Chemical compounds

Abstract

The present disclosure describes compounds of Formula (I), as well as salts thereof, and pharmaceutical compositions comprising the compounds, which modulate the activity of the potassium channels, specifically Kv7.2-7.5 channels These compounds that modulate potassium channels, which are useful in the treatment of disorders, such as neural diseases, neural degenerative diseases, neural behavioral diseases, muscle movement diseases, neuroinflammatory diseases, addiction and substance use disorders, as well as for pain management.

Description

CHEMICAL COMPOUNDSCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No.63 / 727,529, filed December 3, 2024, the contents of which are incorporated by reference in their entirety into the present application.FIELD

[0002] The present disclosure describes novel compounds, as well as salts thereof, and pharmaceutical compositions comprising the compounds, which modulate the activity of the Kv7 potassium ion channels. This disclosure relates to the field of pharmacologically active drugs, and especially relates to the field of drugs active at Kv7 potassium ion channels. These compounds are useful in the treatment of disorders involving potassium channels, the central nervous system, or the peripheral nervous system such as seizures, behavioral diseases, as well as for pain management.BACKGROUND

[0003] The potassium voltage gated ion channel family 7, or Q, contains five proteins that in humans are encoded by the genes KCNQ1, KCNQ2, KCNQ3, KCNQ4, and KCNQ5. The KCNQ proteins form homo- and hetero-tetrameric channels that respond to membrane voltage changes and open to let potassium ions flow out of cell membranes. Homomeric Kv7.2 channels as well as heteromeric Kv7.2 and Kv7.3 channels have been investigated because of their unique distribution and their potential role as primary regulators of neuronal excitability in many CNS and PNS pathways (Wang et al., 1998). Kv7.2 channels control the neuronal resting membrane potential, the spike frequency adaptation of neuronal firing, and presynaptic release. Impairment in their function leads to network instability even when lost exclusively in inhibitory neurons (Soh et al., 2018).

[0004] Voltage-gated Kv7 (or KCNQ) channels play a pivotal role in controlling membrane excitability. The Kv7 subfamily of voltage-gated potassium channels consists of 5 members (Kv7.1-5) each showing characteristic tissue distribution and physiological roles. Kv7.1 is located in the cardiac muscle and is more structurally separate from the nervous system ion channels Kv7.2-Kv7.5. Given their functional heterogeneity, Kv7 channels represent important pharmacological targets for the development of new drugs for neuronal, neuromuscular,neuroinflammatory, vascular, and metabolic diseases. Like typical voltage-gated ion channels, Kv7 channels undergo a closed-to-open transition by sensing changes in transmembrane potential, and thereby mediate inhibitory K (+) currents to reduce membrane excitability.

[0005] The KCNQ proteins form homo- and hetero-tetrameric channels that respond to membrane voltage changes and open to let potassium ions flow out of cell membranes.Homomeric Kv7.2 channels as well as heteromeric Kv7.2 and Kv7.3 channels and heteromeric Kv7.3 and 7.5 and homomeric Kv7.4 have been investigated because of their unique distribution and their potential role as primary regulators of neuronal excitability in many CNS and PNS pathways (Wang et al., 1998). Kv7.2 channels control the neuronal resting membrane potential, the spike frequency adaptation of neuronal firing, and presynaptic release. Impairment in their function leads to network instability even when lost exclusively in inhibitory neurons (Soh et al., 2018).

[0006] A significant percentage of childhood epilepsies are associated with KCNQ2 gene mutations (Lee et al., 2019). Human genetic studies identify de nova mutations in KCNQ2 as the third most robust link to epileptic encephalopathy (EE) (Zhao et al., 2020). Whether primary or secondary EEs, seizure activity worsens clinical outcomes and alters normal neurodevelopment (von Deimling, Helbig and Marsh, 2017).

[0007] Pediatric epilepsies affect about 1 in 200 children (Waaler et al., 2000) driving cognitive, behavioral and neurological deficits (Simkin and Kiskinis, 2018). In the case of specific pathogenic Kv7.2 mutations, despite most individuals eventually becoming seizure-free, developmental delays are experienced by the majority of patients (Kato et al., 2013). Targeting Kv7 channels offers a genetically validated target against epilepsy with a differentiated mode of action amongst anti-epileptics (Gunthorpe, Large and Sankar, 2012). Kv7.2 enhancers show the potential to transform neurodevelopmental trajectories by treating the neural network instability responsible for EEs (Kessi et al., 2020).

[0008] The connection between epilepsy and autism is robust (Srivastava and Sahin, 2017) and derives from the convergent phenotypes driven by a multitude of small genetic contributors, in combination with environmental factors. Kv7.2 is one of the top 5 ion channels associated with Autism Spectrum Disorder (ASD) and one of the top 30 of all de nova mutations known in ASD (Zhao et al., 2020).

[0009] Another defining feature of ASD, Atypical Sensory Processing (ASP) (Thye et al., 2018), is also driven by convergent genetics as seen in co-twin-control studies (Neufeld et al., 2021). The biology responsible for increased sensory sensitivity has been studied in preclinical models. There, multi-sensory neuronal hyper-excitability emerges regardless of the genetic manipulationthat originally drives pathological neurodevelopment. Some genes whose manipulation leads to sensory sensitivity include CNTNAP2 (Pehagarikano et al., 2011), SHANK3 (Holder and Quach, 2016) and GABRB3 (Tanaka et al., 2012). Kv7.2 enhancers show the potential to correct neurodevelopmental trajectories in ASD by normalizing network stability, neural information processing, and sensory abnormalities, ultimately responsible for atypical social and repetitive behaviors in ASD. It is also interesting that KCNQ2 knock-out mice show repetitive behaviors and aberrant exploratory and social behaviors (Kim et al., 2019).

[0010] Kv7.2 enhancers also showed promise in syndromic neurodevelopmental disorders in part because of the prevalence and impact of epilepsies (Budisteanu et al., 2020). For example, epilepsy is prevalent (>80%) in Angleman syndrome, mostly starting before 3 years of age (Fiumara et al., 2010).

[0011] Another neurodevelopmental disorder, Dup15q syndrome (Dup15q), is caused by the partial duplication of Chromosome 15 that confers a considerable risk for autism spectrum disorder, epilepsy, and intellectual disability. Dup15q patient-derived induced pluripotent cells show KCNQ2 anomalies, and retigabine, a pan-Kv7 channel opener, partially corrects their phenotype (Fink et al., 2018). Epilepsies are central to Dup15q, with Kv7.2 enhancers showing potential to transform this neurodevelopmental disorder.

[0012] In Fragile X syndrome, about 15% of individuals experience epilepsy (Berry-Kravis, 2002) together with abnormal sensory processing (McCullagh et al., 2020). KCNQ2 (Kv7.2 gene) is downregulated in the absence of Fragile X Mental Retardation Protein (FMRP) in rodent models (Zhang et al., 2018). Therefore, Kv7.2 enhancers could positively impact Fragile X by acting on both epilepsies and sensory processing.

[0013] Infantile epilepsies are associated with intellectual disabilities, and KCNQ2 de nova mutations are significantly associated with intellectual disability (Zhao et al., 2020). Kv7.2 enhancement may address the underlying biology that exacerbates the disability.

[0014] For all these neurodevelopmental disorders, early diagnosis and the identification of the correct antiepileptic treatment is at the core of the strategies aiming at normalizing neurodevelopmental trajectories.

[0015] Within behavioral disorders, Kv7.2 enhancers showed promise in attention-deficit hyperactivity disorder (ADHD) as well as major depressive disorder (MDD, depression). Some patients with KCNQ2 mutations and mild epilepsy phenotype, show cognitive delay and ADHD (Lee et al., 2019). Kv7.2 enhancers were suggested to treat the neural network instability and the behavioral impulsivity linked to ADHD. In the MDD space, Retigabine (Kv7 opener) showed antidepressant efficacy in patients by acting on the brain's reward centers (Tan et al., 2018).The significant reduction in depressive symptoms observed with retigabine places Kv7.2 enhancers as therapeutic candidates in MDD.

[0016] The therapeutic potential of Kv7.2 enhancers in pain sensitivity is supported by the localization of Kv7.2 channels in dorsal root ganglia and their established role in pain perception (Brown and Passmore, 2009). Non-selective Kv7.2 enhancers showed efficacy in reducing the excitability of human peripheral axons (Lang et al., 2008). Retigabine has shown some efficacy in preclinical pain models (Korsgaard et al., 2005; Xu et al., 2010; Wu et al., 2017). Retigabine also shows efficacy in controlling spreading depression, a wave of cellular depolarization associated with migraines (Aiba and Noebels, 2021).

[0017] Within sensory abnormalities, aberrant plasticity of KCNQ2 channels is strongly linked to the induction of tinnitus (Li, Choi and Tzounopoulos, 2013). This link is based on the localization of Kv7.2 channels in the cochlea (Jin et al., 2009) and how cochlear damage depends on neuronal excitability driven by the closure of Kv7.2 channels (Liu, Glowatzki and Fuchs, 2015). Retigabine prevents the development of tinnitus in preclinical models (Li, Choi and Tzounopoulos, 2013). As evidence in support of how KCNQ2 pathologies are connected between indications, it is interesting to find that tinnitus and hyperacusis are more prevalent in ASD than in the general population (Danesh et aL, 2015).

[0018] In neurodegenerative diseases, dysregulated K+ homeostasis in chronic neuro-inflammatory conditions is central to disease progression. For example, in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease of the motor nervous system (Hardiman et al., 2017), diverse genetics converge onto motor neuron excitotoxicity (Kanai et aL, 2006; Pasinelli and Brown, 2006) and specifically axonal hyperexcitability predicts survival (Kanai et aL, 2012). Patient-derived motor neurons show membrane hyperexcitability and the tool compound Retigabine (pan- Kv7 enhancer) rescues phenotype (Wainger et al., 2014). The motor neuron hyperexcitability was found early in pre- symptomatic in vivo systems (Kuo et aL, 2004) where it is a contributor to disease progression. Recently, clinical trials in ALS with Retigabine showed efficacy on functional biomarkers of ALS (Wainger et al., 2021) and preclinically protects against peripheral neuropathy (Nodera et aL, 2011).

[0019] In Alzheimer's disease (AD), neuronal hyperexcitability and network instability (Frere and Slutsky, 2018) are early features of both IPSC models of sporadic AD (Ghatak et al., 2019), and genetic in vivo models (Palop et aL, 2007; Kazim et al., 2017; Styr and Slutsky,2018). Network instability worsens proteinopathy (Dolev et al., 2013; Frere and Slutsky, 2018) with consequences for patients (Vassel et al., 2013; Lam et al., 2017).

[0020] Because motor neuron and cortical neuron degeneration can be meaningfully slowed down by reducing aberrant neuronal activity, Kv7.2 enhancement could be an effective way to stop such aberrant activity, changing the neurodegenerative trajectory of the disease. Therefore, enhancing the activity of Kv7.2 is a promising strategy for the treatment or prevention of diseases associated with Kv7.2. These include neurodevelopmental disorders like autism and Fragile X, epilepsy, seizures, intellectual disability, depression, attention deficit hyperactivity disorder, obsessive compulsive disorders, substance use disorders, behavioral disorders, motor neuron excitability, pain, migraine, and sensory processing disorders.

[0021] Reduction of Kv7 channel activity as a result of genetic mutation is responsible for various human diseases due to membrane hyperexcitability, including epilepsy, pediatric epilepsy, arrhythmia, and deafness. In the case of specific pathogenic KCNQ2 mutations, despite most individuals eventually becoming seizure-free, developmental delays are experienced by the majority of patients (Kato et al., 2013). Targeting Kv7 channels offers a genetically validated target against epilepsy with a differentiated mode of action amongst antiepileptics (Gunthorpe, Large and Sankar, 2012). Kv7.2 enhancers show the potential to transform neurodevelopmental trajectories by treating the neural network instability responsible for EEs (Kessi et al., 2020).

[0022] 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 a conformational change leading to subthreshold channel opening, there is considerable interest in understanding the molecular basis of these 'gain-of-function' molecules. Although small-molecule activators of cation channels are rare, several novel compounds that activate Kv7 voltage-gated channels have been identified.

[0023] Ezogabine (USAN, or retigabine [INN]) and flupirtine are two examples of compounds which are active at Kv7 K+channels and which have been developed into drugs but are no longer on the market as therapeutics. Azetukalner is another example of a Kv7 channel opener that is in Phase 3 clinical development for seizures and major depressive disorder (MDD).

[0024] Ezogabine had been used along with other medications to control partial onset seizures (seizures that involve only one part of the brain) and focal seizures in adults and works by reducing neuronal hyperexcitability in the peripheral and central nervous system. Overall, themost frequently reported adverse reactions in patients receiving ezogabine provided under the brand name POTIGA®, a registered trademark of Valeant Pharmaceuticals North America, (>4% and occurring at approximately twice the placebo rate) were dizziness (23%), somnolence (22%), fatigue (15%), confusional state (9%), vertigo (8%), tremor (8%), abnormal coordination (7%), diplopia (7%), disturbance in attention (6%), memory impairment (6%), asthenia (5%), blurred vision (5%), gait disturbance (4%), aphasia (4%), dysarthria (4%), and balance disorder (4%). In most cases the reactions were of mild or moderate intensity (Potiga label, revised May 2016).

[0025] Ezogabine has exhibited effects in a range of cells, tissues, animal models and clinical trials related to the locations of these targets. In addition to blocking seizures, ezogabine has demonstrated pharmacological properties consistent with use as an analgesic, a neuroprotectant, in treatment of auditory disorders, a treatment of status epilepticus associated with organophosphate poisoning (Barker 2021, Neuroscience), and treatment of demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis. Ezogabine is providing important information and clues regarding novel mechanistic approaches to the treatment of a range of clinical conditions involving hyper-excitability of neurons.

[0026] Flupirtine has been 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 non-steroidal anti-inflammatory drugs and is well tolerated by the large 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 y-aminobutyric acid type A receptors, but also there is evidence of additional as yet unidentified mechanisms of action involved in the effects of flupirtine.

[0027] Flupirtine has exhibited effects in a range of cells and tissues related to the locations of these targets. In additional to analgesia, flupirtine has demonstrated pharmacological properties consistent with use as an anticonvulsant, a neuroprotectant, skeletal and smooth muscle relaxant, in treatment of auditory and visual disorders, and treatment of memory and cognitive impairment. Flupirtine is providing important information and clues regarding novel mechanistic approaches to the treatment of a range of clinical conditions involving hyper-excitability of cells. However, flupirtine does have some unwanted side effects including nausea, vomiting, dizziness, itching, rash formation, abdominal pain, bloating, tremor, dry mouth, idiopathic hepatic toxicity, and fatigue.

[0028] Kv7 channels present interesting targets for new therapeutic approaches to diseases caused by neuronal hyperexcitability, such as epilepsy, depression, neuropathic pain,and migraine. The molecular mechanism of Kv7 activation by ezogabine, has been elucidated as a stabilization of the open conformation by binding to the pore region of Kv7 channels (J Physiol, Maljevic. 2008).

[0029] Literature research has demonstrated that Kv7 channel openers, such as ezogabine, or pharmacological action that enhances the open state of Kv72-5 subtypes, have demonstrated, or are potentially effective, in treating, ameliorating, or preventing the progress of a disease or a disorder selected from the group diseases associated with neurological indications and pain. In one example, channel opening has demonstrated to be affected in affection the basal M-currents that set the resting membrane threshold. Enhancing the membrane threshold consisting of seizures. Neurons from Kv7.2(S559A) knock-in mice showed normal basal M-currents. Knock-in mice displayed reduced M-current suppression when challenged by a muscarinic agonist, oxotremorine-M. Kv7.2(S559A) mice were resistant to chemoconvulsant-induced seizures with no mortality. Administration of XE991, a Kv7.2 blocker, transiently exacerbated seizures in knock-in mice equivalent to those of wildtype mice. After experiencing status epilepticus, Kv7.2(S559A) knock-in mice did not show seizure-induced cell death nor spontaneous recurring seizures. (L Greene, Epilepsia 2018) This example presents how channel opening blocks seizures and neuroprotection. ICA-105665, a Kv7.2 channel opener reduced the SPR in patients at single doses of 100 (one of four), 400 (two of four), and 500 mg (four of six). This is the first assessment of the effects of activation of Kv7 potassium channels in the photosensitivity proof of concept model. The reduction of SPR in this patient population provides evidence of central nervous system (CNS) penetration by ICA-105665, and preliminary evidence that engagement with neuronal Kv7 potassium channels has antiseizure effects. (Epilepsia, Trenite, 2013).

[0030] In a model of pain, more specifically neuropathic pain, and chronic headache, Paclitaxel-induced peripheral neuropathy and associated neuropathic pain are severe and resistant to intervention. The results of a rodent model demonstrated that ezogabine can be used to attenuate the development of paclitaxel-induced peripheral neuropathy. (J Pain, Li. 2019).

[0031] Several drugs including flupirtine and retigabine enhance neural Kv7 / M-channel activity, principally through a hyperpolarizing shift in their voltage gating. In consequence they reduce neural excitability and can inhibit nociceptive stimulation and transmission. Flupirtine was one of the bestselling non-opioid analgesics in Europe that work as a central analgesic before being removed from the market; retigabine is an analog of flupirtine and approved as adjunctive therapy in partial onset seizures and is a broad-spectrum anticonvulsant in animalsand is an effective analgesic in animal models of chronic inflammatory and neuropathic pain central pain, pain related to diabetic neuropathy, to postherpetic neuralgia and to peripheral nerve injury (Brown Br J Pharmacology, 2009).

[0032] Czuzcwar has additionally summarized preclinical data that indicate that ezogabine may possibly be applied in patients with neuropathic pain and affective disorders, such as drug addiction and affective disorders. Initial clinical data suggest that retigabine may be also effective in Alzheimer’s disease or stroke. (Czuzcwar, Pharmacological Reports 2010).

[0033] There have been articles that indicate that Kv7 channel opening can be effective in a number of neurological therapeutic targets, such as but not limited to, anxiety, CNS damage caused by neurodegenerative / neuroinflammatory illness or diseases or injury, cognitive deficits, compulsive behavior, dementia, depressions, Huntington's disease, dystonia, mania. Since ezogaibine and flupirtine are well tolerated in humans, the present finding of pronounced antidystonic efficacy in the dtsz mutant mice suggests that neuronal Kv7 channel activators are interesting candidates for the treatment of dystonia-associated dyskinesias and probably of other types of dystonias. The established analgesic effects of Kv7 channel openers might contribute to improvement of these disorders which are often accompanied by painful muscle spasms (Richter, Br J Pharmacology 2006).

[0034] In a recent article, ezogabine could delay spreading depolarization onset following submaximal OGD stimulation. (Aiba, Brain 2021). Interestingly, Kv7.2 activators are neuroprotective in experimental ischemia and brain trauma studies and the anti-spreading depolarization properties of the activator may contribute to these neuroprotective effects.Further review of recent studies supports the emerging roles of Kv7 channels in intrinsic and synaptic plasticity, and their contributions to cognition and behavior. The voltage-gated potassium channels of the Kv7 family (Kv7.2–5) play important roles in controlling neuronal excitability and are therefore attractive targets for treatment of CNS disorders linked to hyperexcitability and such diseases associated with hyperexcitability such as cognitive disorders, memory impairment, memory disorders, memory dysfunction. (See, for example, Boehm, Pain 2019; Maghera, Epilepsia 2020; De Jong, Physiological Reports 2018;Jakubowski, Epilepsy Behav 2013; Zizhen Wu, J Pharmacol Exp Ther 2020; J E 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) ( JGunthrope,Epilepsia 2012; Epilepsia, Villalba. 2018) (Frontal Physiol, Baculis. 2020; Frontal Physiol, Vigil. 2020).

[0035] Considering that Kv7 channels are critical for development and inhibition of neonatal brain (Peters et al., 2005; Soh et al., 2014), the memory impairment in these genetic models could be attributed to abnormal hippocampal morphology and / or hyperexcitability (Peters et al., 2005; Milh et al., 2020). Kv7 channels also regulate multiple behaviors.Behavioral phenotyping of the global or conditional homozygous KCNQ2 knock-out mice has not been possible due to their early postnatal lethality or premature death, respectively (Watanabe et al., 2000; Soh et al., 2014). However, heterozygous KCNQ2 knock-out mice are viable and display increased locomotor activity and exploratory behavior (Kim et al., 2020), consistent with behavioral hyperactivity induced by transgenic suppression of Kv7 currents (Peters et al., 2005) and amphetamine and XE991 (Sotty et al., 2009). These mice also show decreased sociability and increased repetitive and compulsive behavior (Kim et al., 2020), reminiscent of autism seen in some EE patients with dominant KCNQ2 mutations (Weckhuysen et al., 2012, 2013; Milh et al., 2013).

[0036] Recent animal research indicates that enhancing the M current (Kv7 opening) to be a therapeutic target for multiple brain disorders, including those with no current treatments, such as TBI and psychostimulant addiction and motion disorders, (Lee, J Neurophysio 2017), motor disorders, neurodegenerative diseases, Parkinson's disease, Parkinson-like motor disorders, (Jama Neurol, Wainger. 2021; Neurosci Bull, chen. 2017; Neural Plast, Ramirez. 2015) phobias, Pick's disease, psychosis, and bipolar disorder, (Frontal Physiol, Vigil. 2020).

[0037] Spinal cord damage can potential be treated with reducing the activity of neurons 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. One study by We et al. demonstrated repeated application of retigabine to open these channels in the acute stage of injury promotes neurobehavioral recovery after spinal cord injury (Wu, J Pharmacol 2020).

[0038] Because of their key role in physiology, dysfunctional Kv7 channels are often linked to disorders characterized by abnormal potassium ion conductance, including cardiac arrhythmia, hearing impairment, epilepsy, pain, and hypertension (Front Physiol, larsson.2020; J Physoil, Maljevic. 2008).

[0039] Psychogenic non-epileptic seizures (PNES) associated with Functional Neurological Disorder (FND) are attacks that appear to be epileptic seizures but are not caused by abnormal electrical discharges. They are, instead, stress-related, psychological, or emotional. PNES may be referred to as pseudoseizures. Kv7 channel modulation may beuseful in treating PNES as well as other somatoform disorders, conversion disorders, or functional neurological symptom disorder. Additional physical manifestations include chronic pain or fibromyalgia. Many antiseizure medications targeted toward abnormal electrical activity will not be effective against PNES. In addition to seizure-like episodes, patients with FND may also experience movement problems, problems with cognitive function, dizziness, speech difficulties, problems with vision or hearing, pain (including chronic migraine), extreme slowness and fatigue, numbness or inability to sense touch. FND can cause multiple symptoms that significantly interfere with how a person functions and copes with daily life. Symptoms of FND are not intentionally produced and can involve any part of the body. Symptoms may appear suddenly, increase with attention to them, and decrease when the person is distracted. The Kv7 channel platform, however, offers therapeutic potential for PNES, FND, migraine, depression and other neurological and psychological disorders.

[0040] Finally, Kv7 channels present interesting targets for new therapeutic approaches to diseases caused by neuronal hyperexcitability, such as epilepsy, neuropathic pain, and migraine. The molecular mechanism of Kv7 activation by ezogabine has been elucidated as a stabilization of the open conformation by binding to the pore region which may be critical in the treatment of migraine and tension headache. (J Physoil, Maljevic. 2008).

[0041] Further experiments demonstrated that M current inhibition required concurrent rises in cytosolic Ca2+ concentration and depletion of membrane phosphatidylinositol 4,5-bisphosphate (PIP2). It is possible that PLC- and Ca 2 / PIP2-mediated inhibition of M current in sensory neurons may represent one of the general mechanisms underlying pain produced by inflammatory mediators, and may therefore open up a new therapeutic window for treatment of this major clinical problem in bowel disorders, an inflammatory disease, such as ulcerative colitis, Crohn's disease and Creutzfeid-Jacobs disease (J Neurosci, Linley. 2008).

[0042] Additional Kv7 channel openers, such as QO58 can specifically activate Kv7.2 / 7.3 M-channels. Oral or intraperitoneal administration of QO58, can reverse inflammatory pain in rodent animal models (Acta Pharmacol Sin, Teng. 2016) and may be effective in peripheral hypertension.

[0043] Published data suggest that by stabilizing the KG NQ4- mediated conductance (Kv7.4) in cells associate with hearing, chemical channel openers can protect against degeneration and progression of hearing loss in DFNA2 mouse model which may be useful in progressive hearing loss or tinnitus (J Physoil, Maljevic. 2008).

[0044] Behavioral studies demonstrated that SF0034 was a more potent and less toxic anticonvulsant than retigabine in rodents. Furthermore, SF0034 prevented the development oftinnitus in mice. It is proposed that SF0034 provides, not only a powerful tool for investigating ion channel properties, but, most importantly, it provides a potential clinical candidate for treating epilepsy and preventing tinnitus (Br J Pharmacol, Leithner. 2014; J Neurosci, Kalappa.2015).

[0045] The functional role of Kv7 channels may vary depending on the cell type. Several studies have demonstrated that the impairment of Kv7 channel has a strong impact on pulmonary physiology contributing to the pathophysiology of different respiratory diseases such as cystic fibrosis, asthma, chronic obstructive pulmonary disease, chronic coughing, lung cancer, and pulmonary hypertension. Kv7 channels are now recognized as playing relevant physiological roles in many tissues, which have encouraged the search for Kv7 channel modulators with potential therapeutic use in many diseases including those affecting the lung. Modulation of Kv7 channels has been proposed to provide beneficial effects in a number of lung conditions. Therefore, Kv7 channel openers / enhancers or drugs acting partly through these channels have been proposed as bronchodilators, expectorants, antitussives, chemotherapeutics, and pulmonary vasodilators (Front Physiol, Mondejar-Parreno.2020), and obesity, and disease associated hypertension (Front Cardivasc Med, Fosmo. 2017).

[0046] Further research into autism, autism spectrum disorders may suggest that administering a compound that has the potential to positively modulate Kv7 channels may be effective in these neurological diseases. Data suggest that dysfunction of the heteromeric Kv7.3 / Kv7.5 channel is implicated in the pathogenesis of some forms of autism spectrum disorders, epilepsy, and possibly other psychiatric disorders and therefore, KCNQ3 and KCNQ5 are suggested as candidate genes for these disorders (Gilling, Front Genet. 2013; Guglielmi, Front Cell Neurosci. 2015).

[0047] The several background references are hereby incorporated by reference with regard to such teaching.BRIEF SUMMARY OF THE DISCLOSURE

[0048] The present disclosure provides compounds which, inter alia, are useful in the treatment of diseases through the modulation of potassium ion flux through voltage-dependent potassium channels. More particularly, the disclosure provides prodrugs of compounds, compositions and methods that are useful in the treatment of central or peripheral nervous system disorders (e.g., migraine, ataxia, Parkinson's disease, bipolar disorders, trigeminal neuralgia, spasticity, mood disorders, functional neurological disorders, brain tumors, psychotic disorders, myokymia, seizures, epilepsy, hearing and vision loss, dysmenorrhea, vulvodynia,dysperunia, pain associated with endometriosis, multiple sclerosis, neuroinflammatory disorders, behavioral disorders, substance use disorders, amyotrophic lateral sclerosis, spasticity, spasms, autism, Alzheimer's disease, age-related memory loss, learning deficiencies, organophosphate exposure, anxiety and motor neuron diseases, central and peripheral neuropathic pain conditions), and as neuroprotective agents (e.g., to prevent stroke, spinal and brain injury, retinal degeneration and the like). Compounds of the disclosure have use for treating convulsive states, for example those following grand mal, petit mal, psychomotor epilepsy or focal seizure.

[0049] Moreover, compounds of the disclosure are useful in the treatment of pain, for example, neuropathic pain, diabetic pain, inflammatory pain, cancer pain, migraine pain, vulvar pain, abdominal pain, and musculoskeletal pain. The compounds are also useful to treat conditions, which may themselves be the origin of pain, for example, inflammatory conditions, including arthritic conditions (e.g., rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and gouty arthritis) and non-articular inflammatory conditions (e.g., herniated, ruptured and prolapsed disc syndrome, bursitis, tendonitis, tenosynovitis, fibromyalgia syndrome, and other conditions associated with ligamentous sprain and regional musculoskeletal strain) and pain associated with neuronal demyelinating diseases. Particularly preferred compounds of the disclosure may exhibit lower central nervous system side effects, such as dizziness and somnolence, due to a more controlled release of the active drug. Furthermore, the compounds are useful in treating conditions and pain associated with abnormally raised skeletal muscle tone.

[0050] The compounds of the disclosure are also of use in treating anxiety (e.g., anxiety disorders) and depression. These disorders include separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder (social phobia), panic disorder, agoraphobia, generalized anxiety disorder, substance / medication-induced anxiety disorder, and anxiety disorder due to another medical condition.

[0051] Anxiety also occurs as a symptom associated with other psychiatric disorders, for example, obsessive compulsive disorder, post-traumatic stress disorder, schizophrenia, mood disorders, functional neurological disorders and major depressive disorders, and with organic clinical conditions including, but not limited to, Parkinson's disease, multiple sclerosis, and other physically incapacitating disorders.

[0052] In view of the above-noted discovery, the present disclosure provides compounds, as well as compositions comprising these compounds, and methods for increasing ion flux in voltage-dependent potassium channels, particularly those channels responsible for the M-current. As used herein, the term " M-current," "channels responsible for the M-current" and the like, refers to a slowly activating, non-inactivating, slowly deactivating voltage-gated K+channels. M-current is active at voltages close to the threshold for action potential generation in a wide variety of neuronal cells, and thus, is an important regulator of neuronal excitability.

[0053] Members of the voltage-dependent potassium channel family have been shown to be directly involved in diseases of the central or peripheral nervous system. The prodrugs of compounds provided herein are now shown to be metabolized and release compounds which act as potassium channel modulators, particularly openers, for KCNQ2 and KCNQ3, KCNQ4, and KCNQ5 as well as the hetero-multimer channels such as KCNQ2 / 3, KCNQ3 / 5 or the M-current.

[0054] One aspect of the present disclosure includes a compound of formula (I),or a pharmaceutically acceptable salt, solvate, hydrate, amorphous, or crystalline form thereof.

[0055] In some embodiments of the present disclosure, m is 1, 2, or 3.

[0056] In some embodiments of the present disclosure, R1is selected from the group consisting of hydrogen, (CH2)wCN, (CH2)WOH, Ci-Ci2alkyl, (CH2)WG3-Ci2cycloalkyl, (CH2)WC3-Ci2heterocycloalkyl, (CH2)wCi-Ci2alkoxy, (CH2)WO(CH2)WC3-C6cycloalkyl, (CH2)WO(CH2)WC3-Ceheterocycloalkyl, (CH2)WC6-Cioaryl, (CH2)WC5-Cioheteroaryl, halogen, (CH2)wCi-Ci2haloalkyl, and (CH2)WCI-CI2haloalkoxy.

[0057] In some embodiments of the present disclosure, each of R2, R3, and R4independently is selected from the group consisting of hydrogen, (CH2)WCN, (CH2)WOH, (CH2)WNO2, Ci-Ci2alkyl, (CH2)WG3-Ciocycloalkyl, (CH2)WC3-Cioheterocycloalkyl, (CH2)WC2-CI2alkenyl, (CH2)wC3-Ciocycloalkenyl, (CH2)WC3-Cioheterocycloalkenyl, (CH2)WC2-CI2alkynyl, (CH2)WC3-Ci2cycloalkynyl, (CH2)WC3-Ci2heterocycloalkynyl, (CH2)WC6-Cioaryl, (CH2)wCs-Cwheteroaryl, halogen, (CH2)wCi-Ci2haloalkyl, (CH2)WCI-CI2haloalkoxy, (CH2)WSR13, (CH2)WCH3-NHC(=NH), (CH2)WCH3C(=NH)NH, (CH2)WCH2C(=NH)NH2, (CH2)WNR14C(=O)R15, (CH2)WNR14C(=NH)R15, (CH2)WC(=O)NR16R117, (CH2)WCH2G(=O)NR16R117, (CH2)WCH3NHC(=NH), (CH2)WCH3C(=NH)NH, (CH2)WCH2C(=NH)NH2, (CH2)WNR18R19, (CH2)WSO2R20, (CH2)WNR21SO2R22, and (CH2)WSO2NR23R24.

[0058] In some embodiments of the present disclosure, each of R5, R6, and R7, independently is selected from the group consisting of hydrogen, Ci-Ci2alkyl, and Ci-Ci2haloalkyl.

[0059] In some embodiments of the present disclosure, G is selected from the group consisting of O, S, C(Rg1), C(Rg1)(Rg2), N, or N(Rg1), where each Rg1and Rg2independently is hydrogen, Ci-Ci2alkyl, (CH2)wCi-Ci2alkoxy, halogen, Ci-Ci2haloalkyl, or phenyl.

[0060] In some embodiments of the present disclosure, Z is O or S.

[0061] In some embodiments of the present disclosure, each X is O, S, CR25, CR25R26, or CR27R28, where R27and R28combine with the carbon to which they are attached to form a 3- to 6-membered cycloalkyl.

[0062] In some embodiments of the present disclosure, q is 0, 1, 2, 3, 4, 5, or 6. In some embodiments of the present disclosure, if q is 2 or higher, each X is independently selected from, S, CR25, CR25R26, or CR27R28, where R27and R28combine with the carbon to which they are attached to form a 3- to 6-membered cycloalkyl. In some embodiments of the present disclosure, if q is 2 or higher, each X may be the same. In some embodiments of the present disclosure, X may be a divalent alkenyl.

[0063] In some embodiments of the present disclosure, Y is selected from the group consisting of Ci-Ci2alkyl, (CH2)WC3-Ci2cycloalkyl, (CH2)WC3-Ci2heterocycloalkyl, (CH2)WC2-Ci2alkenyl, (CH2)WC3-Ci2cycloalkenyl, (CH2)WC3-Ci2heterocycloalkenyl, (CH2)WC2-Ci2alkynyl, (CH2)WC2-Ci2cycloalkynyl, (CH2)WC2-Ci2heterocycloalkynyl, (CH2)WC6-Cioaryl, and (CH2)WC5-Cwheteroaryl.

[0064] In some embodiments of the present disclosure, B1is a 5- to 10-membered mono-cyclic ring system containing one or more degrees of unsaturation, optionally containing 1-4 heteroatoms selected independently from N, O, and S. In some embodiments of the present disclosure, B1is a 5- to 10-membered bi-cyclic ring system containing one or more degrees of unsaturation, optionally containing 1-4 heteroatoms selected independently from N, O, and S.

[0065] In some embodiments of the present disclosure, each of R9-R26independently is selected from the group consisting of H, Ci-C6alkyl, C3-C6cycloalkyl, C2-C6alkenyl, C3-C6cycloalkenyl, C2-C6alkynyl, C3-C6cycloalkynyl, C3-C6heterocycloalkyl, C3-C6heterocycloalkenyl, C3-C6heterocycloalkynyl, (CH2)WC6-Cioaryl, and (CH2)wC5-C10heteroaryl. In some embodiments of the present disclosure, each w is 0, 1, 2, 3, 4, 5, or 6. In some embodiments of the present disclosure, each instance of alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkynyl, heterocycloalkynyl, aryl, and heteroaryl groups may be optionally substituted with one, two, or three substituents selected independently from Ci-C6alkyl, OH, Ci-C6alkoxy, CN, halogen, and Ci-C6haloalkyl.

[0066] One aspect of the present disclosure includes a compound of formula (I), wherein m is 1 or 2, R1is hydrogen; one or two of R2, R3, and R4is halogen or Ci-i2haloalkyl; one or two of R5, R6, and R7is Ci-i2alkyl or halogen; G is N or N(Rg1); Rg1is H; Z is O; q is 1 or 2; X is CR25R26; each of R25and R26is hydrogen or Ci-i2alkyl; Y is Ci-i2alkyl; and B1is phenyl.

[0067] One aspect of the present disclosure includes a compound of formula (I), wherein m is 1.

[0068] One aspect of the present disclosure includes a compound of formula (I), wherein R3is halogen.

[0069] One aspect of the present disclosure includes a compound of formula (I), wherein R3is CF3.

[0070]

[0071] One aspect of the present disclosure includes a compound of formula (I), wherein one or R2is halogen.

[0072] One aspect of the present disclosure includes a compound of formula (I), wherein one or R4is halogen.

[0073]

[0074] One aspect of the present disclosure includes a compound of formula (I), wherein G is N.

[0075] One aspect of the present disclosure includes a compound of formula (I), wherein q is 1 and X is CH2.

[0076] One aspect of the present disclosure includes a compound of formula (I), wherein halogen is Br, Cl, or F.

[0077] One aspect of the present disclosure includes a compound of formula (I), wherein C1-12 is C1-6 and C2-12 is C2-6.

[0078] One aspect of the present disclosure includes a compound of formula (I), wherein C3-12 is C3-6.

[0079] One aspect of the present disclosure includes a compound of formula (I), wherein the compound has one or more chiral center.

[0080] One aspect of the present disclosure includes a compound of formula (I), wherein w is 0, 1, 2, or 3

[0081] One aspect of the present disclosure includes a compound selected from Table #1 or a pharmaceutically acceptable salt thereof.

[0082] One aspect of the present disclosure includes a compound selected from Table #2 or a pharmaceutically acceptable salt thereof.

[0083] One aspect of the present disclosure includes a compound of formula (I), wherein m is 2, G is N, B1is a six membered monocyclic ring, R3is a halogen, Z is O, X is CH2, q is 1, and Y is C(CH3)3.

[0084] One aspect of the present disclosure includes a compound of formula (I), wherein m is 1, G is N, B1is a six membered monocyclic ring, R3is a halogen, Z is O, X is CH2, q is 1, and Y is C(CH3)3.

[0085] One aspect of the present disclosure includes a compound of formula (I), wherein m is 2, G is N, B1is a six membered monocyclic ring, R3is a halogen, R4is a halogen, R6is halogen, Z is O, X is CH2, q is 1, and Y is C(CH3)3.

[0086] One aspect of the present disclosure includes a compound of formula (I), wherein m is 1, G is N, B1is a six membered monocyclic ring, R3is a halogen, R4is a halogen, R6is halogen, Z is O, X is CH2, q is 1, and Y is C(CH3)3.

[0087] One aspect of the present disclosure includes a compound of formula (I), wherein m is 2, G is N, B1is a six membered monocyclic ring, R3is a halogen, R6is C1-6 alkyl, R7is C1-6 alkyl, Z is O, X is CH2, q is 1, and Y is C(CH3)3.

[0088] One aspect of the present disclosure includes a compound of formula (I), wherein m is 1, G is N, B1is a six membered monocyclic ring, R3is a halogen, R6is C1-6 alkyl, R7is C1-6 alkyl, Z is O, X is CH2, q is 1, and Y is C(CH3)3.

[0089] One aspect of the present disclosure includes a compound of formula (I), wherein m is 2, G is NH, B1is a six membered monocyclic ring, R3is a halogen, R6is C1-6 alkyl, R7is C1-6 alkyl, Z is O, X is CH2, q is 1, and Y is C(CH3)3.

[0090] One aspect of the present disclosure includes a compound of formula (I), wherein m is 1, G is NH, B1is a six membered monocyclic ring, R3is a halogen, R6is C1-6 alkyl, R7is C1-6 alkyl, Z is O, X is CH2, q is 1, and Y is C(CH3)3.

[0091] One aspect of the present disclosure includes a compound of formula (I), wherein m is 2, G is N, B1is a six membered monocyclic ring, R2is halogen, R3is a halogen, R6is a C1-6 alkyl, R7is a C1-6 alkyl, Z is O, X is CH2, q is 1, and Y is C(CH3)3.

[0092] One aspect of the present disclosure includes a compound of formula (I), wherein m is 1, G is N, B1is a six membered monocyclic ring, R2is a halogen, R3is a halogen, R6is a C1-6 alkyl, R7is a C1-6 alkyl, Z is O, X is CH2, q is 1, and Y is C(CH3)3.

[0093] One aspect of the present disclosure includes a compound for use in the treatment of a disease of disorder where modulation of a Kv7 channel is beneficial, for a patient in needed thereof.

[0094] One aspect of the present disclosure includes a method of treating a disease of disorder in a patient in needed thereof where modulation of Kv7 channels is beneficial comprising administering a compound of listed in Table 1 or Table 2.

[0095] One aspect of the present disclosure includes a compound in the manufacture of a medicament for the treatment of a disease or disorder disease of disorder where modulation of the Kv7 channels is beneficial, for a patient in needed thereof.

[0096] One aspect of the present disclosure includes a compound, method, use, or compound for use, to treat one or more of neural disease or disorder, neurodegenerative disease or disorder, cardiac diseases, muscle movement disease or disorder, addiction, and pain.

[0097] In some embodiments, the disease is one of a seizure disorder, epilepsy, developmental epileptic encephalopathy, muscle relaxing, acute analgesia, central and or peripheral inflammatory or neuropathic analgesic, pain related to diabetic neuropathy, phantom limb pain; depression in all forms, including manic depressive illness with mixed episodes and manic depressive illness with depressive episodes, seasonal affective disorder, bipolar, anxiety, mania; chemical dependencies, including addictions to alcohol, cocaine, amphetamine and other psychostimulants, morphine, heroin and other opioid agonists; Parkinson's diseases, including dementia in Parkinson's disease, neuroleptic-induced parkinsonism or tardive dyskinesias; headache, chronic headache, migraine; withdrawal syndrome; age-associated learning and mental disorders; apathy; bipolar disorder; chronic fatigue syndrome; functional neurological disorder; somatoform disorders such as somatization disorder, conversion disorder, pain disorder; mania; autism, autism spectrum disorders; substance use disorder; addition treatment; schizophrenia; post-traumatic stress disorder; tinnitus, amyotrophic lateral sclerosis, Alzheimer’s disease, multiple sclerosis, optic neuritis, neuro-ophthalmic disorders. CNS damage caused by neurodegenerative illness or diseases or injury, cognitive deficits,compulsive behavior, dementia, Huntington's disease, dystonia, memory impairment, memory disorders, memory dysfunction, motion disorders, motor disorders, neurodegenerative diseases, an ophthalmic condition, progressive hearing loss or tinnitus, drug induced dystonia / dyskinesia, tardive dystonia, neuroleptics induced dystonia, dystonia in Tourette's syndrome patients, dystonia in Restless Leg syndrome patients, dystonia like symptoms in patients with Tics, dystonia-associated dyskinesias, paroxysmal dyskinesias, paroxysmal non-kinesigenic dyskinesia, paroxysmal dystonic choreoathetosis, paroxysmal kinesigenic dyskinesia, as well as attention deficit hyperactivity disorder (ADHD) in a patient in need thereof comprising administering an effective amount of a compound of the present disclosure. 9i’i

[0098] One embodiment of the present disclosure includes a pharmaceutical composition comprising a compound of the present disclosure and one or more pharmaceutically acceptable excipients.

[0099] One embodiment of the present disclosure includes a method of eliciting one or more of an anti-epileptic, muscle relaxing, fever reducing, peripherally analgesic, reduction in neuronal hyperexcitability or anticonvulsive effect in a patient in need thereof comprising administering an effective amount of a compound of the present disclosure.

[0100] One embodiment of the present disclosure includes a method of treating, suppressing, mitigating, ameliorating, or inhibiting the progress one or more of depression, including depression in cancer patients, depression in Parkinson's patients, post-myocardial infarction depression, depression in patients with human immunodeficiency virus (HIV), Subsyndromal Symptomatic depression, depression in infertile women, pediatric 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 illness, including manic depressive illness with mixed episodes and manic depressive illness with depressive episodes, seasonal affective disorder, bipolar depression BP I, bipolar depression BP II, or major depression with dysthymia; dysthymia; phobias, including agoraphobia, social phobia or simple phobias; eating disorders, including anorexia nervosa or bulimia nervosa; chemical dependencies, including addictions to alcohol, cocaine, amphetamine and other psychostimulants, morphine, heroin and other opioid agonists, Phenobarbital and other barbiturates, nicotine, diazepam, benzodiazepines and other psychoactive substances; Parkinson's diseases, including dementia in Parkinson's disease, neuroleptic-induced parkinsonism or tardive dyskinesias; headache, including headache associated with vascular disorders; withdrawal syndrome; age-associated learning and mental disorders; apathy; bipolardisorder; chronic fatigue syndrome; chronic or acute stress; conduct disorder; cyclothymic disorder; somatoform disorders such as somatization disorder, conversion disorder, pain disorder, hypochondriasis, body dysmorphic disorder, undifferentiated disorder, and somatoform NOS; incontinence; inhalation disorders; intoxication disorders; mania; oppositional defiant disorder; peripheral neuropathy; post-traumatic stress disorder; late luteal phase dysphoric disorder; specific developmental disorders; SSRI "poop out" syndrome, or a patient's failure to maintain a satisfactory response to SSRI therapy after an initial period of satisfactory response; and tic disorders including Tourette's disease, comprising administering a compound of the present disclosure.

[0101] One embodiment of the present a method of treating, suppressing, mitigating, ameliorating, or inhibiting the progress of a disease or a disorder selected from the group consisting of seizures including but not limited to psychogenic non-epileptic seizures, pain, neuropathic pain, chronic headache, central pain, pain related to diabetic neuropathy, to postherpetic neuralgia and to peripheral nerve injury, drug addiction, affective disorders, tinnitus, Alzheimer’s disease, ALS, anxiety, CNS damage caused by neurodegenerative illness or diseases or injury, cognitive deficits, compulsive behavior, dementia, depressions, Huntington's disease, dystonia, mania, cognitive disorders, memory impairment, memory disorders, memory dysfunction, motion disorders, motor disorders, neurodegenerative diseases, Parkinson's disease, Parkinson-like motor disorders, phobias, Pick's disease, psychosis, a bipolar disorder, Schizophrenia, schizophrenia subtypes being the catatonic-subtype, the paranoid-subtype, the disorganized subtype or the residual subtype, spinal cord damage, cardiomyopathy, cardiac arrhythmia, long QT syndrome, a motion disorder, or a motor disorder, myasthenia gravis, migraine, tension headache, a bowel disorder, an inflammatory disease, ulcerative colitis, Crohn's disease, Creutzfeid-Jacobs disease, an ophthalmic condition, progressive hearing loss or tinnitus, fever, multiple sclerosis, diabetes, or metastatic tumor growth, a pneumoconiosis, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis, sinosis, and a chronic obstructive pulmonary disease (COPD), and obesity and disease associated hypertension, comprising administering a compound of the present disclosure.

[0102] One embodiment of the present disclosure includes a method of treating, suppressing, mitigating, ameliorating, or inhibiting the progress of one or more movement disorder selected from primary dystonia, paroxysmal dystonia, secondary dystonia, drug induced dystonia / dyskinesia, tardive dystonia, neuroleptics induced dystonia, treatment induced dystonia / dyskinesia in Parkinson's disease patients, heredodegenerative dystonia, dystonia inHuntington's disease patients, dystonia in Tourette's syndrome patients, dystonia in Restless Leg syndrome patients, dystonia like symptoms in patients with Tics, dystonia- associated dyskinesias, paroxysmal dyskinesias, paroxysmal non-kinesigenic dyskinesia, paroxysmal dystonic choreoathetosis, paroxysmal kinesigenic dyskinesia, paroxysmal kinesigenic choreoathetosis, the exertion-induced dyskinesia, hypnogenic paroxysmal dyskinesia, drug-induced dyskinesia, myokymia, neuromyotonia, autism, autism spectrum disorders, comprising administering a compound of the present disclosure.

[0103] One embodiment of the present disclosure includes a method of treating, suppressing, mitigating, ameliorating, or inhibiting the progress of one or more neurodevelopmental disorder selected from Angleman syndrome, Dup15q syndrome (Dup15q), Fragile X syndrome, intellectual disability, attention-deficit hyperactivity disorder (ADHD) as well as other disorders associated with autism.

[0104] One embodiment of the present disclosure includes a method of delivering a broad spectrum Kv7.2-7.5 active molecule to systemic circulation and releasing said active Kv channel opener in an effective concentration at therapeutic concentrations to treat one or more susceptible disease or disorder comprising administering a compound of the present disclosure.

[0105] In one aspect, release of the active molecule is provided under one or more of: enhanced by increased absorption by the clinical route of administration; delayed in the time to onset to improve treatment emergent adverse events; and increase the half-life or residence time through delayed circulation and release, thus negating the need for development of a modified, sustained, delayed, or extended release formulation.

[0106] One embodiment of the present disclosure includes a method of enhancing chemical stability and reduction of impurities and degradants in the manufacturing of drug substance and drug product thus improving the use and tolerability of the drug.

[0107] One embodiment of the present disclosure includes a compound of the present disclosure for use in eliciting one or more of an anti-epileptics, muscle relaxing, fever reducing, peripheral or central analgesic, or behavior modifiying or anticonvulsive effect in a patient in need thereof.

[0108] One or more aspects and embodiments may be incorporated in a different embodiment although not specifically described. That is, all aspects and embodiments may be combined in any way or combination.

[0109] The scope of the present disclosure includes all combinations of aspects, embodiments, and preferences herein described.DETAILED DESCRIPTION OF THE DISCLOSURE

[0110] The present disclosure provides compounds of Formula (I), as well as salts thereof, and pharmaceutical compositions comprising the compounds, for the modulation of Kv7 channel activity. Thus, described herein are compounds and compositions which are useful in the treatment of Kv7 channel mediated disorders, including but not limited to neural disorders, muscle movement disorders, and other diseases, as well as for pain management.Definitions

[0111] The following definitions are meant to clarify, but not limit, the terms defined. If a particular term used herein is not specifically defined, such term should not be considered indefinite. Rather, terms are used within their accepted meanings.

[0112] As used throughout this specification, the preferred number of atoms, such as carbon atoms, will be represented by, for example, the phrase " Cx_y alkyl," which refers to an alkyl group, as herein defined, containing the specified number of carbon atoms. Similar terminology will apply for other preferred terms and ranges as well. Thus, for example, C1-4 alkyl represents a straight or branched chain hydrocarbon containing one to four carbon atoms.

[0113] As used herein, “alkyl” refers to monovalent saturated aliphatic hydrocarbon groups having from 1 to 20 carbon atoms, preferably 1-8 carbon atoms, preferably 1-6 carbon atoms. The hydrocarbon chain may be either straight-chained or branched. Illustrative alkyl groups include methyl, ethyl, n-propyl, / so-propyl, n-butyl, / so-butyl, sec-butyl, and tert-butyl. Similarly, an “alkenyl” group refers to an alkyl group having one or more double bonds present in the chain, and an “alkynyl” group refers to an alkyl group having one or more triple bonds present in the chain.

[0114] As used herein “halogen” or “halo” refers to a halogen. In some embodiments, the halogen is preferably Br, Cl, or F.

[0115] As used herein, “haloalkyl” refers to monovalent saturated aliphatic hydrocarbon groups having from 1 to 20 carbon atoms, preferably 1-8 carbon atoms, preferably 1-6 carbon atoms, wherein at least one hydrogen atom is substituted by a halogen, including but not limited to perhalo groups where all hydrogen atoms are replaced with halogen atoms. The haloalkyl chain can be either straight-chained or branched. Illustrative alkyl groups include trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluorobutyl, and pentafluoroethyl. Similarly, a “haloalkenyl” group refers to a haloalkyl group having one or more double bonds present in the chain, and a “haloalkynyl” group refers to a haloalkyl group having one or more triple bonds present in thechain. Moreover, an “alkylene” linker group refers to a divalent alkyl group, namely (CH2)x, where x is 1 to 20, preferably 1 to 8, preferably 1 to 6, and more preferably 1 to 3.

[0116] The term “haloalkoxy” refers to O-haloalkyL

[0117] As used herein, “alkoxy” refers to an O-alkyl group having the specified number of carbon atoms.

[0118] An “alkylene,” group is an alkyl group, as defined hereinabove, that is positioned between and serves to connect two other chemical groups. Exemplary alkylene groups include, without limitation, methylene, ethylene, propylene, and butylene.

[0119] The term “heteroalkyl” refers to an alkyl group, as defined hereinabove, wherein one or more carbon atoms in the chain are 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 for a nonhydrogen group.

[0120] As used herein, “hydroxyalkyl” refers to an alkyl group as herein defined substituted with one or more -OH group. Similarly, a “hydroxyalkenyl” group refers to a hydroxyalkyl group having one or more double bonds present in the chain, and a “hydroxyalkynyl” group refers to a hydroxyalkyl group having one or more triple bonds present in the chain. Likewise, a “dihydroxyalkyl” group provides two -OH substituents.

[0121] As used herein, “aryl” refers to a substituted or unsubstituted carbocyclic aromatic ring system, either pendent or fused, such as phenyl, naphthyl, anthracenyl, phenanthryl, tetrahydronaphthyl, indane, or biphenyl. A preferred aryl group is phenyl.

[0122] An “aralkyl” or “arylalkyl” group comprises an aryl group covalently linked to an alkyl group as defined herein above, either of which may independently be optionally substituted or unsubstituted. An example of an aralkyl group is (Ci -C6)alkyl(C6-Ci o)aryl, including, without limitation, benzyl, phenethyl, and naphthylmethyl. An example of a substituted aralkyl is wherein the alkyl group is substituted with hydroxyalkyl.

[0123] As used herein, “cycloalkyl” refers to an unsaturated or partially saturated hydrocarbon ring, containing from 3 to 15 ring atoms. Illustrative cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, as well as partially saturated versions thereof, such as cyclohexenyl, and cyclohexadienyl. Moreover, bridged rings, such as adamantane, are included within the definition of “cycloalkyl.”

[0124] As used herein, the term “heterocyclyl” refers to an unsaturated or partially saturated hydrocarbon ring, containing from 3 to 15 ring atoms, wherein one or more carbon atom is replaced with a heteroatom selected from O, N, or S, where each N, S, or Si may beoxidized, and where each N may be quarternized. A heterocyclyl group may be attached to the remainder of the molecule through a heteroatom. Heterocyclyl does not include heteroaryl.

[0125] The term “heterocyclylalkyl” refers to a heterocyclyl group as defined herein covalently linked to an alkyl group as defined hereinabove wherein the radical is on the alkyl group, wherein the alkyl group of the heterocyclylalkyl may be optionally substituted with hydroxy or hydroxyalkyl.

[0126] As used herein, the term “heteroaryl” or “heteroaromatic” refers to aromatic ring groups having 5 to 14 ring atoms selected from carbon and at least one (typically 1-4, more typically 1 or 2) heteroatom (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), pyridazinyl (e.g., 3-pyridazinyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), triazolyl (e.g., 2-triazolyl, 5-triazolyl), tetrazolyl (e.g., tetrazolyl) and thienyl (e.g., 2-thienyl, 3-thienyL Examples of monocyclic six-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.

[0127] The terms "arylalkyl," "heteroarylalkyl," and “heterocyclylalkyl” refers to those radicals in which an aryl, heteroaryl, or heterocyclyl group is linked through an alkyl group. Examples includes benzyl, phenethyl, pyridylmethyl, and the like. The terms also include alkyl linking groups in which a carbon atom, for example, a methylene group, has been replaced by, for example, an oxygen atom. Examples include phenoxymethyl, pyrid-2-yloxymethyl, 3-(naphth-l-yloxy)propyl, and the like. Similarly, the term “benzyl” as used herein is a radical in which a phenyl group is attached to a CH2group, thus, a CH2Ph group. Benzyl groups may be substituted or unsubstituted. The term substituted benzyl refers to radicals in which the phenyl group or CH2contains one or more substituents. In one embodiment, the phenyl group may have 1 to 5 substituents, or in another embodiment 2 to 3 substituents.

[0128] A “heteroarylalkyl” group comprises a heteroaryl group covalently linked to an alkyl group, wherein the radical is on the alkyl group, either of which is independently optionallysubstituted or unsubstituted. Examples of heteroarylalkyl groups include a heteroaryl group 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, benzimidazolylethyl quinazolinylmethyl, quinolinylmethyl, quinolinylethyl, benzofuranylmethyl, indolinylethyl isoquinolinylmethyl, isoinodylmethyl, cinnolinylmethyl, and benzothiophenylethyl. Specifically excluded from the scope of this term are compounds having adjacent annular O and / or S atoms.

[0129] As used herein “optionally substituted” refers to a substitution of a hydrogen atom, which would otherwise be present for the substituent. When discussing ring systems, the optional substitution is typically with 1, 2, or 3 substituents replacing the normally present hydrogen. When referencing straight and branched moieties, however, the number of substitutions may be more, occurring wherever hydrogen is present. The substitutions may be the same or different.

[0130] Illustrative substituents, which with multiple substituents can be the same or different, 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')2, OC(O)N(R')2, NH2, NHR', N(R')2, NHCOR', NHCOH, NHCONH2, NHCONHR', NHCON(R')2, NRCOR', NRCOH, NHCO2H, NHCO2R', NHC(S)NH2, NHC(S)NHR', NHC(S)N(R')2, CO2R', CO2H, CHO, CONH2, CONHR', CON(R')2, S(O)2H, S(O)2R', SO2NH2, S(O)H, S(O)R', SO2NHR', SO2N(R')2, NHS(O)2H, NR'S(O)2H, NHS(O)2R', NR'S(O)2R', Si(R')3, where each of the preceding may be linked through a divalent alkylene linker, (CH2)X, where x is 1, 2, or 3. In embodiments where a saturated carbon atom is optionally substituted with one or more substituent groups, the substituents may be the same or different and also include =0, =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 preceding, each may be linked through an alkylene linker, (CH2)X, where x is 1, 2, or 3, 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 heterocyclic ring containing from 4 to 6 ring atoms.

[0131] As used herein, “an effective amount” of a compound is an amount that is sufficient to negatively modulate or inhibit the activity of the target. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.

[0132] As used herein, a “therapeutically effective amount” of a compound is an amount that is sufficient to ameliorate, or in some manner reduce a symptom or stop or reverse progression of a condition, or negatively modulate or inhibit the activity of the target. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.

[0133] As used herein, treatment means any manner in which the symptoms or pathology of a condition, disorder or disease are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein.

[0134] As used herein, amelioration of the symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting, or transient that can be attributed to or associated with administration of the composition.

[0135] As used herein, the term “about” when used to modify a numerically defined parameter (e.g., the dose of the inhibitor detailed herein or a pharmaceutically acceptable salt thereof, or the length of treatment time described herein) means that the parameter may vary by as much as 25%, 20%, 15%, 10%, or 5% below or above the stated numerical value 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” when used at the beginning of a listing of parameters is meant to modify each 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. Likewise, 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.

[0136] As used herein, a salt refers to any salt of a compound disclosed herein which retains its biological properties and which is not toxic or otherwise undesirable for pharmaceutical use.

[0137] Such salts may be derived from a variety of organic and inorganic counter-ions known in the art. Such salts include acid addition salts formed with organic or inorganic acids such as 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, benzenesulfonic, 4-chlorobenzenesulfonic, 2-naphthalenesulfonic, 4-toluenesulfonic, camphoric, camphorsulfonic, 4-methylbicyclo[2.2.2]-oct-2-ene-1 -carboxylic, glucoheptonic, 3-phenylpropionic, trimethylacetic,tert-butylacetic, lauryl sulfuric, gluconic, benzoic, glutamic, hydroxynaphthoic, salicylic, stearic, cyclohexylsulfamic, quinic, muconic acid, and like acids.

[0138] Salts further include, by way of example only, salts of non-toxic organic or inorganic acids, such as halides, such as, chloride and bromide, sulfate, phosphate, sulfamate, nitrate, acetate, trifluoroacetate, trichloroacetate, propionate, hexanoate, cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate, malonate, succinate, sorbate, ascorbate, malate, maleate, fumarate, tartarate, citrate, benzoate, 3-(4-hydroxybenzoyl)benzoate, picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate), ethanesulfonate, 1,2-ethane-disulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1 -carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate, muconate, and the like.

[0139] Examples of inorganic bases that may 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.

[0140] Examples of organic bases that may be used to form base addition salts include, but are not limited to, metal alkoxides, such as lithium, sodium, and potassium alkoxides including lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, and potassium tert-butoxide; quaternary ammonium hydroxides, such as choline hydroxide; and amines including, but not limited to, aliphatic amines (i.e., alkylamines, alkenylamines, alkynylamines, and alicyclic amines), heterocyclic amines, arylamines, heteroarylamines, basic amino acids, amino sugars, and polyamines.

[0141] The base may be a quaternary ammonium hydroxide, wherein one or more of the alkyl groups of the quaternary ammonium ion are 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, and is preferably choline hydroxide. An 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. A substituted alkylamine base may be substitutedwith one or more hydroxyl groups, and 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.

[0142] The compounds of the present invention, including salts, hydrates and solvates thereof, may inherently or by design form polymorphs.

[0143] The compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure embrace both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form.

[0144] In certain cases, the depicted substituents may contribute to optical isomers and / or stereoisomerism. Compounds having the same molecular formula but differing in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example when it is bonded to four different groups, a pair of enantiomers is possible. A molecule with at least one stereocenter may be characterized by the absolute configuration of its asymmetric center and is designated (R) or (S) according to the rules of Cahn and Prelog (Cahn etal., 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 may be characterized by the manner in which the molecule rotates the plane of polarized light and is designated dextrorotatory or levorotatory (namely, as (+)- or (-)-isomers, respectively). A chiral compound may exist as either an individual enantiomer or as a mixture thereof. A mixture containing equal proportions of enantiomers is called a “racemic mixture.”

[0145] In certain embodiments, the compounds disclosed herein may possess one or more asymmetric centers, and such compounds may therefore be produced as a racemic mixture, an enantiomerically enriched mixture, or as an individual enantiomer. Unless indicated otherwise, for example by designation of stereochemistry at any position of a formula, the description or naming of a particular compound in the specification and claims is intended to include bothindividual enantiomers and mixtures, racemic or otherwise, thereof. Methods for determination of stereochemistry and separation of stereoisomers are well-known in the art.

[0146] 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 of skilled in the art. Of course, this level of purity may be less than 100%. In certain embodiments, “stereochemically pure” designates a compound that is substantially free, i.e., at least about 85% or more, of alternate isomers. In particular 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.

[0147] As used herein, the terms “subject” and “patient” may be used interchangeably herein. 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 domestic fowl (e.g., chicken, turkey, duck, or goose). In another embodiment, the subject is a primate such as a monkey such as a cynomolgus monkey, rhesus or a chimpanzee.

[0148] As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician. The term “therapeutically effective amount” means any amount which, ascompared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.

[0149] The compounds of the present disclosure are believed useful in the treatment or prevention of several diseases, disorders, conditions, and / or indications (which are cumulatively referred to herein as “disorders”). One of skill in the art will recognize that when a disorder, or a method of treatment or prevention, is disclosed herein, such disclosure encompasses second medical uses (e.g., a compound for use in the treatment of the disorder, use of a compound for the treatment of the disorder, and use of a compound in the manufacture of a medicament for the treatment of the disorder).Compounds of the Disclosure

[0150] In one embodiment, the invention provides a composition comprising a pharmaceutically acceptable carrier or diluent and at least one of the following: apharmaceutically effective amount of a compound of formula I, a pharmaceutically acceptable salt of a compound of formula I, a pharmaceutically acceptable solvate of a compound of formula I, and a pharmaceutically acceptable ester of a compound of formula I.

[0151] In another embodiment, the invention provides a pediatric pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent, a syrup for pediatric use, and at least one of the following: a pharmaceutically effective amount of a compound of formula I, a pharmaceutically acceptable salt of a compound of formula I, a pharmaceutically acceptable ester of a compound of formula I, and a pharmaceutically acceptable solvate of a compound of formula I.

[0152] In yet another embodiment, the invention provides to a chewable tablet, suitable for pediatric pharmaceutical use, comprising a pharmaceutically acceptable carrier or diluent, and at least one of the following: a pharmaceutically effective amount of a compound of formula I, a pharmaceutically acceptable salt of a compound of formula I, a pharmaceutically acceptable solvate of a compound of formula I, and a pharmaceutically acceptable ester of a compound of formula I.

[0153] The compounds of the invention containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound contains an alkenyl or alkenylene group, geometric cis / trans (or Z / E) isomers are possible. Where the compound contains, for example, a keto or oxime group or an aromatic moiety, tautomeric isomerism (‘tautomerism’) can occur. It follows that a single compound can exhibit more than one type of isomerism.

[0154] All stereoisomers, geometric isomers and tautomeric forms of the compounds of the invention are included within the scope of the invention, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof, also included are acid addition or base salts wherein the counterion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine.

[0155] Cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.

[0156] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).

[0157] Alternatively, the racemate (or a racemic precursor) can be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of the invention contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomerA) by means well known to a skilled person.

[0158] Chiral compounds of the invention (and chiral precursors thereof) can be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.

[0159] Mixtures of stereoisomers can be separated by conventional techniques known to those skilled in the art [see, for example, “Stereochemistry of Organic Compounds” by E. L. Eliel (Wiley, New York, 1994)].

[0160] The invention includes all pharmaceutically acceptable isotopically-labeled compounds of the invention, wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

[0161] Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as2H and3H, carbon, such as11C,13C and14C, chlorine, such as36CI, fluorine, such as18F, iodine, such as123l and125l, nitrogen, such as13N and15N, oxygen, such as150,17O and18O, phosphorus, such as32P, and sulphur, such as35S.

[0162] Certain isotopically-labelled compounds of the invention, for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.,3H, and carbon-14, i.e.,14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

[0163] Substitution with heavier isotopes such as deuterium, i.e.,2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence can be preferred in some circumstances.

[0164] Substitution with positron emitting isotopes, such as11C,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0165] Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.

[0166] As used herein, the expressions “reaction-inert solvent” and “inert solvent” refers to a solvent which does not interact with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product.

[0167] The parenthetical negative or positive sign used herein in the nomenclature denotes the direction plane polarized light is rotated by the particular stereoisomer.

[0168] One of ordinary skill will recognize that certain compounds of the invention can contain one or more atoms which can be in a particular stereochemical or geometric configuration, giving rise to stereoisomers and configurational isomers, all such isomers and mixtures thereof are included in the invention. Solvates (hydrates) of the compounds of the invention are also included.

[0169] Other features and advantages will be apparent from the specification and claims which describe the invention.

[0170] Illustrative examples of compounds of this invention have been provided above and are exemplified further below in the Examples. These illustrative examples are provided in order to indicate that a wide range of compounds and substitution patterns is included within the scope of the invention as described herein. This group of examples should not be construed as limiting the scope of this invention.

[0171] In one embodiment, the invention provides a compound of formula I, where m is 1, G is N, B1is a six membered monocyclic ring, R3is a halogen, Z is O, X is CH2, q is 1, and Y is C(CH3)3.

[0172] In one embodiment, the invention provides a compound of formula I, where m is 2, G is N, B1is a six membered monocyclic ring, R3is a halogen, Z is O, X is CH2, q is 1, and Y is C(CH3)3.

[0173] In one embodiment, the invention provides a compound of formula I, where m is 2, G is N, Bi is a six membered monocyclic ring, R3is a halogen, R5is a halogen, Z is O, X is CH2, q is 1, and Y is C(CH3)3.

[0174] In one embodiment, the invention provides a compound of formula I, where m is 1, G is N, Bi is a six membered monocyclic ring, R3is a halogen, R6is a halogen, Z is O, X is CH2, q is 1, and Y is C(CH3)3.

[0175] In one embodiment, the invention provides a compound of formula I, where m is 1, G is N, Bi is a six membered monocyclic ring, R3is a halogen, R4is a halogen, R6is a halogen, Z is O, X is CH2, q is 1, and Y is C(CH3)3.

[0176] In one embodiment, the invention provides a compound of formula I, where m is 1, G is N, Bi is a six membered monocyclic ring, R3is CH3, R6is a halogen, Z is O, X is CH2, q is 1, and Y is C(CH3)3.

[0177] In one embodiment, the invention provides a compound of formula I, where m is 1, G is N, Bi is a six membered monocyclic ring, R3is a halogen, R5is a CH3, Z is O, X is CH2, q is 1, and Y is C(CH3)3.

[0178] In one embodiment, the invention provides a compound of formula I, where m is 1, G is N, Bi is a six membered monocyclic ring, R3is a halogen, R6is a CH3, Z is O, X is CH2, q is 1, and Y is C(CH3)3.

[0179] In one embodiment, the invention provides a compound of formula I, where m is 1, G is N, Bi is a six membered monocyclic ring, R3is a halogen, R6is a CH3, R7is a CH3, Z is O, X is CH2, q is 1, and Y is C(CH3)3.

[0180] In one embodiment, the invention provides a compound of formula I, where m is 2, G is N, Bi is a six membered monocyclic ring, R3is a halogen, R6is a CH3, R7is a CH3, Z is O, X is CH2, q is 1, and Y is C(CH3)3.

[0181] In one embodiment, the invention provides a compound of formula I, where m is 1, G is N, Bi is a six membered monocyclic ring, R2is a halogen, R3is a halogen, R6is a CH3, R7is a CH3, Z is O, X is CH2, q is 1, and Y is C(CH3)3.

[0182] In one aspect, there is provided a compound selected from the group consisting of the compounds disclosed in Table 1 or a salt thereof.Table 1. Compound StructuresCompoundID CompoundfF CHN i j Y^fFD< jT T Z ^NHHN If ]\f °FE< jf T / ^^ HNXNHIf |\ 01QlY^ciClF< jT Y / ^^NHHN Iff ”FID CompoundG(jT TDH HD n |\ IL 01QF^ THccxHN |f |\f °F1COT° HDHIff ”FJccxHD 1DHIf |\f ”F KHN i rfF

[0183] In another aspect, there is provided a compound selected from the group consisting of the compounds disclosed in Table 2.Table 2. Compound Structures

[0184] In some embodiments, the disclosure relates to the foregoing compound in salt, hydrate, or solvated form. Such compound is considered to be a “compound of the disclosure,” as that term is used herein.

[0185] In other embodiments, the disclosure relates to the foregoing compound in non-salt, non-solvate, or non-hydrated form. Such compound is considered to be a “compound of the disclosure,” as that term is used herein.Pharmaceutically acceptable salts and compositions

[0186] As discussed herein, the disclosure provides compounds, and pharmaceutically acceptable salts thereof, that are modulators of Kv7 channels, and thus the present compounds, and pharmaceutically acceptable salts thereof, are useful for the treatment of diseases, disorders, and conditions affected by potassium channels. Accordingly, in another aspect of the disclosure, pharmaceutical compositions are provided, wherein these compositions comprise a compound as described herein, or a pharmaceutically acceptable salt thereof, and optionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents. In some embodiments, the additional therapeutic agent is a soluble macromolecular entity, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, that is used to improve solubility, dissolution rate, taste-masking, bioavailability and / or stability for use in any of the modes of administration. Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and noninclusion complexes can be used, as an alternative to direct complexation with the drug, the cyclodextrin can be used as an auxiliary additive, i.e. as a carrier, diluent, or solubilizer. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which can be found in International Patent Applications Nos. WO 91 / 11172, WO 94 / 02518 and WO 98 / 55148.

[0187] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. A “pharmaceutically acceptable salt” of a compound of this disclosure includes any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this disclosure or an inhibitory active metabolite or residue thereof. The salt may be in pure form, in a mixture (e.g.,solution, suspension, or colloid) with one or more other substances, or in the form of a hydrate, solvate, or co-crystal.

[0188] Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compound of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(C1-4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0189] As described herein, the pharmaceutically acceptable compositions of the disclosure additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington’s Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except in so far as any conventional carrier medium is incompatible with the compounds of thedisclosure, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this disclosure. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0190] In another aspect, the disclosure features a pharmaceutical composition comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0191] In another aspect, the disclosure features a pharmaceutical composition comprising a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.Uses of Compounds and Pharmaceutically Acceptable Salts and Compositions

[0192] In another aspect, the disclosure features a method of modulating Kv7 channels, comprising administering to the subject a compound of the disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0193] In yet another aspect, the disclosure features a method of treating a disease or a condition identified above, comprising administering an effective amount of a compound of the disclosure, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0194] In yet another aspect, the disclosure features a method of treating a disease and / or condition comprising administering an effective amount of a compound of the disclosure, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0195] In some aspects, the disease and / or condition is a disorder involving potassium channels. In some aspects, the disease and or condition is a nervous system disease. In some aspects, the disease and / or condition is a central nervous system disease. In some aspects, the disease and / or condition is a peripheral nervous system disease. In some aspects, the disease and / or condition is migraine. In some aspects, the disease and / or condition is ataxia. In some aspects, the disease and / or condition is Parkinson’s disease. In some aspects, the disease and / or condition is bipolar disorder. In some aspects, the disease and / or condition is trigeminal neuralgia. In some aspects, the disease and / or condition is spasticity. In some aspects, the disease and / or condition is mood disorders. In some aspects, the disease and / or condition is brain tumor. In some aspects, the disease and / or condition is psychotic disorders. In some aspects, the disease and / or condition is myokymia. In some aspects, the disease and / or condition is seizures. In some aspects, the disease and / or condition is epilepsy. In some aspects, the disease and / or condition is hearing loss. In some aspects, the disease and / or condition is vision loss. In some aspects, the disease and / or condition is Alzheimer’s disease. In some aspects, the disease and / or condition is age related memory loss. In some aspects, the disease and / or condition is learning deficiencies. In some aspects, the disease and / or condition is pain. In some aspects, the disease and / or condition is peripheral pain. In some aspects, the disease and / or condition is neuropathic pain. In some aspects, the disease and / or condition is anxiety. In some aspects, the disease and / or condition is motor neuron diseases. In some aspects, the disease and / or condition is stroke. In some aspects, the disease and / or condition affects the neural system. In some aspects, the disease and / or condition affects muscle movement.

[0196] Assays for Modulators of Kv7 Channels

[0197] Kv7 channels were previously identified as KCNQ channels. Assays for determining the ability of active molecules to maintain Kv7 channels in higher probability within the open position, i.e., positive allosteric modulators, are generally known in the art. One of skill in the art is able to determine an appropriate assay for investigating the activity of a selected compound of the disclosure towards a particular ion channel. For simplicity, portions of the followingdiscussion focus on Kv7.2 (KCNQ2) as a representative example, however, the discussion is equally applicable to other Kv7 subtype potassium ion channels.

[0198] KCNQ (Kv7) monomers as well as KCNQ alleles and polymorphic variants are subunits of potassium channels. The activity of a potassium channel comprising KCNQ subunits can be assessed using a variety of in vitro and in vivo assays, e.g., measuring current, measuring membrane potential, measuring ion flux, e.g., potassium or rubidium, measuring potassium concentration, measuring second messengers and transcription levels, using potassium-dependent yeast growth assays, and using e.g., voltage-sensitive dyes, radioactive tracers, and patch-clamp electrophysiology.

[0199] Furthermore, such assays can be used to test for inhibitors and activators of channels comprising KCNQ. Such modulators of a potassium channel are useful for treating various disorders involving potassium channels, including but not limited to, for example, central and peripheral nervous system disorders (e.g., migraine, ataxia, Parkinson's disease, bipolar disorders, trigeminal neuralgia, spasticity, mood disorders, brain tumors, psychotic disorders, myokymia, seizures, epilepsy, hearing and vision loss, Alzheimer's disease, age-related memory loss, learning deficiencies, anxiety and motor neuron diseases, and can also be used as neuroprotective agents (e.g., to prevent stroke and the like). Such modulators are also useful for investigation of the channel diversity provided by KCNQ and the regulation / modulation of potassium channel activity provided by KCNQ. Prodrugs which are metabolized by amidases, esterases and other metabolic or hydrolytic mechanisms in a mammal, or cells are able to produce active modulators of channels comprising KCNQ. Some prodrugs, themselves, may also have weak activity as KCNQ channel modulators. But it is likely, any activity may be due to degradation in the test system to the active drug and in most of these cases that the metabolized prodrug produces a more active KCNQ modulator than the prodrug itself.

[0200] Modulators of the potassium channels are tested using biologically active KCNQ, either recombinant or naturally occurring, or by using native cells, like cells from the nervous system expressing the M-current. KCNQ can be isolated, co-expressed or expressed in a cell, or expressed in a membrane derived from a cell. In such assays, KCNQ2 is expressed alone to form a homomeric potassium channel or is co-expressed with a second subunit (e.g., another KCNQ family member, preferably KCNQ3) so as to form a heteromeric potassium channel. Modulation is tested using one of the in vitro or in vivo assays described above. Samples or assays that are treated with a potential potassium channel inhibitor or activator are compared to control samples without the test compound, to examine the extent of modulation. Control samples (untreated with activators or inhibitors) are assigned a relative potassium channelactivity value of 100. Activation of channels comprising KCNQ2 is achieved when the potassium channel activity value relative to the control is 130%, more preferably 150%, more preferably 170% higher. Compounds that increase the flux of ions will cause a detectable increase in the ion current density by increasing the probability of a channel comprising KCNQ2 being open, by decreasing the probability of it being closed, by increasing conductance through the channel, and increasing the number or expression of channels.

[0201] The activity of these compounds of the disclosure can also be represented by ECso. Preferred compounds of the disclosure have an ECso in a potassium ion channel assay of from about 0.1 nM to about 1 mM, preferably from about 1 nM to about 10 pM, and more preferably from about 1 nM to about 2 pM.

[0202] Changes in ion flux may be assessed by determining changes in polarization (i.e., electrical potential) of the cell or membrane expressing an exemplary potassium channel such as KCNQ2, KCNQ2 / 3 or the M-current. A preferred means to determine changes in cellular polarization is by measuring changes in current or voltage with the voltage-clamp and patchclamp techniques, using the "cell-attached" mode, the "inside-out" mode, the "outside-out" mode, the "perforated cell" mode, the "one or two electrode" mode, or the "whole cell" mode (see, e.g., Ackerman etal., New Engl. J. Med. 336: 1575-1595 (1997)). Whole cell currents are conveniently determined using the standard methodology (see, e.g., Hamil etal., Pflugers. Archiv. 391: 85 (1981). Other known assays include radiolabeled rubidium flux assays and fluorescence assays using voltage-sensitive dyes (see, e.g., Vestergarrd-Bogind etal., 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 the channel proteins comprising KCNQ2 or heteromultimers of KCNQ subunits can be performed by application of the compounds to a bath solution in contact with and comprising cells having a channel of the present disclosure (see, e.g., Blatz etal., Nature 323: 718-720 (1986); Park, J. Physiol. 481: 555-570 (1994)). Generally, the compounds to be tested are present in the range from about 1 pM to about 1 mM, preferably from about 10 pM to about 100 pM.

[0203] The effects of the test compounds upon the function of the channels can be measured by changes in the electrical currents or ionic flux or by the consequences of changes in currents and flux. Changes in electrical current or ionic flux are measured by either increases or decreases in 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 concentration changes of the ions or indirectly by membrane potential or by radio-labeling of the ions. Consequences of thetest compound on ion flux can be quite varied. Accordingly, any suitable physiological change can be used to assess the influence of a test compound on the channels of this disclosure. Pharmaceutical Compositions of Potassium Channel Modulators

[0204] In another aspect, the present disclosure provides pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a compound of Formula I provided above.

[0205] Formulation of the Compounds (Compositions)

[0206] 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, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the compounds described herein can be administered by inhalation, for example, intranasally or by dry powder inhaler. Additionally, the compounds of the present disclosure can be administered transdermally, ocularly, intracochlearly, or intrarectally. Accordingly, the present disclosure also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and either a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0207] For preparing pharmaceutical compositions from the compounds of the present disclosure, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid form can be either an immediate release, sustained release, modified release, or delayed release. A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

[0208] In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

[0209] The powders and tablets preferably contain from 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, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges areincluded. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0210] In one method for preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.

[0211] 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.

[0212] Aqueous solutions suitable for oral use can be prepared by dissolving the active component 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 component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

[0213] Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

[0214] The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, pill, cachet, sachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

[0215] The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 10,000 mg, more typically 1.0 mg to 5000 mg, most typically 1 mg to 500 mg, according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.Effective Dosages

[0216] Pharmaceutical compositions provided by the present disclosure include compositions wherein the active ingredient is contained in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose. The actual amount effective for aparticular application will depend, inter alia, on the condition being treated. For example, when administered in methods to treat pain, epilepsy, depression, or anxiety, such compositions will contain an amount of active ingredient effective to achieve a clinically relevant degree of reduction in the condition being treated. Similarly, when the pharmaceutical composition is used to treat or prevent a central or peripheral nervous system disorder, e.g., Parkinson's disease a therapeutically effective amount will reduce one or more symptoms characteristic of the diseases (e.g., tremors) to below a predetermined pressure threshold. Determination of a therapeutically effective amount of a compound of the disclosure is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure herein.

[0217] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. Target plasma concentrations will be those concentrations of active compound(s) that are capable of modulating, e.g., activating or opening the KCNQ channel. In preferred embodiments, the KCNQ channel activity is altered by at least 3 mV at clinical effective free drug concentrations for certain diseases or treatments and at least 20 mV in other diseases or treatments. The shift in half-maximal voltage activiation of alteration of the KCNQ channel in the patient with a Kv7 positive allosteric modulator can be adjusted based on plasma drug concentration of the active, and the dosage can be adjusted upwards or downwards to achieve the desired therapeutic effect.

[0218] As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a circulating concentration that has been found to be effective in animals. A particularly useful animal model for predicting anticonvulsant dosages is the maximal electroshock assay (Fischer R S, Brain Res. Rev. 14: 245-278 (1989)). The dosage in humans can be adjusted by monitoring KCNQ channel activation and adjusting the dosage upwards or downwards, as described above.

[0219] A therapeutically effective dose can also be determined from human data for compounds which are known to exhibit similar pharmacological activities, such as ezogabine (Rudnfeldt et al., Neuroscience Lett. 282: 73-76 (2000)).

[0220] Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods as are well-known in the art is well within the capabilities of the ordinarily skilled artisan.

[0221] By way of example, when a compound of the disclosure is used in the prophylaxis and / or treatment of an exemplary disease such as epilepsy and pain, a circulating concentrationof administered compound of about 0.001 pM to 100 pM is considered to be effective, with about 0.005 pM to 5 pM being preferred.

[0222] Patient doses for oral administration of the compounds described herein, which is the preferred mode of administration for prophylaxis and for treatment of an exemplary disease such as epilepsy, typically range from about 0.1 mg / day to about 10,000 mg / day, more typically from about 1 mg / day to about 3,000 mg / day, and most typically from about 1 mg / day to about 100 mg / day. Stated in terms of patient body weight, typical dosages range from about 0.001 to about 150 mg / kg / day, more typically from about 0.01 to about 50 mg / kg / day, and most typically from about 0.02 to about 5 mg / kg / day.

[0223] For other modes of administration, dosage amount and interval can be adjusted individually to provide plasma levels of the administered compound effective for the particular clinical indication being treated. For example, if acute epileptic seizures are the most dominant clinical manifestation, in one embodiment, a compound according to the disclosure can be administered in relatively high concentrations multiple times per day. Alternatively, if the patient exhibits only periodic epileptic seizures, migraines, or other acute onset clinical signs or symptoms from chronic or acute disease states on an infrequent, periodic or irregular basis, in one embodiment, it may be more desirable to administer a compound of the disclosure at minimal effective concentrations and to use a less frequent administration regimen. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease.

[0224] Utilizing the teachings provided herein, an effective prophylactic or therapeutic treatment regimen can be planned which does not cause substantial toxicity and yet is entirely effective to treat the clinical symptoms demonstrated by the particular patient.

[0225] This planning should involve the careful choice of active compound by considering factors such as compound potency, relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode of administration and the toxicity profile of the selected agent. As examples, without limitation, an intranasal route of administration may be useful to treat migraine and an ocular route may be useful to treat one or more diseases of the eye. Thus, a particular route of administration may be selected based on the intended therapeutic indication of the compound of the present disclosure.Compound Toxicity

[0226] The ratio between toxicity and therapeutic effect for a particular compound is its therapeutic index and can be expressed as the ratio between LD50(the amount of compound lethal in 50% of the population) and ED50(the amount of compound effective in 50% of the population). Compounds that exhibit high therapeutic indices are preferred. Therapeutic indexdata obtained from cell culture assays and / or animal studies can be used in formulating a range of dosages for use in humans. The dosage of such compounds preferably lies within a range of plasma concentrations that include the ED50with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. See, e.g., Fingl et al., In: THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, Ch.1, p. 1, 1975. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition and the particular method in which the compound is used.Methods for Treating Conditions Mediated by Voltage-Dependent Potassium Channels

[0227] In still another aspect, the present disclosure provides a method for the treatment of a central or peripheral nervous system disorder or condition through modulation of a voltagedependent potassium channel. In this method, a subject in need of such treatment is administered an effective amount of a compound having the formula provided above.

[0228] The compounds provided herein are useful prodrugs of potassium channel modulators and find therapeutic utility via modulation through improvements in pharmacokinetics, solubility, stability of molecules that are active on voltage-dependent potassium channels in the treatment of diseases or conditions. The potassium channels targets for the compounds of the disclosure are described herein as voltage-dependent potassium channels such as the KCNQ potassium channels. As noted above, these channels may include homomultimers and heteromultimers of KCNQ2, KCNQ3, KCNQ4, and KCNQ5. A heteromultimer of two proteins, e.g., KCNQ2 and KCNQ3 is referred to as, for example, KCNQ2 / 3, KCNQ3 / 5, etc. The 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 disorders, trigeminal neuralgia, spasticity, mood disorders, brain tumors, psychotic disorders, myokymia, seizures, epilepsy, hearing and vision loss, Alzheimer's disease, age-related memory loss, learning deficiencies, anxiety, and motor neuron diseases). The compounds and compositions of the present disclosure may also serve as neuroprotective agents (e.g., to prevent stroke, retinal degeneration, demyelinating diseases and the like). 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 hearing loss or treatment of diseases associated with neuronal demyelination or neuronal hyperexcitability.

[0229] 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.

[0230] The following cited references may be incorporated by reference with regard to such teaching for the nexus of the mechanism to the applicable disease or disorder.

[0231] a. Seizures (L Greene, Epilepsia 2018; J Neurosci, Qiu. 2008).

[0232] Neurons from Kv7.2(S559A) knock-in mice showed normal basal M-currents. Knock-in mice displayed reduced M-current suppression when challenged by a muscarinic agonist, oxotremorine-M. Kv7.2(S559A) mice were resistant to chemoconvulsant-induced seizures with no mortality. Administration of XE991 transiently exacerbated seizures in knock-in mice equivalent to those of wildtype mice. After experiencing status epilepticus, Kv7.2(S559A) knock-in mice did not show seizure-induced cell death nor spontaneous recurring seizures.

[0233] Using M-channel blockers, we found that SST4 coupling to M-channels is critical to its inhibition of epileptiform activity. This is the first demonstration of an endogenous enhancer of IM that is important in controlling seizure activity. SST4 receptors could therefore be an important novel target for developing new antiepileptic and antiepileptogenic drugs.

[0234] b. Pain, neuropathic pain, chronic headache (J Pain, Li. 2019).

[0235] 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 medicine) can be used to attenuate the development of paclitaxel-induced peripheral neuropathy.

[0236] c. Central pain, pain related to diabetic neuropathy, postherpetic neuralgia and to peripheral nerve injury, (Brown Br J Pharmacology, 2009; Epilepsia, Trenite.2013).

[0237] Several drugs including flupirtine and retigabine enhance neural Kv7 / M-channel activity, principally through a hyperpolarizing shift in their voltage gating. In consequence they reduce neural excitability and can inhibit nociceptive stimulation and transmission. Flupirtine is in use as a central analgesic; retigabine is under clinical trial as a broad-spectrum anticonvulsant and is an effective analgesic in animal models of chronic inflammatory and neuropathic pain.

[0238] ICA-105665 reduced the SPR in patients at single doses of 100 (one of four), 400 (two of four), and 500 mg (four of six). This is the first assessment of the effects of activation of Kv7 potassium channels in the photosensitivity proof of concept model. The reduction of SPR in this patient population provides evidence of central nervous system (CNS) penetration by IGA-105665, and preliminary evidence that engagement with neuronal Kv7 potassium channels has antiseizure effects.

[0239] d. Alzheimer’s disease, (Czuzcwar, Pharmacological Reports 2010).

[0240] The most prominent adverse effects due to retigabine combined with the existing antiepileptic treatment were dizziness, somnolence, and fatigue. The preclinical data indicate that this antiepileptic drug may possibly be applied in patients with neuropathic pain and affective disorders. Initial clinical data suggest that retigabine may be also effective in Alzheimer’s disease or stroke.

[0241] e. Anxiety, CNS damage caused by neurodegenerative illness or diseases or injury, cognitive deficits, compulsive behavior, dementia, depressions, Huntington's disease, dystonia, mania, (Richter, Br J Pharmacology 2006; Aiba, Brain 2021; Boehm, Pain 2019; Maghera, Epilepsia 2020; De Jong, Physiological Reports 2018; Jakubowski, Epilepsy Behav 2013;Zizhen Wu, J Pharmacol Exp Ther 2020; J E 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).

[0242] Since retigabine and flupirtine are well tolerated in humans, the present finding of pronounced antidystonic efficacy in the dtsz mutant suggests that neuronal Kv7 channel activators are interesting candidates for the treatment of dystonia- associated dyskinesias and probably of other types of dystonias. The established analgesic effects of Kv7 channel openers might contribute to improvement of these disorders which are often accompanied by painful muscle spasms.

[0243] Retigabine was shown to delay spreading depolarization onset following submaximal OGD stimulation. Interestingly, Kv7.2 activators are neuroprotective in experimental ischaemia and brain trauma studies, and the anti-spreading depolarization properties of the activator may contribute to these neuroprotective effects.

[0244] Studies support the emerging roles of Kv7 channels in intrinsic and synaptic plasticity, and their contributions to cognition and behavior.

[0245] The voltage-gated potassium channels of the KV7 family (KV7.1–5) play important roles in controlling neuronal excitability and are therefore attractive targets for treatment of CNS disorders linked to hyperexcitability.

[0246] f. Cognitive disorders, memory impairment, memory disorders, memory dysfunction, (Frontal Physiol, Baculis. 2020; Frontal Physiol, Vigil. 2020).

[0247] Considering that Kv7 channels are critical for development and inhibition of neonatal brain (Peters et al., 2005; Soh et al., 2014), the memory impairment in these genetic models could be attributed to abnormal hippocampal morphology and / or hyperexcitability (Peters et al., 2005; Milh et al., 2020). Kv7 channels also regulate multiple behaviors.Behavioral phenotyping of the global or conditional homozygous KCNQ2 knock-out mice has not been possible due to their early postnatal lethality or premature death, respectively (Watanabe et al., 2000; Soh et al., 2014).

[0248] However, heterozygous KCNQ2 knock-out mice are viable and display increased locomotor activity and exploratory behavior (Kim et al., 2020), consistent with behavioral hyperactivity induced by transgenic suppression of Kv7 currents (Peters et al., 2005) and amphetamine and XE991 (Sotty et al., 2009). These mice also show decreased sociability and increased repetitive and compulsive behavior (Kim et al., 2020), reminiscent of autism seen in some EE patients with dominant KCNQ2 mutations (Weckhuysen et al., 2012, 2013; Milh et al., 2013). International Kv7 symposium in Naples, Italy in 2019, show great translational promise. Animal research indicates M current to be a therapeutic target for multiple brain disorders, including those with no current treatments, such as TBI and psychostimulant addiction.

[0249] g. Schizophrenia, (Transl Psychiatry, Nielsen. 2017; Br J Pharmacol, Wang. 2020).

[0250] Genetic or pharmacological inhibition of neuronal Kv7 channels can alleviate PPI and cognitive deficits induced by NMDA antagonists, thus suggesting a therapeutic potential for such inhibition of Kv7 channels in the treatment of schizophrenia or cognitive deficit disorder.

[0251] h. Spinal cord damage (J Pharmacol, Wu. 2020).

[0252] Reducing the activity of neurons by opening KCNQ / Kv7 channels may protect spinal neurons and axons from degeneration after SCI, thereby promoting recovery of motor and sensory function. Repeated application of retigabine to open these channels at the acute stage promotes neurobehavioral recovery after SCI.

[0253] i. Cardiomyopathia, cardiac arrhythmia (Front Physiol, larsson.2020; J Physoil, Maljevic. 2008; Lee, Microcirculation.2015).

[0254] Because of their significant role in physiology, dysfunctional KV7 channels are often linked to disorders characterized by abnormal potassium ion conductance, including cardiac arrhythmia, hearing impairment, epilepsy, pain, and hypertension.

[0255] Mouse Kv7 channels may contribute differently to regulating the functional properties of cerebral and coronary arteries. Such heterogeneity has important implications for developing novel therapeutics for cardiovascular dysfunction.

[0256] j. Long QT Syndrome, (J Physoil, Maljevic. 2008; Acta Pyhsoil. Skarsfeldt. 2020: Acta Physoil, Bahannon. 2019).

[0257] Polyunsaturated fatty acids with double bonds closer to the head group had higher apparent affinity for I Ks channels and increased IKs current more; shifting the bonds further away from the head group reduced apparent binding affinity for and effects on the IKs current. Interestingly, we found that ω-6 and ω-9 PUFAs, with the first double bond closer to the head group, left-shifted the voltage dependence of activation the most. These results allow for informed design of new therapeutics targeting IKs channels in Long QT Syndrome

[0258] Kv7 channels present interesting targets for new therapeutic approaches to diseases caused by neuronal hyperexcitability, such as epilepsy, neuropathic pain, and migraine. The molecular mechanism of Kv7 activation by retigabine has been elucidated as a stabilization of the open conformation by binding to the pore region.

[0259] k. Bowel disorder, an inflammatory disease, ulcerative colitis, Grohn's disease, (J Neurosci, Linley. 2008).

[0260] Further experiments demonstrated that M current inhibition required concurrent rises in cytosolic Ca 2 concentration and depletion of membrane phosphatidylinositol 4,5-bisphosphate (PIP2). We propose that PLC- and Ca 2 / PIP2-mediated inhibition of M current in sensory neurons may represent one of the general mechanisms underlying pain produced by inflammatory mediators and may therefore open up a new therapeutic window for treatment of this major clinical problem.

[0261] I. Creutzfeid-Jacobs disease, (Acta Pharmacol Sin, Teng. 2016).

[0262] A 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 approximately 3 h in plasma, can reverse inflammatory pain in rodent animal models.

[0263] m. Progressive hearing loss or tinnitus (J Physoil, Maljevic. 2008; Br J Pharmacol, Leithner. 2014; J Neurosci, Kalappa. 2015).

[0264] Stabilizing the KCNQ4-mediated conductance in OHGs, chemical channel openers can protect against OHG degeneration and progression of hearing loss in DFNA2.

[0265] Behavioral studies demonstrated that SF0034 was a more potent and less toxic anticonvulsant than retigabine in rodents. Furthermore, SF0034 prevented the development oftinnitus in mice. We propose that SF0034 provides, not only a powerful tool for investigating ion channel properties, but, most importantly, it provides a clinical candidate for treating epilepsy and preventing tinnitus.

[0266] n. Diabetes, (Front Cardivasc Med, Fosmo. 2017).

[0267] Kv7 channel activity may contribute to the development of the cardiovascular risk factors such as hypertension, diabetes, and obesity. Questions and hypotheses regarding previous and future research have been raised. Alterations in the Kv7 channel may contribute to the development of cardiovascular disease (CVD). Pharmacological modification of Kv7 channels may represent a possible treatment for CVD in the future.

[0268] o. Chronic obstructive pulmonary disease (COPD) (Front Physiol, Mondejar-Parreno.2020).

[0269] The functional role of Kv7 channels may vary depending on the cell type. Several studies have demonstrated that the impairment of Kv7 channel has a strong impact on pulmonary physiology contributing to the pathophysiology of different respiratory diseases such as cystic fibrosis, asthma, chronic obstructive pulmonary disease, chronic coughing, lung cancer, and pulmonary hypertension. Kv7 channels are now recognized as playing relevant physiological roles in many tissues, which have encouraged the search for Kv7 channel modulators with potential therapeutic use in many diseases including those affecting the lung. Modulation of Kv7 channels has been proposed to provide beneficial effects in a number of lung conditions. Therefore, Kv7 channel openers / enhancers or drugs acting partly through these channels have been proposed as bronchodilators, expectorants, antitussives, chemotherapeutics, and pulmonary vasodilators.

[0270] p. Movement disorder selected from primary dystonia (A Richter Br J Pharmacol 2006).

[0271] These data indicate that dysfunctions of neuronal Kv7 channels deserve attention in dyskinesias. Since retigabine and flupirtine are well tolerated in humans, the present finding of pronounced antidystonic efficacy in the dtsz mutant suggests that neuronal Kv7 channel activators are interesting candidates for the treatment of dystonia- associated dyskinesias and probably of other types of dystonias. The established analgesic effects of Kv7 channel openers might contribute to improvement of these disorders which are often accompanied by painful muscle spasms.

[0272] q. Autism, autism spectrum disorders, comprising administering a compound of the present disclosure. (Gilling, Front Genet. 2013; Guglielmi, Front Cell Neurosci. 2015).

[0273] One embodiment of the present disclosure includes a method of delivering a broad spectrum Kv7.2-7.5 active molecule to systemic circulation and releasing said active Kv channel opener in an effective concentration at therapeutic concentrations to treat one or more susceptible disease or disorder comprising administering a compound of the present disclosure. In one aspect, release of the active molecule is provided under one or more of: enhanced by increased absorption.

[0274] Since retigabine and flupirtine were tolerated in humans, the present finding of pronounced antidystonic efficacy in the dtsz mutant suggests that neuronal Kv7 channel activators are interesting candidates for the treatment of dystonia- associated dyskinesias and probably of other types of dystonias.

[0275] Mutations in neuronal Kv7 (KCNQ) potassium channels can cause episodic neurological disorders. Paroxysmal dyskinesias with dystonia are a group of movement disorders which are regarded as ion channelopathies, but the role of Kv7 channels in the pathogenesis and as targets for the treatment have so far not been examined.

[0276] The results suggest that dysfunction of the heteromeric KV7.3 / 5 channel is implicated in the pathogenesis of some forms of autism spectrum disorders, epilepsy, and possibly other psychiatric disorders and therefore, KCNQ3 and KCNQ5 are suggested as candidate genes for these disorders.Compounds, Pharmaceutically Acceptable Salts, and Compositions for Use

[0277] In another aspect, the disclosure features a compound of the disclosure, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use as a medicament.

[0278] In another aspect, the disclosure features a compound of the disclosure, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for modulating potassium channels.

[0279] In another aspect, the disclosure features a compound of the disclosure, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating seizure, epilepsy, or any other disease and / or condition described above, or which requires modulation of potassium channels.

[0280] In another aspect, the disclosure features a compound of the disclosure, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating a disease and / or condition described above, or which requires modulation of potassium channels.

[0281] Manufacture of Medicaments

[0282] In another aspect, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for the manufacture of a medicament.

[0283] In another aspect, the disclosure provides the use of a compound of the disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for modulating potassium channels.

[0284] In yet another aspect, the disclosure provides the use of a compound of the disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating a disease and / or condition described above, or which requires modulation of potassium channels.

[0285] Administration of Compounds, Pharmaceutically Acceptable Salts, and Compositions

[0286] In certain embodiments of the disclosure, an “effective amount” of a compound of the disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is that amount effective for treating or lessening the severity of one or more of the conditions recited above.

[0287] The compounds, salts, and compositions, according to the method of the disclosure, may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of the diseases and / or conditions described above. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the condition, the particular agent, its mode of administration, and the like. The compounds, salts, and compositions of the disclosure are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the subject to be treated. It will be understood, however, that the total daily usage of the compounds, salts, and compositions of the disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular subject or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound or salt employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound or salt employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound or salt employed, and like factors wellknown in the medical arts. The term “subject” or “patient,” as used herein, means an animal, preferably a mammal, and most preferably a human.

[0288] The pharmaceutically acceptable compositions of this disclosure can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the condition being treated. In certain embodiments, the compound, salts, and compositions of the disclosure may be administered orally or parenterally at dosage levels of about 0.001 mg / kg to about 100 mg / kg, one or more times a day, effective to obtain the desired therapeutic effect.

[0289] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound or salt, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0290] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, U. S. P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0291] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0292] In order to prolong the effect of the compounds of the disclosure, it is often desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0293] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compound or salt of this disclosure with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0294] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound or salt is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0295] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees,capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0296] The active compound or salt can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, releasecontrolling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms, the active compound or salt may be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0297] Dosage forms for topical or transdermal administration of a compound or salt of this disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this disclosure. Additionally, the disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms are prepared by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0298] As described generally above, the compounds of the disclosure are useful as modulators of potassium channels. In one embodiment, the compounds are modulators ofpotassium channels, and thus, without wishing to be bound by any particular theory, the compounds, salts, and compositions are particularly useful for treating or lessening the severity of a disease, condition, or disorder where modulation of potassium channels is implicated in the disease, condition, or disorder. When activation or hyperactivity of potassium channels is implicated in a particular disease, condition, or disorder, the disease, condition, or disorder may also be referred to as a “potassium channel disease, condition or disorder.” Accordingly, in another aspect, the disclosure provides a method for treating or lessening the severity of a disease, condition, or disorder where modulation of potassium channels is implicated in the disease state.Additional Therapeutic Agents

[0299] It will also be appreciated that the compounds, salts, and pharmaceutically acceptable compositions of the disclosure can be employed in combination therapies, that is, the compounds, salts, and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and / or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.” For example, exemplary additional therapeutic agents include, but are not limited to macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers. Additional appropriate therapeutic agents or approaches are described generally in The Merck Manual, Nineteenth Edition, Ed. Robert S. Porter and Justin L. Kaplan, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., 2011, and the Food and Drug Administration website, www.fda.gov, the entire contents of which are hereby incorporated by reference.

[0300] The amount of additional therapeutic agent present in the compositions of this disclosure may be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. The amount of additional therapeutic agent in the presently disclosed compositions may range from about 10%to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[0301] The compounds and salts of this disclosure or pharmaceutically acceptable compositions thereof may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents, and catheters. Accordingly, the disclosure, in another aspect, includes a composition for coating an implantable device comprising a compound or salt of the disclosure as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. In still another aspect, the disclosure includes an implantable device coated with a composition comprising a compound or salt of the disclosure as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device.

[0302] Another aspect of the disclosure relates to inhibiting activity in a biological sample or a subject, which method comprises administering to the subject, or contacting said biological sample with a compound of the disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. The term “biological sample,” as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

[0303] Modulation of potassium channels activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, the study of potassium channels in biological and pathological phenomena, and the comparative evaluation of new potassium channel modulators.Synthesis of the Compounds of the Disclosure

[0304] The compounds of the disclosure can be prepared from known materials by the methods described in the Examples, other similar methods, and other methods known to one skilled in the art. As one skilled in the art would appreciate, the functional groups of the intermediate compounds in the methods described below may need to be protected by suitable protecting groups. Protecting groups may be added or removed in accordance with standard techniques, which are well-known to those skilled in the art. The use of protecting groups is described in detail in T. G. M. Wuts et al., Greene’s Protective Groups in Organic Synthesis (4th ed. 2006).EXAMPLESAbbreviations:

[0305] As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Specifically, the following abbreviations may be used in the examples and throughout the specification:g grams mg milligramsL liters mL millilitersμL microliters psi pounds per square inch M molar mM millimolarHz Hertz MHz megahertzmol moles mmol millimolesmin minutes hr hoursmp melting point RT or rt room temperatureTLC thin layer chromatography RP reverse phaseTrretention time atm atmosphereTFA trifluoroacetic acid TEA triethylamineTHF tetrahydrofuran TFAA trifluoroacetic anhydride CD3OD deuterated methanol CDC deuterated chloroform DMSO dimethylsulfoxide SiO₂ silica gelEtOAc ethyl acetate CHCl₃ chloroformHCI hydrochloric acid Ac acetylDMF N,N-dimethylformamide Me methylCs₂CO₃ cesium carbonate EtOH ethanolEt ethyl t-Bu tert-butylMeOH methanol p-TsOH p-toluenesulfonic acid DCM dichloromethane DCE dichloroethaneEt20 diethyl ether K2CO3 potassium carbonate Na₂CO₃ sodium carbonate i-PrOH isopropyl alcohol NaHCO₃ sodium bicarbonate ACN acetonitrilePr propyl i-Pr isopropylPE petroleum ether Hex hexanesH₂SO₄ sulfuric acid Et₃N triethylamineNa₂SO₄ sodium sulfate MTBE methyl tert-butyl ether Boc tert-butoxycarbonyl DIPEA diisopropylethylamineIPA isopropanol HMDS hexamethyldisilazane NH₄Cl ammonium chloride NH₄CO₃ ammonium carbonate MgSO₄ magnesium sulfate NH4OH ammonium hydroxide

[0306] All solvents and chemicals were reagent grade. Unless otherwise mentioned, all reagents and solvents were purchased from commercial vendors and used as received. Flash column chromatography was carried out on a Teledyne ISCO CombiFlash Rf system using prepacked columns. Solvents used include hexane, ethyl acetate (EtOAc), dichloromethane(DCM) and methanol. Purity and characterization of compounds were established by a combination of NMR, mass spectrometry, TLC, and HPLC analyses.1H and13C NMR spectra were recorded on a Bruker Avance DPX-300 (300 MHz) spectrometer and were determined in CDCl₃, DMSO-d₆, or CD₃OD with tetramethylsilane (TMS) (0.00 ppm) or solvent peaks as the internal reference. Chemical shifts are reported in ppm relative to the reference signal and coupling constant (J) values are reported in hertz (Hz). Nominal mass spectra were obtained using an Agilent InfinityLab MSD single quadrupole mass spectrometer system (ESI). Thin layer chromatography (TLC) was performed on EMD precoated silica gel 60 F₂₅₄ plates, and spots were visualized with UV light or iodine staining. All final compounds were greater than 95% pure as determined by HPLC on a Waters 2695 Separation Module equipped with a Waters 2996 Photodiode Array Detector and a Phenomenex Synergi 4 mm Hydro-RP 80A C18250 x 4.6 mm column using a flow rate of 1 mL / min starting with 1 min at 5% solvent B, followed by a 15 min gradient of 5-95% solvent B, followed by 9 min at 95% solvent B (solvent A, water with 0.1% TFA; solvent B, acetonitrile with 0.1% TFA and 5% water; absorbance monitored at 280 nm).

[0307] Thin layer chromatography (TLC) was performed on EMD precoated silica gel 60 F254 plates, and spots were visualized with UV light or iodine staining. Low resolution mass spectra were obtained using a Waters Alliance HT / Micromass ZQ system (ESI). All test compounds were greater than 95% pure as determined by HPLC on an Agilent 1100 system using an Agilent Zorbax SB-Phenyl, 2.1 mm x 150mm, 5 pm column with gradient elution using the mobile phases (A) H2O containing 0.1% CF3COOH and (B) MeCN, with a flow rate of 1.0 mL / min.

[0308] Example 1: Chemistry

[0309] Compounds of the present disclosure can be prepared according to Scheme 1 below.

[0310] The following examples provide a description of the process conditions for preparing compounds on the present invention. It is to be understood, however, that the invention, as fully described herein and as recited in the claims, is not intended to be limited by the details of the following schemes or modes of preparation. Certain abbreviations may be used in describing the examples of the present disclosure. The abbreviations are believed to be used consistently within commonly accepted use of those skilled in the art. In the following schemes, general substituent groups are represented with assignments that may not align with the formulae of the present disclosure. The following schemes provide a key for such substituent groups that should be followed for the schemes and not applied to the formulae of the present disclosure.

[0311] Preparation of Structure 1

[0312] Structures, such as I are commercially available, or can be prepared according to literature methods, Structure I can be treated with an acyl chloride in the presence of base such as diisopropylethyl amine in a solvent such as tetrahydrofuran at 0°C to ambient temperature for 2 to 18 h to give structure II. Treating compound II with a reducing agent such as sodium borohydride in a protic solvent, such as methanol at 0°C for 1 to 2 h results in the formation of compound III. Compound III can be reacted with aromatic or heteroaromatic amines, such as 4-fluoroan iline and para toluene sulfonic acid in a high boiling solvent such as dichloroethane at 100°C over the course of 2 to 18h to produce compound IV.

[0313] Structure 1 can also prepared according to Scheme 2. A compound such as structure V is treated with a reducing agent such as sodium borohydride in a protic solvent such as methanol at 0°C for 1-2 h to form structure IV (structure B).NaBH4solvent

[0314] Preparation of Structure 2Y is absent, CH2, or CH2CH2

[0315] Structure 2 can be prepared according to Scheme 3. Structure II can be treated with aromatic or heteroaromatic amines in solvents such as toluene in the presence of an acid such as p-toluene sulfonic acid with removal of water to form structure V (structure G).Structure C

[0316] Preparation of compound J illustrated in Table #1

[0317] In a round bottom flask under nitrogen 1 equivalent of compound 1 and 3 equivalents of DIPEA were dissolved in anhydrous THF and cooled to 0°C. 1.6 eq. of 3,3-dimethylbutanoyl chloride was added dropwise and the reaction was allowed to warm up to room temperature overnight. The next day the solvent was removed in vacuo followed by addition of water. The mixture was then extracted three times with ethyl acetate, the combined organic extracts were dried over sodium sulfate and the solvent removed in vacuo. The resulting residue was purified by flash chromatography (Biotage: SiO2, EtOAc / Hexanes gradient) to give compound 2 in 54% yield.1.5 eq NaBH4MeOHOC-rt2 6

[0318] To 1 eq. of compound 2 under nitrogen was added anhydrous methanol. The reaction was cooled to 0°C with ice / water bath. Added sodium borohydride (1.5 eq) in several batches. Stirred the reaction under nitrogen without removing the cold bath or adding more ice. After 2h, the reaction was quenched with water (dropwise). The reaction was concentrated to dryness on the rotovap. Additional water was added, and the reaction was extracted with ethyl acetate (3x). The organic layer was dried over sodium sulfate, filtered, and concentrate on the rotovap. Compound 6 was isolated in 90 % yield and was used in the next step without additional purification.

[0319] To a 50 ml round bottom flask added 1 eq. of compound 6, 2eq. of para fluoroaniline and 1 eq. of para toluene sulfonic acid in anhydrous dichloroethane. The reaction was heated at 100°C at reflux under nitrogen and followed by LC / MS. After the reaction was completed, it was cooled to ambient temperature and diluted with ethyl acetate, followed by a wash with saturated sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated on the rotovap. The crude product was purified by silica gel chromatography (hexane / ethyl acetate eluent) and compound J was isolated in 34% yield.

[0320] Preparation of compound K illustrated in Table #1

[0321] Compound K was prepared similar to compound J and was isolated in 70% yield after re-crystallization with hexane / ethyl acetate.

[0322] Preparation of compound C illustrated in Table #1

[0323] Compound C was prepared similar to compound J and was isolated in 12% yield after silica gel chromatography (hexane / ethyl acetate eluent).

[0324] Preparation of compound A illustrated in Table #1

[0325] To a 50 ml round bottom flask was added 1 eq. of compound 2, 2eq. of para fluoroaniline and 1 eq. of para toluene sulfonic acid in anhydrous toluene. The reaction was fitted with a Dean Stark trap and a reflux condenser and heated to 1400C under nitrogen. The reaction was followed by LC / MS and after the reaction was completed, it was cooled to ambient temperature and the solvent was removed in vacuo. The resulting residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate followed by water and then brine. The organic layer was dried over sodium sulfate and concentrated on the rotovap. The crude product was purified by silica gel chromatography (hexane / ethyl acetate eluent) and compound A was isolated in 21% yield.

[0326] Preparation of compound B illustrated in Table #1

[0327] Compound B was prepared similar to compound A and was isolated in 18% yield after silica gel chromatography (hexane / ethyl acetate eluent).

[0328] All of the compounds of the present disclosure may be made using similar procedures.Example 2: PharmacologyRubidium Efflux Test for Kv7.2 Activity

[0329] PC-12 is harvested from a pheochromocytoma rat adrenal medulla and is one of the most common neuronal precursor cell lines used in neuroscience research including studying neuronal degenerations, neuronal differentiation, and neural networks. Cultured under normal conditions, PC-12 cells present morphological and physiological characteristics of the adrenal gland cells. When nerve growth factor (NGF) is added to the culture, this type of cells suffers a differentiation process and start to manifest morphological and functional characteristics of sympathetic ganglion neurons. PC-12 cells have been widely used as a neuronal line study model in many biosensing devices, mainly due to the neurogenic characteristics acquired after differentiation, such as high level of secreted neurotransmitter, neuron morphology characterized by neurite outgrowth, and expression of ion and neurotransmitter receptors. For understanding the pathophysiology processes involved in brain disorders, PC-12 cell line is extensively assessed in neuroscience research, including studies on neurotoxicity, neuroprotection, or neurosecretion. PC-12 cells were grown at 37° C. and 5% CO, in DMEM / F12 Medium (Dulbecco's Modified Eagle Medium with Nutrient Mix F-12, available from Invitrogen of Carlsbad, Calif.), supplemented with 10% horse serum, 5% fetal bovine serum, 2 mM glutamine, 100 U / ml penicillin, and 100 U / ml streptomycin. They were plated in poly-D-lysine-coated 96-well cell culture microplates at a density of 40,000 cells / well and differentiated with 100 ng / ml NGF-7s for 2-5 days. For the assay, the medium was aspirated, and the cells were washed once with 0.2 ml inwash buffer (25 mM HEPES, pH 7.4, 150 mM. NaCI, 1 mM MgCl, 0.8 mM NaH2PO 2 mM CaCl). The cells were then loaded with 0.2 ml Rb" loading buffer (wash buffer plus 5.4 mM RbCI, 5 mM glucose) and incubated at 37° C. for 2 h. Attached cells were quickly washed three times with buffer (same as Rb" loading buffer but containing 5.4 mM KCI instead of RbCl) to remove extra cellular Rb". Immediately following the wash, 0.2 ml of depolarization buffer (wash buffer plus 15 mM KCI) with or without compounds was added to the cells to activate efflux of potassium ion channels. After incubation for 10 min at room temperature, the Supernatant was carefully removed and collected. Cells were lysed by the addition of 0.2 ml of lysis buffer (depolarization buffer plus 0.1% TritonX-100) and the cell lysates were also collected. If collected samples were not immediately analyzed for Rb" contents by atomic absorption spectroscopy (see below), they were stored at 4°C. without any negative effects on Subsequent Rb" analysis. The concentrations of Rb in the supernatants and the cell lysates were quantified using an ICR8000 flame atomic absorption spectrometer (Aurora Biomed Inc., Vancouver, B. C.) under conditions defined by the manufacturer. Samples 0.05 ml in volume were processed automatically from microtiter plates by dilution with an equal volume of sample analysis buffer and injection into an air-acetylene flame. The amount of Rb inthe sample was measured by absorption at 780 nm using a hollow cathode lamp as light source and a PMT detector. A calibration curve covering the range 0-5 mg / L Rb in sample analysis buffer was generated with each set of plates. The percent Rb efflux (F) was defined where the F is the efflux in the presence of compound in depolarization buffer, F, is the efflux in basal buffer, and F is the efflux in depolarization buffer, and F is the efflux in the presence of compound in depolarization buffer. The efflux (F) and compound concentration relationship was plotted to calculate an EC50s value, a compounds concentration for 50% of maximal Rb efflux.Maximal Electroshock Seizure (MES) Test

[0330] The MES testing protocol is based on procedures established at the National Institute of Neurological Disorders and Stroke in conjunction with the Epilepsy Therapeutic Screening Program (ETSP) at the University of Utah.

[0331] Rat MES- Each solution was prepped on the day of dosing and dosed within 30 minutes of preparation. A 60 mg / mL DMSO stock was prepared for test compounds and used for aliquoting for each dosing. The stocks were diluted to the appropriate concentration with 0.5% Methylcellulose and vortexed for 1 minute. The resulting formulation for was 1% DMSO: 99% Methylcellulose (0.5%) in water for injection (WFI). PO doses were administered by bulbtipped gavage directly to the stomach at the dose volume of 5 mL / kg. Actual volumes were based on most recently recorded body weight. At 30 minutes after dosing, animals underwent MES testing. Prior to the test, each animal was dosed topically with ophthalmic proparacaine (0.5%). For MES, each animal was stimulated with an electrical current via transcorneal electrodes by a Rodent Shocker generator set to 150 mA at 0.2 msec pulse for a maximum duration of 6 sec. Time of hindlimb extension was recorded. If no hindlimb extension was observed, 6 sec maximum was noted. The ED50 is determined by a 4 PL nonlinear fit with the top fixed at 6 seconds. The rat MES screen was conducted at 30 minutes post dose at 10 mg / kg PO.

[0332] Mouse MES- Each solution was prepped on the day of dosing and dosed within 30 minutes of preparation. A 60 mg / mL DMSO stock was prepared for test compounds and used for aliquoting for each dosing. The stocks were diluted to the appropriate concentration with 0.5% Methylcellulose and vortexed for 1 minute. The resulting formulation for was 1% DMSO: 99% Methylcellulose (0.5%) in water for injection (WFI). PO doses were administered by bulbtipped gavage directly to the stomach at the dose volume of 5 mL / kg. Actual volumes were based on most recently recorded body weight. At 30 minutes after dosing, animals underwent MES testing. Prior to the test, each animal was dosed topically with ophthalmic proparacaine(0.5%). For MES, each animal was stimulated with an electrical current via transcorneal electrodes by a Rodent Shocker generator set to 50 mA at 0.2 msec pulse for a maximum duration of 6 sec. Time of hindlimb extension was recorded. If no hindlimb extension was observed, 6 sec maximum was noted.Rodent Pharmacokinetics and In vitro Liver Microsome Stability

[0333] Rat Pharmacokinetics (IV and PO)- Bioanalytical LC-MS / MS methods were developed to analyzed compounds on an Agilent 1100 HPLC coupled to a Sciex 4000 triple quadrupole mass spectrometer. Pharmacokinetic parameters were derived using full sampling profiles with noncompartmental analysis (NCA) methods in Phoenix WinNonlin® version 8.3 (Certara USA, Inc., Princeton, NJ). The NCA consistent with extravascular dosing for the plasma data was used for the estimation of parameters (WinNonlin model 200-202). PK parameters requiring λz were not included if the calculation of λz did not have a minimum of 3 data points (not including Cmax) and the adjusted R2 for linear regression was at least 0.8. The area under the concentration-time curve will be determined on calculations of λz that have a minimum of 3 data points, not including Cmax. However, in some instances where data points are limited, Cmax may be included in the calculation of λz. The pharmacokinetic parameters were based upon an N=3 rats per treatment group (IV or PO) with repeated sampling at 0.083, 0.25, 0.5, 1, 2, 4, 6, 24, 30, 48 h. The oral (PO) formulation consisted of 1% DMSO: 99% (0.5% Methylcellulose solution). The IV formulation consisted of 1% DMSO in PEG300:0.5% methylcellulose. Oral dosing was at 5 mL / kg and IV dosing was 2 mL / kg.

[0334] Human and Rat Liver Microsome Stability- Microsomes from IVtBio were purchased as a pooled mixed gender at a concentration of 20 mg protein / mL. The test compound + buffer consisted of 2 uM test compounds in Tris-HCI, 200 mM, pH 7.0, 2 mM MgCI2 and metabolic activity was activated with 2mM MgCI2 and 2 mM NaDPH. At time points 0, 10, 20, 40, 60, and 120 min, 25µL (in Triplicate) is aliquoted from the incubation well and 100µL of ice cold MeOH / ACN (50 / 50), containing 1000 ng / mL tolbutamide (TBT), is added to quench the reaction. The samples were vortexed and then centrifuged at 3500 rpm for 10 mins and the supernatants were collected. The supernatants were dried down under heated nitrogen gas, resuspended with 100µL of 95% H2O, 5% ACN, 0.1% FA, and 20µL was injected for each replicate. The percent remaining of test compounds after incubation was calculated by dividing the peak area ratios of remaining peak area at each time point by the peak area ratio at time 0, or final time point before compound degradation, times one hundred.Kv7.2 / Kv7.3 Agonist V ½ shift Qube Assay (half-maximal voltage shift)

[0335] Electrophysiological assays conducted on compounds for activities using the Qube electrophysiological platform. Methods employed in this study have been developed and validated with reliability and reproducibility. Retigabine was run as an integral part of each assay to ensure the validity of the results obtained. Results showing AV1 / 2 greater than a ±20 mV shift are considered to represent significant effects of test compounds. Retigabine 3 pM = -10 to -20 mV AV1 / 2 with an EG50 in the range of 2 - 5 uM). The parameters measured were the tail current evoked from the testing pulse from -120mV to 30mV from a holding potential of -120mV. All data were filtered for seal quality, seal drop, and current amplitude. The tail current amplitude was calculated before and after compound addition and the amount of activation was assessed by fitting with the Boltzmann function. The shift of the V1 / 2 between Control condition and different compound concentration treatment is calculated, summarized, and compared to the value from the reference compound Retigabine. Whole cell hKv7.2 / hKv7.3 currents are evoked from the testing potential of -120mV to 30mV in 10 mV increment for 1s from a holding potential of -120mV. This paradigm is delivered once every 20s to monitor the tail current amplitude. All compounds were tested in the presence of 0.1% Poloxamer 188 Non-lonic Surfactant and at approximately room temperature.hKv7.2 / 7.3 Agonist Potassium Channel Qube Assay

[0336] The parameters measured were the maximum peak current evoked on stepping from -120mV to -40mV. All data were filtered for seal quality, seal drop, and current amplitude. The peak current amplitude was calculated before and after compound addition and the amount of activity was assessed by dividing the Test compound current amplitude by the Control current amplitude. Control data is the mean hKv7.2 / Kv7.3 current amplitude collected 10 seconds at the end of the control period; Test compound data is the mean hKv7.2 / Kv7.3 current amplitude collected 10 seconds at the end of test concentration application for each concentration. After whole cell configuration is achieved, the cell is held at -120 mV. Then the cell is depolarized to -40 mV for 1 s and then back to -120 mV. This paradigm is delivered once every 20s to monitor the current amplitude. The current amplitude in the presence of test compound is normalized to that under the control 0.33% DMSO concentration and reported as percent relative to the highest concentration of the reference control Retigabine. All compounds were tested in the presence of 0.1% Pluronic F-68 Non-lonic Surfactant and at approximately room temperature.Table 3. Structure and biological data of exemplary compounds.ID Compound Kv7.2 Rat Rat Rat IV Rat PO Rat Liver Human Activity MES MES 1 mg / kg 3 mg / kg Microsome Liver Screen ED50 AUCIast AUCIast Microsome (hr*ng / (hr*ng / mL)mL)A E ND ND ND B B BN 1 1]F B D ND ND ND A B BF C D ND ND ND ND ND NDS -VxHN 1 Jf ISF D D ND ND ND ND B B<2X JHN If [X o1FID Compound Kv7.2 Rat Rat Rat IV Rat PO Rat Liver Human Activity MES MES 1 mg / kg 3 mg / kg Microsome Liver Screen ED50 AUCIast AUCIast Microsome (hr*ng / (hr*ng / mL)mL)E D ND ND ND ND ND ND<2X JLHN o fy^ciClF D ND ND ND ND B B<jT THN If 7X o1fF G D B ND ND ND A An TA °0Jf FF^ TH E ND ND ND ND ND NDHN |f AF1 0 ND ND ND ND ND ND QLX DH x\HD if Tf “FID Compound Kv7.2 Rat Rat Rat IV Rat PO Rat Liver Human Activity MES MES 1 mg / kg 3 mg / kg Microsome Liver Screen ED50 AUCIast AUCIast Microsome (hr*ng / (hr*ng / mL)mL)J c B B A B B B HN I || |\F K B A A A A B BHN I J TSF L B A ND B ND B BHN i rXJci^yCl

[0337] Legend: For Rb+ efflux cellular assay: A: EC50 < 1 nM; B: = 1 nM < EC50 <_10 nM; C: 10 nM < EC50 < 50 nM; D: 50 nM < EC50 < 500 nM; E: > 500 nM. For Rat MES ED50: A: ED50 < 10 mg / kg; B: > 10 mg / kg. Rat MES: A > 50% protected; B < 50% protected. For Rat IV PK AUG: A: AUG > 300 h*ng / mL; B < 300 h*ng / mL. For Rat PO PK AUG: A: AUC> 500 h*ng / mL; B < 500 h*ng / ml_. Rat and Human Microsome % Remaining: A>50% remaining; B<50% remaining. ND: not determined.Table 4. Kv7.2 / 7.3 Gv Shift,, Kv7.2 / 7.3 ECso, Mouse MESActivities of Exemplary CompoundsID Compound A V1 / 2Kv7.2 / 7.3 Mouse Kv7.2 / 7.3 EC50 MES A ND C ND COT□ 1 n |\F B C C NDF C F ND C ND HN 1 JF J B B A COT°HHD i n |\FActivities of Exemplary CompoundsID Compound A V1 / 2Kv7.2 / 7.3 Mouse Kv7.2 / 7.3 EC50 MES K B B AHN I jfF L C ND NDHN I J10ci'^yCl

[0338] Legend- A V1 / 2Kv7.2 / 7.3: Ezogabine EC50 >3uM where 3uM exhibits > -10 mV change in half maximal voltage shift (V 1 / 2) on Kv7.2 / 7.3. Thus, A= > -10mV at >0.01 uM; B= >-10 mV at >0.1 uM; C = > -10 mV at >1 uM; D= > - 10 mV at >10 uM. Kv7.x EC50 (where x = 7.217.3, 7.4, 7.5, 7.3Z7.5): A: EC50 < 10 nM; B: = 10 nM < EC50 <_100 nM; C: 100 nM < EC50 < 500 nM; D: 500 nM < EC50 < 5000 nM; E: > 5000 nM. For mouse MES test at PO dosing of 3 mg / kg: A: Active; B: inactive. ND: not determined.

[0339] The present disclosure enables one of skill in the relevant art to make and use the disclosures provided herein in accordance with multiple and varied embodiments. Various alterations, modifications, and improvements of the present disclosure that readily occur to those skilled in the art, including certain alterations, modifications, substitutions, and improvements are also part of this disclosure. Accordingly, the foregoing description are by way of example to illustrate the discoveries provided herein. Furthermore, the foregoing Description and Examples are exemplary of the present disclosure and not limiting thereof. The scope of the disclosure is therefore set out in the appended claims.

[0340] Although specific embodiments of the present disclosure are herein illustrated and described in detail, the disclosure is not limited thereto. The above detailed descriptions are provided as exemplary of the present disclosure and should not be construed as constituting any limitation of the disclosure. Modifications will be obvious to those skilled in the art, and all modifications that do not depart from the spirit of the disclosure are intended to be included with the scope of the appended claims.

Claims

CLAIMS1. A compound of formula (I),or a pharmaceutically acceptable salt, solvate, hydrate, amorphous, or crystalline form thereof,whereinm is 1, 2, or 3;R1is selected from the group consisting of hydrogen, (CH2)WCN, (CH2)WOH, Ci- Ci2alkyl, (CH2)WC3-Ci2cycloalkyl, (CH2)WC3-Ci2heterocycloalkyl, (CH2)wCi-Ci2alkoxy, (CH2)WO(CH2)WC3-C6cycloalkyl, (CH2)wO(CH2)wC3-C6heterocycloalkyl, (CH2)WC6-Cioaryl, (CH2)WC5-Cioheteroaryl, halogen, (CH2)wCi-Ci2haloalkyl, and (CH2)WCI-CI2haloalkoxy;each of R2, R3, and R4independently is selected from the group consisting of hydrogen, (CH2)WCN, (CH2)WOH, (CH2)WNO2, Ci-Ci2alkyl, (CH2)WC3-Ciocycloalkyl, (CH2)wC3-Cioheterocycloalkyl, (CH2)WC2-CI2alkenyl, (CH2)WC3-Ciocycloalkenyl, (CH2)WC3- Cwheterocycloalkenyl, (CH2)WC2-CI2alkynyl, (CH2)WC3-Ci2cycloalkynyl, (CH2)WC3- Ci2heterocycloalkynyl, (CH2)WC6-Cioaryl, (CH2)WC5-Cioheteroaryl, halogen, (CH2)WCI- Ci2haloalkyl, (CH2)WCI-CI2haloalkoxy, (CH2)WSR13, (CH2)WCH3-NHC(=NH), (CH2)WCH3C(=NH)NH, (CH2)WCH2C(=NH)NH2, (CH2)WNR14C(=O)R15, (CH2)WNR14C(=NH)R15, (CH2)WC(=O)NR16R117, (CH2)WCH2C(=O)NR16R117, (CH2)WCH3NHC(=NH), (CH2)WCH3C(=NH)NH, (CH2)WCH2C(=NH)NH2, (CH2)WNR18R19, (CH2)WSO2R20, (CH2)WNR21SO2R22, and (CH2)WSO2NR23R24,each of R5, R6, and R7, independently is selected from the group consisting of hydrogen, C1-C12 alkyl, and C1-C12 haloalkyl;G is selected from the group consisting of O, S, C(Rg1), C(Rg1)(Rg2), N, or N(Rg1), where each Rg1and Rg2independently is hydrogen, C1-C12 alkyl, (CH2)wCi-Ci2alkoxy, halogen, Ci-Ci2haloalkyl, or phenyl;Z is O or S;each X is O, S, CR25, CR25R26, or GR27R28, where R27and R28combine with the carbon to which they are attached to form a 3- to 6-membered cycloalkyl;q is 0, 1, 2, 3, 4, 5, or 6;Y is selected from the group consisting of Ci-Ci2alkyl, (CH2)wC3-Ci2cycloalkyl, (CH2)WC3-Ci2heterocycloalkyl, (CH2)WC2-Ci2alkenyl, (CH2)WC3-Ci2cycloalkenyl, (CH2)wC3- Ci2heterocycloalkenyl, (CH2)wC2-Ci2alkynyl, (CH2)WC2-Ci2cycloalkynyl, (CH2)wC2- Ci2heterocycloalkynyl, (CH2)WC6-Cioaryl, and (CH2)wC5-Cioheteroaryl;B1is a 5- to 10-membered mono- or bi-cyclic ring system containing one or more degrees of unsaturation, optionally containing 1-4 heteroatoms selected independently from N, O, and S;each of R9-R26independently is selected from the group consisting of H, Ci- Cealkyl, Cs-Cecycloalkyl, C2-C6alkenyl, Cs-Cecycloalkenyl, C2-C6alkynyl, C3- Cecycloalkynyl, Cs-Ceheterocycloalkyl, Cs-Ceheterocycloalkenyl, C3- Ceheterocycloalkynyl, (CH2)wC6-Cioaryl, and (CH2)WC5-Cioheteroaryl;each w is 0, 1, 2, 3, 4, 5, or 6; andwhere each instance of alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, cycloalkynyl, heterocycloalkynyl, aryl, and heteroaryl groups may be optionally substituted with one, two, or three substituents selected independently from Ci-Cealkyl, OH, Ci-Cealkoxy, ON, halogen, and Ci-Cehaloalkyl;2. The compound of claim 1, whereinm is 1 or 2;R1is hydrogen;one or two of R2, R3, and R4is halogen or Ci-i2haloalkyl;one or two of R5, R6, and R7is Ci-i2alkyl or halogen;G is N or N(Rg1);Rg1is H;Z is O;q is 1 or 2;X is CR25R26;each of R25and R26is hydrogen or Ci isalkyl;Y is Ci-izalkyl; andB1is phenyl.

3. The compound of claim 1 or 2, wherein m is 1.

4. The compound of any one of claims 1 to 3, wherein R3is halogen or CF3.

5. The compound of any one of claims 1 to 4, wherein one or R2or R4is halogen.

6. The compound of any one of claims 1 to 5, wherein G is N.

7. The compound of any one of claims 1 to 6, wherein q is 1 and X is CH2.

8. The compound of any one of claims 1 to 7, wherein halogen is Br, Cl, or F.

9. The compound of any one of claims 1 to 8, wherein C1-12 is C1-6 and C2-12 is C2-6.

10. The compound of any one of claims 1 to 9, wherein C3-12 is C3-6.

11. The compound of any one of claims 1 to 10, wherein the compound has one or more chiral center.

12. The compound of any one of claims 1 to 11, wherein w is 0, 1, 2, or 313. A compound selected from Table #1 or a pharmaceutically acceptable salt thereof.

14. A compound selected from Table #2 or a pharmaceutically acceptable salt thereof.

15. The compound of any one of claims 1 to 15, wherein m is 2, G is N, B1is a six membered monocyclic ring, R3is a halogen, Z is O, X is CH2, q is 1, and Y is C(CH3)3.

16. The compound of any one of claims 1 to 15, wherein m is 1, G is N, B1is a six membered monocyclic ring, R3is a halogen, Z is O, X is CH2, q is 1, and Y is C(CH3)3.

17. The compound of any one of claims 1 to 15, wherein m is 2, G is N, B1is a six membered monocyclic ring, R3is a halogen, R4is a halogen, R6is halogen, Z is O, X is CH2, q is 1, and Y is C(CH3)3.

18. The compound of any one of claims 1 to 15, wherein m is 1, G is N, B1is a six membered monocyclic ring, R3is a halogen, R4is a halogen, R6is halogen, Z is O, X is CH2, q is 1, and Y is C(CH3)3.

19. The compound of any one of claims 1 to 15, wherein m is 2, G is N, B1is a six membered monocyclic ring, R3is a halogen, R6is C1-6 alkyl, R7is C1-6 alkyl, Z is 0, X is CH2, q is 1, and Y is C(CH3)3.

20. The compound of any one of claims 1 to 15, wherein m is 1, G is N, B1is a six membered monocyclic ring, R3is a halogen, R6is C1-6 alkyl, R7is C1-6 alkyl, Z is O, X is CH2, q is 1, and Y is C(CH3)3.

21. The compound of any one of claims 1 to 15, wherein m is 2, G is NH, B1is a six membered monocyclic ring, R3is a halogen, R6is C1-6 alkyl, R7is C1-6 alkyl, Z is O, X is CH2, q is 1, and Y is C(CH3)3.

22. The compound of any one of claims 1 to 15, wherein m is 1, G is NH, B1is a six membered monocyclic ring, R3is a halogen, R6is C1-6 alkyl, R7is C1-6 alkyl, Z is O, X is CH2, q is 1, and Y is C(CH3)3.

23. The compound of any one of claims 1 to 15, wherein m is 2, G is N, B1is a six membered monocyclic ring, R2is halogen, R3is a halogen, R6is a C1-6 alkyl, R7is a C1-6 alkyl, Z is O, X is CH2, q is 1, and Y is C(CH3)3.

24. The compound of any one of claims 1 to 15, wherein m is 1, G is N, B1is a six membered monocyclic ring, R2is a halogen, R3is a halogen, R6is a C1-6 alkyl, R7is a C1-6 alkyl, Z is O, X is CH2, q is 1, and Y is C(CH3)3.

25. A compound of any one of claims 1 -- 24, for use in the treatment of a disease of disorder where modulation of a Kv7 channel is beneficial, for a patient in needed thereof.

26. A method of treating a disease of disorder in a patient in needed thereof where modulation of Kv7 channels is beneficial comprising administering a compound of any one of claims 1 to 24.

27. Use of a compound of any one of claims 1 - 24 in the manufacture of a medicament for the treatment of a disease or disorder disease of disorder where modulation of the Kv7 channels is beneficial, for a patient in needed thereof.

28. The compound, method, use, or compound for use of claims 1-27, to treat one or more of neural disease or disorder, neurodegenerative disease or disorder, vascular diseases, muscle movement disease or disorder, addiction, and pain.

29. The compound, method, use, or compound for use of claim 1-28, wherein the disease is one of a seizure disorder, epilepsy, developmental epileptic encephalopathy, muscle relaxing, acute analgesia, central and or peripheral inflammatory or neuropathic analgesic, pain related to diabetic neuropathy, phantom limb pain; vulvodynia, vulvar vestibulitis syndrome, pelvic pain, endometriotic pain, fibromylagia; depression in all forms, including manic depressive illness with mixed episodes and manic depressive illness with depressive episodes, seasonal affective disorder, bipolar, anxiety, mania; chemical dependencies, including addictions to alcohol, cocaine, amphetamine and other psychostimulants, morphine, heroin and other opioid agonists; Parkinson's diseases, including dementia in Parkinson's disease, neuroleptic-induced parkinsonism or tardive dyskinesias; headache, chronic headache, migraine; withdrawal syndrome; age-associated learning and mental disorders; apathy; bipolar disorder; chronic fatigue syndrome; functional neurological disorder; somatoform disorders such as somatization disorder, conversion disorder, pain disorder; mania; autism, autism spectrum disorders; substance use disorder; addition treatment; schizophrenia; post-traumatic stress disorder; tinnitus, amyotrophic lateral sclerosis, Alzheimer’s disease, multiple sclerosis, optic neuritis, neuro-ophthalmic disorders, CNS damage caused by neurodegenerative illness or diseases or injury, cognitive deficits, compulsive behavior, dementia, Huntington's disease, dystonia, memory impairment, memory disorders, memory dysfunction, motion disorders, motor disorders, neurodegenerative diseases, an ophthalmic condition, progressive hearing loss or tinnitus, drug induced dystonia / dyskinesia, tardive dystonia, neuroleptics induced dystonia, dystonia in Tourette's syndrome patients, dystonia in Restless Leg syndrome patients, dystonia like symptoms in patients with Tics, dystonia-associated dyskinesias, paroxysmal dyskinesias, paroxysmal non-kinesigenic dyskinesia, paroxysmal dystonic choreoathetosis, paroxysmal kinesigenic dyskinesia, as well as attention deficit hyperactivity disorder (ADHD); diabetic hypertension, obesity induced hypertension in a patient in need thereof comprising administering an effective amount of a compound of the present disclosure.

30. The compound, method, use, or compound for use of claims 1-28, to treat the disease is one of a seizure disorder, epilepsy, developmental epileptic encephalopathy, muscle relaxing, acute analgesia, central and or peripheral inflammatory or neuropathic analgesic, pain related todiabetic neuropathy, phantom limb pain; vulvodynia, vulvar vestibulitis syndrome, pelvic pain, endometriotic pain, fibromylagia; depression in all forms, including manic depressive illness with mixed episodes and manic depressive illness with depressive episodes, seasonal affective disorder, bipolar, anxiety, mania; chemical dependencies, including addictions to alcohol, cocaine, amphetamine and other psychostimulants, morphine, heroin and other opioid agonists; Parkinson's diseases, including dementia in Parkinson's disease, neuroleptic-induced parkinsonism or tardive dyskinesias; headache, chronic headache, migraine; withdrawal syndrome; age-associated learning and mental disorders; apathy; bipolar disorder; chronic fatigue syndrome; functional neurological disorder; somatoform disorders such as somatization disorder, conversion disorder, pain disorder; mania; autism, autism spectrum disorders; substance use disorder; addition treatment; schizophrenia; post-traumatic stress disorder; tinnitus, amyotrophic lateral sclerosis, Alzheimer’s disease, multiple sclerosis, optic neuritis, neuro-ophthalmic disorders. CNS damage caused by neurodegenerative illness or diseases or injury, cognitive deficits, compulsive behavior, dementia, Huntington's disease, dystonia, memory impairment, memory disorders, memory dysfunction, motion disorders, motor disorders, neurodegenerative diseases, an ophthalmic condition, progressive hearing loss or tinnitus, drug induced dystonia / dyskinesia, tardive dystonia, neuroleptics induced dystonia, dystonia in Tourette's syndrome patients, dystonia in Restless Leg syndrome patients, dystonia like symptoms in patients with Tics, dystonia-associated dyskinesias, paroxysmal dyskinesias, paroxysmal non-kinesigenic dyskinesia, paroxysmal dystonic choreoathetosis, paroxysmal kinesigenic dyskinesia, as well as attention deficit hyperactivity disorder (ADHD); diabetic hypertension, obesity induced hypertension in a patient in need thereof comprising administering an effective amount of a compound of the present disclosure.

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