiovascular risk factors such as hypertension, diabetes, and obesity. Questions about past studies and hypotheses for future research have been raised. Alterations in Kv7 channels may contribute to the development of cardiovascular disease (CVD). Pharmacological modification of Kv7 channels may represent a possible treatment for CVD in the future.

[0174] m. Chronic obstructive pulmonary disease (COPD) (Front Physiol, Mondejar-Parreno.2020). The functional role of Kv7 channels may vary depending on the cell type. Several studies have demonstrated that impairment of Kv7 channels has a strong impact on lung physiology contributing to the pathophysiology of various respiratory diseases such as cystic fibrosis, asthma, chronic obstructive pulmonary disease, chronic cough, lung cancer, and pulmonary hypertension. Kv7 channels are now recognized to play a relevant physiological role in many tissues, which has prompted the search for Kv7 channel modulators with potential therapeutic applications in many diseases, including those affecting the lung. Modulation of Kv7 channels has been proposed to provide beneficial effects in many pulmonary conditions. Thus, Kv7 channel openers / enhancers or drugs acting in part through these channels have been proposed as bronchodilators, expectorants, antitussives, chemotherapeutic agents, and pulmonary vasodilators.

[0175] n.A movement disorder selected from primary dystonias (A Richter Br J Pharmacol 2006). These data indicate that dysfunction of neuronal Kv7 channels is noteworthy in dyskinesia. Because retigabine and flupirtine are well tolerated in humans, the current findings of significant antidystonic efficacy in dtsz mutants suggest that neuronal Kv7 channel activators are interesting candidates for the treatment of dystonia-associated dyskinesias and possibly other types of dystonia. The established analgesic effect of Kv7 channel openers may contribute to the amelioration of these disorders, which are often accompanied by painful muscle spasms.

[0176] o. Autism, autism spectrum disorder, comprising administering a compound of the present disclosure. (Gilling, Front Genet. 2013; Guglielmi, Front Cell Neurosci. 2015). One embodiment of the present disclosure includes a method of delivering a broad spectrum Kv7.2-7.5 active molecule to the systemic circulation, comprising administering a compound of the present disclosure, and releasing the active Kv channel opener at an effective therapeutic concentration to treat one or more susceptible diseases or disorders. In one aspect, the release of the active molecule is enhanced by increased absorption as provided under one or more of:

[0177] Because retigabine and flupirtine are well tolerated in humans, the current findings of pronounced antitonic efficacy in dtsz mutants suggest that neuronal Kv7 channel activators are interesting candidates for the treatment of dystonia-associated dyskinesias and possibly other types of dystonia.

[0178] Mutations in neuronal Kv7 (KCNQ) potassium channels can cause episodic neurological disorders. Paroxysmal dyskinesia with dystonia is a group of movement disorders considered as ion channelopathies, but the role of Kv7 channels in pathogenesis and as therapeutic targets has not been explored so far.

[0179] Our results suggest that dysfunction of heteromeric KV7.3 / 5 channels is involved in the pathogenesis of some forms of autism spectrum disorder, epilepsy, and possibly other psychiatric disorders, and therefore suggest KCNQ3 and KCNQ5 as candidate genes for these disorders. EXAMPLES

[0180] In the following examples, temperatures are given in degrees Celsius (°C) unless otherwise stated. Operations were carried out at room or ambient temperature (typically in the range of about 18-25°C). Evaporation of solvents was carried out using a rotary evaporator under reduced pressure (typically 4.5-30 mmHg) with a bath temperature of up to 60°C. Reaction progress was typically followed by TLC and reaction times are provided for illustration only. Melting points are uncorrected. Products are fully soluble in water. 1 H-NMR data and / or microanalytical data are given. Yields are provided for illustration only. The following conventional abbreviations are also used: mp (melting point), L (liter), mL (milliliter), mmol (millimol), g (gram), mg (milligram), min (minute), and h (hour).

[0181] Unless otherwise stated, all solvents (HPLC grade) and reagents were purchased from the supplier and used without further purification. Analytical thin-layer chromatography (TLC) was performed on Whatman Inc. 60 silica gel plates (0.25 mm thickness). Compounds were visualized under a UV lamp (254 nM) or by developing with KMnO4 / KOH, ninhydrin or hanessan solutions. Flash chromatography was performed using silica gel from Selectro Scientific (particle size 32-63). 1 H NMR spectrum, 19 F NMR spectrum, and 13 C NMR spectra were recorded on a Varian 300 machine at 300 MHz, 282 MHz, and 75.7 MHz, respectively. Melting points were recorded on an Electrothermal IA9100 instrument and are uncorrected.

[0182] The following examples are provided to illustrate, but not to limit, the present disclosure. The general procedures of Examples 1 and 2 can be modified by one skilled in the art for use in synthesizing compounds within Formula III by appropriate substitution of appropriate amounts of ezogabine, flupirtine, and other starting materials for the acylating agent.

[0183] One of ordinary skill in the art will further recognize that human clinical trials, including first in man, dose ranging and efficacy studies in healthy patients and / or patients suffering from a given disorder, can be completed according to methods well known in the clinical and medical arts.

[0184] The present disclosure expressly includes the compounds presented below, including their salt forms. The present disclosure also includes the compounds presented below, including their stereoisomers. Compositions containing a therapeutically acceptable amount of any of these compounds are also within the scope of the present disclosure. The composition may further include a pharma- ceutically acceptable excipient, diluent, carrier, or mixture thereof. Such compositions may be administered to a subject in need thereof to treat or control a disease or disorder mediated, in whole or in part, directly or indirectly, by one or more voltage-dependent potassium channels. The composition may further include an additional activator as described herein.

[0185] The following examples provide more detailed descriptions of the process conditions for preparing the compounds of the present disclosure. However, it should be understood that the present disclosure, as fully described and claimed herein, is not intended to be limited by the details of the following schemes or preparation modes.

[0186] In describing the embodiments of the present disclosure, certain abbreviations may be used, which are believed to be used consistently within generally accepted usage by those of ordinary skill in the art.

[0187] The compounds of the invention may be prepared using commercially available reagents and intermediates in the synthetic methods and reaction schemes described herein, or may be prepared using other reagents and conventional methods well known to those of skill in the art.

[0188] In the following schemes, generic substituents are represented with assignments that may not align with the formulas of the present disclosure. The following schemes provide a key to such substituents that should be followed in the schemes and do not apply to the formulas of the present disclosure.

[0189] Scheme General scheme 1: Prodrug synthesis from Kv7-active drug molecules [ka] In general scheme 1, the Kv7 pharmacophore is a drug moiety active at the Kv7 potassium ion channel. 1 teeth 、 Represents an activated carbonyl reagent or intermediate 、 L is a leaving group. G represents H or various substituents, R 1 is as used herein. The resulting product is a hydrolyzable prodrug that forms a Kv7 active drug upon hydrolysis.

[0190] Example 1 General procedure for the preparation of acetal / ketal diester prodrugs of ezogabine: In a 500 mL round-bottom flask equipped with a magnetic stir bar, place 200 mL of dichloromethane at room temperature. Stirring is begun and the following materials are added, in order: ezogabine (10.0 g, 33.00 mmol, 1.0 equiv, 303.33 g / mol, [CAS number 150812-12-7]), triethylamine (6.68 g, 66.00 mmol, 2.0 equiv, 101.19 g / mol), the desired 1-(((4-nitrophenoxy)carbonyl)oxy)alkyl carboxylate (34.62 mmol, 1.05 equiv, and HOBt (0.446 g, 3.30 mmol, 0.1 equiv, 135.12 g / mol). The flask is flushed with nitrogen gas and sealed with a septum. The nitrogen atmosphere is maintained at approximately 100°C for 10 min. One atmosphere of N2 is maintained using a needle attached to a nitrogen line and the reaction progress is monitored by TLC. If no ezogabine remains by TLC, the reaction is treated by adding 100 mL of water and stirring under nitrogen for 10 minutes. The contents of the flask are transferred to a separatory funnel and the layers are separated. The organic layer is washed twice with 0.1 M sodium hydroxide solution and dried over sodium sulfate. The volatiles are removed under vacuum and the residue is purified by column chromatography or recrystallization to give the desired ezogabine-derived prodrug.

[0191] Example 2 General procedure for the preparation of acetal / ketal diester prodrugs of flupirtine: In a 500 mL round-bottom flask equipped with a magnetic stir bar, place 200 mL of dichloromethane at room temperature. Stirring is started and the following materials are added in order: flupirtine (10.0 g, 33.00 mmol, 1.0 equiv, 303.33 g / mol, [CAS number 56995-20-1]), triethylamine (6.68 g, 66.00 mmol, 2.0 equiv, 101.19 g / mol), the desired 1-(((4-nitrophenoxy)carbonyl)oxy)carboxylate alkyl (34.62 mmol, 1.05 equiv), and HOBt (0.446 g, 3.30 mmol, 0.1 equiv, 135.12 g / mol). The flask is flushed with nitrogen gas and sealed with a septum. A nitrogen atmosphere is maintained using a needle attached to a nitrogen line of approximately 1 atm N2 and reaction progress is monitored by TLC. If no flupirtine remains by TLC, the reaction is treated by adding 100 mL of water and stirring under nitrogen for 10 minutes. The contents of the flask are transferred to a separatory funnel and the layers are separated. The organic layer is washed twice with 0.1 M sodium hydroxide solution and dried over sodium sulfate. Volatiles are removed under vacuum and the residue is purified by column chromatography or recrystallization to give the desired flupirtine-derived prodrug.

[0192] The general procedures of Examples 3 and 4 can be modified by one of skill in the art for use in synthesizing compounds within Formula IV by appropriate substitution of appropriate amounts of ezogabine, flupirtine, and other starting materials for the acylating agent.

[0193] Example 3 General procedure for the preparation of amino acid prodrugs of ezogabine: Step 1: Place dichloromethane (200 mL) at room temperature in a 500 mL round-bottom flask equipped with a magnetic stir bar. Stirring is started and the following materials are added in order: ezogabine (10.0 g, 33.00 mmol, 1.0 equiv, 303.33 g / mol, [CAS number 150812-12-7]), triethylamine (6.68 g, 66.00 mmol, 2.0 equiv, 101.19 g / mol), desired Boc-protected amino acid O-succinimide ester (34.62 mmol, 1.05 equiv, and HOBt (0.446 g, 3.30 mmol, 0.1 equiv, 135.12 g / mol). The flask is flushed with nitrogen gas and sealed with a septum. The nitrogen atmosphere is maintained using a needle attached to a nitrogen line at approximately 1 atm of N2, and the reaction progress is monitored by TLC. When no ezogabine remains by TLC, the reaction is worked up by adding 100 mL of water and stirring under nitrogen for 10 minutes. The contents of the flask are transferred to a separatory funnel and the layers are separated. The organic layer is washed twice with 0.1 M sodium hydroxide solution and dried over sodium sulfate. The volatiles are removed under vacuum and the residue is purified by column chromatography or recrystallization to give the desired prodrug in BOC-protected form.

[0194] Step 2: The product of Step 1 is added to a stirred solution of 25% trifluoroacetic acid in dichloromethane (100 mL) at room temperature. The flask is flushed with nitrogen gas and sealed with a septum. A nitrogen atmosphere is maintained using a needle attached to a nitrogen line at approximately 1 atm of N2, and reaction progress is monitored by TLC. When no starting material or intermediates remain by TLC, the reaction is worked up by removing the volatile solvents under vacuum. The crude product is obtained as a mixture of the trifluoroacetic acid salts of the desired prodrug free bases. The material is purified by recrystallization or reverse phase HPLC to give the desired prodrug material.

[0195] Example 4 General procedure for the preparation of amino acid prodrugs of flupirtine: Step 1: A 500 mL round bottom flask equipped with a magnetic stir bar is placed in dichloromethane (200 mL) at room temperature. Stirring is started and the following materials are added in order: flupirtine (10.0 g, 33.00 mmol, 1.0 equiv, 303.33 g / mol, [CAS number 56995-20-1]), triethylamine (6.68 g, 66.00 mmol, 2.0 equiv, 101.19 g / mol), desired Boc-protected amino acid O-succinimide ester (34.62 mmol, 1.05 equiv), and HOBt (0.446 g, 3.30 mmol, 0.1 equiv, 135.12 g / mol). The flask is flushed with nitrogen gas and sealed with a septum. The nitrogen atmosphere is maintained using a needle attached to a nitrogen line at approximately 1 atm of N2, and the reaction progress is monitored by TLC. When no flupirtine remains by TLC, the reaction is worked up by adding 100 mL of water and stirring under nitrogen for 10 minutes. The contents of the flask are transferred to a separatory funnel and the layers are separated. The organic layer is washed twice with 0.1 M sodium hydroxide solution and dried over sodium sulfate. The volatiles are removed under vacuum and the residue is purified by column chromatography or recrystallization to give the desired prodrug in BOC-protected form.

[0196] Step 2: The product of Step 1 is added to a stirred solution of 25% trifluoroacetic acid in dichloromethane (100 mL) at room temperature. The flask is flushed with nitrogen gas and sealed with a septum. A nitrogen atmosphere is maintained using a needle attached to a nitrogen line at approximately 1 atm of N2, and reaction progress is monitored by TLC. When no starting material or intermediates remain by TLC, the reaction is worked up by removing the volatile solvents under vacuum. The crude product is obtained as a mixture of the trifluoroacetic acid salts of the desired prodrug free bases. The material is purified by recrystallization or reverse phase HPLC to give the desired prodrug material.

[0197] Example 5 Synthesis of acetal prodrugs of ezogabine. Step 1: Zinc oxide (44.73 g, 0.55 mol) was added to a solution of toluene (1800 mL) and 2-methylpropanoic acid (450 mL) and the flask was heated to 120 °C. Water produced in the process was removed by a Dean-Stark trap. After 5 h of heating, the temperature was lowered to 70 °C and then (1-chloroethyl)(4-nitrophenyl)carbonate (45 g, 0.18 mol) was added along with NaI (43.97 g, 0.29 mol). The reaction mixture was stirred at 70 °C for 36 h. After completion, the mixture was evaporated and the residue was dissolved in EtOAc and washed with saturated NaHCO3 solution and then with brine. The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: EtOAc = 50: 1) to give the desired product as a yellow solid (32.6 g, 55.68% yield).

[0198] Step 2: To a stirred solution of ethyl N-(2-amino-4-{[(4-fluorophenyl)methyl]amino}phenyl)carbamate (24 g, 0.079 mol) in dichloromethane (480 mL) was added triethylamine (16.01 g, 0.16 mol), 1-[(4-nitrophenoxycarbonyl)oxy]ethyl 2-methylpropanoate (30.57 g, 0.10 mol), 1-hydroxybenzotrizole (1.07 g, 0.007 mol) and stirred under nitrogen atmosphere at 25° C. for 24 hours. After completion, the mixture was treated by adding 300 mL of water and stirring under nitrogen for 10 minutes. The contents of the flask were transferred to a separatory funnel and the layers were separated. The organic layer was washed twice with 0.1 M sodium hydroxide solution and dried over sodium sulfate. The volatiles were removed under vacuum and the residue was purified by column chromatography (petroleum ether: EtOAc = 6:1) to give compound 3 as a yellow solid (3.4 g, 9.3% yield).

[0199] 11H-NMR: (DMSO-d6): δ (ppm): (multiplicity, J (Hz), integration): 8.8 - 8.7 (bs, 1H), 8.3 - 8.2 (bs, 1H), 7.4 (m, 2H), 7.1 (m, 2H), 7.0 - 6.9 (bs, 1H), 6.8 (bs, 1H), 6.7 (q, 1H), 6.3 (m, 2H), 4.2 (m, 2H), 4.0 (m, 2H), 2.5 (m, 1H), 1.4 (m, 3H), 1.2 (m, 3H), 1.1 (m, 6H).

[0200] 13 13C-NMR: (DMSO-d6): δ (ppm): 174.9, 162.7, 160.3, 152.0, 146.8, 136.7, 136.7, 129.3, 118.9, 115.5, 115.3, 109.0, 107.2, 89.5, 60.6, 46.3, 39.6, 33.6, 20.0, 19.0, 18.9, 15.0 ppm.

[0201] LCMS R t = 1.38 min, [M + H] = 462

[0202] General Scheme A

Chemical Structure

[0203] Step 2: A mixture of tert-butyl N-(5-{[(tert-butoxy)carbonyl]amino}-5-({2[(ethoxycarbonyl)amino]-5-{[(4fluorophenyl)methyl]amino}phenyl}carbamoyl)pentyl)carbamate (8.67 g, 0.014 mol) and HCl in dioxane (17.5 mL, 0.069 mol) was prepared in dichloromethane (86 mL). The mixture was continuously stirred at room temperature for 18 hours. After completion, the mixture was filtered, the filter cake was washed with dichloromethane and dried under reduced pressure to give compound 4 as a white solid (6.3 g, 98.1% yield).

[0204] 1H-NMR: (DMSO-d6): δ (ppm), (multiplicity, J (Hz), integral): 10.0-10.2 (bs, 1H), 8.5-8.4 (bs, 3H), 8.1-7.9 (bs, 3H), 7.4 (m, 2H), 7.2 (m, 3) H),7.1(bs,1H),6.7(bs,1H),4.3-4.2(bs,2H),4.1(m,3H),2.7(bm,2H),1.8(bm,2H),1.6(m,2H),1.4(m,2H),1.2(m,3H).

[0205] 13 C-NMR:(DMSO-d6):δ(ppm):168.3,161.2,154.6,132.3,125.4,115.7,115.5,61.0,52.8,38.7,30.7,26.8,21.6,15.0ppm.

[0206] LCMS R t =0.94min, [M+H]=432

[0207] General Scheme B [ka] Example 7 Aqueous and organic solubility and stability studies of exemplary ezogabine prodrugs. A study was conducted to evaluate the solubility of two prodrugs of ezogabine (compound 1) in different aqueous and organic media and to assess their stability for up to 7 days by measuring UV absorption at 230 nm with a HPLC-UV / Vis mass spectrometer detector for mass confirmation. The solubility of compound 1 was known and is presented in Table 1. Solvent row The solubility of compound 1 in 0.1N Na2HPO4 was measured in 0.1N K2HPO4.

[0208] Compounds 3 and 4 were evaluated in various solvents to compare their solubility to compound 1. Compounds were weighed into 4 dram vials and solvent was added to the target concentration. Compounds were vortexed and visually inspected for particles and deemed soluble if they were clear on visual inspection with or without magnification. Solubility was reported as either greater than (>) or less than (<) from the concentration prepared. Compound 4 was evaluated for solubility at a maximum concentration of 20 mg / mL in water and 0.1 N HCl and was freely soluble. Compound 4 was evaluated at 10 mg / mL in 0.1 N NaCl and was freely soluble. Compound 4 was evaluated at 1 mg / mL in 0.1 N NaOH and 0.1 N Na2HPO4 and was freely soluble. Compound 4 was freely soluble at a concentration of 75 mg / mL in ethanol and methanol.

[0209] By visual inspection, compound 3 was not freely soluble at 1 mg / mL in 0.1 N HCl, 0.1 N NaOH, 0.1 N NaCl, water, 0.1 N Na2HPO4. Compound 3 was freely soluble at 75 mg / mL in methanol and ethanol. Compound 3 was soluble at 1 mg / mL in 1 N HCl.

[0210] Both prodrug compounds are more soluble in alcohol than compound 1. Compound 3 may have similar absolute solubility in aqueous media as compound 1, while compound 4 has superior solubility in aqueous solvents. For in vivo studies, compound 4 was formulated as a freely soluble solution in 0.9% w / v NaCl at a concentration of 150 mg / mL. [Table 1]

[0211] Compound 1 is known to degrade in light within 3-7 days, so the compound in the solvent was left exposed to light on the benchtop for up to 7 days.

[0212] Stability was assessed by taking aliquots from the solubility vials on each test day. A single replicate was injected for each test condition. Samples from compound 4 were diluted in water to a test concentration of 100 μg / mL. Samples from alcohol from compound 3 were diluted in methanol to 200 μg / mL and then further diluted to 100 μg / mL in water. Samples from aqueous solvent from compound 3 were diluted in methanol to 500 μg / mL.

[0213] Samples were injected into an HPLC system with an aqueous mobile phase and an acetonitrile organic phase, and compounds were separated on a C8 50x2mm column. Wavelength 230nm was monitored for absorbance, integrated for peak area, and mass confirmed using a mass spectrometer. Samples were tested on day 1 and every day thereafter up to day 7.

[0214] The increase in stability and solubility of compound 3 is shown in Figure 1. Compound 3 increases in solubility over time in 0.1N Na2HPO4, HO, 0.1N NaCl from day 1 to day 3. Compound 3 appears to be stable in 0.1N HCl over 4 days, but is not stable in 1N HCl over 7 days. Compound 3 is soluble and stable in ethanol and methanol over 3 days, but shows degradation on day 4.

[0215] The stability of compound 4 is shown in Figure 2. Compound 4 appears to be stable in all tested conditions except 0.1N NaOH over a 4 day period. There is a typical variation in peak area integral of + / - 20%, suggesting a stability trend for all solvents except 0.1N NaOH where compound 4 decreased in peak area by >50%.

[0216] Taken together, these results suggest that compounds 3 and 4 are more soluble in alcohol than compound 1, and compound 4 is more soluble in aqueous solvents than compound 1. With the exception of selected solvents, both prodrugs of ezogabine are stable in the solvents over a period of 3 days.

[0217] Figure 1 illustrates the stability and solubility of compound 3 over a period of 3-7 days, and Figure 2 shows the stability of compound 4 over a period of 4 days.

[0218] Example 8 Plasma Stability Studies of Examples of Ezogabine Prodrugs A study was conducted to evaluate the in vitro stability of two prodrugs of ezogabine (compound 1) in mouse and rat plasma at 37° C. for up to 23 hours.

[0219] Dry Compound #3 and Compound #4 were dissolved in dimethylsulfoxide (DMSO) at a concentration of 1 mg / mL and frozen at -20°C.

[0220] Plasma was collected by a biomaterials vendor and stored frozen at -20°C.

[0221] 1 mg / mL DMSO solutions of Compound 3 and Compound 4 were diluted to a final concentration of 1000 ng / mL in rat and mouse plasma, vortexed, and an aliquot was immediately removed and the plasma precipitated with 4 volumes of acetonitrile containing tolbutamide as an internal standard for mass spectrometer detection. The residue was incubated at 37° C. for up to 23 hours. Samples were stopped with a solution of ACN and tolbutamide (internal standard) at 0, 5, 30, 1, 2, 4, 6, and 23 hours. Samples were analyzed by HPLC separation and mass spectrometric detection for the amount of prodrug compared to the baseline time 0 control sample. Triplicate samples were generated at each time point and peak area responses were averaged and converted to percentages of baseline control.

[0222] Compound 3 is not stable in mouse and rat plasma, showing complete degradation by 1 hour in vitro (Figure 3). Compound 4 degrades by 6 hours in mouse plasma, but is stable by 6 hours in rat plasma, after which less than 50% remains at 23 hours (Figure 4). Ezogabine prodrugs elicit different stability profiles in plasma in vitro, suggesting that they may have different release kinetics in vivo.

[0223] Figure 3 shows compound 3 in vitro mouse and rat plasma stability at 37° C. Figure 4 shows compound 4 in vitro mouse and rat plasma stability at 37° C.

[0224] Example 9 Pharmacokinetics of ezogabine prodrugs in mice. A bioanalytical method was developed to detect compound 1, its primary metabolite N-acetyl metabolite, and either compound 3 or compound 4 on an API 4000 MS / MS system coupled to an Agilent 1100 HPLC and CTC PAL autosampler set at 4°C. HPLC separation was achieved on a 50×2 mm C8 column, and the HPLC was operated in reversed phase. Blood was collected by cardiac stick using a 25G 3 / 4 length needle attached to a 1 mL syringe and transferred to K2EDTA tubes containing either 500 mM citric acid in water for studies performed with compound 4, or 500 mM citric acid with 50 mM dichlorvos for studies performed with compound 3. Blood was diluted to 10% with these stabilizers. These solutions were identified to determine the best way to stabilize compounds 3 and 4 from a series of experiments and preserve the ezogabine prodrug in plasma prior to extraction.

[0225] Molecular extraction was performed by taking a 50uL aliquot of plasma and adding 200uL of acetonitrile containing 200ng / mL tolbutamide as an internal standard. Samples were precipitated into a 96-well plate, centrifuged, and aliquots were transferred to a new plate, dried under heat and nitrogen, and then reconstituted in the initial mobile phase conditions of the LC-MS / MS method. Standard curves were prepared for compound 1 with and without the N-acetyl metabolite separated from the prodrug. Standard curves were prepared from 5000ng / mL to 1ng / mL for each analyte. Concentration data from the bioanalytical runs were analyzed by Phoenix Winnonlin version 8 for non-compartmental sparse sampling PK analysis, plotting of concentration time curves, and tabulation of PK parameters.

[0226] Male mice weighing 20-25 g were administered either compound 1, compound 3 or compound 4 by subcutaneous or oral administration route, with 4 mice at each time point. Animals were asphyxiated with carbon dioxide gas, blood was collected with a heart stick, and euthanized by cervical dislocation. Compound 4 was administered subcutaneously at a solution dose of 100 mg / kg in saline in a volume of 10 mL / kg. Time points for concentration analysis of compound 1 and compound 4 were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, 24 hours (N=4 / time point). Figure 5 shows the mean (standard deviation) of compound 4 after subcutaneous (SC) administration. Compounds 1, 3, and 4 were administered to male mice at a dose close to the equimolar dose of compound 1 by oral administration route. Compounds 3 and 4 were administered at 30 mg / kg in solution in a volume of 10 mL / kg, while compound 1 was administered at 20 mg / kg. Compounds 1 and 3 were formulated in 5% ethanol:20% Cremophor EL and 75% saline. Compound 4 was formulated in saline. Plasma concentrations of Compound 1 and the N-acetyl metabolite were evaluated at 0.5, 1, 1.5, 2, 4, and 6 hours. Plasma concentrations of Compound 1 following oral administration of either Compounds 1, 3, or 4 are shown in Figure 6 and metabolite concentrations are shown in Figure 7.

[0227] Sparsely sampled noncompartmental pharmacokinetic (PK) parameters are from these two studies and are summarized in Table 2. Compounds 3 and 4 delivered more Compound 1 to the systemic circulation after 6 hours oral administration based on AUClast at similar molar doses than Compound 1 administered by itself. Compound 4 delivered a lower Cmax compared to Compound 1, which may confer a reduced adverse event profile in clinical trials due to a lower Cmax and slower Tmax. Metabolites are formed at similar exposure levels regardless of prodrug or ezogabine, but on a ratio basis, less is produced when Compound 1 is administered as Compound 3. Compound 1 has a slightly longer MRTlast (mean residence time over 6 hours when administered as a prodrug, and a longer half-life in mice when administered subcutaneously as Compound 4. The SC route of administration delivers more Compound 1 when administered as Compound 4 than the PO route based on AUClast / D. [Table 2]

[0228] Figures 5A and 5B show linear and semi-log plots of Compound 1 and Compound 4 after administration of 100 mg / kg Compound 4 SC to male mice. Figure 6 shows semi-log plots of Compound 1 after administration of either 20 mg / kg Compound 1, 30 mg / kg Compound 3, or 30 mg / kg Compound 4 by oral route to male mice. Figure 7 shows semi-log plots of N-acetyl metabolites after administration of either 20 mg / kg Compound 1, 30 mg / kg Compound 3, or 30 mg / kg Compound 4 by oral route to male mice.

[0229] Example 10 Pharmacokinetics of ezogabine prodrugs in rats. A bioanalytical method was developed to detect compound 1, its primary metabolite N-acetyl metabolite, and either compound 3 or compound 4 on an API 4000 MS / MS system coupled to an Agilent 1100 HPLC and CTC PAL autosampler set at 4°C. HPLC separation was achieved on a 50×2 mm C8 column, and the HPLC was operated in reversed phase. Blood was collected by cardiac stick using a 25G 3 / 4 length needle attached to a 1 mL syringe and transferred to K2EDTA tubes containing either 500 mM citric acid in water for studies performed with compound 4, or 500 mM citric acid with 50 mM dichlorvos for studies performed with compound 3. Blood was diluted to 10% with these stabilizers. These solutions were identified to determine the best way to stabilize compounds 3 and 4 from a series of experiments and preserve the ezogabine prodrug in plasma prior to extraction.

[0230] Extraction of molecules was performed by taking a 50uL aliquot of plasma and adding 200uL of acetonitrile containing 200ng / mL tolbutamide as an internal standard. Samples were precipitated into a 96-well plate, centrifuged, and aliquots were transferred to a new plate, dried under heat and nitrogen, and then reconstituted in the initial mobile phase conditions of the LC-MS / MS method. Standard curves were prepared for compound 1 with and without the N-acetyl metabolite separated from the prodrug. Standard curves were prepared from 5000ng / mL to 1ng / mL for each analyte. Concentration data from the bioanalytical runs were analyzed by Phoenix Winnonlin version 8 for noncompartmental PK analysis, plotting of concentration-time curves, and tabulation of PK parameters.

[0231] Male Sprague Dawley rats weighing 225-250g were cannulated in the jugular vein for IV dosing and / or blood sample collection. Rats were dosed with either Compound 1, Compound 3, or Compound 4 by intravenous, intramuscular, or oral routes of administration, with two rats per dose group. 150uL of blood was collected at pre-specified time points. At the end of the study, animals were asphyxiated with carbon dioxide gas and exsanguinated for euthanasia. Compounds 1 and 3 were formulated in 5% ethanol:20% Cremophor EL and 75% saline. Compound 4 was formulated in saline. Compounds 3 and 4 were administered by IV bolus in a volume of 4mL / kg at a dose of 5mg / kg. Compound 4 was administered by IM in the upper limb in a volume of 0.5mL / kg at a dose of 75mg / kg, with four rats per time point. Compounds 1, 3 and 4 were administered by oral route at equimolar doses of compound 1. Compounds 3 and 4 were administered at 30 mg / kg in a solution with a volume of 5 mL / kg, while compound 1 was administered at 20 mg / kg.

[0232] Figure 8 shows the mean (standard deviation) of Compound 4 after intramuscular (IM) administration. Plasma concentrations of Compound 1 after oral administration of either Compounds 1, 3, or 4 are shown in Figure 9, and metabolite concentrations are shown in Figure 10.

[0233] Noncompartmental pharmacokinetic (PK) parameters were generated from individual rats and averaged for each study, and are summarized in Table 3. Compound 3 delivered more Compound 1 to the systemic circulation after 24-hour oral administration of Compound 1 than after administration of Compound 1 by itself, based on AUClast at similar molar doses and lower Cmax. Compound 4 delivered a lower Cmax and comparable AUClast throughout 24 hours for Compound 1 compared to itself, but it may have been higher because there was no time point between 6 hours and 24 hours, when Compound 1 had not begun to clear. The rate of formation of Compound 1 was slower in the prodrug compared to the rate of absorption of Compound 1 administered as itself. This may result in a later Tmax and reduced early onset treatment-emerged adverse events. The longer the half-life of the prodrug, the longer the half-life of Compound 1. The IM route of administration delivers more Compound 1 when administered as Compound 4 than the oral route based on AUClast / D. Compound 1 has a slightly longer MRTlast (mean residence time over 24 hours when administered as a prodrug, and a longer half-life in rats when administered compared to administration by itself. Compound 3 had very little exposure in the systemic circulation after PO administration (not reported), while compound 4 was slightly more detectable in the systemic circulation after PO administration (not reported). [Table 3]

[0234] Figure 8 shows semi-log plots of Compound 1 and Compound 4 after administration of Compound 4 IM at 75 mg / kg in male rats. Figure 9 shows semi-log plots of Compound 1 after administration of either Compound 1 at 20 mg / kg, Compound 3 at 30 mg / kg, or Compound 4 at 30 mg / kg by oral route to male Sprague Dawley rats. Figure 10 shows semi-log plots of N-acetyl metabolites after administration of either Compound 1 at 20 mg / kg, Compound 3 at 30 mg / kg, or Compound 4 at 30 mg / kg by oral route to male mice.

[0235] Example 11 Ezogabine prodrugs are inactive against the molecular target Kv7.2 / 7.3. Human Kv7.2 / 7.3 cells were harvested, counted, and plated in black clear-bottom 96-well plates at a density of 50,000 cells per well in a 100 μl volume and incubated overnight. The next day, medium was removed and 40 μl of loading buffer (4.895 mL HBSS:HEPES, 50 μL probenecid, 50 μL Powerload, 5 μl FluxOR reagent) was added and incubated for 30 min at room temperature. After incubation, loading buffer was removed and 40 μl of assay buffer (4.45 ml HBSS:HEPES, 500 μl FluxOR assay buffer, and 50 μL probenecid) was added and incubated for 10 min. The FLIPR was then run with 10 μl of stimulation buffer with either vehicle, test compound or reference agonist, and fluorescence was monitored for 5 min at ex / em. 488 nm / 510-570 nm. Compounds 3 and 4 were tested in a seven-point concentration response from 0.03 to 30 μM, and ezogabine was tested in a seven-point concentration response from 0.01 to 10 μM, with relative fluorescence units (RFU) plotted against concentration. Compounds 3 and 4 are inactive against the primary target of Kv7.2 / 7.3. Compound 1 has an EC of 1.6 μM in this assay. 50 has.

[0236] FIG. 11 shows in vitro screening of Kv7.2 / 7.3 voltage-gated potassium channels.

[0237] Example 11 Ezogabine prodrugs deliver concentrations of ezogabine effective in vivo to block maximal electroshock (MES) in mice. CF-1 male mice (N=8) were treated IP with vehicle, Compound 3, Compound 4, Compound 1, phenytoin, or diazepam (0, 150, 100, 100, 8, and 20 mg / kg, respectively) and then subjected to a 60 Hz corneal stimulus (50 mA). All treatments were administered 30 min prior to MES, except for phenytoin, which was administered 1 h prior.

[0238] All mice in the vehicle group exhibited colonic seizures seconds after receiving MES. Mice treated with the remaining treatments generally reached the maximum time limit of 6 seconds without showing any signs of seizure.

[0239] FIG. 12 shows the CF-1 mouse maximal electric shock (MES) test.

[0240] CF-1 mice (N=8) were treated with Compound 1, Compound 3, and Compound 4 (150, 100, and 100 mg / kg, respectively) by IP administration, and blood was collected after MES for analysis of Compound 1 concentrations. The concentration of Compound 1 present in plasma was greater after administration of Compound 3 or Compound 4 than Compound 1 alone (FIG. 13). Compound 3 was 5.5-fold higher than Compound 1, and Compound 4 was 9-fold higher than Compound 1.

[0241] FIG. 13 shows compound 1 concentrations in CF-1 mice.

[0242] Example 12 Ezogabine prodrugs deliver concentrations of ezogabine effective in vivo to block maximal electroshock (MES) in mice.

[0243] SD rats (N=4) were treated IM with Compound 4 (75 mg / kg) and subjected to 60 Hz corneal stimulation (100 mA). All treatments were 0.083, 0.25, 0.5, 1, 2, 4, and 8 hours prior to administration of the MES test, and 6 seconds without seizures was considered protected.

[0244] Rats showed increasing protection from seizures as time increased, being nearly completely protected at 1 hour and completely protected 2-8 hours after dosing. Figure 14 summarizes the mean (SD) group average time to seizure.

[0245] FIG. 14 shows protection of SD rats from MES-induced seizures by Compound 4 after IM administration.

[0246] Example 13 Compound 3 was tested in the CCI model of neuropathic pain for reversal of mechanical hypersensitivity to the pin pick test for hind paw withdrawal and von Frey hair for gram force mechanical allodynia. Male Sprague Dawley rats (n=8 / group) were tested for baseline sensitivity on day 1 (ipsilateral and contralateral paws) and orally dosed with XYG-203. 40 mg / kg on day 1, 20 mg / kg on day 3, 10 mg / kg on day 5, 5 mg / kg on day 7, 1 mg / kg on day 10, and baseline dose on day 12. Mechanical hypersensitivity was tested 1 hour after pretreatment. Data (mean ± SD) were analyzed with repeated measures ANOVA with Dunnett's adjustment for multiple comparisons. At 5 mg / kg, the 95% confidence interval did not exceed the baseline mean for Compound 3, and 40 mg / kg reduced the latency of withdrawal of the neuropathic ipsilateral paw to 9.2 seconds (p=0.0003) and significantly increased the gram force of paw lift. There were no significant differences between baseline values ​​on days 0 and 12 for either the ipsilateral or contralateral hind paw, indicating no accumulation of learned behavior and drug effects in the ipsilateral hind paw. Furthermore, responses of the contralateral paw did not change significantly over the course of the study. The results are shown in Figures 15, 16, and 17.

[0247] Compound 3 was dosed at equimolar doses to ezogabine (20 mg / kg) in the same formulation (0.5% methylcellulose in water) in male jugular cannulated rats. Blood samples were taken at the same time points over 24 hours to generate concentration-time profiles. Two male rats were dosed per group. Plasma samples were analyzed by LC / MS / MS to provide the resulting concentration-time profiles and PK parameters. Compound 3 provided more than twice the total exposure of ezogabine at a given molar dose than ezogabine. There was essentially no detectable Compound 3 in the systemic circulation. [Table 4]

[0248] Compound 4 was evaluated in a rat formalin inflammation model. After intraplant administration of 50 μL of 5% formalin, the number of flicks / licks was recorded in male CD-1 mice during the acute phase of 0-10 min and the inflammatory phase of 15-40 min. Saline or compound 4 (100 mg / kg in water) was administered SC 5 mL / kg 30 min prior to application of formalin (n=8 / group). In both phases, a 50% reduction in behavioral responses was observed with compound 4 compared to vehicle. Data are presented in 2-min bins over the duration of the observation period. Compound 4 demonstrates a reduction in inflammatory pain. Results are shown in Figure 18. [ka]

[0249] Compounds 4, 6 and 29 were dosed equimolar to ezogabine (20mg / kg) in the same formulation (0.5% methylcellulose in water) in male jugular cannulated rats. Blood samples were taken at the same time points over 24 hours to generate concentration-time profiles. Two male rats were dosed per group. Plasma samples were analyzed by LC / MS / MS to provide the resulting concentration-time profiles and PK parameters. Compounds 4, 6 and 29 delivered a dose-normalized AUC total exposure of ezogabine similar to ezogabine itself. However, compound 4 showed the lowest exposure to itself in plasma, followed by compound 29. Compounds 4 and 29 delivered approximately half the ezogabine Cmax of ezogabine itself, while compound 6 delivered approximately twice the ezogabine Cmax of ezogabine itself. [Table 5]

[0250] The results are shown in Figure 19. [ka]

[0251] Compound 28 was tested in a maximal electroshock assay in CF-1 mice 30 minutes after drug administration by IP route to determine its ability to release ezogabine and provide protection in the assay. Drug concentration analysis of compound 28, ezogabine, and pregabalin was determined by LC / MS / MS assay in plasma and brain. Compound 28 was evaluated in a dose response at maximal electroshock at vehicle, 1.5, 3, 6, 12, and 24 mg / kg. Drug levels of ezogabine and compound 28 were evaluated. An additional group at 24 mg / kg was evaluated for exposure of compound 28, ezogabine, and pregabalin in plasma and brain. None of the doses provided complete protection against MES-induced seizures. 12 mg / kg protected 1 of 9 animals and 24 mg / kg protected 3 of 9 animals from MES-induced seizures. However, there was a clear increase in protection with increasing concentrations of ezogabine. Compound 28 was also present at a higher concentration than ezogabine, and it still showed that it had not completely released ezogabine. The results are illustrated in Figures 20 and 21.

[0252] Compound 28 was also administered in male jugular cannulated rats at equimolar doses to ezogabine (20 mg / kg) in the same formulation (0.5% methylcellulose in water). Blood samples were taken at the same time points over 24 hours to generate concentration-time profiles. Two male rats were administered per group. Plasma samples were analyzed by LC / MS / MS to provide the resulting concentration-time profiles and PK parameters. Compound 28 provided lower exposure to ezogabine at a given molar dose than ezogabine. Both ezogabine and compound 28 were present at similar concentrations in rats. [Table 6]

[0253] The results are shown in Figure 22. [ka]

[0254] Compound 29 was evaluated in the mouse maximal electroshock (MES) assay for efficacy at an oral dose of 30 mg / kg. After completion of the assay, blood samples were collected for plasma analysis of compound 29 and ezogabine by LC / MS / MS. Each male CF-1 mouse provided one data point in the MES assay and one data point in the concentration analysis. There were eight mice per time point. Ezogabine exposure was very high in plasma and present in the brain, with concentrations decreasing over three time points, 0.25, 0.5, and 1 hour. The pharmacological response decreased in parallel with the decrease in brain concentrations. The results are shown in Figure 23.

[0255] Example 14 Acid and organic solution stability of ezogabine and prodrugs. Ezogabine is not soluble at neutral pH, but is soluble at low pH. However, at low pH (1N HCl) and simulated gastric fluid (hydrochloric acid, sodium chloride, and pepsin), it decomposes to form a chromophore dimer. An HPLC-UV Vis method was developed using 0.1% formic acid in water as mobile phase A and 0.1% formic acid in acetonitrile as mobile phase B. A gradient method was developed, ramping from 10% A to 90% B over 8 minutes, then back to 10% A in 8.5 minutes on a 4.6×50 mm Zorbax C-18 column. 10 uL of the stability solution was injected for analyte detection. [ka]

[0256] When ezogabine was prepared at 8 mg / mL in simulated gastric fluid (SGF) and stored at 38° C., the concentration of the dimer over an 8 hour period increased to 1980 ng / mL in solution, see the table below for the percentage conversion to dimer and the concentration. The structure of the dimer is presented. [Table 7]

[0257] Ezogabine at 5 mg / mL was prepared in weak acid (0.1 N HCl), methanol, and acetonitrile and evaluated for degradation at room temperature for up to 2 weeks. Aliquots were collected at successive time points and then diluted to a nominal concentration of 100 ug / mL for injection into the HPLC and monitored at 250 nm by a diode array detector. Data for approximately 10 days is presented. The acid solution turned light purple (indicating degradation) by day 2, and the organic solvent solution did not begin to turn purple until day 7. [Table 8]

[0258] Compound 3 at 5 mg / mL was prepared in acidic solutions (0.1N and 1.0N HCl), ethanol, methanol, and acetonitrile and evaluated for degradation at room temperature for up to 3 weeks. Aliquots were collected at successive time points and then diluted to a nominal concentration of 100ug / mL for injection into HPLC and monitored at 250nm by a diode array detector. Compound 3 in 0.1N HCl turned light brown, while 1N HCl turned golden yellow by day 9. Organic solvents remained clear and colorless by day 18. Compound 3 converts to ezogabine under acidic conditions but not in organic solvents. [Table 9]

[0259] Compound 4 at 5 mg / mL was prepared in acidic solutions (0.1N, 1N, 2N HCl), phosphate buffered saline (PBS), and methanol and evaluated for degradation up to 3 weeks at room temperature. It was also evaluated in 2N HCl at 37°C. Aliquots were collected at successive time points and then diluted to a nominal concentration of 100ug / mL for injection into HPLC and monitored at 250nm by a diode array detector. Compound 4 remained clear and colorless up to 18 days. Compound 4 does not form a dimer under acidic conditions as there is very little degradation to ezogabine. [Table 10]

[0260] Compound 6 at 5 mg / mL was prepared in acidic solutions (1N, 2N HCl) and methanol and evaluated for degradation up to 3 weeks at room temperature. It was also evaluated in 2N HCl at 37°C. Aliquots were collected at successive time points and then diluted to a nominal concentration of 100ug / mL for injection into HPLC and monitored at 250nm by a diode array detector. Compound 6 remained clear and colorless up to 18 days. Compound 6 showed little degradation to ezogabine and is therefore unlikely to form dimers under acidic conditions. [Table 11]

[0261] Compound 28 at 5 mg / mL was prepared in acidic solutions (0.1N, 1N, 2N HCl) and methanol and evaluated for degradation at room temperature for up to 3 weeks. It was also evaluated in 2N HCl at 37°C. Aliquots were collected at successive time points and then diluted to a nominal concentration of 100ug / mL for injection into HPLC and monitored at 250nm by a diode array detector. Compound 28 remained clear and colorless for up to 11 days in acidic solutions and acetonitrile and up to 7 days in methanol. Compound 28 shows degradation to ezogabine as the strength of the acidic solution increases. [Table 12]

[0262] Compound 29 at 5 mg / mL was prepared in acidic solution (0.1N, 1N, 2N HCl), acetonitrile, and methanol and evaluated for degradation at room temperature for up to 3 weeks. It was also evaluated in 2N HCl at 37°C. Aliquots were collected at successive time points and then diluted to a nominal concentration of 100ug / mL for injection into HPLC and monitored at 250nm by a diode array detector. Compound 28 remained clear and colorless up to 18 days for acidic solution and 3 days for methanol. Compound 29 showed degradation under acidic conditions and also conversion to ezogabine, which may therefore form a dimer under acidic conditions. [Table 13]

[0263] All publications, patents, and patent applications cited herein are hereby incorporated by reference for the teachings to which such citations are applied.

[0264] Test compounds for the experiments described herein were used in free or salt form.

[0265] The specific pharmacological response observed may vary according to and depending on the particular active compound selected, or whether a pharmaceutical carrier is present, as well as the type of formulation and mode of administration used, and such expected variations or differences in results are contemplated in accordance with the practice of the present disclosure.

[0266] Although specific embodiments of the present disclosure are illustrated and described in detail herein, the present disclosure is not limited thereto.The above detailed description is provided as an example of the present disclosure and should not be interpreted as constituting any limitation of the present disclosure.Modifications are obvious to those skilled in the art, and all modifications that do not depart from the spirit of the present disclosure are intended to be included in the scope of the appended claims.

Claims

1. Compounds of Formula I: 【Chemical 27】 (In the formula, R １ But, C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkyl-C ３～６ is cycloalkyl, R ２ But, H, C １～３ Alkyl, C １～３ Alkoxy, halogen, C １～３ is haloalkoxy; Z is N or CH; R ３ is "Pro" and "Pro" is C(O)R １０ is selected from the group consisting of R １０ is the structure C(O)OL １ O.C.(O)R １１ is a hydrolyzable prodrug moiety of R １１ is unsubstituted or substituted C １ ~C １０ Alkyl, aryl, C １ ~C １０ It is aralkyl, L １ But, C １ ~C １０ alkylene, and L １ The two oxygen atoms shown bonded to L １ on the same carbon atom in R ４ and R ５ each is independently H; or R ４ and R ５ together with the atoms to which they are attached form a 5- to 6-membered ring, optionally containing one or more degrees of unsaturation; R ６ａ , R ６ｂ , and R ６ｃ are each independently H or halogen; R ６ａ , R ６ｂ , and R ６ｃ at least one of is H; or a pharma- ceutically acceptable salt thereof.

2. Compound of Formula II 【Chemistry 28】 (In the formula, R １ But, C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkyl-C ３～６ is cycloalkyl, R ２ But, H, C １～３ Alkyl, C １～３ Alkoxy, halogen, C １～３ is haloalkoxy; R ３ is "Pro" and "Pro" is C(O)R １０ is selected from the group consisting of R １０ is the structure C(O)OL １ O.C.(O)R １１ is a hydrolyzable prodrug moiety of R １１ is unsubstituted or substituted C １ ~C １０ Alkyl, aryl, C １ ~C １０ It is aralkyl, L １ But, C １ ~C １０ alkylene, and L １ The two oxygen atoms shown bonded to L １ on the same carbon atom in R ４ and R ５ each is independently H; or R ４ and R ５ together with the atoms to which they are attached form a 5- to 6-membered ring, optionally containing one or more degrees of unsaturation; R ６ａ , R ６ｂ , and R ６ｃ are each independently H or halogen; R ６ａ , R ６ｂ , and R ６ｃ at least one of is H; or a pharma- ceutically acceptable salt thereof.

3. Compound of Formula III: 【Chemical Formula 29】 (In the formula, R １ But, C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkyl-C ３～６ is cycloalkyl, R ２ But, H, C １～３ Alkyl, C １～３ Alkoxy, halogen, C １～３ is haloalkoxy; Z is N or CH; R ４ and R ５ each is independently H; or R ４ and R ５ together with the atoms to which they are attached form a 5- to 6-membered ring, optionally containing one or more degrees of unsaturation; R ６ａ , R ６ｂ , and R ６ｃ are each independently H or halogen; R ６ａ , R ６ｂ , and R ６ｃ at least one of is H; R ７ But, C １～６ Alkyl, phenyl, or C １～２ alkyl-phenyl), or a pharma- ceutically acceptable salt thereof.

4. The compound is of formula III-A: 【Chemistry 30】 (In the formula, L １ But, C １ ~C １０ alkylene, and L １ The two oxygen atoms depicted above are L １ 4. The compound of claim 3, wherein:

5. A compound or a pharma- ceutically acceptable salt thereof: 【Chemistry 31】

6. Compound of Formula IV: 【Chemistry 32】 (In the formula, R １ But, C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkyl-C ３～６ is cycloalkyl, R ２ But, H, C １～３ Alkyl, C １～３ Alkoxy, halogen, C １～３ is haloalkoxy; Z is N or CH; R １０ is the structure C(O)OL １ O.C.(O)R １１ is a hydrolyzable prodrug moiety of R １１ is unsubstituted or substituted C １ ~C １０ Alkyl, aryl, C １ ~C １０ It is aralkyl, L １ But, C １ ~C １０ alkylene, and L １ The two oxygen atoms shown bonded to L １ on the same carbon atom in R ４ and R ５ each is independently H; or R ４ and R ５ together with the atoms to which they are attached form a 5- to 6-membered ring, optionally containing one or more degrees of unsaturation; R ６ａ , R ６ｂ , and R ６ｃ are each independently H or halogen; R ６ａ , R ６ｂ , and R ６ｃ at least one of is H; or a pharma- ceutically acceptable salt thereof.

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients.

8. A composition for eliciting one or more of antiepileptic, muscle relaxant, fever reducing, peripheral analgesic, or anticonvulsant effects in a patient in need of such effects, the composition comprising a compound according to any one of claims 1 to 6 or a pharma- ceutical acceptable salt thereof.

9. Depression in cancer patients, depression in patients with Parkinson's disease, post-myocardial infarction depression, depression in patients with human immunodeficiency virus (HIV), subsyndromal symptomatic depression, depression in infertile women, childhood depression, major depression, single episode depression, recurrent depression, child abuse induced depression, postpartum depression, DSM-IV major depression, treatment refractory major depression, severe depression, psychotic depression, post-stroke depression, neuropathic pain, manic-depressive disorders including manic-depressive disorders with mixed episodes and manic-depressive disorders with depressive episodes, seasonal affective disorder, bipolar depression BP I, bipolar depression BP II, or depression, including major depression with dysthymia; dysthymia; phobias, including agoraphobia, social phobia or simple phobias; eating disorders, including anorexia nervosa or bulimia nervosa; drug dependence, including dependence on alcohol, cocaine, amphetamines and other psychostimulants, morphine, heroin and other opioid agonists, phenobarbital and other barbiturates, nicotine, diazepam, benzodiazepines and other psychoactive substances; Parkinson's disease, including Parkinson's dementia, neuroleptic-induced parkinsonism or tardive dyskinesia; headache, including headache associated with vascular disorders; withdrawal syndromes; age-related learning and psychiatric disorders; apathy; bipolar disorder, chronic fatigue syndrome; chronic or acute stress; behavioral disorders; cyclothymic disorder; somatization disorder, conversion disorder, pain disorder, hypochondriasis, body dysmorphic disorder, undifferentiated 10. A composition for treating one or more of the following: somatoform disorders, such as bronchial asthma, bronchial asthma, and somatoform NOS; incontinence; inhalation disorders; intoxication disorders; mania; oppositional defiant disorder; peripheral neuropathy; post traumatic stress disorder; late luteal phase dysphoric disorder; certain developmental disorders; SSRI "POOP OUT" syndrome or failure of a patient to maintain a satisfactory response to SSRI therapy after an initial period of satisfactory response; and tic disorders, including Tourette's disease, comprising a compound of claim 1 or a pharmacologic salt thereof.

10. seizures, pain, neuropathic pain, chronic headache, central pain, diabetic neuropathy, post-herpetic neuralgia and pain associated with peripheral nerve injury; drug addiction, affective disorders, Alzheimer's disease, anxiety, neurodegenerative illness or CNS injury caused by disease or injury, cognitive impairment, obsessive-compulsive behavior, dementia, depression, Huntington's disease, dystonia, mania, cognitive impairment, memory impairment, memory impairment disorder), memory impairment, movement disorder, motility disorder, neurodegenerative diseases, Parkinson's disease, Parkinson-like movement disorder, phobias, Pick's disease, psychosis, bipolar disorder, schizophrenia (schizophrenia subtypes are catatonic subtype, paranoid subtype, disorganized subtype or residual subtype), spinal cord injury, cardiomyopathy, cardiac arrhythmia, long QT syndrome, movement disorder or motility disorder, myasthenia gravis, migraine, tension headache, bowel disease, inflammatory disease, ulcerative colitis, Crohn's disease, Kreutzfeldt's disease, 7. A composition for treating, ameliorating or preventing the progression of a disease or disorder selected from the group consisting of Feid-Jakob disease, eye conditions, progressive hearing loss or tinnitus, fever, multiple sclerosis, diabetes, or metastatic tumor growth, aluminosis, anthracosis, asbestosis, lithiasis, lash loss, siderosis, silicosis, pneumoconiosis such as tobacco disease and sinusitis, and chronic obstructive pulmonary disease (COPD), and hypertension associated with obesity and disease, comprising a compound according to any one of claims 1 to 6 or a pharmacologic salt thereof.

11. Primary dystonia, Paroxysmal dystonia, Secondary dystonia, Drug-induced dystonia / dyskinesia, Tardive dystonia, Neuroleptic-induced dystonia, Treatment-induced dystonia / dyskinesia in patients with Parkinson's disease, Genetically degenerative dystonia, Dystonia in patients with Huntington's disease, Dystonia in patients with Tourette's syndrome, Dystonia in patients with Restless Legs Syndrome, Dystonia-like symptoms in patients with tics, Dystonia-associated dyskinesia, Paroxysmal dyskinesia, Seizures 7. A composition for treating one or more movement disorders selected from paroxysmal non-kinesiogenic dyskinesia, paroxysmal dystonic choreoathetosis, paroxysmal kinesiogenic dyskinesia, paroxysmal kinesiogenic choreoathetosis, kinesiogenic dyskinesia, paroxysmal sleep-induced dyskinesia, drug-induced dyskinesia, myokymia, neuromyotonia, autism, and autism spectrum disorder, comprising a compound according to any one of claims 1 to 6 or a pharmacologic acceptable salt thereof.

12. 10. A composition for delivering a broad spectrum Kv7.2-7.5 active molecule into the systemic circulation and releasing an active Kv channel opener in an effective therapeutic concentration to treat one or more susceptible diseases or disorders, comprising a compound according to any one of claims 1 to 6 or a pharma- ceutically acceptable salt thereof.

13. The release of the active molecule Enhanced by increased absorption, Delayed time to onset to ameliorate treatment-emergent adverse events; and Increase half-life or residence time by slowing circulation and release; 13. The composition of claim 12, wherein said composition is provided under one or more of the following conditions: thereby obviating the need for development of modified, sustained, delayed, or extended release formulations.

14. 7. Use of a compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for eliciting one or more of antiepileptic, muscle relaxant, fever reducer, peripheral analgesic, or anticonvulsant effects in a patient in need thereof.

15. Depression in cancer patients, depression in patients with Parkinson's disease, post-myocardial infarction depression, depression in patients with human immunodeficiency virus (HIV), subsyndromal symptomatic depression, depression in infertile women, childhood depression, major depression, single episode depression, recurrent depression, child abuse induced depression, postpartum depression, DSM-IV major depression, treatment refractory major depression, severe depression, psychotic depression, post-stroke depression, neuropathic pain, manic-depressive disorders including manic-depressive disorders with mixed episodes and manic-depressive disorders with depressive episodes, seasonal affective disorder, bipolar depression BP I, bipolar depression BP II, or depression, including major depression with dysthymia; dysthymia; phobias, including agoraphobia, social phobia or simple phobias; eating disorders, including anorexia nervosa or bulimia nervosa; drug dependence, including dependence on alcohol, cocaine, amphetamines and other psychostimulants, morphine, heroin and other opioid agonists, phenobarbital and other barbiturates, nicotine, diazepam, benzodiazepines and other psychoactive substances; Parkinson's disease, including Parkinson's dementia, neuroleptic-induced parkinsonism or tardive dyskinesia; headache, including headache associated with vascular disorders; withdrawal syndromes; age-related learning and psychiatric disorders; apathy; bipolar disorder, chronic fatigue syndrome; chronic or acute stress; behavioral disorders; cyclothymic disorder; somatization disorder, conversion disorder, pain disorder, hypochondriasis, body dysmorphic disorder, undifferentiated 7. Use of a compound according to any one of claims 1 to 6, or a pharmacologic acceptable salt thereof, for the manufacture of a medicament for treating one or more of the following: somatoform disorders, such as bronchial asthma, ...

16. seizures, pain, neuropathic pain, chronic headache, central pain, diabetic neuropathy, post-herpetic neuralgia and pain associated with peripheral nerve injury; drug addiction, affective disorders, Alzheimer's disease, anxiety, neurodegenerative illness or CNS injury caused by disease or injury, cognitive impairment, obsessive-compulsive behavior, dementia, depression, Huntington's disease, dystonia, mania, cognitive impairment, memory impairment, memory impairment disorder), memory impairment, movement disorder, motility disorder, neurodegenerative disease, Parkinson's disease, Parkinson-like movement disorder, phobia, Pick's disease, psychosis, bipolar disorder, schizophrenia (schizophrenia subtypes are catatonic subtype, paranoid subtype, disorganized subtype or residual subtype), spinal cord injury, cardiomyopathy, cardiac arrhythmia, long QT syndrome, movement disorder or motility disorder, myasthenia gravis, migraine, tension headache, bowel disease, inflammatory disease, ulcerative colitis, Crohn's disease, Creutzfeldt's disease, 7. Use of a compound according to any one of claims 1 to 6 or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for treating, ameliorating or preventing the progression of a disease or disorder selected from the group consisting of Feldt-Jakob disease, eye conditions, progressive hearing loss or tinnitus, fever, multiple sclerosis, diabetes, or metastatic tumor growth, aluminosis, anthracosis, asbestosis, lithiasis, lash loss, siderosis, silicosis, pneumoconiosis such as tobacco disease and sinusitis, and chronic obstructive pulmonary disease (COPD), and hypertension associated with obesity and disease.

17. Primary dystonia, paroxysmal dystonia, secondary dystonia, drug-induced dystonia / dyskinesia, tardive dystonia, neuroleptic-induced dystonia, treatment-induced dystonia / dyskinesia in patients with Parkinson's disease, genetically degenerative dystonia, dystonia in patients with Huntington's disease, dystonia in patients with Tourette's syndrome, dystonia in patients with restless legs syndrome, dystonia-like symptoms in patients with tics, dystonia-associated dyskinesia, paroxysmal dyskinesia, epilepsy 7. Use of the compound according to any one of claims 1 to 6 or a pharmacologic acceptable salt thereof for the manufacture of a medicament for treating one or more movement disorders selected from paroxysmal non-kinesiogenic dyskinesia, paroxysmal dystonic choreoathetosis, paroxysmal kinesiogenic dyskinesia, paroxysmal kinesiogenic choreoathetosis, kinesiogenic dyskinesia, paroxysmal sleep-induced dyskinesia, drug-induced dyskinesia, myokymia, neuromyotonia, autism, and autism spectrum disorder.

18. 13. Use of a compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of one or more susceptible diseases or disorders by delivering a broad-spectrum Kv7.2-7.5 active molecule into the systemic circulation and releasing an active Kv channel opener in a therapeutically effective concentration.

19. The release of the active molecule Enhanced by increased absorption, Delayed time to onset to ameliorate treatment-emergent adverse events; and Increase half-life or residence time by slowing circulation and release; 20. The use of claim 18, provided under one or more of the following conditions, thereby obviating the need for development of modified, sustained, delayed, or extended release formulations.

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