Kv7 channel opener prodrug

Abstract

A prodrug of a pharmacologically active 1,2,4-triaminobenzene derivative of general formula (I) or a pharma- ceutically acceptable salt thereof, represented by the symbol R 1 , R 2 , R 3 , R 4 , R 5 , and R 6a , R 6b , and R 6c and the symbol Z is defined. Methods are provided for the synthesis, purification, testing, and use as prodrugs of pharmacologically active agents at Kv7 ion channels. The present disclosure provides, inter alia, compounds useful for the treatment of diseases via modulation of potassium ion flux through voltage-gated potassium channels. JPEG2024511997000049.jpg6687

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefits of U.S. Provisional Application No. 63 / 163,470, filed on 19 March 2021, the contents of which are incorporated herein by reference.

[0002] This disclosure relates to the field of prodrugs of pharmacologically active drugs, and more particularly to the field of prodrugs of drugs active on the Kv7 potassium ion channel. The prodrugs of this disclosure comprise one or more hydrolyzable bonds between a pharmacologically active drug or compound, such as ezogavin, flupirtin, or other chemicals active on the Kv7 potassium ion channel, and a carbonyl-containing prodrug side group, such as a prodrug side group from an amino acid or a carbonyl-containing side group, such as a prodrug side group found in various acetal diester derivatives or ketal diester derivatives, such as a prodrug side group exemplified by gabapentin enacarbil, which is not itself active on the Kv7 potassium ion channel. The hydrolyzable bonds of the prodrugs of this disclosure are cleaved in the body of a mammal to produce a pharmacologically active drug. [Background technology]

[0003] Prodrugs:

[0004] A prodrug is a bioreversible derivative of a drug molecule that must undergo enzymatic and / or chemical transformation in vivo to release the active parent drug, after which it can exert its desired pharmacological effect.

[0005] Generally, prodrugs are biologically inactive compounds that are activated after administration to their pharmacologically active forms. Often, prodrugs are formulated to overcome pharmacokinetic barriers such as poor solubility and absorption, broad first-pass metabolism, lack of brain penetration, or rapid excretion, as well as physicochemical barriers such as instability, undesirable degradation products, or impurities, or pharmacokinetic barriers such as impurities and pharmacodynamic barriers such as toxicity, tolerability, side effects, and insufficient efficacy. Activation of prodrugs usually occurs either through enzymatic processes involving cytochrome enzymes, esterases, and amidases, or through (intermolecular or intramolecular) chemical processes such as hydrolysis and oxidation.

[0006] The development of prodrugs is now a well-established strategy for improving the physicochemical, biopharmaceutical, or pharmacokinetic properties of pharmacologically potent compounds, thereby overcoming barriers to drug development and efficacy.

[0007] Compounds active in the Kv7 potassium ion channel:

[0008] Voltage-gated Kv7 (or KCNQ) channels play a crucial role in regulating membrane excitability. The Kv7 subfamily of voltage-gated potassium channels consists of five members (Kv7.1-5), each exhibiting characteristic tissue distribution and physiological roles. Given their functional heterogeneity, Kv7 channels represent important pharmacological targets for the development of new drugs for neurological, neuromuscular, cardiovascular, and metabolic diseases. Similar to typical voltage-gated ion channels, Kv7 channels undergo a transition from closure to opening by sensing changes in intermembrane potential, thereby reducing membrane excitability through the mediation of an inhibitory K(+) current. Reduced Kv7 channel activity as a result of genetic mutations is a contributing factor to various human diseases resulting from membrane hyperexcitability, including epilepsy, arrhythmias, and hearing loss. Consequently, the discovery of small compounds that activate voltage-gated ion channels is a key strategy for clinical intervention in such disorders. Ligand binding can induce conformational changes that lead to channel opening below the threshold, making it of great interest to understand these "gain-of-function" molecules at a molecular level. Small molecule activators of cation channels are rare, but several novel compounds that activate Kv7 voltage-gated channels have been identified.

[0009] Ezogabin (USAN, or Retigabin [INN]) and Flupirtin are Kv7 K + These are two examples of compounds that were active in the channel and developed into drugs, but are no longer on the market as therapeutic agents.

[0010] Ezogabine is used in conjunction with other medications to control partially originating seizures (seizures involving only a portion of the brain) and focal seizures in adults, acting by reducing neuronal hyperexcitability in the peripheral and central nervous systems. Overall, the most frequently reported adverse reactions (occurring in ≥4% of patients, approximately twice the placebo rate) in patients receiving ezogabine, offered under the brand name POTIGA®, a registered trademark of Valeant Pharmaceuticals North America, were dizziness (23%), somnolence (22%), fatigue (15%), confusion (9%), spatial disorientation (8%), tremor (8%), abnormal coordination (7%), diplopia (7%), attention deficit (6%), memory impairment (6%), asthenia (5%), blurred vision (5%), gait disturbance (4%), aphasia (4%), dysarthria (4%), and balance disturbance (4%). In most cases, the reactions were mild to moderate in severity (Potiga label, revised May 2016).

[0011] Ezogabine has demonstrated efficacy in various cell, tissue, and animal models and clinical trials related to the location of these targets. In addition to blocking seizures, ezogabine has demonstrated pharmacological properties consistent with its use as an analgesic and neuroprotective agent in the treatment of hearing impairment, status epilepticus associated with organophosphate poisoning (Barker 2021, Neuroscience), and demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis. Ezogabine provides important information and clues regarding a novel mechanistic approach to the treatment of a range of clinical conditions involving neuronal hyperexcitability.

[0012] Flupirutin is used as a primary analgesic in patients with a range of acute and persistent pain conditions without the characteristic adverse effects of opioids and nonsteroidal anti-inflammatory drugs, and is well-tolerated by the majority of the patient population. The pharmacological profile exhibited by flupirutin involves action on several cellular targets, including Kv7 channels, G protein-regulated inward rectifying K channels, and γ-aminobutyric acid type A receptors, although there is also evidence of further unconfirmed mechanisms of action involved in the effects of flupirutin.

[0013] Flupirutin demonstrated efficacy against various cells and tissues associated with these target locations. In addition to analgesia, flupirutin demonstrated pharmacological properties consistent with its use as an anticonvulsant, neuroprotective, and skeletal and smooth muscle relaxant in the treatment of hearing and visual impairments, as well as memory and cognitive impairments. Flupirutin provides important information and clues regarding a novel mechanistic approach to the treatment of a range of clinical conditions involving cellular hyperexcitability. However, flupirutin has several undesirable side effects, including nausea, vomiting, dizziness, itching, rash formation, abdominal pain, bloating, tremor, dry mouth, idiopathic hepatotoxicity, and fatigue.

[0014] More specifically, pharmacologically active compounds that interact with the Kv7.2 channel subtype have also been studied (https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC2932606 / ), and these may be useful as compounds that could potentially be developed into drugs in the future. However, to date, only two drugs, ezogavin and flupirtin, have been approved and administered to humans as pharmaceuticals.

[0015] The Kv7 channel presents an intriguing target for novel therapeutic approaches to neuronal hyperexcitability-induced disorders such as epilepsy, neuropathic pain, and migraine. The molecular mechanism of retigabine-mediated Kv7 activation has been elucidated as stabilization of the open structure by binding to the pore region of the Kv7 channel (J Physiol, Maljevic. 2008).

[0016] Literature reviews demonstrate, or are potentially effective in treating, improving, or preventing the progression of, Kv7 channel openers such as retigabine, or pharmacological effects that enhance the opening state of Kv72-5 subtypes, in a group of diseases or disorders selected from neurological indications and pain-related disorders. In one example, channel opening has been demonstrated to be influenced by the basal channel current that sets the resting membrane threshold. Enhancement of the membrane threshold, consisting of seizure neurons from Kv7.2(S559A) knock-in mice, showed normal basal M currents. The knock-in mice showed reduced M current suppression when challenged with muscarinic agents, and oxotremol-M.Kv7.2(S559A) mice were resistant to chemospasmodic-induced seizures and did not die. Administration of the Kv7.2 blocker XE991 transiently worsened seizures in knock-in mice to a degree comparable to wild-type mice. After experiencing an epileptic state, Kv7.2(S559A) knock-in mice showed neither seizure-induced cell death nor spontaneous recurrent seizures. (L Greene, Epilepsia 2018) This example demonstrates how channel opening blocks seizures and neuroprotection. The Kv7.2 channel opener ICA-105665 reduced patient SPR with single doses of 100 mg (1 in 4), 400 mg (2 in 4), and 500 mg (4 in 6). This is the first evaluation of the effect of Kv7 potassium channel activation in photosensitivity demonstration of a conceptual model. The reduction in SPR in this patient population provides evidence of central nervous system (CNS) penetration of ICA-105665 and preliminary evidence that engagement with neuronal Kv7 potassium channels has an anti-seizure effect. (Epilepsia, Trenite, 2013).

[0017] In models of pain, more specifically neuropathic pain, and chronic headache, paclitaxel-induced peripheral neuropathy and associated neuropathic pain are severe and resistant to intervention. Results from rodent models demonstrated that retigabine / ezogabine may be used to suppress the development of paclitaxel-induced peripheral neuropathy (J Pain, Li. 2019).

[0018] Several drugs, including flupirtin and retigabine, enhance neuronal Kv7 / M channel activity, primarily through a hyperpolarization shift in their voltage gating. As a result, they can reduce neuronal excitability and inhibit nociceptive stimulation and transmission. Flupirtin is one of the best-selling non-opioid analgesics in Europe and served as a central analgesic before being removed from the market. Retigavin, an analog of flupirtin, is approved as an adjunctive therapy for partially originating seizures and is a broad-spectrum anticonvulsant in animals, effective analgesic in animal models of chronic inflammatory and neuropathic pain, central pain, pain associated with diabetic neuropathy, postherpetic neuralgia, and peripheral nerve injury (Brown Br J Pharmacology, 2009).

[0019] Czuzcwar further summarizes preclinical data indicating that retigabine / ezogabine may be applicable to patients with neuropathic pain and mood disorders, such as drug dependence and mood disorders. Early clinical data suggest that retigabine may also be effective in Alzheimer's disease or stroke. (Czuzcwar, Pharmacological Reports 2010)

[0020] Numerous studies have shown that Kv7 channel opening may be effective for many neurological therapeutic targets, including but not limited to anxiety, CNS damage caused by neurodegenerative diseases or illnesses or injuries, cognitive impairment, obsessive-compulsive behavior, dementia, depression, Huntington's disease, dystonia, and mania. Since retigabine / ezogaibin and flupirtin are well-tolerated in humans, current findings of their remarkable anti-dystonia efficacy in dtsz mutant mice suggest that neuronal Kv7 channel activators are interesting candidates for the treatment of dystonia-associated dyskinesia and possibly other types of dystonia. The established analgesic effects of Kv7 channel openers may contribute to the improvement of these disorders, which often involve painful muscle spasms (Richter, Br J Pharmacology 2006).

[0021] Recent studies suggest that retigabine may delay the progression of depolarization signs after submaximal OGD stimulation (Aiba, Brain 2021). Interestingly, Kv7.2 activators have been neuroprotective in experimental ischemia and traumatic brain injury studies, and the anti-diffusion depolarizing properties of activators may contribute to these neuroprotective effects. Further reviews of recent studies support a new role for Kv7 channels in essential and synaptic plasticity, as well as their contributions to cognition and behavior. Voltage-gated potassium channels of the KV7 family (KV7.2-5) play a crucial role in regulating neuronal excitability and are therefore attractive targets for the treatment of CNS disorders associated with hyperexcitability, and such disorders as cognitive impairment, memory impairment, memory disorder, and memory failure. (For example, Boehm,Pain 2019, Maghera,Epilepsia 2020, De Jong,Physiological Reports 2018, Jakubowski,Epilepsy Behav 2013, Zizhen Wu,J Pharmacol Exp Ther 2020, JE Larsson,In Physiology 2020, Yadav,Saudi J Anaesth 2017, Garakani,Front Psychiatry 2020, Maljevic,J Physiol 2008, R.Brant,Gastroenterology 2017, Hui Sun,JCI Insight 2019, R Brant,Gastroenterology 2017, Ravi Misra,Gastroenterology 2017, Parreno,Front Physiol 2020, Blom,PLoS One.2014)(Feng neuroscience (2019) (E Redford, Physiol Biochem 2021) (J Gunthrope, Epilepsia 2012, Epilepsia, Villalba. 2018) (See Frontal Physiol, Baculis. 2020, Frontal Physoil, Vigil. 2020).

[0022] Given the importance of Kv7 channels for neonatal brain development and inhibition (Peters et al., 2005; Soh et al., 2014), memory impairment in these gene models may be due to abnormal hippocampal morphology and / or hyperexcitability (Peters et al., 2005; Milh et al., 2020). Kv7 channels also regulate several behaviors. Behavioral phenotyping of global or conditional homozygous KCNQ2 knockout mice was impossible due to early postnatal lethality or premature death, respectively (Watanabe et al., 2000; Soh et al., 2014). However, heterozygous KCNQ2 knockout mice are viable and exhibit increased spontaneous motor activity and exploratory behavior, consistent with behavioral hyperactivity induced by transgenic suppression of Kv7 current (Peters et al., 2005) and amphetamine and XE991 (Sotty et al., 2009) (Kim et al., 2020). These mice also exhibit reduced socialization and increased repetitive and compulsive behaviors (Kim et al., 2020), reminiscent of autism observed in some EE patients with dominant KCNQ2 mutations (Weckhuysen et al., 2012, 2013, Milh et al., 2013).

[0023] Recent animal studies have shown that enhancing M current (Kv7 opening) makes it a potential therapeutic target for multiple brain disorders, including those for which there are currently no treatments, such as TBI and stimulant addiction and movement disorders (Lee, J Neurophysio 2017), motor disorders, neurodegenerative diseases, Parkinson's disease, Parkinsonian movement disorders (Jama Neurol, Wainger. 2021, Neurosci Bull, Chen. 2017, Neural Plast, Ramirez. 2015), phobias, Pick's disease, psychosis, and bipolar disorder (Frontal Physoil, Vigil. 2020).

[0024] Spinal cord injury may be treatable by reducing neuronal activity, thereby opening the KCNQ / Kv7 channel to protect spinal cord neurons and axons from degeneration after injury, and thereby promoting the recovery of motor and sensory functions. Our study demonstrated that repeated application of retigabine to open these channels in the acute phase of injury promoted neurobehavioral recovery after spinal cord injury (Wu, J Pharmacol 2020).

[0025] Because organophosphates play a physiologically important role, dysfunctional Kv7 channels are often associated with disorders characterized by abnormal potassium ion conductance, including cardiac arrhythmias, hearing impairment, epilepsy, pain, and hypertension (Front Physiol, Larsson. 2020, J Physoil, Maljevic. 2008).

[0026] Lee et al.'s research provides evidence that mouse Kv7 channels may contribute in different ways to the modulation of the functional characteristics of cerebral and coronary arteries. Such heterogeneity has important implications for the development of new therapeutic agents for cardiovascular dysfunction. (Lee, Microcirculation, 2015).

[0027] Finally, the Kv7 channel presents an intriguing target for novel therapeutic approaches to neuronal hyperexcitability-induced disorders such as epilepsy, neuropathic pain, and migraine. The molecular mechanism of retigabine-mediated Kv7 activation has recently been elucidated as stabilization of opening conformation through binding to foramen regions, which may be important in the treatment of migraine and tension headaches (J Physoil, Maljevic. 2008).

[0028] Further experiments demonstrated that M-current inhibition requires simultaneous elevation of cytoplasmic Ca2+ concentration and depletion of membrane phosphatidylinositol 4,5-bisphosphate (PIP2). Inhibition of M-currents in sensory neurons mediated by PLC and Ca2 / PIP2 may represent one of the common mechanisms underlying pain generated by inflammatory mediators, and thus may open a new therapeutic window for treating this major clinical problem in intestinal diseases, which are inflammatory diseases such as ulcerative colitis, Crohn's disease, and Creutzfeldt-Jakob disease (J Neurosci, Linley. 2008).

[0029] 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 for peripheral hypertension.

[0030] Published data suggest that chemical channel openers can protect against degeneration and progression of hearing loss in a DFNA2 mouse model that may be useful for progressive hearing loss or tinnitus by stabilizing KCNQ4-mediated conductance (Kv7.4) in cells related to hearing (J Physoil, Maljevic. 2008).

[0031] Behavioral studies demonstrated that SF0034 is a more potent and less toxic anticonvulsant than retigabine in rodents. Furthermore, SF0034 prevented the development of tinnitus in mice. We propose that SF0034 not only provides a powerful tool for studying ion channel properties, but most importantly, offers a clinical candidate for the treatment of epilepsy and the prevention of tinnitus (Br J Pharmacol, Leithner. 2014, J Neurosci, Kalappa. 2015).

[0032] The functional role of Kv7 channels can vary depending on cell type. Several studies have demonstrated that Kv7 channel dysfunction strongly impacts pulmonary physiology, contributing to the pathophysiology of various respiratory diseases such as cystic fibrosis, asthma, chronic obstructive pulmonary disease, chronic cough, lung cancer, and pulmonary hypertension. Kv7 channels are now recognized to play relevant physiological roles in many tissues, which has spurred the search for Kv7 channel modulators with potential therapeutic applications in many diseases, including those affecting the lungs. Modulation of Kv7 channels has been proposed to provide beneficial effects in many lung conditions. Therefore, Kv7 channel openers / enhancers or drugs that act partially through these channels have been proposed as bronchodilators, expectorants, antitussives, chemotherapeutic agents and pulmonary vasodilators (Front Physiol, Mondejar-Parreno. 2020), and agents for obesity and disease-related hypertension (Front Cardivasc Med, Fosmo. 2017).

[0033] Further research on autism and autism spectrum disorder may suggest that administering compounds that have the potential to positively modulate Kv7 channels may be effective in treating these neurological disorders. Data suggest that dysfunction of heteromeric KV7.3 / 5 channels is involved in the pathogenesis of several forms of autism spectrum disorder, 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).

[0034] Several background documents are incorporated herein by reference with respect to such teachings.

[0035] These compounds, which can interact with the Kv7.2 channel subtype, specifically need to be delivered more effectively as prodrugs possessing improved properties in one or more of the physicochemical, biopharmaceutical, or pharmacokinetic characteristics of pharmacologically potent compounds. [Overview of the project] [Means for solving the problem]

[0036] This disclosure provides compounds useful for treating diseases, particularly through the regulation of potassium ion flux through voltage-dependent potassium channels. More specifically, this disclosure provides prodrugs, compositions, and methods of compounds useful for treating central or peripheral nervous system disorders (e.g., migraine, ataxia, Parkinson's disease, bipolar disorder, trigeminal neuralgia, convulsions, mood disorders, brain tumors, psychiatric disorders, myokymia, seizures, epilepsy, hearing and vision loss, dysmenorrhea, vulvodynia, dyspareunia, pain associated with endometriosis, multiple sclerosis, amyotrophic lateral sclerosis, spasticity, spasms, autism, Alzheimer's disease, age-related memory loss, learning disabilities, organophosphate exposure, anxiety and motor neuron diseases, central and peripheral neuropathic pain conditions), as well as neuroprotective agents (e.g., for preventing stroke, spinal cord and brain injury, retinal degeneration, etc.). The compounds of this disclosure are used as prodrugs for the treatment of convulsive states, such as grand mal seizures, petit mal seizures, psychomotor epilepsy, or focal seizures. When metabolized or converted into active compounds, the prodrug compounds of this disclosure are also useful for the treatment of disease conditions such as restless limb syndrome and postherpetic neuralgia.

[0037] Furthermore, the compounds of this disclosure are useful as prodrugs in the treatment of pain, such as neuropathic pain, diabetic pain, inflammatory pain, cancer pain, migraine, vulvar pain, abdominal pain, and musculoskeletal pain. The compounds are also prodrugs that are metabolized in vivo to produce active compounds useful for treating pain, such as conditions that may be the origin of inflammatory conditions, including arthritis (e.g., rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, and gouty arthritis) and non-arthritis inflammatory conditions (e.g., herniated, ruptured, and prolapsed disc syndrome, bursitis, tendinitis, tenosynovitis, fibromyalgia syndrome, and other conditions associated with ligament sprains and focal musculoskeletal tension) and pain associated with neurodemyelinating diseases. Particularly preferred compounds of this disclosure may exhibit lower central nervous system side effects, such as dizziness and somnolence, due to more controlled release of the active drug. Furthermore, the compounds of this disclosure are prodrugs that are metabolized in vivo to compounds useful for treating conditions and pain associated with abnormally elevated skeletal muscle tone.

[0038] The compounds of this disclosure are also prodrugs of compounds used to treat anxiety (e.g., anxiety disorders) and depression. These disorders include separation anxiety disorder, situational mutism, specific phobias, social anxiety disorder (sociophobia), panic disorder, agoraphobia, generalized anxiety disorder, substance / drug-induced anxiety disorder, and anxiety disorders due to other medical conditions.

[0039] Anxiety can also occur as a symptom associated with other mental disorders, such as obsessive-compulsive disorder, post-traumatic stress disorder, schizophrenia, mood disorders, and major depressive disorder, as well as organic clinical conditions including, but not limited to, Parkinson's disease, multiple sclerosis, and other physical disabilities.

[0040] In light of the above findings, this disclosure provides prodrugs of compounds, compositions comprising these prodrugs of compounds, and methods for increasing the ion flux of voltage-dependent potassium channels, particularly channels carrying M current. As used herein, terms such as “M current” and “channels carrying M current” refer to slowly activated, deactivated, and slowly deactivated voltage-gated K+ Refers to a channel. The M current is active at voltages near the threshold for action potential generation in a variety of nerve cells and is thus an important modulator of nerve excitability.

[0041] Members of the voltage-dependent potassium channel family have been shown to be directly involved in diseases of the central or peripheral nervous system. Here, prodrugs of the compounds provided herein have been shown to metabolize and release compounds that act as potassium channel regulators, particularly openers, for heteromultimer channels such as KCNQ2 and KCNQ3, KCNQ4 and KCNQ5, and KCNQ2 / 3, KCNQ3 / 5 or the M current.

[0042] One embodiment of the present disclosure is a compound of formula (I): [Chemical formula] (wherein, R 1 is C 1~6 alkyl, C 1~6 alkoxy, C 1~6 alkyl-C 3~6 cycloalkyl, R 2 is H, C 1~3 alkyl, C 1~3 alkoxy, halogen, C 1~3 haloalkoxy, Z is N or CH, R 3 is "Pro", and "Pro" is selected from the group consisting of C(O)R 10 , R 10 is an alkylamine-containing residue, a glycine residue, a theanine residue, a lysine residue, and a D-serine residue, and is selected from the group consisting of R 4 and R 5 each independently is H, or R 4and R 5 However, together with the atoms to which they bond, they optionally form a 5-6 membered ring containing a degree of unsaturation of 1 or more. R 6a , R 6b , and R 6c Each of them is independently H or halogen, and R 6a , R 6b , and R 6c (At least one of them is H), or a pharmaceutically acceptable salt thereof.

[0043] One embodiment of the present disclosure is a compound of formula II. [ka] (In the formula, R 1 However, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkyl-C 3~6 It is a cycloalkyl, R 2 However, H, C 1~3 Alkyl, C 1~3 Alkyl, halogen, C 1~3 It is a haloalkoxy, R 3 However, it is "Pro", and "Pro" is C(O)R 10 Selected from the group consisting of, R 10 but, alkylamine-containing residues, Glycine residue, Theanine residue, Lysine residues, and, Selected from the group consisting of D-serine residues, R 4 and R 5 Each of them independently is H, or R 4 and R 5 However, together with the atoms to which they bond, they optionally form a 5-6 membered ring containing a degree of unsaturation of 1 or more. R 6a , R 6b , and R6c Each of them is independently H or halogen, and R 6a , R 6b , and R 6c (At least one of them is H), or a pharmaceutically acceptable salt thereof.

[0044] One embodiment of the present disclosure is a compound of formula IV: [ka] (In the formula, R 1 However, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkyl-C 3~6 It is a cycloalkyl, R 2 However, H, C 1~3 Alkyl, C 1~3 Alkyl, halogen, C 1~3 It is a haloalkoxy, Z is either N or CH, R 10 but, alkylamine-containing residues, Glycine residue, Theanine residue, Lysine residues, and, Selected from the group consisting of D-serine residues, R 4 and R 5 Each of them independently is H, or R 4 and R 5 However, together with the atoms to which they bond, they optionally form a 5-6 membered ring containing a degree of unsaturation of 1 or more. R 6a , R 6b , and R 6c Each of them is independently H or halogen, and R 6a , R 6b , and R 6c (At least one of them is H), or a pharmaceutically acceptable salt thereof.

[0045] One embodiment of the present disclosure is a compound of formula IV-A: [ka] (In the formula, The dashed lines that are drawn represent enantiomers. or a pharmaceutically acceptable salt thereof.

[0046] One embodiment of this disclosure comprises a compound or a pharmaceutically acceptable salt thereof: [ka]

[0047] One embodiment of this disclosure comprises a compound or a pharmaceutically acceptable salt thereof: [ka]

[0048] One embodiment of this disclosure comprises a compound or a pharmaceutically acceptable salt thereof: [ka]

[0049] One embodiment of the present disclosure includes a pharmaceutical composition comprising a compound of the present disclosure and one or more pharmaceutically acceptable excipients.

[0050] One embodiment of the present disclosure includes a pharmaceutical composition comprising a compound of the present disclosure and one or more pharmaceutically acceptable excipients.

[0051] One embodiment of the present disclosure includes a method for inducing one or more of the following effects in a patient who requires the induction of one or more of the following effects: antiepileptic, muscle relaxant, fever reducer, peripheral analgesic, or anticonvulsant, comprising administering an effective amount of the compound of the present disclosure.

[0052] One embodiment of the present disclosure describes depression in cancer patients, depression in Parkinson's disease patients, depression after myocardial infarction, depression in human immunodeficiency virus (HIV) patients, subsyndromal symptomatic depression, depression in infertile women, childhood depression, major depression, single-episode depression, recurrent depression, child abuse-induced depression, postpartum depression, DSM-IV major depression, treatment-refractory major depression, severe depression, psychotic depression, post-stroke depression, neuropathic pain, manic-depressive disorders including mixed episodes and manic-depressive disorders including depressive episodes, seasonal affective disorder, bipolar depression BP I, and bipolar depression BP II. Depression, including major depressive disorder with mood swings; mood swings; phobias, including agoraphobia, social phobia, or simple phobias; eating disorders, including anorexia nervosa or bulimia nervosa; drug dependence, including dependence on alcohol, cocaine, amphetamines and other psychostimulants, morphine, heroin and other opioid agonists, phenobarbital and other barbiturates, nicotine, diazepam, benzodiazepines and other psychoactive substances; Parkinson's disease, including dementia, neuroleptic dysphoria, or tardive dyskinesia; headaches, including headaches associated with vascular disorders; withdrawal syndromes; age-related learning and mental disorders; apathy; bipolar disorder, chronic fatigue syndrome; chronic or acute stress; behavioral disorders; cyclothymic disorders; somatization disorders, conversion disorders, pain disorders, hypochondriasis, body dysmorphic disorder, undifferentiated disorder, and somatoform disorders such as somatoform NOS; incontinence; inhalation disorders; intoxication disorders Methods for treating one or more of the following: disorder; mania; oppositional defiant disorder; peripheral neuropathy; post-traumatic stress disorder; late luteal phase dysphoria; certain developmental disorders; SSRI "poop out" syndrome, or the inability of a patient to maintain a satisfactory response to SSRI therapy after an initial period of satisfactory response; and tic disorders, including Tourette's disease.

[0053] One embodiment of the present disclosure involves administering the compounds of the present disclosure for the treatment of seizures, pain, neuropathic pain, chronic headache, central pain, diabetic neuropathy, postherpetic neuralgia and pain associated with peripheral nerve injury; drug addiction, mood disorders, Alzheimer's disease, anxiety, CNS damage caused by neurodegenerative disease (illness) or disease or injury, cognitive impairment, obsessive-compulsive behavior, dementia, depression, Huntington's disease, dystonia, mania, cognitive impairment, memory impairment, memory loss Disorder, memory impairment, movement disorders, motor dysfunction, neurodegenerative diseases, Parkinson's disease, Parkinsonian movement disorder, phobias, Pick's disease, psychosis, bipolar disorder, schizophrenia (subtypes of schizophrenia include catatonic subtype, paranoid subtype, disorganized subtype, or residual subtype), spinal cord injury, cardiomyopathy, cardiac arrhythmias, QT prolongation syndrome, movement disorders, or motor dysfunction, myasthenia gravis, migraines, tension headaches, bowel disorders, inflammation The present invention includes methods for treating, improving, or preventing the progression of a disease or disorder selected from the group consisting of symptomatic diseases, ulcerative colitis, Crohn's disease, Creutzfeldt-Jakob disease, eye conditions, progressive hearing loss or tinnitus, fever, multiple sclerosis, diabetes mellitus, or metastatic tumor growth, aluminism, anthrax, asbestos disease, lithiasis, trichiasis, iron deposition, silicosis, tobacco-related diseases and pulmonary contaminants such as sinusitis, as well as chronic obstructive pulmonary disease (COPD), and obesity and disease-related hypertension.

[0054] One embodiment of the present disclosure includes a method for treating one or more motor disorders, including primary dystonia, paroxysmal dystonia, secondary dystonia, drug-induced dystonia / dyskinesia, tardive dystonia, neuroleptic-induced dystonia, treatment-induced dystonia / dyskinesia in patients with Parkinson's disease, genetically altered dystonia, dystonia in patients with Huntington's disease, dystonia in patients with Tourette syndrome, dystonia in patients with restless limb syndrome, dystonia-like symptoms in patients with tics, dystonia-associated dyskinesia, paroxysmal dyskinesia, paroxysmal non-exercise-induced dyskinesia, paroxysmal dystonic choreoatetosis, paroxysmal motion-induced dyskinesia, paroxysmal exercise-induced choreoatetosis, exercise-induced dyskinesia, paroxysmal sleep-induced dyskinesia, drug-induced dyskinesia, myokymia, neuromyotonia, autism, autism spectrum disorder, and administration of the compounds of the present disclosure.

[0055] One embodiment of the present disclosure includes a method for treating one or more susceptible diseases or susceptible disorders by administering a compound of the present disclosure, thereby delivering a broad-spectrum Kv7.2-7.5 active molecule into the systemic circulation and releasing the active Kv channel opener at an effective therapeutic concentration. In one embodiment, the release of the active molecule is Enhanced by increased absorption via clinical administration routes, The time to onset is delayed in order to improve adverse events that occur during treatment, and By delaying circulation and release, the half-life or residence time is increased. This eliminates the need to develop formulations for modification, sustained release, delayed release, or extended release, provided under one or more of the following conditions.

[0056] One embodiment of the present disclosure includes a method for enhancing chemical stability and reducing impurities and degradation products in the manufacture of active pharmaceutical ingredients and medicinal products, thereby improving the use and tolerability of the drug.

[0057] One embodiment of the present disclosure involves the use of a compound of the present disclosure for the manufacture of a drug to induce one or more of the following effects in a patient who requires the induction of one or more of the following effects: antiepileptic, muscle relaxant, fever reducer, peripheral analgesic, or anticonvulsant.

[0058] One embodiment of the present disclosure describes depression in cancer patients, depression in Parkinson's disease patients, depression after myocardial infarction, depression in human immunodeficiency virus (HIV) patients, subsyndromal symptomatic depression, depression in infertile women, childhood depression, major depression, single-episode depression, recurrent depression, child abuse-induced depression, postpartum depression, DSM-IV major depression, treatment-refractory major depression, severe depression, psychotic depression, post-stroke depression, neuropathic pain, manic-depressive disorders including mixed episodes and manic-depressive disorders including depressive episodes, seasonal affective disorder, bipolar depression BP I, and bipolar depression BP II. Depression, including major depressive disorder with mood swings; mood swings; phobias, including agoraphobia, social phobia, or simple phobias; eating disorders, including anorexia nervosa or bulimia nervosa; drug dependence, including dependence on alcohol, cocaine, amphetamines and other psychostimulants, morphine, heroin and other opioid agonists, phenobarbital and other barbiturates, nicotine, diazepam, benzodiazepines and other psychoactive substances; Parkinson's disease, including dementia, neuroleptic dysphoria, or tardive dyskinesia; headaches, including headaches associated with vascular disorders; withdrawal syndromes; age-related learning and mental disorders; apathy; bipolar disorder, chronic fatigue syndrome; chronic or acute stress; behavioral disorders; cyclothymic disorders; somatization disorders, conversion disorders, pain disorders, hypochondriasis, body dysmorphic disorder, undifferentiated disorder, and somatoform disorders such as somatoform NOS; incontinence; inhalation disorders; intoxication disorders This includes the use of the compounds of this disclosure for the manufacture of agents for the treatment of one or more of the following conditions: disorder; mania; oppositional defiant disorder; peripheral neuropathy; post-traumatic stress disorder; late luteal phase dysphoria; certain developmental disorders; SSRI "poop out" syndrome, or the inability of a patient to maintain a satisfactory response to SSRI therapy after an initial period of satisfactory response; and tic disorders, including Tourette's disease.

[0059] One embodiment of the present disclosure relates to pain associated with seizures, pain, neuropathic pain, chronic headache, central pain, diabetic neuropathy, postherpetic neuralgia and peripheral nerve injury; drug addiction, mood disorders, Alzheimer's disease, anxiety, CNS damage caused by neurodegenerative disease (illness) or disease or injury, cognitive impairment, obsessive-compulsive behavior, dementia, depression, Huntington's disease, dystonia, mania, cognitive impairment, memory impairment, memory loss Disorders, memory impairment, motor disorders, motor dysfunction, neurodegenerative diseases, Parkinson's disease, Parkinsonian-like motor dysfunction, phobias, Pick's disease, psychosis, bipolar disorder, schizophrenia (subtypes of schizophrenia include catatonic subtype, paranoid subtype, disorganized subtype, or residual subtype), spinal cord injury, cardiomyopathy, cardiac arrhythmias, QT prolongation syndrome, motor disorders, or motor dysfunction, myasthenia gravis, migraines, tension headaches, bowel diseases, inflammatory diseases, ulcerative colon This includes the use of the compounds of this disclosure for the manufacture of agents for treating, improving or preventing the progression of diseases or disorders selected from the group consisting of inflammation, Crohn's disease, Creutzfeldt-Jakob disease, eye conditions, progressive hearing loss or tinnitus, fever, multiple sclerosis, diabetes mellitus, or metastatic tumor growth, aluminism, anthrax, asbestositis, lithiasis, trichiasis, iron deposition, silicosis, tobacco-related diseases and pulmonary contaminants such as sinusitis, and chronic obstructive pulmonary disease (COPD), as well as obesity and disease-related hypertension.

[0060] One embodiment of the present disclosure relates to primary dystonia, paroxysmal dystonia, secondary dystonia, drug-induced dystonia / dyskinesia, tardive dystonia, neuroleptic-induced dystonia, treatment-induced dystonia / dyskinesia in Parkinson's disease patients, genetically altered dystonia, dystonia in Huntington's disease patients, dystonia in Tourette syndrome patients, dystonia in restless limb syndrome patients, dystonia-like symptoms in tic patients, and dystonia-associated dyskinesia. The use of the compounds of this disclosure for the manufacture of agents for treating one or more movement disorders, including dialysis, paroxysmal dyskinesia, paroxysmal non-exercise-induced dyskinesia, paroxysmal dystonic choreoatetosis, paroxysmal motion-induced dyskinesia, paroxysmal exercise-induced choreoatetosis, exercise-induced dyskinesia, paroxysmal sleep-induced dyskinesia, drug-induced dyskinesia, myokymia, neuromyotonia, autism, autism spectrum disorder, and administration of the compounds of this disclosure.

[0061] One embodiment of the present disclosure includes the use of the compounds of the present disclosure for the manufacture of agents for treating one or more susceptible diseases or susceptibility disorders by delivering broad-spectrum Kv7.2-7.5 active molecules into the systemic circulation and releasing the active Kv channel opener at an effective concentration of therapeutic value. In one embodiment, the release of the active molecule is Enhanced by increased absorption, The time to onset is delayed in order to improve adverse events that occur during treatment, and By delaying circulation and release, the half-life or residence time is increased. This eliminates the need to develop formulations for modification, sustained release, delayed release, or extended release, provided under one or more of the following conditions.

[0062] One embodiment of the present disclosure includes a compound of the present disclosure for use in inducing one or more of the following effects in a patient who requires the induction of one or more of the following effects: antiepileptic, muscle relaxant, fever reducer, peripheral analgesic, or anticonvulsant.

[0063] One embodiment of the present disclosure describes depression in cancer patients, depression in Parkinson's disease patients, depression after myocardial infarction, depression in human immunodeficiency virus (HIV) patients, subsyndromal symptomatic depression, depression in infertile women, childhood depression, major depression, single-episode depression, recurrent depression, child abuse-induced depression, postpartum depression, DSM-IV major depression, treatment-refractory major depression, severe depression, psychotic depression, post-stroke depression, neuropathic pain, manic-depressive disorders including mixed episodes and manic-depressive disorders including depressive episodes, seasonal affective disorder, bipolar depression BP I, and bipolar depression BP II. Depression, including major depressive disorder with mood swings; mood swings; phobias, including agoraphobia, social phobia, or simple phobias; eating disorders, including anorexia nervosa or bulimia nervosa; drug dependence, including dependence on alcohol, cocaine, amphetamines and other psychostimulants, morphine, heroin and other opioid agonists, phenobarbital and other barbiturates, nicotine, diazepam, benzodiazepines and other psychoactive substances; Parkinson's disease, including dementia, neuroleptic dysphoria, or tardive dyskinesia; headaches, including headaches associated with vascular disorders; withdrawal syndromes; age-related learning and mental disorders; apathy; bipolar disorder, chronic fatigue syndrome; chronic or acute stress; behavioral disorders; cyclothymic disorders; somatization disorders, conversion disorders, pain disorders, hypochondriasis, body dysmorphic disorder, undifferentiated disorder, and somatoform disorders such as somatoform NOS; incontinence; inhalation disorders; intoxication disorders The compounds of this disclosure are for use in the treatment of one or more of the following: disorder; mania; oppositional defiant disorder; peripheral neuropathy; post-traumatic stress disorder; late luteal phase dysphoria; certain developmental disorders; SSRI "POOP OUT" syndrome, or the inability of a patient to maintain a satisfactory response to SSRI therapy after an initial period of satisfactory response; and tic disorders, including Tourette's disease.

[0064] One embodiment of the present disclosure describes conditions such as seizures, pain, neuropathic pain, chronic headache, central pain, diabetic neuropathy, postherpetic neuralgia and pain associated with peripheral nerve injury; drug addiction, mood disorders, Alzheimer's disease, anxiety, CNS damage caused by neurodegenerative diseases (illness) or diseases or injuries, cognitive impairment, obsessive-compulsive behavior, dementia, depression, Huntington's disease, dystonia, mania, cognitive impairment, memory impairment, memory disorder, memory failure, movement disorders, motor disorders, neurodegenerative diseases, Parkinson's disease, Parkinsonian movement disorders, phobias, Pick's disease, psychosis, bipolar disorder, schizophrenia (schizophrenia subtypes being catatonic subtype, paranoid subtype, disorganized subtype or residual subtype), spinal cord injury, cardiomyopathy (cardiomyopathia), cardiac arrhythmias, QT prolongation syndrome, movement disorders or motor disorders, myasthenia gravis, migraines, tension headaches, bowel diseases, and inflammatory diseases. The present disclosure includes compounds for use in the treatment, improvement, or prevention of progression of diseases or disorders selected from the group consisting of ulcerative colitis, Crohn's disease, Creutzfeldt-Jakob disease, eye conditions, progressive hearing loss or tinnitus, fever, multiple sclerosis, diabetes mellitus, or metastatic tumor growth, aluminism, anthrax, asbestositis, lithiasis, trichiasis, iron deposition, silicosis, tobacco-related diseases and pulmonary contaminants such as sinusitis, as well as chronic obstructive pulmonary disease (COPD), and obesity and disease-related hypertension.

[0065] One embodiment of the present disclosure includes a compound of the present disclosure for use in the treatment of one or more movement disorders, including primary dystonia, paroxysmal dystonia, secondary dystonia, drug-induced dystonia / dyskinesia, tardive dystonia, neuroleptic-induced dystonia, treatment-induced dystonia / dyskinesia in patients with Parkinson's disease, genetically altered dystonia, dystonia in patients with Huntington's disease, dystonia in patients with Tourette syndrome, dystonia in patients with restless limb syndrome, dystonia-like symptoms in patients with tics, dystonia-associated dyskinesia, paroxysmal dyskinesia, paroxysmal non-exercise-induced dyskinesia, paroxysmal dystonic choreoatetosis, paroxysmal motion-induced dyskinesia, paroxysmal exercise-induced choreoatetosis, exercise-induced dyskinesia, paroxysmal sleep-induced dyskinesia, drug-induced dyskinesia, myokymia, neuromyotonia, autism, autism spectrum disorder, and administration of the compounds of the present disclosure.

[0066] One embodiment of the present disclosure includes a compound of the present disclosure for use in treating one or more susceptible diseases or susceptibility disorders by delivering a broad-spectrum Kv7.2-7.5 active molecule into the systemic circulation and releasing the active Kv channel opener at an effective therapeutic concentration. In one embodiment, the release of the active molecule is: Enhanced by increased absorption, The time to onset is delayed in order to improve adverse events that occur during treatment, and By delaying circulation and release, the half-life or residence time is increased. This eliminates the need to develop formulations for modification, sustained release, delayed release, or extended release, provided under one or more of the following conditions.

[0067] One or more aspects and embodiments, which are not specifically described, may be incorporated into different embodiments. That is, all aspects and embodiments may be combined in any way or in any combination. In embodiments of the present invention, for example, the following items are provided. (Item 1) Compounds of formula I: [ka] (In the formula, R 1 However, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkyl-C 3~6 It is a cycloalkyl, R 2 However, H, C 1~3 Alkyl, C 1~3 Alkyl, halogen, C 1~3 It is a haloalkoxy, Z is either N or CH, R 3 However, it is "Pro", and "Pro" is C(O)R 10 Selected from the group consisting of, R 10 but, alkylamine-containing residues, Glycine residue, Theanine residue, Lysine residues, and, Selected from the group consisting of D-serine residues, R 4 and R 5 Each of them independently is H, or R 4 and R 5 However, together with the atoms to which they bond, they optionally form a 5-6 membered ring containing a degree of unsaturation of 1 or more. R 6a 、R 6b , and R 6c Each of them is independently H or halogen, and R 6a 、R 6b , and R 6c (At least one of them is H), or a pharmaceutically acceptable salt thereof. (Item 2) Compound of formula II

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Brief Description of the Drawings

[0068] [Figure 1]Graphical representation of the test of Compound 3 for stability and solubility over 3 to 7 days.

[0069] [Figure 2] Graphical representation of the test of Compound 4 for stability over 4 days.

[0070] [Figure 3] Graphical representation of the test of Compound 3 for in vitro mouse and rat plasma stability at 37°C.

[0071] [Figure 4] Graphical representation of the test of Compound 4 for in vitro mouse and rat plasma stability at 37°C.

[0072] [Figure 5A] Graphical representation of the linear plot of Compound 1 and Compound 4 after administering Compound 4 SC at 100 mg / kg to male mice. [Figure 5B] Graphical representation of the semi-log plot of Compound 1 and Compound 4 after administering Compound 4 SC at 100 mg / kg to male mice.

[0073] [Figure 6] Graphical representation of the semi-log plot of Compound 1 after orally administering either 20 mg / kg of Compound 1, 30 mg / kg of Compound 3, or 30 mg / kg of Compound 4 to male mice.

[0074] [Figure 7] Graphical representation of the semi-log plot of the N-acetyl metabolite after orally administering either 20 mg / kg of Compound 1, 30 mg / kg of Compound 3, or 30 mg / kg of Compound 4 to male mice.

[0075] [[ID=四十三]] [Figure 8] Graphical representation of the semi-log plot of Compound 1 and Compound 4 after administering Compound 4 IM at 75 mg / kg to male rats.

[0076] [Figure 9] There is a graph display of the semilogarithmic plot of Compound 1 after administration of either 20 mg / kg of Compound 1, 30 mg / kg of Compound 3, or 30 mg / kg of Compound 4 to male Sprague Dawley rats via the oral route.

[0077] [Figure 10] There is a graphical representation of the semilogarithmic plot of the N-acetyl metabolite after administration of either 20 mg / kg of Compound 1, 30 mg / kg of Compound 3, or 30 mg / kg of Compound 4 to male mice via the oral route.

[0078] [Figure 11] There is a graphical representation of the in vitro screening of the Kv7.2 / 7.3 voltage-gated potassium channel.

[0079] [Figure 12] It is a graphical representation of the test within the CF-1 mouse maximal electroshock (MES) test.

[0080] [Figure 13] It is a graphical representation of the concentration of Compound 1 in CF-1 mice.

[0081] [Figure 14] It is a graphical representation of the protection of Compound 4 in SD rats after IM administration against MES-induced seizures.

[0082] [Figure 15] It is a table showing the dose-related response to XYZ-203 / Compound 3 from the CCI model of neuropathic pain.

[0083] [Figure 16] It is a graphical representation of the results of XYZ-203 (Compound 3) from the CCI model of neuropathic pain.

[0084] [Figure 17]A graph showing the results for XYZ-203 (compound 3) from the CCI model of neuropathic pain is provided.

[0085] [Figure 18] This graph shows the hind paw flick or lick behavior of mice after injection of 5% formalin into the soles of their feet.

[0086] [Figure 19] This graph shows the effects of compounds 4, 6, and 2 administered in equimolar doses to ezogavin (20 mg / kg) using the same formulation (0.5% methylcellulose in water) in rats with male jugular vein cannulas.

[0087] [Figure 20] The concentrations of compound 28 and ezogavin per dose group (ng / mL) and the effects of MES protection are explained with graphs.

[0088] [Figure 21] This graph illustrates the concentrations (ng / mL) of compound 28, ezogavin, and pregabalin 0.5 hours after a 24 mg / kg dose.

[0089] [Figure 22] A graph illustrating the concentrations (ng / mL) of compound 28 and ezogavin over a 24-hour period is provided.

[0090] [Figure 23] The mouse MES assay for ezogavin after administration of compound 29, with graphs showing brain and plasma concentrations, is available. [Modes for carrying out the invention]

[0091] As used herein, “alkyl” refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, and preferably 1 to 6 carbon atoms. The hydrocarbon chain may be linear or branched. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Similarly, an “alkenyl” group refers to an alkyl group having one or more double bonds in the chain, and an “alkynyl” group refers to an alkyl group having one or more triple bonds in the chain.

[0092] As used herein, "halogen" or "halo" refers to a halogen. In some embodiments, the halogen is preferably Br, Cl, or F.

[0093] As used herein, “haloalkyl” refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, and including, but not limited to, perhalo groups in which all hydrogen atoms are substituted with halogen atoms, and in which at least one hydrogen atom is substituted with a halogen. The haloalkyl chain may be either linear or branched. Exemplary alkyl groups include trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluorobutyl, and pentafluoroethyl. Similarly, a “haloalkenyl” group refers to a haloalkyl group having one or more double bonds in the chain, and a “haloalkynyl” group refers to a haloalkyl group having one or more triple bonds in the chain. Furthermore, an “alkylene” linking group refers to a divalent alkyl group, i.e., (CH2) x pointing to 、 x is 1 to 20, preferably 1 to 8, preferably 1 to 6, and more preferably 1 to 3.

[0094] The term "haloalkyloxy" refers to O-haloalkyl groups.

[0095] As used herein, “alkoxy” refers to an O-alkyl group having a specified number of carbon atoms.

[0096] An alkylene group is an alkyl group, as defined above, that is located between two other chemical groups and functions to connect them. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0097] The term "heteroalkyl" refers to the alkyl group as defined above, in which one or more carbon atoms in the chain are replaced by heteroatoms selected from the group consisting of O, S, and N, such as NH or NR', where R' is a common indicator of a non-hydrogen group.

[0098] As used herein, “hydroxyalkyl” refers to an alkyl group as defined herein, substituted with one or more -OH groups. Similarly, a “hydroxyalkenyl” group refers to a hydroxyalkyl group having one or more double bonds in the chain, and a “hydroxyalkynyl” group refers to a hydroxyalkyl group having one or more triple bonds in the chain. Similarly, a “dihydroxyalkyl” group provides two -OH substituents.

[0099] The term "alkylaminyl" is NR x - refers to alkyl, R x It is hydrogen.

[0100] The term "dialkylaminyl" is N(R y ) refers to 2, and each R y These are independently C1-C3 alkyl groups.

[0101] The term "alkylaminylalkyl" is an alkyl-NR term. x - refers to alkyl, R x It is hydrogen.

[0102] The term "dialkylaminylalkyl" refers to alkyl-N(R y ) refers to 2, and each Ry These are independently C1-C4 alkyl groups, and alkyl-N(R y The alkyl group in )2 is an alkyl group as defined above, and can be optionally substituted with hydroxyl or hydroxyalkyl groups.

[0103] As used herein, “aryl” refers to a pendant or condensed substituted or unsubstituted carbocyclic aromatic ring system, such as phenyl, naphthyl, anthracenyl, phenanthryl, tetrahydronaphthyl, indan, or biphenyl. The preferred aryl group is phenyl.

[0104] The "aralkyl" or "arylalkyl" group includes an aryl group covalently bonded to the alkyl group as defined above, and each of these may be independently substituted or unsubstituted by choice. An example of an aralkyl group is (C1~C6)alkyl(C6~C 10 These are aryl groups, which include, but are not limited to, benzyl, phenethyl, and naphthylmethyl. Examples of substituted aralkyl groups are those in which the alkyl group is substituted with a hydroxyalkyl group.

[0105] As used herein, “cycloalkyl” refers to an unsaturated or partially saturated hydrocarbon ring containing 3 to 15 ring atoms. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and their partially saturated versions, such as cyclohexenyl and cyclohexadienyl. Furthermore, crosslinked rings, such as adamantane, are included in the definition of “cycloalkyl.”

[0106] As used herein, the term “heterocyclyl” refers to an unsaturated or partially saturated hydrocarbon ring containing 3 to 15 ring atoms, where one or more carbon atoms are replaced by heteroatoms selected from O, N, or S, each N, S, or Si may be oxidized, and each N may be quaternized. The heterocyclyl group may be bonded to the rest of the molecule via heteroatoms. Heterocyclyls do not contain heteroaryls.

[0107] The term "heterocyclylalkyl" refers to a heterocyclyl group as defined herein that is covalently bonded to an alkyl group as defined herein, wherein the radical is located on the alkyl group, and the alkyl group of the heterocyclylalkyl may be optionally substituted with a hydroxyl or hydroxyalkyl group.

[0108] As used herein, the terms “heteroaryl” or “heteroaromatic” refer to aromatic ring groups having carbon and 5 to 14 ring atoms selected from at least one (typically 1 to 4, more typically 1 or 2) heteroatoms (e.g., oxygen, nitrogen, sulfur, or silicon). They include monocyclic rings and polycyclic rings in which a monocyclic heteroaromatic ring is fused with 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-pyridinyl, 4-pyridinyl, 5-pyridinyl), Examples of monocyclic six-membered nitrogen-containing heteroaryl groups include 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, benzofuranil, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, or benzisoxazolyl.

[0109] The terms “arylalkyl,” “heteroarylalkyl,” and “heterocyclylalkyl” refer to radicals in which an aryl, heteroaryl, or heterocyclyl group is linked via an alkyl group. Examples include benzyl, phenethyl, and pyridylmethyl. The terms also include alkyl groups in which a carbon atom, for example, a methylene group, is replaced by, for example, an oxygen atom. Examples include phenoxymethyl, pyrido-2-yloxymethyl, and 3-(naphtha-1-yloxy)propyl. Similarly, as used herein, the term “benzyl” refers to a radical in which a phenyl group is bonded to a CH2 group, and therefore CH2Ph. The heteroaryl group may be substituted or unsubstituted. The term substituted benzyl refers to a radical in which the phenyl group or CH2 contains one or more substituents. In one embodiment, the phenyl group may have 1 to 5 substituents, or in another embodiment, it may have 2 to 3 substituents.

[0110] A "heteroarylalkyl" group includes a heteroaryl group covalently bonded to an alkyl group, where the radical lies on the alkyl group, and the alkyl group is independently and optionally substituted or unsubstituted. Examples of heteroarylalkyl groups include heteroaryl groups having 5, 6, 9, or 10 ring atoms bonded to a C1-C6 alkyl group. Examples of heteroaryl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolylethyl, benzimidazolylmethyl, benzimidazolylethylquinazolinylmethyl, quinolinylmethyl, quinolinylethyl, benzofuranylmethyl, indolinylethylisoquinolinylmethyl, isoinodylmethyl, synnolinylmethyl, and benzothiophenylethyl. Compounds having O atoms and / or S atoms on adjacent rings are specifically excluded from the scope of this term.

[0111] As used herein, "optionally substituted" refers to the substitution of hydrogen atoms that would otherwise be present in the substituent. When discussing cyclic systems, optional substitutions are typically one, two, or three substituents that replace normally present hydrogens. However, when referring to linear and branched portions, the number of substitutions may be greater, if hydrogens are present. The substitutions may be the same or different.

[0112] Exemplary substituents having multiple substituents may be the same or different, including halogens, haloalkyls, R', OR', OH, SH, SR', NO2, CN, C(O)R', C(O)(alkyl substituted with one or more of halogens, haloalkyls, 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', and 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, each of the above being a divalent alkylene linking group (CH2) x (x is 1, 2, or 3) may be linked via an alkylene linking group ((CH2) xThey may be bonded through (where x is 1, 2, or 3), and each appearance of R' may be the same or different, representing hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, or if two R's are each bonded to a nitrogen atom, they may form a saturated or unsaturated heterocycle containing 4 to 6 ring atoms.

[0113] As used herein, an “effective amount” of a compound is an amount sufficient to negatively modulate or inhibit the activity of a target. Such an amount may be administered as a single dose or according to a regimen, thereby being effective.

[0114] As used herein, a “therapeutic dose” of a compound is an amount sufficient to improve a condition, reduce, halt, or reverse the progression of symptoms in a certain manner, or negatively modulate or inhibit the activity of a target. Such a dose may be administered as a single dose or according to a regimen, thereby being effective.

[0115] As used herein, treatment means any form of treatment that improves or favorably alters the symptoms or pathology of a condition, disorder, or disease. Treatment also encompasses any pharmaceutical use of the compositions herein.

[0116] As used herein, improvement of symptoms of a particular disorder by administration of a particular pharmaceutical composition means any relief, whether permanent or temporary, persistent or transient, that may be caused by or associated with the administration of the composition.

[0117] Where used herein, the term “about” means that, when used to modify a numerically defined parameter (for example, a dose of an inhibitor or a pharmaceutically acceptable salt thereof as detailed herein, or the duration of treatment as described herein), the parameter may vary by 25%, 20%, 15%, 10%, or 5% below the numerical value given for that parameter. For example, a dose of about 5 mg / kg may vary between 3.75 mg / kg and 6.25 mg / kg. When “about” is used at the beginning of a list of parameters, it means modifying 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. Similarly, about 5% or more, 10% or more, 15% or more, 20% or more, and 25% or more means about 5% or more, about 10% or more, about 15% or more, about 20% or more, and about 25% or more.

[0118] As used herein, salt means any salt of a compound disclosed herein that retains its biological properties and is not toxic or otherwise undesirable for pharmaceutically acceptable use.

[0119] Such salts may be derived from a variety of organic and inorganic counterions known in the art. These salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, glutaric acid, pyruvic acid, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, picric acid, cinnamic acid, mandelic acid, phthalic acid, lauric acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, and 2-hydroxyethane. These are acid-added salts formed with organic or inorganic acids, such as sulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphor acid, camphor sulfonic acid, 4-methylbicyclo[2.2.2]-octo-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylsulfamic acid, quinic acid, muconic acid, and similar acids.

[0120] Salts also include, simply as examples, halides, such as chlorides and bromides, sulfates, phosphates, sulfamates, nitrates, acetates, trifluoroacetates, trichloroacetates, propions, hexanoates, cyclopentylpropions, glycolates, glutarates, pyruvates, lactates, malons, succinates, sorbates, ascorbicates, malates, maleates, fumarates, tartrates, citrates, benzoates, 3-(4-hydroxybenzoyl)benzoates, picrates, cinnamates, mandelates, phthalates, laurates, methanesulfonates (mesylates), ethanesulfonates, and 1,2-ethane-dipropyl alcohols. These are salts of non-toxic organic or inorganic acids, such as sulfonates, 2-hydroxyethanesulfonates, benzenesulfonates (besylates), 4-chlorobenzenesulfonates, 2-naphthalenesulfonates, 4-toluenesulfonates, camphorates, camphor sulfonates, 4-methylbicyclo[2.2.2]-octo-2-ene-1-carboxylates, glucoheptonates, 3-phenylpropionates, trimethylacetates, tert-butylacetates, lauryl sulfates, glucons, benzoates, glutamates, hydroxynaphthoates, salicylates, stearates, cyclohexyl sulfamates, quinates, muconates, and similar salts.

[0121] Examples of inorganic bases that can be used to form base addition salts include, but are not limited to, metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; metal amides such as lithium amide and sodium amide; metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate; and ammonium bases such as ammonium hydroxide and ammonium carbonate.

[0122] Examples of organic bases that can 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 aliphatic amines (i.e., alkylamines, alkenylamines, alkynylamines, and alicyclic amines), heterocyclic amines, arylamines, heteroarylamines, basic amino acids, amino sugars, and polyamines.

[0123] The base may be a quaternary ammonium hydroxide, in which one or more 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 according to this disclosure include choline hydroxide, trimethylethylammonium hydroxide, and tetramethylammonium hydroxide, preferably choline hydroxide. The alkylamine base may be substituted or unsubstituted. Non-limiting examples of unsubstituted alkylamine bases that may be used according to this disclosure include methylamine, ethylamine, diethylamine, and triethylamine. The substituted alkylamine base may be substituted with one or more hydroxyl groups, preferably one to three hydroxyl groups. Non-limiting examples of substituted alkylamine bases that may be used according to this disclosure include 2-(diethylamino)ethanol, N,N-dimethylethanolamine (Deanol), tromethamine, ethanolamine, and diolamine.

[0124] In certain cases, the substituents depicted can contribute to optical isomers and / or stereoisomers. Compounds having the same molecular formula but differing in the bonding properties or arrangement of their atoms, or in the spatial arrangement of their atoms, are called "isomers." Isomers with different spatial arrangements of atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that cannot be superimposed on each other are called "enantiomers." When a compound has a chiral center, for example, when bonded to four different groups, a pair of enantiomers is possible. Molecules having at least one stereocenter can be characterized by the absolute configuration of their asymmetric center, and are denoted as (R) or (S) according to the rules of Cahn and Prelog (Cahn et al., 1966, Angew. Chem. 78:413-447, Angew. Chem., Int. Ed. Engl. 5:385-414 (errata: Angew. Chem., Int. Ed. Engl. 5:511), Prelog and Helmchen, 1982, Angew. Chem. 94:614-631, Angew. Chem. Internat. Ed. Eng. 21:567-583, Mata and Lobo, 1993, Tetrahedron: Asymmetry Chiral compounds can be characterized by a rotation of the plane of polarization, either by dextrorotatory or levorotatory properties (i.e., as (+)- or (-)- isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0125] In certain embodiments, the compounds disclosed herein may have one or more asymmetric centers, and such compounds may be produced as racemic mixtures, enantiomeric-enriched mixtures, or individual enantiomeric compounds. Unless otherwise indicated, the descriptions or naming of specific compounds in the specification and claims are intended to include both individual enantiomers and mixtures thereof, racemics, or otherwise, for example, by specifying the stereochemistry at any position in the formula. Methods for determining stereochemistry and separating stereoisomers are well known in the art.

[0126] In certain embodiments, the compounds disclosed herein are “stereochemically pure.” A stereochemically pure compound has a level of stereochemical purity that would be recognized as “pure” by those skilled in the art. Of course, this level of purity may be less than 100%. In certain embodiments, “stereochemically pure” refers to a compound that is substantially free of alternative isomers, i.e., at least about 85% or more. In certain embodiments, the compound is free of other isomers in amounts of 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%.

[0127] As used herein, the terms “subject” and “patient” are interchangeable. In one embodiment, the subject is a human. In one embodiment, the subject is a pet such as a dog or cat. In a further embodiment, the subject is an animal such as a sheep, cow, horse, goat, fish, pig, or poultry (e.g., chicken, turkey, duck, or goose). In another embodiment, the subject is a primate such as a monkey such as a crab-eating macaque or chimpanzee. I. Voltage-dependent potassium channel modulators

[0128] Compound 1 is a potassium ion channel modulator. [ka]

[0129] This disclosure provides novel prodrugs that are metabolized in vitro to release potassium ion channel modulators, such as those presented as Compound 1, and in particular, novel prodrugs that release compounds effective in regulating KCNQ follow the formula of this disclosure.

[0130] The embodiments of this disclosure are, [ka] [ka] (R 1 However, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkyl-C 3~6 It is a cycloalkyl, R 2 However, H, C 1~3 Alkyl, C 1~3 Alkyl, halogen, C 1~3 It is a haloalkoxy, R 3 However, the "Pro" is the prodrug portion described herein, R 4 and R 5 Each of them independently is H, or R 4 and R 5 However, together with the atoms to which they bond, they optionally form a 5-6 membered ring containing a degree of unsaturation of 1 or more. R 6a , R 6b , and R 6c Each of them is independently H or halogen, and R 6a , R 6b , and R 6c (At least one of them is H), or containing pharmaceutically acceptable salts thereof, C 1~3Haloalkoxys are -OCF3, -OCF2H, -OCFH2, -OC2F5, -OC2F4H, -OC2F3H2, -OC2F2H3, -OC2FH4, -OC3F7, -OC3F6H, -OC3F5H2, -OC3F4H3, -OC3F3H4, -OC3F2H5, or -OC3FH6.

[0131] In one embodiment, the variable "Pro" is C(O)R 10 Selected from the group consisting of, in the formula, R 10 teeth, Alkylamine-containing residues such as the alkylamine-containing portion of natural L-amino acids or D-amino acids, or Glycine, or The alkylamine-containing portion of theanine, gabapentin, or pregabalin, or R 10 is -C(O)OL 1 OC(O)R 11 Selected from hydrolyzable prodrug moieties such as those found in groups having the structure, R 11 C1~C 10 Alkyl, Bn, t-Bu, and other C3-C3, substituted or unsubstituted C3-C3 10 It is a secondary or tertiary alkyl group, or Ar, and L 1 C1~C 10 It is a branched chain or chain alkylene, L 1 The two oxygen atoms above are L 1 Located on the same carbon atom within (i.e., a divalent alkyl group forming a ketal or acetal-like moiety).

[0132] One embodiment of the present disclosure is a compound of formula I: [ka] (In the formula, R 1 However, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkyl-C 3~6 It is a cycloalkyl, R 2 However, H, C1~3 Alkyl, C 1~3 Alkyl, halogen, C 1~3 It is a haloalkoxy, Z is either N or CH, R 3 However, it is "Pro", and "Pro" is C(O)R 10 Selected from the group consisting of, R 10 but, a) Alkylamine-containing residues such as the alkylamine-containing portion of natural L-amino acids or D-amino acids, or b) Glycine residue, c) Theanine residue, d) Gabapentin residue, e) Pregabalin residues, and f) Structure C(O)OL 1 OC(O)R 11 Selected from the hydrolyzable prodrug portion, R 11 However, non-substitutable or substituted C1~C 10 Alkyl, aryl, C1-C 10 It is Aralkir, L 1 However, C1~C 10 It is alkylene, L 1 Two oxygen atoms are depicted as being bonded to L 1 It is located on the same carbon atom within (i.e., it is a divalent alkyl that forms a ketal or acetal-like moiety), R as alkylamine from naturally occurring amino acids 10 An example is, (CH2)-NH2 from glycine, CH(CH3)-NH2 from alanine, CH(CH(CH3)2)-NH2 from valine, CH(CH2CH(CH3)2)-NH2 from leucine, CH(CH(CH3)CH2CH3)-NH2 from isoleucine, CH(CH2Ph)-NH2 from phenylalanine, Cyclo-CHCH2CH2CH2NH- from proline, CH(CH2OH)-NH2 from serine CH(CH(OH)CH3)-NH2 from threonine, CH(CH2(PhOH))-NH2 from tyrosine, CH(CH2SH)-NH2 from cysteine, CH(CH2CH2SCH3)-NH2 from methionine, CH(CH2CH2CH2CH2NH2)-NH2 from lysine, CH(CH2CH2CH2NHC(NH)NH2)-NH2 from arginine, CH(CH2(C3N2H3))NH2 from histidine, CH(CH2-indole-3-yl)NH2 from tryptophan, CH(CH2CO2H)-NH2 from aspartic acid, CH(CH2CH2CO2H)-NH2 from glutamic acid, CH(CH2CONH2)-NH2 from asparagine, and CH(CH2CH2CONH2)-NH2 from glutamine, or CH(CH2CH2CONHCH2CH3)-NH2 from theanine or CH2C(-CH2CH2CH2CH2CH2-)CH2NH2 from gabapentin, or It is CH2CH(CH2CH(CH3)2)CH2NH2 derived from pregabalin, Alkylamine moieties from the D-isomers or S-isomers of the above amino acids are also examples of alkylamine moieties from amino acids as intended in this disclosure. R 4 and R 5 Each of them independently is H, or R 4 and R 5 However, together with the atoms to which they bond, they optionally form a 5-6 membered ring containing a degree of unsaturation of 1 or more. R 6a , R 6b , and R 6c Each of them is independently H or halogen, and R 6a , R 6b, and R 6c (At least one of them is H), or a pharmaceutically acceptable salt thereof.

[0133] In further exemplary embodiments, the disclosure relates to formula III, more specifically formula III-A, and specifically compound 3: [ka] (R 1 However, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkyl-C 3~6 It is a cycloalkyl, R 2 However, H, C 1~3 Alkyl, C 1~3 Alkyl, halogen, C 1~3 It is a haloalkoxy, Z is either N or CH, R 3 However, the Pro portion is defined as the prodrug portion in this specification. R 4 and R 5 Each of them independently is H, or R 4 and R 5 However, together with the atoms to which they bond, they optionally form a 5-6 membered ring containing a degree of unsaturation of 1 or more. R 6a , R 6b , and R 6c Each of them is independently H or halogen, and R 6a , R 6b , and R 6c At least one of them is H, R 7 However, C 1-6 Alkyl (including branched or linear as described herein), phenyl, or C 1-2 A prodrug (which is an alkylphenyl), Or provide a pharmaceutically acceptable salt thereof.

[0134] The embodiments of this disclosure are, [ka] (L 1 C1~C 10 It is a branched or chain alkylene, L 1 The two oxygen atoms above are L 1 It contains a divalent alkyl group located on the same carbon atom within it (i.e., a divalent alkyl group that forms a ketal or acetal-like moiety).

[0135] Embodiments of this disclosure include the following: [ka]

[0136] In further exemplary embodiments, the disclosure relates to formula IV, more specifically formula IV-A, and specifically compound 4: [ka] (R 1 However, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkyl-C 3~6 It is a cycloalkyl, R 2 However, H, C 1~3 Alkyl, C 1~3 Alkyl, halogen, C 1~3 It is a haloalkoxy, Z is either N or CH, R 3 However, the "Pro" is the prodrug portion described herein, R 4 and R 5 Each of them independently is H, or R 4 and R 5 However, together with the atoms to which they bond, they optionally form a 5-6 membered ring containing a degree of unsaturation of 1 or more. R 6a , R 6b , and R 6c Each of them is independently H or halogen, and R6a , R 6b , and R 6c At least one of them is H, R 10 However, alkylamines derived from naturally occurring amino acids include -(CH2)-NH2) from glycine, -CH(CH3)-NH2 from alanine, -CH(CH3)-NH2 from valine, -CH(CH2CH(CH3)2)-NH2 from leucine, -CH(CH(CH3)CH2CH3)-NH2 from isoleucine, -CH(CH2Ph)-NH2 from phenylalanine, cyclo-CHCH2CH2CH2NH- from proline, -CH(CH2OH)-NH2 from serine, -CH(CH(OH)CH3)-NH2 from threonine, -CH(CH2(PhOH))-NH2 from tyrosine, -CH(CH2SH)-NH2 from cysteine, -CH(CH2CH2SCH3)-NH2 from methionine, -CH(CH2CH2CH2CH2NH2)-NH2 from lysine, and -CH(CH2CH2CH2NH) from arginine A prodrug compound having C(NH)NH2)-NH2, -CH(CH2(C3N2H3))-NH2 from histidine, CH(CH2-indole-3-yl)NH2 from tryptophan, -CH(CH2CO2H)-NH2 from aspartic acid, -CH(CH2CH2CO2H)-NH2 from glutamic acid, -CH(CH2CONH2)-NH2 from asparagine, -CH(CH2CH2CONH2)-NH2 from glutamine, or -CH(CH2CH2CONHCH2CH3)-NH2 from theanine, or -CH2C(-CH2CH2CH2CH2CH2-)CH2NH2 from gabapentin, or -CH2CH(CH2CH(CH3)2)CH2NH2 from pregabalin, and the alkylamine moiety from the D-isomer of the above amino acids is also an example of the alkylamine moiety from amino acids intended in this disclosure. Or provide a pharmaceutically acceptable salt thereof.

[0137] The embodiments of this disclosure are: [ka] (The dashed lines depicting the bonds represent either of the enantiomers.)

[0138] One embodiment of this disclosure comprises a compound or a pharmaceutically acceptable salt thereof: [ka]

[0139] One embodiment of this disclosure comprises a compound or a pharmaceutically acceptable salt thereof: [ka]

[0140] One embodiment of this disclosure comprises a compound or a pharmaceutically acceptable salt thereof: [ka]

[0141] One embodiment of the present disclosure is R 10 However, it includes compounds that are CH2C(-CH2CH2CH2CH2CH2-)CH2NH2 from gabapentin, or CH2CH(CH2CH(CH3)2)CH2NH2 from pregabalin.

[0142] One embodiment of this disclosure comprises a compound or a pharmaceutically acceptable salt thereof: [ka]

[0143] II. Assay for Kv7 channel modulators The Kv7 channel, formerly identified as the KCNQ channel, is one of the same channels. Assays for determining the ability of active molecules, i.e., positive allosteric modulators, to maintain the Kv7 channel in the open position with a higher probability are generally known in the art. Those skilled in the art can determine appropriate assays for investigating the activity of selected compounds of this disclosure against specific ion channels. For brevity, some of the following discussion focuses on Kv7.2 (KCNQ2) as a representative example, but the discussion is equally applicable to other Kv7 subtype potassium ion channels.

[0144] The KCNQ(Kv7) monomer, as well as the KCNQ allele and polymorphic mutants, are subunits of potassium channels. The activity of potassium channels containing the KCNQ subunit can be evaluated using various in vitro and in vivo assays, such as current measurement, membrane potential measurement, ion flux measurement (e.g., potassium or rubidium ion flux measurement), potassium concentration measurement, measurement of second messenger and transcription levels using potassium-dependent yeast growth assays, and, for example, voltage-sensitive dyes, radiotracers, and patch-clamp electrophysiology.

[0145] Furthermore, such assays can be used to test inhibitors and activators of channels, including KCNQ. Such modulators of potassium channels are useful in treating a variety of disorders involving potassium channels, including, for example, central and peripheral nervous system disorders (including, but not limited to, migraines, ataxia, Parkinson's disease, bipolar disorder, trigeminal neuralgia, convulsions, mood disorders, brain tumors, psychiatric disorders, myokymia, seizures, epilepsy, hearing and vision loss, Alzheimer's disease, age-related memory loss, learning disabilities, anxiety, and motor neuron diseases), and may also be used as neuroprotective agents (for example, to prevent stroke, etc.). Such modulators can be used to investigate the channel diversity provided by KCNQ and It is also useful for regulating / modulating potassium channel activity provided by KCNQ. Prodrugs metabolized in mammals or cells by amidases, esterases, and other metabolic or hydrolytic mechanisms can produce KCNQ-containing channel activity modulators. Some prodrugs themselves may have weak activity as KCNQ channel modulators. However, any activity may be due to degradation to the active drug in the test system, and in most of these cases, the metabolized prodrug produces a more active KCNQ modulator than the prodrug itself.

[0146] Potassium channel modulators are tested using recombinant or naturally occurring biologically active KCNQ, or using native cells such as cells from the nervous system that express M currents. KCNQ may be isolated, co-expressed or expressed intracellularly, or expressed in the membrane derived from the cell. In such assays, KCNQ2 is expressed alone to form a homomeric potassium channel, or co-expressed with a second subunit (e.g., another KCNQ family member, preferably KCNQ3) to form a heteromeric potassium channel. Modulation is tested using one of the in vitro or in vivo assays described above. The degree of modulation is examined by comparing samples or assays treated with potential potassium channel inhibitors or activators to control samples that do not contain the test compound. The control sample (not treated with an activator or inhibitor) is assigned a relative potassium channel activity value of 100. Activation of a channel containing KCNQ2 is achieved when the potassium channel activity value is 130%, more preferably 150%, and more preferably 170% higher than the control. Compounds that increase ion flux cause an increase in detectable ion current density by increasing the probability that channels containing KCNQ2 are open, decreasing the probability that channels are closed, increasing conductance through the channels, and increasing the number or expression of channels. In these experiments, it is important to have materials available in each experiment that are known to metabolize the prodrugs of this disclosure to compounds active at the target receptor site. Alternatively, these experiments can be performed using the actual drug compounds themselves, and it can be assumed that the metabolized prodrugs, once entered the mammalian body, will have similar activity at the desired ion channel site.

[0147] The activity of the metabolites of these prodrug compounds disclosed herein is EC 50 It can also be expressed as follows. Preferred compounds of this disclosure release active molecules upon hydrolysis or metabolism, which, in a potassium ion channel assay, produce about 0.1 nM to about 1 mM, preferably about 1 nM to about 10 μM, more preferably about 10 nM to about 2 μM of EC. 50 It holds.

[0148] Changes in ion flux can be assessed by determining changes in the polarization (i.e., potential) of cells or membranes expressing exemplary potassium channels such as KCNQ2, KCNQ2 / 3, or M current. Preferred means for determining changes in cellular polarization are to measure changes in current or voltage using voltage clamp and patch clamp techniques, using “cell adhesion” mode, “inside-out” mode, “outside-out” mode, “through-hole” mode, “one or two electrode” mode, or “whole cell” mode (see, e.g., Ackerman et al., New Engl. J. Med. 336:1575-1595 (1997)). Total cellular current can be easily determined using standard methodologies (e.g., Hamil et al., 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 et al., J.Membrane Biol.88:67-75 (1988), Daniel et al., J.Pharmacol.Meth.25:185-193 (1991), Holevinsky et al., J.Membrane Biology 137:59-70 (1994)). Assays of compounds that can inhibit or increase potassium flux via channel proteins containing KCNQ2 or heteromultimers of KCNQ subunits can be performed by contacting cells having the channels of this disclosure and applying the compound to a bath solution containing them (e.g., Blatz et al., Nature). See 323:718-720 (1986) and Park, J. Physiol. 481:555-570 (1994). Generally, the compound being tested is present in a concentration of about 1 pM to about 1 mM, preferably about 10 pM to about 100 μM.

[0149] The effect of the test compound on the channel function can be measured by changes in current or ion flux, or as a result of changes in both current and flux. Changes in current or ion flux are measured by either an increase or decrease in the flux of ions such as potassium or rubidium ions. Cations can be measured by various standard methods. These can be measured directly by changes in ion concentration or indirectly by membrane potential or radiolabeling of ions. The effect of the test compound on the ion flux can be very diverse. Therefore, any suitable physiological change can be used to evaluate the effect of the test compound on the channel of this disclosure. III. Pharmaceutical Compositions of Potassium Channel Modulators

[0150] In another embodiment, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula I described above.

[0151] Formulation of compounds (compositions)

[0152] The compounds of this disclosure can be prepared and administered in a wide variety of oral, parenteral, and topical dosage forms. Accordingly, the compounds of this disclosure can be administered by injection, i.e., intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally, or intraperitoneally. The compounds described herein can also be administered by inhalation, for example, intranasally. In addition, the compounds of this disclosure can be administered percutaneously, ocularly, intracochlearly, or rectally. Accordingly, this disclosure also provides pharmaceutically acceptable carriers or excipients, and pharmaceutical compositions comprising any of the compounds of formula I, or any pharmaceutically acceptable salts thereof.

[0153] For preparing pharmaceutical compositions from the compounds of this disclosure, pharmaceutically acceptable carriers may be either solid or liquid. Examples of solid preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid form may be immediate-release, sustained-release, modified-release, or delayed-release. The solid carrier may be one or more substances that also act as diluents, flavorings, binders, preservatives, tablet disintegrants, or encapsulating materials.

[0154] In powder form, the carrier can be a finely divided solid, or a mixture of finely divided active compounds. In tablet form, the active compound is mixed in a suitable proportion with a carrier having the required compressibility properties and compressed to the desired shape and size.

[0155] Powders and tablets preferably contain 5% or 10% to 85% of the active compound. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugars, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting wax, and cocoa butter. The term “preparation” is intended to include formulations of the active compound having an encapsulating material as a carrier that provides a capsule in which the active ingredient is surrounded by the carrier and thus associates with it, either with or without other carriers. Similarly, cachets and lozenges are also included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0156] In one method of preparing suppositories, a low-melting-point wax, such as a mixture of fatty acid glycerides or cocoa butter, is first dissolved, and the active ingredient is uniformly dispersed therein, for example, by stirring. The dissolved homogeneous mixture is then poured into a mold of a suitable size and cooled to solidify.

[0157] Liquid preparations include solutions, suspensions, and emulsions, such as water or water / propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in an aqueous polyethylene glycol solution.

[0158] Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, fragrances, stabilizers, and thickeners as desired. Aqueous suspensions suitable for oral use can be prepared by dispersing finely divided active ingredients in water using viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

[0159] The preparations also include solid-state preparations intended to be converted into liquid preparations for oral administration immediately before use. Such liquid preparations include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active ingredient, colorants, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

[0160] Pharmaceutical preparations are preferably in unit dosage forms. In such dosage forms, the preparation is subdivided into unit doses containing an appropriate amount of the active ingredient. The unit dosage form may be a packaged preparation, and the packaging contains discrete quantities of the preparation, such as packetized tablets, capsules, and powders in vials or ampoules. Alternatively, the unit dosage form may be the capsules, tablets, pills, cachets, sachets, or lozenges themselves, or an appropriate number of any of these may be packaged.

[0161] The amount of the active ingredient in a unit dose preparation may vary or be adjusted from 0.1 mg to 10,000 mg, more typically 1.0 mg to 5,000 mg, and most typically 20 mg to 1,000 mg, depending on the specific use and the potency of the active ingredient. The composition may also contain other suitable therapeutic agents if desired. IV. Effective Dosage

[0162] The pharmaceutical compositions provided herein include compositions containing an active ingredient in a therapeutically effective amount, i.e., an amount effective to achieve its intended purpose. The actual amount effective for a particular use depends, among other things, on the condition being treated. For example, when administered in a manner to treat pain, epilepsy, depression, or anxiety, such a composition contains an amount of the active ingredient effective to achieve a clinically relevant degree of reduction of the condition being treated. Similarly, when a pharmaceutical composition is used to treat or prevent a central or peripheral nervous system disorder, such as Parkinson's disease, a therapeutically effective amount would reduce one or more symptoms characteristic of the disease (e.g., tremor) to below a predetermined pressure threshold. Determining the therapeutically effective amount of the compounds of this disclosure is well within the capabilities of those skilled in the art, particularly in light of the detailed disclosure herein.

[0163] For any compound described herein, the therapeutically effective dose can be determined first from a cell culture assay. The target plasma concentration is the concentration of the active compound that can modulate, for example, activate or open KCNQ channels. In preferred embodiments, KCNQ channel activity changes by at least 5% at a clinically effective free drug concentration for a particular disease or treatment, and by at least 10% for other diseases or treatments. The rate of change in a patient's KCNQ channels with a prodrug of a Kv7-positive allosteric modulator can be adjusted based on the plasma drug concentration of the active substance, and the dose can be adjusted upward or downward to achieve the desired therapeutic effect.

[0164] As is well known in the art, therapeutically effective doses for human use can also be determined from animal models. For example, human doses can be formulated to achieve circulating concentrations found to be effective in animals. A particularly useful animal model for predicting anticonvulsant doses is the maximal electroshock assay (Fischer RS, Brain Res. Rev. 14:245-278 (1989)). Human doses can be adjusted by monitoring KCNQ channel activation and adjusting the dose upward or downward as described above.

[0165] The therapeutically effective dose can also be determined from human data for compounds known to exhibit similar pharmacological activity, such as ezogabine (Rudnfeldt et al., Neuroscience Lett. 282:73-76 (2000)).

[0166] Adjusting the dosage to achieve maximum efficacy in humans based on the above method and other methods is well known in the art and well within the capabilities of those skilled in the art.

[0167] For example, when the compounds of this disclosure are used for the prevention and / or treatment of exemplary diseases such as epilepsy and pain, a circulating concentration of the administered compound of about 0.001 μM to 1 mM is considered effective, and is preferably about 0.01 μM to 100 μM.

[0168] Patient doses for oral administration of the compounds described herein, which are preferred modes of administration for the prevention and treatment of exemplary diseases such as epilepsy, are typically in the range of about 1 mg / day to about 10,000 mg / day, more typically about 10 mg / day to about 3,000 mg / day, and most typically about 1 mg / day to about 1,000 mg / day. In terms of patient body weight, typical dosages are in the range of about 0.01 to about 150 mg / kg / day, more typically about 0.1 to about 50 mg / kg / day, and most typically about 0.5 to about 25 mg / kg / day.

[0169] For other modes of administration, the dosage and interval may be individually adjusted to provide plasma levels of the compound being administered that are effective for the specific clinical indication being treated. For example, if acute epileptic seizures are the most prevalent clinical symptom, in one embodiment, the compound according to the Disclosure may be administered multiple times a day at relatively high concentrations. Alternatively, if a patient rarely, periodically, or irregularly exhibits only clinical signs or symptoms of cyclical epileptic seizures, migraines, or other acute onsets from a chronic or acute disease state, in one embodiment, it may be more preferable to administer the compound according to the Disclosure at the lowest effective concentration and use a less frequent dosing regimen. This provides a treatment regimen that is appropriate to the severity of the individual's disease state.

[0170] Using the teachings provided herein, it is possible to design effective prophylactic or therapeutic treatment regimens that do not cause substantial toxicity but are fully effective in treating the clinical symptoms exhibited by specific patients.

[0171] This plan should involve careful selection of the active compound by considering factors such as the compound's potency, relative bioavailability, patient weight, presence and severity of adverse side effects, preferred administration method, and the toxicity profile of the selected drug. For example, but not limited to, an intranasal route may be useful for the treatment of migraines, and an ocular route may be useful for the treatment of one or more eye diseases. Thus, a specific route of administration may be selected based on the intended therapeutic indication of the compound of this disclosure. V. Toxicity of Compounds

[0172] The ratio between the toxicity and therapeutic effect of a particular compound is its therapeutic index, LD50. 50 (Lethal dose of the compound in 50% of the population) and ED 50It can be expressed as a ratio between (the amount of the compound effective in 50% of the population). Compounds exhibiting a high therapeutic index are preferred. Therapeutic index data obtained from cell culture assays and / or animal studies can be used when formulating a series of doses for use in humans. Doses of such compounds have little to no toxicity. 50 It is preferable that the plasma concentration is within the range containing [the compound]. The dosage may vary within this range depending on the dosage form used and the route of administration utilized. See, for example, Fingl et al., In: THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, Ch.1, p.1, 1975. The exact formulation, route of administration, and dosage may be selected by the individual physician, taking into account the patient's condition and the specific method by which the compound is used. VII. Methods for treating voltage-dependent potassium channel-mediated conditions

[0173] In yet another aspect, the present disclosure provides a method for treating a disorder or condition of the central or peripheral nervous system by modulating voltage-dependent potassium channels. In this method, an effective amount of a compound having the above formula is administered to a subject in need of such treatment.

[0174] The compounds provided herein are useful prodrugs of potassium channel modulators that find therapeutic utility through modulation by improving the pharmacokinetics, solubility, and stability of molecules active to voltage-dependent potassium channels in the treatment of diseases or conditions. The potassium channel targets of the compounds disclosed herein are described herein as voltage-dependent potassium channels such as KCNQ potassium channels. As described above, these channels may include homopolymers and heteropolymers of KCNQ2, KCNQ3, KCNQ4, and KCNQ5. A heteropolymer of two proteins, for example, KCNQ2 and KCNQ3, is referred to, for example, KCNQ2 / 3, KCNQ3 / 5, etc. Conditions that can be treated with the compounds and compositions of this disclosure include, but are not limited to, central or peripheral nervous system disorders (e.g., migraine, ataxia, Parkinson's disease, bipolar disorder, trigeminal neuralgia, convulsions, mood disorders, brain tumors, psychiatric disorders, myokymia, seizures, epilepsy, hearing and vision loss, Alzheimer's disease, age-related memory loss, learning disabilities, anxiety, and motor neuron diseases). The compounds and compositions of this disclosure may also function as neuroprotective agents (e.g., to prevent stroke, retinal degeneration, demyelinating diseases, etc.). In preferred embodiments, the condition or disorder to be treated is epilepsy or seizures, central or peripheral neuropathic pain, chronic pain, or inflammatory pain. In another preferred embodiment, the condition or disorder is the treatment of hearing loss or a disorder related to neuronal demyelination or neuronal hyperexcitability.

[0175] Subsequently, the dosage should be gradually increased until the optimal effect is achieved under the given circumstances. For convenience, if desired, the total daily dose may be divided and administered in installments throughout the day.

[0176] One embodiment of the present disclosure describes the following conditions: seizures, pain, neuropathic pain, chronic headache, central pain, diabetic neuropathy, postherpetic neuralgia and pain associated with peripheral nerve injury, drug addiction, affective disorders, Alzheimer's disease, anxiety, neurodegenerative diseases or CNS damage caused by disease or injury, cognitive impairment, obsessive-compulsive behavior, dementia, depression, Huntington's disease, dystonia, mania, cognitive impairment, memory impairment, memory disorder, memory failure, movement disorders, motor disorders, neurodegenerative diseases, Parkinson's disease, Parkinsonian movement disorder, phobias, Pick's disease, psychosis, bipolar disorder, schizophrenia (the schizophrenia subtype being catatonic subtype, paranoid subtype, disorganized subtype or residual subtype), spinal cord injury, cardiomyopathy (cardiomyopathia), cardiac arrhythmias, QT prolongation syndrome, movement disorders or motor disorders, myasthenia gravis, migraines, tension headaches, and bowel disorders. The present invention includes methods for treating, improving, or preventing the progression of a disease or disorder selected from the group consisting of inflammatory diseases, ulcerative colitis, Crohn's disease, Creutzfeldt-Jakob disease, eye conditions, progressive hearing loss or tinnitus, fever, multiple sclerosis, diabetes mellitus, or metastatic tumor growth, aluminism, anthrax, asbestos disease, powdery mildew, trichiasis, iron deposition, silicosis, tobacco poisoning, and pulmonary contaminants such as sinusitis, as well as chronic obstructive pulmonary disease (COPD), obesity, and disease-related hypertension.

[0177] One embodiment of the present disclosure includes a method for treating one or more motor disorders selected from primary dystonia, paroxysmal dystonia, secondary dystonia, drug-induced dystonia / dyskinesia, tardive dystonia, neuroleptic-induced dystonia, treatment-induced dystonia / dyskinesia in patients with Parkinson's disease, genetically altered dystonia, dystonia in patients with Huntington's disease, dystonia in patients with Tourette syndrome, dystonia in patients with restless limb syndrome, dystonia-like symptoms in patients with tics, dystonia-associated dyskinesia, paroxysmal dyskinesia, paroxysmal non-exercise-induced dyskinesia, paroxysmal dystonic choreoatetosis, paroxysmal motion-induced dyskinesia, paroxysmal exercise-induced choreoatetosis, exercise-induced dyskinesia, paroxysmal sleep-induced dyskinesia, drug-induced dyskinesia, myokymia, neuromyotonia, autism, and autism spectrum disorder. The following references may be incorporated by reference with respect to such teachings regarding the relevance of the Agency to the relevant disease or disorder. a. Seizures (L Greene,Epilepsia 2018, J Neurosci,Qiu.2008).

[0178] Neurons derived from Kv7.2(S559A) knock-in mice exhibited normal basal M-currents. Knock-in mice showed reduced M-current suppression when challenged with muscarinic agonists, and oxotremol-M.Kv7.2(S559A) mice were resistant to chemospasmodic-induced seizures, with no deaths. XE991 administration transiently exacerbated seizures in knock-in mice comparable to wild-type mice. After experiencing an epileptic state, Kv7.2(S559A) knock-in mice showed neither seizure-induced cell death nor spontaneous recurrent seizures.

[0179] Using M channel blockers, we found that coupling of SST4 to M channels is crucial for inhibiting epilepsy-like activity. This is the first demonstration of an endogenous enhancer of IM, which is important for controlling seizure activity. Therefore, the SST4 receptor may be an important novel target for developing new antiepileptic and antipileptogenic agents. b. Pain, neuropathic pain, chronic headache (J Pain, Li.2019).

[0180] Paclitaxel-induced peripheral neuropathy and associated neuropathic pain are severe and resistant to intervention. Our study demonstrated that retigabine (a clinically available drug) can suppress the development of paclitaxel-induced peripheral neuropathy. c. Pain associated with central pain, diabetic neuropathy, postherpetic neuralgia, and peripheral nerve injury (Brown Br J Pharmacology, 2009; Epilepsia, Trenite, 2013).

[0181] Several drugs, including flupirtine and retigabine, enhance neuronal Kv7 / M channel activity primarily through hyperpolarization shifts in their voltage gating. As a result, they can reduce neuronal excitability and inhibit nociceptive stimulation and transmission. Flupirtine is used as a central analgesic, while retigabine is in clinical trials as a broad-spectrum anticonvulsant and is an effective analgesic in animal models of chronic inflammatory and neuropathic pain.

[0182] ICA-105665 reduced SPR in patients with single doses of 100 mg (1 out of 4), 400 mg (2 out of 4), and 500 mg (4 out of 6). This is the first evaluation of the effect of Kv7 potassium channel activation in a conceptual model of photosensitivity proof. The reduction in SPR in this patient population provides evidence of central nervous system (CNS) penetration of ICA-105665 and preliminary evidence that engagement with neuronal Kv7 potassium channels has an antiseizure effect. d. Alzheimer's disease (Czuzcwar, Pharmacological Reports 2010).

[0183] The most significant adverse effects of retigabine in combination with existing antiepileptic treatments were dizziness, somnolence, and fatigue. Preclinical data suggest that this antiepileptic drug may be applicable to patients with neuropathic pain and mood disorders. Early clinical data suggest that retigabine may also be effective in Alzheimer's disease or stroke. e. Anxiety, neurodegenerative diseases or CNS damage caused by disease or injury, cognitive impairment, obsessive-compulsive behavior, dementia, depression, Huntington's disease, dystonia, mania, (Richter, Br J Pharmacology 2006; Aiba, Brain 2021; Boehm, Pain 2019; Maghera, Epilepsy 2020; De Jong, Physiological Reports 2018; Jakubowski, Epilepsy Behav 2013; Zizhen Wu, J Pharmacol Exp Ther 2020; JE Larsson, In Physiology 2020; Yadav, Saudi J Anaesth 2017; Garakani, Front Psychiatry 2020; Maljevic, J Physiol 2008; R. Brant, Gastroenterology 2017; Hui Sun, JCI Insight 2019;R Brant,Gastroenterology 2017;Ravi Misra,Gastroenterology 2017;Parreno,Front Physiol 2020;Blom,PLoS One.2014)(Feng Neuroscience 2019)(E Redford,Physiol Biochem 2021)(J Gunthrope,Epilepsia 2012; Epilepsia, Villalba. 2018). Since retigabine and flupirtin are well-tolerated in humans, the current findings of their remarkable anti-dystonic efficacy in dtsz variants suggest that neuronal Kv7 channel activators are interesting candidates for the treatment of dystonia-associated dyskinesia and possibly other types of dystonia. The established analgesic effects of Kv7 channel openers may contribute to the improvement of these disorders, which often involve painful muscle spasms.

[0184] Retigabine has been shown to delay the onset of diffusion depolarization after submaximal OGD stimulation. Interestingly, Kv7.2 activators are neuroprotective in experimental ischemia and traumatic brain injury studies, and the anti-diffusion depolarization properties of activators may contribute to these neuroprotective effects.

[0185] The research supports a new role for Kv7 channels in essential and synaptic plasticity, as well as their contributions to cognition and behavior.

[0186] Voltage-gated potassium channels of the KV7 family (KV7.1-5) play a crucial role in regulating neuronal excitability and are therefore attractive targets for the treatment of CNS disorders associated with hyperexcitability. f. Cognitive impairment, memory impairment, memory disorder, memory failure (Frontal Physiol, Baculis. 2020, Frontal Physiol, Vigil. 2020).

[0187] Given the importance of Kv7 channels for neonatal brain development and inhibition (Peters et al., 2005; Soh et al., 2014), memory impairment in these gene models may be due to abnormal hippocampal morphology and / or hyperexcitability (Peters et al., 2005; Milh et al., 2020). Kv7 channels also regulate several behaviors. Behavioral phenotyping of global or conditional homozygous KCNQ2 knockout mice was impossible due to early postnatal lethality or premature death, respectively (Watanabe et al., 2000; Soh et al., 2014).

[0188] However, heterozygous KCNQ2 knockout mice are viable and exhibit increased spontaneous motor activity and exploratory behavior (Kim et al., 2020), consistent with behavioral hyperactivity induced by transgenic inhibition of Kv7 current (Peters et al., 2005) and amphetamine and XE991 (Sotty et al., 2009). These mice also exhibit reduced socialization and increased repetitive and compulsive behaviors (Kim et al., 2020), reminiscent of autism observed in some EE patients with dominant KCNQ2 mutations (Weckhuysen et al., 2012, 2013, Milh et al., 2013). The International Kv7 Symposium held in Naples, Italy in 2019 highlighted significant translational potential. Animal studies suggest that the Kv7 current is a therapeutic target for multiple brain disorders, including those currently untreated such as TBI and psychostimulant addiction. g. Schizophrenia, (Transl Psychiatry, Nielsen.2017, Br J Pharmacol, Wang.2020).

[0189] Genetic or pharmacological inhibition of neuronal Kv7 channels can alleviate PPIs and cognitive impairments induced by NMDA antagonists, thus suggesting the therapeutic potential of such inhibition of Kv7 channels in the treatment of schizophrenia or cognitive impairment. h. Spinal cord injury (J Pharmacol, Wu.2020).

[0190] Reducing neuronal activity by opening the KCNQ / Kv7 channel can protect spinal cord neurons and axons from degeneration after SCI, thereby promoting the recovery of motor and sensory functions. Repeated application of retigabine to open these channels in the acute phase promotes neurobehavioral recovery after SCI. i. Cardiomyopathy, cardiac arrhythmias (Front Physiol, Larsson. 2020, J Physoil, Maljevic. 2008, Lee, Microcirculation. 2015).

[0191] Dysfunction of KV7 channels is often associated with disorders characterized by abnormal potassium ion conductance, including cardiac arrhythmias, hearing impairment, epilepsy, pain, and hypertension, due to their crucial physiological roles.

[0192] Mouse Kv7 channels may contribute in different ways to the modulation of the functional characteristics of cerebral and coronary arteries. Such heterogeneity has important implications for the development of new therapeutic agents for cardiovascular dysfunction. h. Long QT syndrome, (J Physoil,Maljevic.2008, Acta Pyhsoil.Skarsfeldt.2020:Acta Physoil,Bahannon.2019).

[0193] Polyunsaturated fatty acids with double bonds closer to the head group exhibited higher apparent affinity for IK channels, increasing IK current, while further away from the head group reduced apparent binding affinity and effect on IK current. Interestingly, ω-6 and ω-9 PUFAs were found to exhibit the most left-shifted voltage dependence of activation, due to the proximity of the first double bond to the head group. These results enable the information-driven design of new therapies targeting IK channels in QT prolongation syndrome.

[0194] The KV7 channel presents an intriguing target for novel therapeutic approaches to neuronal hyperexcitability-induced disorders such as epilepsy, neuropathic pain, and migraine. The molecular mechanism of KV7 activation by retigabine during a Phase III clinical trial for the treatment of drug-resistant focal epilepsy has recently been elucidated as stabilization of the opening conformation through binding to the pore region. i. Intestinal diseases, inflammatory diseases, ulcerative colitis, Crohn's disease (J Neurosci, Linley. 2008).

[0195] Further experiments demonstrated that M-current inhibition requires a simultaneous increase in cytoplasmic Ca2 concentration and depletion of membrane phosphatidylinositol 4,5-bisphosphate (PIP2). We propose that inhibition of M-currents in sensory neurons mediated by PLC and Ca2 / PIP2 may represent one of the common underlying mechanisms of pain generated by inflammatory mediators, and thus may open a new therapeutic window for treating this major clinical problem. J. Creutzfeldt-Jakob disease, (Acta Pharmacol Sin, Teng. 2016).

[0196] The modified QO58 compound (QO58-lysine) can specifically activate the Kv7.2 / 7.3 / M channel. Oral or intraperitoneal administration of QO58-lysine, with improved bioavailability and a plasma half-life of approximately 3 hours, can reverse inflammatory pain in rodent animal models. k. Progressive hearing loss or tinnitus (J Physoil,Maljevic.2008, Br J Pharmacol,Leithner.2014, J Neurosci,Kalappa.2015).

[0197] By stabilizing KCNQ4-mediated conductance in OHC, chemical channel openers can protect against OHC degeneration and the progression of hearing loss in DFNA2.

[0198] Behavioral studies demonstrated that SF0034 is a more potent and less toxic anticonvulsant than retigabine in rodents. Furthermore, SF0034 prevented the development of tinnitus in mice. We propose that SF0034 not only provides a powerful tool for studying ion channel properties, but most importantly, offers a clinical candidate for the treatment of epilepsy and the prevention of tinnitus. l. Diabetes, (Front Cardiovasc Med, Fosmo.2017).

[0199] Kv7 channel activity may contribute to the development of cardiovascular risk factors such as hypertension, diabetes, and obesity. Questions about past research and hypotheses for future studies have been raised. Alterations in Kv7 channels may contribute to the development of cardiovascular disease (CVD). Pharmacological modifications of Kv7 channels may represent possible treatments for future CVD. m. Chronic obstructive pulmonary disease (COPD) (Front Physiol, Mondejar-Parreno.2020).

[0200] The functional role of Kv7 channels can vary depending on cell type. Several studies have demonstrated that Kv7 channel dysfunction strongly impacts pulmonary physiology, contributing to the pathophysiology of various respiratory diseases such as cystic fibrosis, asthma, chronic obstructive pulmonary disease, chronic cough, lung cancer, and pulmonary hypertension. Kv7 channels are now recognized to play relevant physiological roles in many tissues, which has led to the search for Kv7 channel modulators with potential therapeutic applications in many diseases, including those affecting the lungs. Modulation of Kv7 channels has been proposed to provide beneficial effects in many lung conditions. Therefore, Kv7 channel openers / enhancers or drugs that act partially through these channels have been proposed as bronchodilators, expectorants, antitussives, chemotherapeutic agents, and pulmonary vasodilators. n. Movement disorders selected from primary dystonia (A Richter Br J Pharmacol 2006).

[0201] These data indicate that neuronal Kv7 channel dysfunction is noteworthy in dyskinesia. Since retigabine and flupirtin are well-tolerated in humans, the current findings of their remarkable anti-dystonic efficacy in dtsz variants suggest that neuronal Kv7 channel activators are interesting candidates for the treatment of dystonia-associated dyskinesia and possibly other types of dystonia. The established analgesic effects of Kv7 channel openers may contribute to the improvement of these disorders, which often involve painful muscle spasms. o. Autism, autism spectrum disorder, including administration of the compounds of this disclosure. (Gilling, Front Genet. 2013, Guglielmi, Front Cell Neurosci. 2015).

[0202] One embodiment of the present disclosure includes a method for treating one or more susceptible diseases or susceptible disorders by administering a compound of the present disclosure, thereby delivering a broad-spectrum Kv 7.2-7.5 active molecule into the systemic circulation and releasing the active Kv channel opener at an effective concentration of therapeutic value. In one embodiment, the release of the active molecule is enhanced by increased absorption, as provided under one or more of the following conditions.

[0203] Since retigabine and flupirtin are well-tolerated in humans, the current findings of remarkable antitonic efficacy in dtsz variants suggest that neuronal Kv7 channel activators are interesting candidates for the treatment of dystonia-associated dyskinesia and possibly other types of dystonia.

[0204] Mutations in the neuronal Kv7 (KCNQ) potassium channel may cause episodic neuropathy. Paroxysmal dyskinesia with dystonia is a group of movement disorders considered to be ion channel opathies, but the role of the Kv7 channel as a pathogenesis and therapeutic target has not been investigated to date.

[0205] Our results suggest that dysfunction of the heteromeric KV7.3 / 5 channel is involved in the pathogenesis of several forms of autism spectrum disorder, epilepsy, and possibly other mental disorders, and therefore KCNQ3 and KCNQ5 are suggested as candidate genes for these disorders. [Examples]

[0206] In the following examples, temperatures are given in degrees Celsius (°C) unless otherwise specified. Operations were carried out at room temperature or ambient temperature (typically in the range of about 18–25°C). Evaporation of the solvent was carried out using a rotary evaporator under reduced pressure (typically 4.5–30 mmHg) with a bath temperature of up to 60°C. The course of the reaction was typically tracked by TLC, and reaction times are provided for illustrative purposes only. Melting points are not corrected. The product is sufficient. 1 H-NMR data and / or microanalysis data are shown. Yields are provided for illustrative purposes only. The following conventional abbreviations are also used: mp (melting point), L (liter), mL (milliliters), mmol (millimoles), g (grams), mg (milligrams), min (minutes), and h (hours).

[0207] Unless otherwise specified, all solvents (HPLC grade) and reagents were purchased from the supplier and used without further purification. Analytical thin-layer chromatography (TLC) was performed on Whatman Inc. 60 silica gel plates (0.25 mm thick). Compounds were visualized under a UV lamp (254 nM) or by development with KMnO4 / KOH, ninhydrin, or honeysian solution. Flash chromatography was performed using Selectro Scientific silica gel (particle size 32-63). 1 H NMR spectrum, 19 F NMR spectrum, and 13 ¹³C NMR spectra were recorded on a Varian 300 machine at 300 MHz, 282 MHz, and 75.7 MHz, respectively. The melting point was recorded using an Electrothermal IA9100 instrument and was not corrected.

[0208] The following examples are provided for illustrative purposes only, and not to limit the disclosure. The general procedures of Examples 1 and 2 can be modified by those skilled in the art to be used for the synthesis of the compounds contained in Formula III by appropriate substitution of other starting materials with appropriate amounts of ezogavin, flupirtin, and acylating agents.

[0209] Those skilled in the art will further recognize that human clinical trials, including initial human, dose-range, and efficacy studies, in healthy patients and / or patients suffering from a given disorder, can be completed in accordance with methods well known in the clinical and medical fields.

[0210] This disclosure expressly includes the compounds presented below, including their salt forms. This disclosure also includes the compounds presented below, including their stereoisomers. Compositions comprising any therapeutically acceptable amount of any of these compounds are also within the scope of this disclosure. Such compositions may further comprise pharmaceutically acceptable excipients, diluents, carriers, or mixtures thereof. Such compositions may be administered to subjects requiring them to treat or control diseases or disorders mediated whole or partially, directly or indirectly, by one or more voltage-dependent potassium channels. The compositions may further comprise additional activators described herein.

[0211] The following examples provide a more detailed description of the process conditions for preparing the compounds of this disclosure. However, it should be understood that this disclosure, as fully described herein and as defined in the claims, is not intended to be limited by the following schemes or preparation methods.

[0212] Certain abbreviations may be used when describing the embodiments of this disclosure. These abbreviations are expected to be used consistently within the scope of generally accepted use for those skilled in the art.

[0213] The compounds of the present invention may be prepared using commercially available reagents and intermediates in the synthesis method and reaction scheme described herein, or they may be prepared using other reagents and conventional methods well known to those skilled in the art.

[0214] In the following scheme, common substituents are represented by assignments that may not align with the formulas of this disclosure. The following scheme provides a key for such substituents, which should follow the scheme and are not applicable to the formulas of this disclosure.

[0215] scheme

[0216] General Scheme 1: Prodrug Synthesis from Kv7 Active Drug Molecules [ka]

[0217] In general scheme 1, the Kv7 pharmacophore is the drug portion that is active in the Kv7 potassium ion channel. Reagent LC(O)-R 1 teeth 、 Represents an activated carbonyl reagent or intermediate. 、 L is a leaving group. G represents H or various substituents, and R 1 This is as used herein. The resulting product is a hydrolyzable prodrug that forms a Kv7 active drug upon hydrolysis.

[0218] Example 1

[0219] General procedure for the preparation of acetal / ketal diester prodrugs of ezogavin:

[0220] Place 200 mL of dichloromethane at room temperature in a 500 mL round-bottom flask equipped with a magnetic stirring rod. Start stirring and add the following materials in order: Ezogavin (10.0 g, 33.00 mmol, 1.0 equivalent, 303.33 g / mol, [CAS No. 150812-12-7]), triethylamine (6.68 g, 66.00 mmol, 2.0 equivalent, 101.19 g / mol), desired 1-(((4-nitrophenoxy)carbonyl)oxy)alkyl carboxylate (34.62 mmol, 1.05 equivalent, and HOBt (0.446 g, 3.30 mmol, 0.1 equivalent, 135.12 g / mol). Flash the flask with nitrogen gas and seal it with the septum. Maintain a nitrogen atmosphere of approximately The reaction is maintained using a needle attached to a nitrogen line of 1 atm N2, and the progress is monitored by TLC. If no ezogavin remains by TLC, the reaction is treated by adding 100 mL of water and stirring under nitrogen for 10 minutes. The contents of the flask are transferred to a separation funnel and the layers are separated. The organic layer is washed twice with 0.1 M sodium hydroxide solution and dried on sodium sulfate. Volatiles are removed under vacuum, and the residue is purified by column chromatography or recrystallization to obtain the desired ezogavin-derived prodrug.

[0221] Example 2

[0222] General procedure for the preparation of acetal / ketal diester prodrugs of flupirtin:

[0223] Place 200 mL of dichloromethane at room temperature in a 500 mL round-bottom flask equipped with a magnetic stirring rod. Start stirring and add the following materials in order: flupirtin (10.0 g, 33.00 mmol, 1.0 equivalent, 303.33 g / mol, [CAS No. 56995-20-1]), triethylamine (6.68 g, 66.00 mmol, 2.0 equivalent, 101.19 g / mol), desired 1-(((4-nitrophenoxy)carbonyl)oxy)carboxylate alkyl (34.62 mmol, 1.05 equivalent), and HOBt (0.446 g, 3.30 mmol, 0.1 equivalent, 135.12 g / mol). Flash the flask with nitrogen gas and seal it with the septum. A nitrogen atmosphere is maintained using a needle attached to a nitrogen line of approximately 1 atmosphere of N2, and the reaction progress is monitored by TLC. If no flupirtin remains by TLC, the reaction is treated by adding 100 mL of water and stirring under nitrogen for 10 minutes. The contents of the flask are transferred to a separation funnel and the layers are separated. The organic layer is washed twice with 0.1 M sodium hydroxide solution and dried on sodium sulfate. Volatile substances are removed under vacuum, and the residue is purified by column chromatography or recrystallization to obtain the desired flupirtin-derived prodrug.

[0224] The general procedures of Examples 3 and 4 can be modified by those skilled in the art to be used for the synthesis of the compounds contained in Formula IV by appropriate substitution of other starting materials with appropriate amounts of ezogavin, flupirtin, and acylating agents.

[0225] Example 3

[0226] General procedure for preparing the amino acid prodrug of ezogavin:

[0227] Step 1: Place 200 mL of dichloromethane at room temperature in a 500 mL round-bottom flask equipped with a magnetic stirring rod. Start stirring and add the following materials in order: ezogavin (10.0 g, 33.00 mmol, 1.0 equivalent, 303.33 g / mol, [CAS No. 150812-12-7]), triethylamine (6.68 g, 66.00 mmol, 2.0 equivalent, 101.19 g / mol), the desired Boc-protected amino acid O-succinimide ester (34.62 mmol, 1.05 equivalent), and HOBt (0.446 g, 3.30 mmol, 0.1 equivalent, 135.12 g / mol). Flash the flask with nitrogen gas and seal it with the septum. Maintain a nitrogen atmosphere using a needle attached to a nitrogen line of N2 at approximately 1 atm, and monitor the reaction progress by TLC. If no ezogavin remains after TLC, add 100 mL of water to the reaction mixture and stir under nitrogen for 10 minutes. Transfer the contents of the flask to a separation funnel and separate the layers. Wash the organic layer twice with 0.1 M sodium hydroxide solution and dry on sodium sulfate. Remove volatiles under vacuum and purify the residue by column chromatography or recrystallization to obtain the desired prodrug in a BOC-protected form.

[0228] Step 2: Add the product from Step 1 to a stirred solution of 25% trifluoroacetic acid in 100 mL of dichloromethane at room temperature. Flash the flask with nitrogen gas and seal it with a septum. Maintain a nitrogen atmosphere using a needle attached to a nitrogen line of approximately 1 atmosphere of N2, and monitor the reaction progress by TLC. If no starting materials or intermediates remain by TLC, treat the reactants by removing the volatile solvent under vacuum. The crude product is obtained as a mixture of trifluoroacetate salts of the desired prodrug free base. The material is purified by recrystallization or reverse-phase HPLC to obtain the desired prodrug material.

[0229] Example 4

[0230] General procedure for preparing the amino acid prodrug of flupirin:

[0231] Step 1: Place 200 mL of dichloromethane at room temperature in a 500 mL round-bottom flask equipped with a magnetic stirring rod. Start stirring and add the following materials in order: flupirtin (10.0 g, 33.00 mmol, 1.0 equivalent, 303.33 g / mol, [CAS No. 56995-20-1]), triethylamine (6.68 g, 66.00 mmol, 2.0 equivalent, 101.19 g / mol), the desired Boc-protected amino acid O-succinimide ester (34.62 mmol, 1.05 equivalent), and HOBt (0.446 g, 3.30 mmol, 0.1 equivalent, 135.12 g / mol). Flash the flask with nitrogen gas and seal it with the septum. Maintain a nitrogen atmosphere using a needle attached to a nitrogen line of N2 at approximately 1 atm, and monitor the reaction progress by TLC. If no flupirtin remains after TLC, add 100 mL of water to the reaction mixture and stir under nitrogen for 10 minutes. Transfer the contents of the flask to a separation funnel and separate the layers. Wash the organic layer twice with 0.1 M sodium hydroxide solution and dry on sodium sulfate. Remove volatiles under vacuum and purify the residue by column chromatography or recrystallization to obtain the desired prodrug in a BOC-protected form.

[0232] Step 2: Add the product from Step 1 to a stirred solution of 25% trifluoroacetic acid in 100 mL of dichloromethane at room temperature. Flash the flask with nitrogen gas and seal it with a septum. Maintain a nitrogen atmosphere using a needle attached to a nitrogen line of approximately 1 atmosphere of N2, and monitor the reaction progress by TLC. If no starting materials or intermediates remain by TLC, treat the reactants by removing the volatile solvent under vacuum. The crude product is obtained as a mixture of trifluoroacetate salts of the desired prodrug free base. The material is purified by recrystallization or reverse-phase HPLC to obtain the desired prodrug material.

[0233] Example 5

[0234] Synthesis of acetal prodrug ezogavin.

[0235] Step 1:

[0236] Zinc oxide (44.73 g, 0.55 mol) was added to a solution of toluene (1800 mL) and 2-methylpropanoic acid (450 mL), and the flask was heated to 120°C. The water produced in this process was removed by a Dean-Stark trap. After heating for 5 hours, the temperature was reduced to 70°C, and then (1-chloroethyl)(4-nitrophenyl)carbonate (45 g, 0.18 mol) was added together with NaI (43.97 g, 0.29 mol). The reaction mixture was stirred at 70°C for 36 hours. After completion, the mixture was evaporated, the residue was dissolved in ethyl acetate, washed with saturated NaHCO3 solution, and then washed with brine. The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1) to obtain the desired product as a yellow solid (32.6 g, yield 55.68%).

[0237] Step 2:

[0238] To a stirred solution of ethyl N-(2-amino-4-{[(4-fluorophenyl)methyl]amino}phenyl)carbamate (24 g, 0.079 mol) in dichloromethane (480 mL), triethylamine (16.01 g, 0.16 mol), 1-[(4-nitrophenoxycarbonyl)oxy]ethyl 2-methylpropanoate (30.57 g, 0.10 mol), and 1-hydroxybenzotrizole (1.07 g, 0.007 mol) were added, and the mixture was stirred under a nitrogen atmosphere at 25°C for 24 hours. After completion, the mixture was treated by adding 300 mL of water and stirring under nitrogen for 10 minutes. The contents of the flask were transferred to a separation funnel, and the layers were separated. The organic layer was washed twice with 0.1 M sodium hydroxide solution and dried on sodium sulfate. The volatile components were removed under vacuum, and the residue was purified by column chromatography (petroleum ether: dimethyl = 6:1) to obtain compound 3 as a yellow solid (3.4 g, yield 9.3%).

[0239] 1¹H-NMR (DMSO-d6): δ (ppm): (multiplicity, J (Hz), integral): 8.8-8.7 (bs, 1H), 8.3-8.2 (bs, 1H), 7.4 (m, 2H), 7.1 (m, 2H), 7.0-6.9 (bs, 1H), 6.8 (bs, 1H), 6.7 (q, 1H), 6.3 (m, 2H), 4.2 (m, 2H), 4.0 (m, 2H), 2.5 (m, 1H), 1.4 (m, 3H), 1.2 (m, 3H), 1.1 (m, 6H).

[0240] 13 C-NMR:(DMSO-d6):δ(ppm):174.9,162.7,160.3,152.0,146.8,136.7,136.7,129.3,118 .9,115.5,115.3,109.0,107.2,89.5,60.6,46.3,39.6,33.6,20.0,19.0,18.9,15.0ppm.

[0241] LCMS R t =1.38min, [M+H]=462

[0242] General スキームA

change

[0243] Example 6

[0244] ステップ1:

[0245] To a stirred solution of ethyl N-(2-amino-4-{[(4-fluorophenyl)methyl]amino}phenyl)carbamate (10 g, 0.033 mol) in dichloromethane (200 mL), triethylamine (6.68 g, 0.066 mol), 2,5-dioxopyrrolidine-1-yl N2, N6-bis(tert-butoxycarbonyl)-L-lysinate (15.34 g, 0.035 mol), and 1-hydroxybenzotrizole (0.44 g, 0.003 mol) were added. The solution was stirred under a nitrogen atmosphere at 25°C for 24 hours. After completion, the mixture was treated by adding 100 mL of water and stirring under nitrogen for 10 minutes. The contents of the flask were transferred to a separation funnel and the layers were separated. The organic layer was washed twice with 0.1 M sodium hydroxide solution and dried on sodium sulfate. The volatile components were removed under vacuum, and the residue was purified by column chromatography (petroleum ether: siRNA = 2:1) to obtain the desired product as a white solid (12.6 g, yield 60.5%).

[0246] Step 2:

[0247] A mixture of tert-butyl N-(5-{[(tert-butoxy)carbonyl]amino}-5-({2[(ethoxycarbonyl)amino]-5-{[(4fluorophenyl)methyl]amino}phenyl}carbamoyl)pentyl)carbamate (8.67 g, 0.014 mol) and HCl (in dioxane) (17.5 mL, 0.069 mol) was prepared in dichloromethane (86 mL). The mixture was continuously stirred at room temperature for 18 hours. After completion, the mixture was filtered, the filter cake was washed with dichloromethane, and dried under reduced pressure to obtain compound 4 as a white solid (6.3 g, yield 98.1%).

[0248] 1H-NMR:(DMSO-d6):δ(ppm), (multiplicity, J(Hz), integral):10.0-10.2(bs,1H),8.5-8.4(bs,3H),8.1-7.9(bs,3H),7.4(m,2H),7.2(m,3) H),7.1(bs,1H),6.7(bs,1H),4.3-4.2(bs,2H),4.1(m,3H),2.7(bm,2H),1.8(bm,2H),1.6(m,2H),1.4(m,2H),1.2(m,3H).

[0249] 13 C-NMR:(DMSO-d6):δ(ppm):168.3,161.2,154.6,132.3,125.4,115.7,115.5,61.0,52.8,38.7,30.7,26.8,21.6,15.0ppm.

[0250] LCMSR t =0.94min, [M+H]=432

[0251] General Scheme B [ka]

[0252] Example 7

[0253] Study of water solubility, organic solubility, and stability of examples of ezogavin prodrugs

[0254] The solubility of two prodrugs of ezogavin (compound 1) in different aqueous and organic media was evaluated by measuring UV absorption at 230 nm using an HPLC-UV / Vis mass spectrometer detector for mass confirmation, and their stability was assessed for up to 7 days. The solubility of compound 1 is known and is shown in Table 1. The solubility of compound 1 in the solvent row of 0.1N Na2HPO4 was measured in 0.1N K2HPO4.

[0255] Compounds 3 and 4 were evaluated in various solvents, and their solubility was compared with that of compound 1. The compounds were weighed, placed in four drum vials, and solvent was added to reach the target concentration. The compounds were vortexed, and the particles were visually inspected. Solubility was considered to have occurred if the particles were clear visually, regardless of whether magnification was used. Solubility was reported as either greater than (>) or less than (<) from the prepared concentration. Compound 4 was evaluated for solubility at a maximum concentration of 20 mg / mL in water and 0.1N HCl and was freely soluble. Compound 4 was evaluated at 10 mg / mL in 0.1N NaCl and was freely soluble. Compound 4 was evaluated at 1 mg / mL in 0.1N NaOH and 0.1N Na2HPO4 and was freely soluble. Compound 4 was freely soluble at a concentration of 75 mg / mL in ethanol and methanol.

[0256] Visual inspection revealed that compound 3 was not freely soluble at 1 mg / mL in 0.1N HCl, 0.1N NaOH, 0.1N NaCl, water, or 0.1N Na2HPO4. Compound 3 was freely soluble in methanol and ethanol at 75 mg / mL. Compound 3 was soluble in 1N HCl at 1 mg / mL.

[0257] Both prodrug compounds are more soluble in alcohol than compound 1. Compound 3 may have similar absolute solubility to compound 1 in aqueous media, but compound 4 exhibits superior solubility in aqueous solvents. For in vivo studies, compound 4 was formulated as a freely soluble solution in 0.9% w / v NaCl at a concentration of 150 mg / mL.

[0258] [Table 1]

[0259] Since compound 1 is known to decompose in light within 3 to 7 days, the compound in solvent was left exposed to light on a benchtop for up to 7 days.

[0260] Stability was assessed by taking aliquots from the solubility vial on each test day. A single replica was injected for each test condition. Samples from compound 4 were diluted with water to a test concentration of 100 μg / mL. Samples from compound 3 (alcohol) were diluted with methanol to 200 μg / mL, and then further diluted with water to 100 μg / mL. Samples from compound 3 (aqueous solvent) were diluted with methanol to 500 μg / mL.

[0261] The sample was injected into an HPLC system containing an aqueous mobile phase and an acetonitrile organic phase, and the compounds were separated on a C8 50 × 2 mm column. Absorption at a wavelength of 230 nm was monitored, the peak area was integrated, and the mass was determined using a mass spectrometer. The sample was tested daily on day 1 and thereafter for up to day 7.

[0262] Figure 1 shows the increase in stability and solubility of compound 3. From day 1 to day 3, compound 3's solubility increased over time in 0.1N Na2HPO4, H2O, and 0.1N NaCl. Compound 3 appeared stable in 0.1N HCl for 4 days, but was unstable in 1N HCl for 7 days. Compound 3 was soluble and stable in ethanol and methanol for 3 days, but decomposed on day 4.

[0263] The stability of compound 4 is shown in Figure 2. Compound 4 appears stable over 4 days under all test conditions except 0.1N NaOH. There is a general variation of + / -20% in the peak area integral, suggesting a trend of stability for all solvents except 0.1N NaOH, which reduced the peak area of ​​compound 4 by >50%.

[0264] Taken together, these results suggest that compounds 3 and 4 are more soluble in alcohol than compound 1, and compound 4 is more soluble in aqueous solvents than compound 1. Except for the selected solvent, both ezogavin prodrugs are stable in solvents for 3 days.

[0265] Figure 1 illustrates the stability and solubility of compound 3 over 3 to 7 days. Figure 2 shows the stability of compound 4 over 4 days.

[0266] Example 8

[0267] Plasma stability test of an example of ezogavin prodrug

[0268] We conducted a study to evaluate the in vitro stability of two prodrugs of ezogavin (compound 1) in mouse and rat plasma at 37°C for up to 23 hours.

[0269] Dried compounds #3 and #4 were dissolved in dimethyl sulfoxide (DMSO) at a concentration of 1 mg / mL and frozen at -20°C.

[0270] The plasma was collected by a biomaterials vendor and cryopreserved at -20°C.

[0271] 1 mg / mL DMSO solutions of compounds 3 and 4 were diluted in rat and mouse plasma to a final concentration of 1000 ng / mL, vortexed, and aliquots were immediately removed. The plasma was precipitated with 4 volumes of acetonitrile containing tolbutamide as an internal standard for mass spectrometry detection. The residue was incubated at 37°C for up to 23 hours. Samples were stopped in a solution of ACN and tolbutamide (internal standard) at 0 min, 5 min, 30 min, 1 hour, 2 hours, 4 hours, 6 hours, and 23 hours. Samples were analyzed by HPLC separation and mass spectrometry detection for the amount of prodrug compared to a baseline control sample at time 0. Triple samples were generated at each time point, and the peak area responses were averaged and converted to the percentage of the baseline control.

[0272] Compound 3 is unstable in mouse and rat plasma and shows complete degradation within 1 hour in vitro (Figure 3). Compound 4 degrades within 6 hours in mouse plasma but remains stable in rat plasma for 6 hours, after which less than 50% remains after 23 hours (Figure 4). Ezogavin prodrugs induce different stability profiles in plasma in vitro, suggesting that they may have different release kinetics in vivo.

[0273] Figure 3 shows the plasma stability of compound 3 in in vitro mice and rats at 37°C. Figure 4 shows the plasma stability of compound 4 in in vitro mice and rats at 37°C.

[0274] Example 9

[0275] Pharmacokinetics of ezogabine prodrugs in mice.

[0276] A bioanalytical method was developed to detect compound 1, its primary metabolite, the N-acetyl metabolite, and either compound 3 or compound 4 using an Agilent 1100HPLC system coupled to a CTC PAL autosampler set to 4°C. Separation by HPLC was achieved using a 50 × 2 mm C8 column, and the HPLC was operated in reverse phase. Blood was collected by cardiac stick using a 25G 3 / 4-inch needle attached to a 1 mL syringe and transferred to a K2EDTA tube containing either 500 mM citrate in water for studies with compound 4, or 500 mM citrate containing 50 mM dichlorvos for studies with compound 3. The blood was diluted to 10% with these stabilizers. These solutions were identified to determine the best method for stabilizing compounds 3 and 4 from a series of experiments and for preserving the ezogavin prodrug in plasma before extraction.

[0277] Molecular extraction was performed by taking 50 μL of aliquot plasma and adding 200 μL of acetonitrile containing 200 ng / mL of tolbutamide as an internal standard. The sample was precipitated in a 96-well plate, centrifuged, and the aliquot was transferred to a new plate, dried under heat and nitrogen, and then reconstituted under initial mobile phase conditions for LC-MS / MS. A standard curve was prepared for compound 1 with or without the N-acetyl metabolite separated from the prodrug. Standard curves were prepared for each analyte from 5000 ng / mL to 1 ng / mL. Concentration data from bioanalysis runs were analyzed using Phoenix Winnonlin version 8 for non-compartmental sparse sampling PK analysis, plotting of concentration-time curves, and table of PK parameters.

[0278] Four male mice weighing 20-25 g were administered either compound 1, compound 3, or compound 4 subcutaneously or orally at each time point. The animals were asphyxiated with carbon dioxide gas, blood was collected using a cardiac stick, and euthanized by neck dislocation. Compound 4 was administered subcutaneously at a solution dose of 100 mg / kg in physiological saline at a volume of 10 mL / kg. Concentration analysis of compound 1 and compound 4 was collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours (N=4 / time point). Figure 5 shows the mean (standard deviation) of compound 4 after subcutaneous (SC) administration. Compounds 1, 3, and 4 were administered orally to male mice at doses close to the equimolar dose of compound 1. Compounds 3 and 4 were administered at a solution dose of 30 mg / kg in a volume of 10 mL / kg, while compound 1 was administered at 20 mg / kg. Compounds 1 and 3 were formulated in 5% ethanol:20% Cremofor EL and 75% physiological saline. Compound 4 was formulated in physiological saline. Plasma concentrations of compound 1 and its N-acetyl metabolite were evaluated at 0.5, 1, 1.5, 2, 4, and 6 hours. Figure 6 shows the plasma concentration of compound 1 after oral administration of any of compounds 1, 3, or 4, and Figure 7 shows the concentrations of its metabolites.

[0279] Sparsely sampled non-compartment pharmacokinetic (PK) parameters are from these two studies and are summarized in Table 2. Compounds 3 and 4, based on AUClast at similar molar doses, delivered more compound 1 into the systemic circulation after 6 hours of oral administration than compound 1 was administered alone. Compound 4 delivered a lower Cmax compared to compound 1, which may contribute to a reduced adverse event profile in clinical trials due to the lower Cmax and slower Tmax. Metabolites are formed at similar exposure levels regardless of whether they are prodrugs or ezogabine, but on a ratio basis, less is produced when compound 1 is administered as compound 3. Compound 1 has a slightly longer MRTlast (average residence time over 6 hours when administered as a prodrug) and a longer half-life in mice when administered subcutaneously as compound 4. The SC administration route delivers more compound 1 when administered as compound 4 than the PO route based on AUClast / D.

[0280] [Table 2]

[0281] Figures 5A and 5B show linear and semi-logarithmic plots of compound 1 and compound 4 after administration of 100 mg / kg of compound 4 SC to male mice. Figure 6 shows a semi-logarithmic plot of compound 1 after oral administration of either 20 mg / kg of compound 1, 30 mg / kg of compound 3, or 30 mg / kg of compound 4 to male mice. Figure 7 shows a semi-logarithmic plot of N-acetyl metabolites after oral administration of either 20 mg / kg of compound 1, 30 mg / kg of compound 3, or 30 mg / kg of compound 4 to male mice.

[0282] Example 10

[0283] Pharmacokinetics of ezogabine prodrugs in rats

[0284] A bioanalytical method was developed to detect compound 1, its primary metabolite, the N-acetyl metabolite, and either compound 3 or compound 4 using an Agilent 1100HPLC system coupled to a CTC PAL autosampler set to 4°C. Separation by HPLC was achieved using a 50 × 2 mm C8 column, and the HPLC was operated in reverse phase. Blood was collected by cardiac stick using a 25G 3 / 4-inch needle attached to a 1 mL syringe and transferred to a K2EDTA tube containing either 500 mM citrate in water for studies with compound 4, or 500 mM citrate containing 50 mM dichlorvos for studies with compound 3. The blood was diluted to 10% with these stabilizers. These solutions were identified to determine the best method for stabilizing compounds 3 and 4 from a series of experiments and for preserving the ezogavin prodrug in plasma before extraction.

[0285] Molecular extraction was performed by taking 50 μL of aliquot plasma and adding 200 μL of acetonitrile containing 200 ng / mL of tolbutamide as an internal standard. The sample was precipitated in a 96-well plate, centrifuged, and the aliquot was transferred to a new plate, dried under heat and nitrogen, and then reconstituted under initial mobile phase conditions for LC-MS / MS. A standard curve was prepared for compound 1 with or without the N-acetyl metabolite separated from the prodrug. Standard curves were prepared for each analyte from 5000 ng / mL to 1 ng / mL. For non-compartmental PK analysis, plotting of concentration-time curves, and tabulation of PK parameters, concentration data from bioanalysis runs were analyzed using Phoenix Winnonlin version 8.

[0286] Male Sprague Dawley rats weighing 225–250 g were indwelled via jugular vein cannula for IV administration and / or blood sample collection. Two rats from each dose group were administered either compound 1, compound 3, or compound 4 via intravenous, intramuscular, or oral route. 150 μL of blood was collected at pre-specified time points. At the end of the study, the animals were asphyxiated with carbon dioxide gas and bled for euthanasia. Compounds 1 and 3 were formulated in 5% ethanol:20% cremofor EL and 75% saline. Compound 4 was formulated in saline. Compounds 3 and 4 were administered at a dose of 5 mg / kg by IV bolus in a volume of 4 mL / kg. Compound 4 was administered at a dose of 75 mg / kg by IM in the upper limb in a volume of 0.5 mL / kg to four rats per time point. Compounds 1, 3, and 4 were administered orally in equimolar doses, with compound 1 being the first to be administered. Compounds 3 and 4 were administered in 5 mL / kg of solution at a dose of 30 mg / kg, while compound 1 was administered at a dose of 20 mg / kg.

[0287] Figure 8 shows the mean (standard deviation) of compound 4 after intramuscular (IM) administration. Figure 9 shows the plasma concentration of compound 1 after oral administration of any of compounds 1, 3, or 4, and Figure 10 shows the concentrations of its metabolites.

[0288] Non-compartmental pharmacokinetic (PK) parameters were generated from individual rats, averaged for each study, and summarized in Table 3. Compound 3 delivered more compound 1 into the systemic circulation after 24-hour oral administration of compound 1 than after administration of compound 1 itself, based on AUClast at similar molar doses and a lower Cmax. Compound 4 delivered a lower Cmax and equivalent AUClast over 24 hours compared to compound 1 itself, although it could have been higher as there was no time point between 6 hours and 24 hours where compound 1 had not yet begun to clear. The rate of compound 1 formation was slower in the prodrug compared to the absorption rate of compound 1 administered as itself. This results in a slower Tmax, which may reduce adverse events occurring in early-onset treatment. The longer the half-life of the prodrug, the longer the half-life of compound 1. The IM administration route delivers more compound 1 when administered as compound 4 than the oral route based on AUClast / D. Compound 1 has a slightly longer MRTlast (average residence time over 24 hours when administered as a prodrug) and a longer half-life in rats when administered compared to administration of the compound alone. Exposure to compound 3 in systemic circulation after PO administration was very low (not reported), while compound 4 was slightly more detectable in systemic circulation after PO administration (not reported).

[0289] [Table 3]

[0290] Figure 8 shows a semi-logarithmic plot of Compound 1 and Compound 4 after administration of Compound 4 IM at 75 mg / kg in male rats. Figure 9 shows a semi-logarithmic plot of Compound 1 after oral administration of either Compound 1 at 20 mg / kg, Compound 3 at 30 mg / kg, or Compound 4 at 30 mg / kg to male Sprague Dawley rats. Figure 10 shows a semi-logarithmic plot of N-acetyl metabolites after oral administration of either Compound 1 at 20 mg / kg, Compound 3 at 30 mg / kg, or Compound 4 at 30 mg / kg to male mice.

[0291] Example 11

[0292] Ezogavin prodrugs are inactive against the molecular targets Kv7.2 / 7.3.

[0293] Human Kv7.2 / 7.3 cells were harvested, counted, and seeded into a 96-well plate with a black clear bottom at a density of 50,000 cells per 100 μl volume well, and incubated overnight. The following day, the medium was removed, and 40 μl of loading buffer (4.895 mL of HBSS:HEPES, 50 μl of probenecid, 50 μl of power load, and 5 μl of FluxOR reagent) was added and incubated at room temperature for 30 minutes. After incubation, the loading buffer was removed, and 40 μl of assay buffer (4.45 mL of HBSS:HEPES, 500 μl of FluxOR assay buffer, and 50 μl of probenecid) was added and incubated for 10 minutes. Next, 10 μl of stimulating buffer was added to the FLIPR with either the vehicle, test compound, or reference agonist, and fluorescence was monitored at ex / em for 5 minutes. 488 nm / 510-570 nm. Compounds 3 and 4 were tested in multiple concentrations from 0.03 to 30 μM using a 7-point concentration response, and ezogavin was tested in multiple concentrations from 0.01 to 10 μM. Relative fluorescence units (RFU) were plotted against concentration. Compounds 3 and 4 are inactive to the primary target of Kv7.2 / 7.3. Compound 1 was inactive in this assay at 1.6 μM EC 50 It holds.

[0294] Figure 11 shows in vitro screening of Kv7.2 / 7.3 voltage-gated potassium channels.

[0295] Example 11

[0296] Ezogabine prodrug delivers an in vivo effective concentration of ezogabine to block maximum electrical shock (MES) in mice.

[0297] CF-1 male mice (N=8) were treated with an IP of vehicle, compound 3, compound 4, compound 1, phenytoin, or diazepam (0, 150, 100, 100, 8, and 20 mg / kg, respectively), followed by corneal stimulation at 60 Hz (50 mA). All treatments were administered 30 minutes prior to MES, except for phenytoin which was administered 1 hour prior.

[0298] All mice in the vehicle group exhibited colonic seizures within seconds of receiving MES. Mice treated with the remaining treatments generally reached the maximum time limit of 6 seconds without showing signs of seizures.

[0299] Figure 12 shows the maximal electroshock (MES) test for CF-1 mice.

[0300] CF-1 mice (N=8) were treated with compound 1, compound 3, and compound 4 (150, 100, and 100 mg / kg, respectively) by intracellular therapy (IP). Blood was collected after MES for concentration analysis of compound 1. The concentration of compound 1 in plasma was higher after administration of compound 3 or compound 4 than after administration of compound 1 alone (Figure 13). Compound 3 was 5.5 times higher than compound 1, and compound 4 was 9 times higher than compound 1.

[0301] Figure 13 shows the CF-1 mouse concentration of compound 1.

[0302] Example 12

[0303] Ezogabine prodrug delivers an in vivo effective concentration of ezogabine to block maximum electrical shock (MES) in mice.

[0304] SD rats (N=4) were treated with compound 4 (75 mg / kg) in IM and given corneal stimulation at 60 Hz (100 mA). All treatments were performed at 0.083, 0.25, 0.5, 1, 2, 4, and 8 hours prior to administration in the MES test, with 6 seconds of seizure-free intervals considered protected.

[0305] The rats showed increased protection from seizures with increasing time, being almost completely protected at 1 hour and completely protected at 2–8 hours after administration. Figure 14 summarizes the mean time to seizure in the mean (SD) group.

[0306] Figure 14 shows the protective effect of compound 4 on SD rats after administration of IM for MES-induced seizures.

[0307] Example 13

[0308] Compound 3 was tested in a CCI model of neuropathic pain for reversal of mechanical hypersensitivity to the pinpick test for hind limb dislocation, and for Gram force mechanical allodynia using von Frey hair. Male Sprague Dawley rats (n=8 / group) were tested for baseline sensitivity on day 1 (ipsilateral and contralateral paws) and orally administered XYG-203. The doses were 40 mg / kg on day 1, 20 mg / kg on day 3, 10 mg / kg on day 5, 5 mg / kg on day 7, 1 mg / kg on day 10, and baseline on day 12. Mechanical hypersensitivity was tested 1 hour after pretreatment. Data (mean ± SD) were analyzed by repeated measures ANOVA with Dunnett adjustment for multiple comparisons. For compound 3, at 5 mg / kg, the 95% confidence interval did not exceed the baseline mean, while 40 mg / kg reduced the latency of neuropathy-induced ipsilateral paw release to 9.2 seconds (p=0.0003) and significantly increased the Gram force used to lift the paw. There were no significant differences between baseline values ​​at day 0 and day 12 for either the ipsilateral or contralateral hind paw, indicating no accumulation of learned behavior or drug effects in the ipsilateral hind paw. Furthermore, the response of the contralateral paw did not change significantly over the course of the study. The results are shown in Figures 15, 16, and 17.

[0309] In male rats with indwelling jugular vein cannulas, compound 3 was administered at an equimolar dose to ezogavin (20 mg / kg) using the same formulation (0.5% methylcellulose in water). Blood samples were collected at the same time point over 24 hours, and concentration-time profiles were generated. Two male rats were administered per group. Plasma samples were analyzed by LC / MS / MS, and the resulting concentration-time profiles and PK parameters are provided. Compound 3 provided more than twice the total exposure to ezogavin at a given molar dose compared to ezogavin alone. Compound 3 is essentially undetectable in systemic circulation. [Table 4]

[0310] Compound 4 was evaluated in a rat formalin inflammation model. Following intrapedictal administration of 50 μL of 5% formalin, the number of flicks / licks in male CD-1 mice was recorded during the acute phase (0–10 minutes) and the inflammatory phase (15–40 minutes). 5 mL / kg of SC was administered 30 minutes prior to formalin application (n=8 / group) using either saline or Compound 4 (100 mg / kg in water). In both phases, a 50% reduction in behavioral responses was observed with Compound 4 compared to the vehicle. Data are presented in a 2-minute vial over the duration of the observation period. Compound 4 demonstrates a reduction in inflammatory pain. The results are shown in Figure 18.

[0311] [ka] Compounds 4, 6, and 29 were administered in equimolar doses to ezogabin (20 mg / kg) using the same formulation (0.5% methylcellulose in water) in male rats with jugular vein cannulas. Blood samples were collected at the same time point over 24 hours to generate concentration-time profiles. Two male rats were administered per group. Plasma samples were analyzed by LC / MS / MS to provide the obtained concentration-time profiles and PK parameters. Compounds 4, 6, and 29 delivered ezogabin at doses similar to ezogabin itself, with normalized total AUC exposure. However, compound 4 showed the lowest exposure in plasma, followed by compound 29. Compounds 4 and 29 delivered approximately half the ezogabin Cmax of ezogabin itself, while compound 6 delivered approximately twice the ezogabin Cmax of ezogabin itself. [Table 5]

[0312] The results are shown in Figure 19. [ka]

[0313] Compound 28 was tested in a maximal electroshock assay in CF-1 mice 30 minutes after drug administration via the IP route to determine its ability to release ezogavine and provide protection in the assay. Drug concentrations of compound 28, ezogavine, and pregabalin were determined by LC / MS / MS assays in plasma and brain. Compound 28 was evaluated in dose response to maximal electroshock at vehicle, 1.5, 3, 6, 12, and 24 mg / kg. Drug levels of ezogavine and compound 28 were assessed. An additional group at 24 mg / kg was evaluated for exposure to compound 28, ezogavine, and pregabalin in plasma and brain. None of the doses demonstrated complete protection against MES-induced seizures. At 12 mg / kg, 1 out of 9 animals was protected from MES-induced seizures, and at 24 mg / kg, 3 out of 9 animals were protected. However, there was a clear increase in protection with increasing ezogavine concentration. Compound 28 was also present at a higher concentration than ezogabin, indicating that it had not yet completely released ezogabin. The results are illustrated in Figures 20 and 21.

[0314] Furthermore, in male rats with indwelling jugular vein cannulas, compound 28 was administered at an equimolar dose to ezogabine (20 mg / kg) using the same formulation (0.5% methylcellulose in water). Blood samples were collected at the same time point over 24 hours to generate concentration-time profiles. Two male rats were administered per group. Plasma samples were analyzed by LC / MS / MS, and the resulting concentration-time profiles and PK parameters are provided. Compound 28 resulted in lower exposure to ezogabine than ezogabine at a given molar dose. Both ezogabine and compound 28 were present at similar concentrations in the rats. [Table 6]

[0315] The results are shown in Figure 22. [ka]

[0316] The efficacy of compound 29 at an oral dose of 30 mg / kg was evaluated in a mouse maximal electroshock (MES) assay. After the assay was completed, blood samples were collected for plasma analysis of compound 29 and ezogabine by LC / MS / MS. Each male CF-1 mouse provided one data point in the MES assay and one data point in the concentration analysis. There were 8 mice per time point. Exposure to ezogabine was very high in plasma and present in the brain, with concentrations decreasing over three time points: 0.25, 0.5, and 1 hour. The pharmacological response decreased in parallel with the decrease in brain concentration. The results are shown in Figure 23.

[0317] Example 14

[0318] Acid and organic solution stability of ezogavine and prodrugs.

[0319] Ezogavin is insoluble at neutral pH but soluble at low pH. However, at low pH (1N HCl) and in simulated gastric juice (hydrochloric acid, sodium chloride, and pepsin), it decomposes to form a chromophore dimer. An HPLC-UV Vis method was developed using 0.1% formic acid in water as mobile phase A and 0.1% formic acid in acetonitrile as mobile phase B. A gradient method was developed, ramping from 10% A to 90% B over 8 minutes, and then returning to 10% A over 8.5 minutes using a 4.6 × 50 mm Zorbax C-18 column. 10 μL of stable solution was injected for analyte detection. [ka]

[0320] When ezogavin was prepared in simulated gastric juice (SGF) at a concentration of 8 mg / mL and stored at 38°C, the dimer concentration in the solution increased to 1980 ng / mL over 8 hours. See the table below for the conversion rate and concentration to the dimer. The structure of the dimer is shown. [Table 7]

[0321] Ezogavin at a concentration of 5 mg / mL was prepared in a weak acid (0.1N HCl), methanol, and acetonitrile, and its degradation over up to two weeks at room temperature was evaluated. Aliquots were collected at consecutive time points and then diluted to a nominal concentration of 100 ug / mL for injection into HPLC, and monitored at 250 nm using a diode array detector. Data for approximately 10 days are presented. The acid solution turned pale purple (indicating degradation) by day 2, while the organic solvent solution did not begin to turn purple until day 7. [Table 8]

[0322] Compound 3 at a concentration of 5 mg / mL was prepared in acidic solutions (0.1 N and 1.0 N HCl), ethanol, methanol, and acetonitrile, and its degradation over up to 3 weeks at room temperature was evaluated. Aliquots were collected at successive time points and then diluted to a nominal concentration of 100 ug / mL for injection into HPLC, and monitored at 250 nm using a diode array detector. Compound 3 in 0.1 N HCl turned light brown, while in 1 N HCl it turned golden yellow by day 9. The organic solvents remained clear and colorless until day 18. Compound 3 converts to ezogavin under acidic conditions but not in organic solvents. [Table 9]

[0323] Compound 4 at a concentration of 5 mg / mL was prepared in acidic solutions (0.1N, 1N, 2N HCl), phosphate-buffered saline (PBS), and methanol, and its degradation was evaluated at room temperature for up to 3 weeks. Evaluation was also performed at 37°C in 2N HCl. Aliquots were collected at successive time points and then diluted to a nominal concentration of 100 ug / mL for injection into HPLC, and monitored at 250 nm using a diode array detector. Compound 4 remained clear and colorless until day 18. Compound 4 does not form dimers under acidic conditions due to its very low degradation to ezogavin. [Table 10]

[0324] Compound 6 at a concentration of 5 mg / mL was prepared in acidic solutions (1N, 2N HCl) and methanol, and its degradation was evaluated for up to 3 weeks at room temperature. Evaluation was also performed at 37°C in 2N HCl. Aliquots were collected at successive time points and then diluted to a nominal concentration of 100 ug / mL for injection into HPLC, and monitored at 250 nm using a diode array detector. Compound 6 remained clear and colorless until day 18. Compound 6 showed little degradation to ezogavin and therefore is unlikely to form dimers under acidic conditions. [Table 11]

[0325] Compound 28 at a concentration of 5 mg / mL was prepared in acidic solutions (0.1N, 1N, 2N HCl) and methanol, and its degradation was evaluated for up to 3 weeks at room temperature. Evaluation was also performed in 2N HCl at 37°C. Aliquots were collected at successive time points and then diluted to a nominal concentration of 100 ug / mL for injection into HPLC, and monitored at 250 nm using a diode array detector. Compound 28 remained clear and colorless up to day 11 in acidic solutions and acetonitrile, and up to day 7 in methanol. Compound 28 showed degradation to ezogavin as the acidity of the solution increased. [Table 12]

[0326] Compound 29 at a concentration of 5 mg / mL was prepared in acidic solutions (0.1N, 1N, 2N HCl), acetonitrile, and methanol, and its degradation was evaluated for up to 3 weeks at room temperature. Evaluation was also performed in 2N HCl at 37°C. Aliquots were collected at successive time points and then diluted to a nominal concentration of 100 ug / mL for injection into HPLC, and monitored at 250 nm using a diode array detector. Compound 29 remained clear and colorless up to day 18 in acidic solutions and up to day 3 in methanol. Compound 29 exhibited degradation under acidic conditions and conversion to ezogavin, and therefore can form dimers under acidic conditions. [Table 13]

[0327] All publications, patents, and patent applications cited herein are incorporated herein by reference for the teachings in which such citations are used.

[0328] The test compounds used for the experiments described herein were used in free or salt form.

[0329] The specific pharmacological responses observed may vary depending on and in accordance with the presence of a particular active compound or pharmaceutical carrier selected, as well as the type of formulation and mode of administration used, and such expected variability or differences in the results are contingent upon implementation of this disclosure.

[0330] Specific embodiments of the Disclosure are illustrated and described in detail herein, but the Disclosure is not limited thereto. The above detailed descriptions are provided as examples of the 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 deviate from the spirit of the Disclosure are intended to be included in the appended claims.

Claims

1. Compounds of formula IV: 【Transformation 3】 (In the formula, R １ However, C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkyl-C ３～６ It is a cycloalkyl, R ２ is H, C １～３ alkyl, C １～３ alkoxy, halogen, C １～３ haloalkoxy, and Z is N or CH, R １０ but, CH(CH 3 )-NH 2 , CH(CH(CH3)2)-NH2, CH(CH 2 CH(CH 3 ) 2 )-NH 2 , CH(CH(CH3)CH2CH3)-NH2, CH(CH 2 Ph)-NH 2 , Cyclo-CHCH2CH2CH2NH-, CH(CH 2 OH)-NH 2 , CH(CH(OH)CH 3 )-NH 2 , CH(CH 2 (PhOH))-NH 2 , CH(CH 2 SH)-NH 2 , CH(CH 2 CH 2 SCH 3 )-NH 2 , CH(CH 2 CH 2 CH 2 CH 2 NH 2 )-NH 2 , CH(CH2CH2CH2NHC(NH)NH2)-NH2, CH(CH2(C3N2H3))NH2, CH(CH 2 -indole-3-yl)NH 2 , CH(CH 2 CO 2 H)-NH 2 , CH(CH 2 CH 2 CO 2 H)-NH 2 , CH(CH 2 CONH 2 )-NH 2 , CH(CH₂CH-₂CONH₂)-NH₂, and Selected from the group consisting of CH(CH₂CH₂CONHCH₂CH₃)-NH₂, R ４ and R ５ Each of them independently is H, or R ４ and R ５ However, together with the atoms to which they bond, they optionally form a 5-6 membered ring containing a degree of unsaturation of 1 or more. R ６ａ , R ６ｂ , and R ６ｃ Each of these is independently H or halogen, and R ６ａ , R ６ｂ , and R ６ｃ At least one of them is H), or a pharmaceutically acceptable salt thereof.

2. The aforementioned compound is the compound of formula IV-A: 【Chemistry 4】 (In the formula, The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the drawn dashed bond is either an enantiomer.

3. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is compound 4: 【Transformation 5】 A compound or a pharmaceutically acceptable salt thereof.

4. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is compound 6: 【Transformation 6】 A compound or a pharmaceutically acceptable salt thereof.

5. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is compound 29: 【Transformation 7】 A compound or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

7. A composition for inducing one or more of the following effects in a patient who requires the induction of one or more of the following effects: antiepileptic, muscle relaxant, fever reduction, peripheral analgesia, or anticonvulsant effect, comprising a compound described in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

8. Depression in cancer patients, depression in Parkinson's disease patients, depression after myocardial infarction, depression in HIV patients, subsyndromal symptomatic depression, depression in infertile women, childhood depression, major depressive disorder, single-episode depression, relapsing depression, child abuse-induced depression, postpartum depression, DSM-IV major depressive disorder, treatment-refractory major depressive disorder, severe depression, psychotic depression, post-stroke depression, neuropathic pain, manic-depressive disorder including mixed episodes and manic-depressive disorder including depressive episodes, seasonal affective disorder, bipolar depression BP1, bipolar depression BP II. Depression, including major depressive disorder with dysthymia; dysthymia; phobias, including agoraphobia, social phobia, or simple phobias; eating disorders, including anorexia nervosa or bulimia nervosa; drug dependence, including dependence on alcohol, cocaine, amphetamines and other psychostimulants, morphine, heroin and other opioid agonists, phenobarbital and other barbiturates, nicotine, diazepam, benzodiazepines and other psychoactive substances; Parkinson's disease, including dementia, neuroleptic laxative-induced parkinsonism, or tardive dyskinesia; headaches, including headaches associated with vascular disorders; withdrawal syndromes; age-related learning and mental disorders; apathy; bipolar disorder; chronic fatigue syndrome; chronic or acute stress; behavioral disorders; cyclothymic disorder; somatization disorder, conversion disorder, pain disorder, hypochondriasis, body dysmorphic disorder, undifferentiated disorder A composition for treating one or more of the following: somatoform disorders such as somatoform NOS; incontinence; inhalation disorders; intoxication disorders (intoxication disorder); mania; oppositional defiant disorder; peripheral neuropathy; post-traumatic stress disorder; late luteal phase dysphoria; certain developmental disorders; SSRI "POP OUT" syndrome, or the inability of a patient to maintain a satisfactory response to SSRI therapy after an initial period of satisfactory response; and tic disorders, including Tourette's disease, comprising a compound according to claims 1 to 5 or a pharmaceutically acceptable salt thereof.

9. Seizures, pain, neuropathic pain, chronic headaches, central pain, diabetic neuropathy, postherpetic neuralgia and pain associated with peripheral nerve injury; drug addiction, mood disorders, Alzheimer's disease, anxiety, CNS damage caused by neurodegenerative diseases or diseases or injuries, cognitive impairment, obsessive-compulsive behavior, dementia, depression, Huntington's disease, dystonia, mania, cognitive impairment, memory impairment, memory loss Disorder, memory impairment, movement disorders, motor dysfunction, neurodegenerative diseases, Parkinson's disease, Parkinsonian movement disorder, phobias, Pick's disease, psychosis, bipolar disorder, schizophrenia (schizophrenia subtypes are catatonic subtype, paranoid subtype, disorganized subtype or residual subtype), spinal cord injury, cardiomyopathy, cardiac arrhythmias, QT prolongation syndrome, movement disorders or motor dysfunction, myasthenia gravis, migraines, tension headaches, intestinal diseases, inflammatory diseases, ulcerative colitis, Crohn's disease, Creutzfeldt-Rich A composition for treating, improving or preventing the progression of a disease or disorder selected from the group consisting of Wert-Jakob disease, eye conditions, progressive hearing loss or tinnitus, fever, multiple sclerosis, diabetes mellitus, or metastatic tumor growth, aluminism, anthrax, asbestos disease, lithiasis, trichiasis, iron deposition, silicosis, tobacco-related diseases and pulmonary contaminants such as sinusitis, and chronic obstructive pulmonary disease (COPD), as well as obesity and disease-related hypertension, comprising a compound described in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

10. Primary dystonia, paroxysmal dystonia, secondary dystonia, drug-induced dystonia / dyskinesia, tardive dystonia, neuroleptic-induced dystonia, treatment-induced dystonia / dyskinesia in Parkinson's disease patients, genetically altered dystonia, dystonia in Huntington's disease patients, dystonia in Tourette syndrome patients, dystonia in restless limb syndrome patients, dystonia-like symptoms in tic patients, dystonia-associated dyskinesia, paroxysmal dyskinesia, seizures A composition for treating one or more movement disorders selected from sexual non-exercise-induced dyskinesia, paroxysmal dystonic choreoatetosis, paroxysmal movement-induced dyskinesia, paroxysmal exercise-induced choreoatetosis, exercise-induced dyskinesia, paroxysmal sleep-induced dyskinesia, drug-induced dyskinesia, myokymia, neuromyotonia, autism, autism spectrum disorder, comprising a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

11. A composition for treating one or more susceptible diseases or susceptibility disorders by delivering broad-spectrum Kv 7.2-7.5 active molecules into the systemic circulation and releasing an active Kv channel opener at an effective therapeutic concentration, comprising a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

12. The release of the aforementioned active molecule Enhanced by increased absorption, The time to onset is delayed in order to improve adverse events that occur during treatment, and The composition according to claim 11, provided under one or more of the following conditions: increasing the half-life or residence time through delayed circulation and release, thereby eliminating the need for the development of a modified, sustained, delayed, or extended-release formulation.

13. Use of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof for the manufacture of a drug for inducing one or more of the following effects: antiepileptic, muscle relaxant, fever reducer, peripheral analgesic, or anticonvulsant.

14. Depression in cancer patients, depression in Parkinson's disease patients, depression after myocardial infarction, depression in HIV patients, subsyndromal symptomatic depression, depression in infertile women, childhood depression, major depressive disorder, single-episode depression, relapsing depression, child abuse-induced depression, postpartum depression, DSM-IV major depressive disorder, treatment-refractory major depressive disorder, severe depression, psychotic depression, post-stroke depression, neuropathic pain, manic-depressive disorder including mixed episodes and manic-depressive disorder including depressive episodes, seasonal affective disorder, bipolar depression BP1, bipolar depression BP II. Depression, including major depressive disorder with dysthymia; dysthymia; phobias, including agoraphobia, social phobia, or simple phobias; eating disorders, including anorexia nervosa or bulimia nervosa; drug dependence, including dependence on alcohol, cocaine, amphetamines and other psychostimulants, morphine, heroin and other opioid agonists, phenobarbital and other barbiturates, nicotine, diazepam, benzodiazepines and other psychoactive substances; Parkinson's disease, including dementia, neuroleptic laxative-induced parkinsonism, or tardive dyskinesia; headaches, including headaches associated with vascular disorders; withdrawal syndromes; age-related learning and mental disorders; apathy; bipolar disorder, chronic fatigue syndrome; chronic or acute stress; behavioral disorders; cyclothymic disorder; somatization disorder, conversion disorder, pain disorder, hypochondriasis, body dysmorphic disorder, undifferentiated disorder Use of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof for the manufacture of a pharmacopoeia

15. Seizures, pain, neuropathic pain, chronic headaches, central pain, diabetic neuropathy, postherpetic neuralgia and pain associated with peripheral nerve injury; drug addiction, mood disorders, Alzheimer's disease, anxiety, CNS damage caused by neurodegenerative diseases or diseases or injuries, cognitive impairment, obsessive-compulsive behavior, dementia, depression, Huntington's disease, dystonia, mania, cognitive impairment, memory impairment, memory loss Disorder, memory impairment, movement disorders, motor dysfunction, neurodegenerative diseases, Parkinson's disease, Parkinsonian movement disorder, phobias, Pick's disease, psychosis, bipolar disorder, schizophrenia (schizophrenia subtypes are catatonic subtype, paranoid subtype, disorganized subtype or residual subtype), spinal cord injury, cardiomyopathy, cardiac arrhythmias, QT prolongation syndrome, movement disorders or motor dysfunction, myasthenia gravis, migraines, tension headaches, intestinal diseases, inflammatory diseases, ulcerative colitis, Crohn's disease, Creutzfeldt-German disease Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 for the manufacture of an agent for treating, improving or preventing the progression of a disease or disorder selected from the group consisting of Felt-Jakob disease, eye conditions, progressive hearing loss or tinnitus, fever, multiple sclerosis, diabetes mellitus, or metastatic tumor growth, aluminism, anthrax, asbestositis, lithiasis, trichiasis, iron deposition, silicosis, tobacco-related illness and pulmonary contaminants such as sinusitis, and chronic obstructive pulmonary disease (COPD), as well as obesity and disease-related hypertension.

16. Primary dystonia, paroxysmal dystonia, secondary dystonia, drug-induced dystonia / dyskinesia, tardive dystonia, neuroleptic-induced dystonia, treatment-induced dystonia / dyskinesia in Parkinson's disease patients, genetically altered dystonia, dystonia in Huntington's disease patients, dystonia in Tourette syndrome patients, dystonia in restless limb syndrome patients, dystonia-like symptoms in tic patients, dystonia-associated dyskinesia, paroxysmal dyskinesia, Use of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof for the manufacture of an agent for treating one or more movement disorders selected from: dyskinetic non-exercise-induced dyskinesia, paroxysmal dystonic choreoatetosis, paroxysmal movement-induced dyskinesia, paroxysmal exercise-induced choreoatetosis, exercise-induced dyskinesia, paroxysmal sleep-induced dyskinesia, drug-induced dyskinesia, myokymia, neuromyotonia, autism, autism spectrum disorder.

17. Use of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof for the manufacture of a drug for treating one or more susceptible diseases or susceptibility disorders by delivering a broad-spectrum Kv 7.2-7.5 active molecule into the systemic circulation and releasing an active Kv channel opener at an effective concentration of therapeutic value.

18. The release of the aforementioned active molecule Enhanced by increased absorption, The time to onset is delayed in order to improve adverse events that occur during treatment, and By delaying circulation and release, the half-life or residence time is increased. The use according to claim 17, provided under one or more of the following conditions: thereby eliminating the need to develop formulations for modification, sustained release, delayed release, or extended release.

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