New bicyclopentane derivatives

Abstract

The present invention relates to novel bicyclopentanyl compounds having the general formula (I) or a solvate or a pharma- ceutically acceptable salt thereof, 1 , R 2 , R 3 , R 4 , and R 5 wherein R is as defined herein, compositions comprising the compounds, processes for making the compounds, and methods for using the compounds are provided. TIFF2025506201000141.tif31161

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to novel bicyclopentanyl compounds useful as Kv7.2 enhancers (or positive modulators), their preparation, pharmaceutical compositions comprising said compounds, kits, and their use as medicaments for the therapeutic and / or prophylactic treatment of Kv7.2-related disorders, diseases or disabilities, which may be selected from behavioral disorders, mood disorders, neurodevelopmental disorders, intellectual disabilities, epilepsy, neurodegenerative diseases, pain, migraine, and tinnitus. [Background technology]

[0002] 2. Background of the Invention The potassium channel family 7 or Q includes five proteins encoded by the genes KCNQ1, KCNQ2, KCNQ3, KCNQ4, and KCNQ5 in humans. KCNQ proteins form homo- and heterotetrameric channels that respond to changes in membrane voltage and open to allow potassium ions to migrate out of the cell membrane. Homomeric Kv7.2 and heteromeric Kv7.2 and Kv7.3 channels have been investigated for their unique distribution and potential role as primary regulators of neuronal excitability in many CNS and PNS pathways (Wang et al., 1998). KCNQ2 channels control neuronal resting membrane potential, spike frequency adaptation of neuronal firing, and presynaptic release. Impairment of their function, even when lost exclusively in inhibitory neurons, leads to network instability (Soh et al., 2018).

[0003] A significant proportion of childhood epilepsy is associated with KCNQ2 mutations (Lee et al., 2019). Human genetic studies have identified de novo mutations in KCNQ2 as the third strongest association with epileptic encephalopathy (EE) (Zhao et al., 2020). Whether primary or secondary EE, seizure activity worsens clinical outcomes and alters normal neurodevelopment (von Deimling, Helbig, & Marsh, 2017).

[0004] Pediatric epilepsy affects approximately 1 in 200 children (Waaler et al., 2000) and causes cognitive, behavioral and neurological disorders (Simkin and Kiskinis, 2018). In the case of certain pathogenic KCNQ2 mutations, developmental delays are experienced by the majority of patients, although most individuals eventually become seizure-free (Kato et al., 2013). Targeting Kv7 channels provides a genetically validated target for epilepsy with a distinct mode of action among antiepileptic drugs (Gunthorpe, Large, and Sankar, 2012). Kv7.2 enhancers show potential to transform neurodevelopmental trajectories by treating neural network instability responsible for EE (Kessi et al., 2020).

[0005] The association between epilepsy and autism is robust (Srivastava and Sahin, 2017) and stems from a convergent phenotype driven by multiple small genetic triggers in combination with environmental factors. KCNQ2 is one of the top five ion channels associated with autism spectrum disorders (ASD) and one of the top 30 of all known de novo mutations in ASD (Zhao et al., 2020).

[0006] Another defining feature of ASD, atypical sensory processing (ASP) (Thye et al., 2018), is also driven by convergent genetics seen in twin comparison studies (Neufeld et al., 2021). The biology responsible for increased sensory sensitivity has been studied in preclinical models, where multisensory neuronal hyperexcitability emerges despite genetic manipulations that initially drive pathological neurodevelopment. Some genes whose manipulations result in sensory sensitivity include CNTNAP2 (Penagarikano et al., 2011), SHANK3 (Holder and Quach, 2016), and GABRB3 (Tanaka et al., 2012). Kv7.2 enhancers show the potential to modify neurodevelopmental trajectories in ASD by normalizing network stability, neural information processing, and sensory abnormalities that ultimately account for atypical social and repetitive behaviors in ASD. It is also interesting that KCNQ2 knockout mice exhibit repetitive behaviors as well as abnormal exploratory and social behaviors (Kim et al., 2019).

[0007] Kv7.2 enhancers have also shown promise in syndromic neurodevelopmental disorders, in part due to the prevalence and impact of epilepsy ( Budisteanu et al., 2020 ), for example, epilepsy is common in Angelman syndrome (>80%), with most beginning before age 3 years ( Fiumara et al., 2010 ).

[0008] Another neurodevelopmental disorder, Dup15q syndrome (Dup15q), is caused by a partial duplication of chromosome 15 that confers a significant risk for autism spectrum disorder, epilepsy, and intellectual disability. Induced pluripotent cells derived from Dup15q patients show KCNQ2 abnormalities, and the pan-Kv7 channel opener retigabine partially corrects their phenotype (Fink et al., 2018). Epilepsy is central to Dup15q, and Kv7.2 enhancers show potential to reverse this neurodevelopmental disorder.

[0009] In fragile X syndrome, approximately 15% of individuals experience epilepsy (Berry-Kravis, 2002) along with abnormal sensory processing (McCullagh et al., 2020). KCNQ2 (Kv7.2 gene) is downregulated in the absence of fragile X mental retardation protein (FMRP) in rodent models (Zhang et al., 2018). Thus, Kv7.2 enhancers may positively impact fragile X by acting on both epilepsy and sensory processing.

[0010] Infantile epilepsy is associated with intellectual disability, and KCNQ2 de novo mutations are significantly associated with intellectual disability (Zhao et al., 2020). Kv7.2 augmentation may address the underlying biology that exacerbates disability.

[0011] For all these neurodevelopmental disorders, early diagnosis and identification of the correct antiepileptic treatment are at the core of strategies aimed at normalizing the neurodevelopmental trajectory.

[0012] Among behavioral disorders, Kv7.2 enhancers have shown promise in attention deficit hyperactivity disorder (ADHD) and major depressive disorder (MDD, depression). Some patients with KCNQ2 mutations and mild epilepsy phenotypes exhibit cognitive delays and ADHD (Lee et al., 2019). Kv7.2 enhancers have been suggested to treat neural network instability and behavioral impulsivity associated with ADHD. In the MDD space, retigabine (a Kv7 opener) has shown antidepressant efficacy in patients by acting on the brain's reward center (Tan et al., 2018). The significant reduction in depressive symptoms observed with retigabine positions Kv7.2 enhancers as a potential treatment for MDD.

[0013] The therapeutic potential of Kv7.2 enhancers in pain sensitivity is supported by the localization of Kv7.2 channels in dorsal root ganglia and their established role in pain perception (Brown and Passmore, 2009). Nonselective Kv7.2 enhancers have shown efficacy in reducing excitability of human peripheral axons (Lang et al., 2008). Retigabine has already shown some efficacy in preclinical pain models (Korsgaard et al., 2005; Xu et al., 2010; Wu et al., 2017). Retigabine also shows efficacy in controlling spreading depression, a wave of cellular depolarization associated with migraine headaches (Aiba and Noebels, 2021).

[0014] Among sensory abnormalities, abnormal plasticity of KCNQ2 channels is strongly related to the induction of tinnitus (Li, Choi, & Tzounopoulos, 2013). This association is based on the localization of Kv7.2 channels in the cochlea (Jin et al., 2009) and how cochlear damage depends on neuronal excitability driven by the closure of Kv7.2 channels (Liu, Glowatzki, & Fuchs, 2015). Retigabine prevents the development of tinnitus in preclinical models (Li, Choi, & Tzounopoulos, 2013). As evidence supporting how KCNQ2 pathology is related across indications, it is interesting to find that tinnitus and hyperacusis are more prevalent in ASD than in the general population (Danesh et al., 2015).

[0015] In neurodegenerative diseases, K+ homeostasis dysregulation in chronic neuroinflammatory conditions is central to disease progression. For example, in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease of the motor nervous system (Hardiman et al., 2017), diverse genetics converge on motor neuron excitotoxicity (Kanai et al., 2006; Pasinelli and Brown, 2006), specifically axonal hyperexcitability predicts survival (Kanai et al., 2012). Patient-derived motor neurons exhibit membrane hyperexcitability, and the tool compound retigabine, a pan-Kv7 enhancer, rescues the phenotype (Wainger et al., 2014). Motor neuron hyperexcitability was discovered early in a presymptomatic in vivo system where it is a trigger for disease progression (Kuo et al., 2004). Recently, clinical trials in ALS with retigabine have shown efficacy against functional biomarkers of ALS ( Wainger et al., 2021 ) and preclinically protect against peripheral neuropathy ( Nodera et al., 2011 ).

[0016] In Alzheimer's disease (AD), neuronal hyperexcitability and network instability (Frere and Slutsky, 2018) are early features of both IPSC models (Ghatak et al., 2019) and genetic in vivo models of sporadic AD (Palop et al., 2007; Kazim et al., 2017; Styr and Slutsky, 2018). Network instability exacerbates proteinopathy (Dolev et al., 2013; Frere and Slutsky, 2018) and affects patients (Vossel et al., 2013; Lam et al., 2017).

[0017] Because the degeneration of motor and cortical neurons can be significantly slowed by reducing aberrant neuronal activity, enhancing Kv7.2 may be an effective way to halt such aberrant activity and alter the neurodegenerative trajectory of the disease.

[0018] Therefore, enhancing the activity of Kv7.2 is a promising strategy for treating or preventing Kv7.2-related diseases, including neurodevelopmental disorders such as autism and fragile X, epilepsy, intellectual disability, depression, attention deficit hyperactivity disorder, motor neuron excitability, pain, migraine, and sensory processing disorders.

[0019] WO 2020 / 163268 relates to pyridine urea derivatives as KCNQ potentiators.

[0020] US Patent No. 5,384,330 relates to pharmacologically active 1,2,4-triaminobenzene derivatives that modulate the potassium ion channels Kv7.2-Kv7.5 (KCNQ2-KCNQ5) for treating drug-resistant epilepsy. These compounds have shown tolerability problems and other side effects. Summary of the Invention [Problem to be solved by the invention]

[0021] To date, no drug that acts on Kv7.2 has been approved for the treatment of any of the diseases, disorders, or disabilities described herein, and therefore, there remains a need for a modulator of Kv7.2 that provides therapeutic benefits.In addition, it would be beneficial to have a modulator of Kv7.2 that is more selective than other Kv7 channels.There is a need for a Kv7.2 modulator that provides a combination of favorable pharmacological properties, such as, for example, potency, selectivity, and metabolic stability.

[0022] It is therefore an object of the present invention to provide selective Kv7.2 enhancers having favorable pharmacological properties useful as Kv7.2 enhancers (or positive modulators) for the therapeutic and / or prophylactic treatment of Kv7.2-associated disorders, diseases or disabilities.

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[0024] Summary of the Invention In some embodiments, the compound of formula (I): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , and R 8 is as defined herein) or Solvates or pharma- ceutically acceptable salts thereof are provided herein.

[0025] In a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof.

[0026] In a further aspect, the present invention provides a compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof or a pharmaceutical composition comprising same for use as a therapeutically active substance.

[0027] In a further aspect, the present invention provides a compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof or a pharmaceutical composition comprising same for use in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2.

[0028] In a further aspect, the present invention provides the use of a compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof or a pharmaceutical composition comprising the same in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2.

[0029] In a further aspect, the present invention provides the use of a compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof or a pharmaceutical composition comprising the same for the manufacture of a medicament for the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2.

[0030] In a further aspect, the present invention provides a method for the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2, comprising administering a therapeutically effective amount of a compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof or a pharmaceutical composition comprising same.

[0031] In a further aspect, the present invention provides a kit for use in the therapeutic and / or prophylactic treatment of a Kv7.2 associated disorder, disease, or disability, comprising: a) a compound of formula (I) or a solvate or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition or pharmaceutical composition for use comprising the same; b) Instructions for use and A kit comprising:

[0032] The compounds of formula (I) or solvates or pharma- ceutically acceptable salts thereof described herein provide a combination of favorable pharmacological properties, such as potency, selectivity, and metabolic stability. Reasonable metabolic stability is important to ensure adequate pharmacological half-life, which is best achieved with compounds that have a human hepatic microsomal clearance of less than 20 μL / min / mg. Selectivity within the Kv7 family is desirable to avoid effects on tissues that are not therapeutic for the indications described in the present invention. For example, effects on Kv7.4 and Kv7.5 in skeletal and smooth muscles affect the function of human arteries, and KCNQ2 expression is minimal or undetectable in these tissues (Ng et al. 2011). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0033] Detailed Description of the Invention definition It is to be understood that any feature, integer, characteristic, compound, chemical moiety or group described in connection with a particular aspect, embodiment or example of the invention is applicable to any other aspect, embodiment or example described herein, except where inconsistent therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive.

[0034] The invention is not limited to the details of any embodiment expressly disclosed herein. Any embodiment described in this application may be combined with any other embodiment. The invention extends to any novel or any novel combination of features disclosed in this specification (including any accompanying claims, and the Abstract), or any novel or any novel combination of any embodiment or any method or process steps so disclosed.

[0035] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0036] The nomenclature used in this application is based on IUPAC systematic nomenclature unless otherwise indicated.

[0037] Any open valency appearing on a carbon, oxygen, sulfur, or nitrogen atom in the structures herein indicates the presence of a hydrogen, unless otherwise indicated.

[0038] When used in the therapeutic and / or prophylactic treatment of a disorder, disease or disability described herein, "administer", "administered" or "administering" means providing a compound of the invention to a patient or subject by any method, such as infusion, inhalation, injection, paste, suppository or tablet, etc.

[0039] As used herein, the terms "including," "containing," and "comprising" are used in an open, non-limiting sense.

[0040] As used in this disclosure, the articles "a" and "an" can refer to one or to more than one (e.g., to at least one) of the grammatical object of the article. For example, "an element" can mean one element or more than one element.

[0041] The term "substituent" refers to an atom or group of atoms that replaces a hydrogen atom of a parent molecule.

[0042] As described herein, chemical groups within the present disclosure may be "unsubstituted" or "substituted" with one or more substituents (e.g., 1, 2, 3, 4, or 5), such as those generally described herein or exemplified by the particular classes, subclasses, and species of the present disclosure. In general, the term "substituted" refers to the replacement of a hydrogen atom in a given structure with a specified substituent. In some embodiments, two or more hydrogen atoms are replaced with a specified substituent (e.g., where two hydrogen atoms are replaced with an oxo substituent). Combinations of substituents contemplated by the present disclosure are typically those that result in the formation of a stable or chemically viable compound. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has a substituent as described herein. As used herein, the term "unsubstituted" may mean that the specified group has no substituents beyond the recited moieties (e.g., where valences are satisfied by hydrogen).

[0043] The term "effective amount" or "therapeutically effective amount" refers to an amount of the compound of the present invention, particularly the compound of formula (I) as described above, or a solvate or pharma- ceutically acceptable salt thereof, or pharmaceutical composition, sufficient to produce a desired therapeutic outcome, such as reducing the severity of the duration of, stabilizing the severity of, or eliminating one or more signs, symptoms, or causes of, a disease, disorder, or disability. With respect to therapeutic use, beneficial or desirable results may include, for example, reducing one or more (biochemical, histological, and / or behavioral) symptoms caused by a disease, disorder, or disability, including its complications and intermediate pathological phenotypes that appear during the progression of the disease, disorder, or disability, increasing the quality of life of a subject suffering from the disease, disorder, or disability, reducing the dose of other medications required to treat the disease, disorder, or disability, enhancing the effect of another medication, delaying the progression of the disease, disorder, or disability, and / or prolonging the survival of the patient.

[0044] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the free base or free acid, which is not biologically or otherwise undesirable. Salts are formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, especially hydrochloric acid, and organic acids, such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, and the like. In addition, these salts can be prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, and the like.

[0045] Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins, and the like.

[0046] The term "excipient" or "pharmaceutical excipient" as used herein refers to any pharma- ceutically acceptable excipient that may be used in the manufacture of a drug or pharmaceutical composition, such as a tablet, containing a compound described herein (or a tautomer or pharma- ceutically acceptable salt) as an active ingredient. A variety of substances may be encompassed by the term excipient, including, but not limited to, any substance used as a diluent, filler, bulking agent, binder, disintegrant, glidant, wetting agent, coating, emulsifier or dispersant, compression / encapsulation aid, cream or lotion, lubricant, solution for parenteral administration, material for chewable tablets, sweetener or flavoring agent, suspending / gelling agent, or wet granulation agent. Disintegrants refer to excipients that swell and dissolve when wetted, causing the tablet to break down in the body and release the active ingredient for absorption. Examples include cross-linked polymers such as crospovidone, croscarmellose sodium, and modified starches such as sodium starch glycolate. Fillers refer to excipients that fill the size of the tablet by increasing the bulk volume. Fillers allow the final product to have a volume suitable for patient handling. Examples of fillers are vegetable cellulose, lactose, starch, mannitol, etc. Specific examples are lactose monohydrate such as Pharmatose 200M, microcrystalline cellulose (MCC) such as Avicel PH101 or Avicel PH102, and Fast Flo 316. (商標)The binder is a spray-dried lactose such as 1,2-diol, ... Coatings may include, for example, cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, and the like; compression / encapsulation aids include, for example, calcium carbonate, dextrose, fructose dc (dc-"directly compressible"), honey dc, lactose (anhydrous or monohydrate; optionally combined with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, and the like. Creams or lotions include, for example, maltodextrin, carrageenan, and the like. Chewable tablet materials include, for example, dextrose, fructose dc, lactose (monohydrate, optionally combined with aspartame or cellulose), and the like. Suspending / gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum, and the like. Sweeteners include, for example, aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc. Wet granulation agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, etc. In some cases, the term "excipient" includes a pharma- ceutically acceptable carrier. Those skilled in the art are aware of the appropriate pharmaceutical compositions to be used in the treatment of patients and methods for their preparation.

[0047] The term "patient" or "subject" may include both mammals and non-mammals. Examples of mammals may include, but are not limited to, any member of the class Mammalia: humans; non-human primates, such as chimpanzees, monkeys, baboons, or rhesus monkeys, as well as other ape and monkey species; livestock animals, such as cows, horses, sheep, goats, and pigs; companion animals, such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish, and the like. A "patient" or "subject" may include both humans and animals. In some preferred embodiments, the "patient" or "subject" is a human.

[0048] As used herein, the term "treat" or "treatment" is meant to refer to postponing the onset of one or more diseases, disorders or disabilities, preventing the onset of one or more diseases, disorders or disabilities, and / or reducing the severity of one or more symptoms of a disease, disorder or disability that will or is expected to develop. Thus, these terms can include alleviating one or more existing disease, disorder or disability symptoms, preventing one or more further symptoms, alleviating or preventing the underlying cause of one or more symptoms, inhibiting a disease, disorder or disability, such as arresting the progression of a disease, disorder or disability, relieving a disease, disorder or disability, inducing regression of a disease, disorder or disability, relieving a symptom caused by a disease, disorder or disability, or arresting or alleviating a symptom of a disease, disorder or disability.

[0049] The compounds of the present disclosure may exist as solvates. The term "solvate" may refer to a complex of variable stoichiometry formed by a solute and a solvent. For the purposes of the present disclosure, such a solvent may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. A solvate in which water is the solvent molecule is typically called a hydrate. Hydrates may include compositions that contain stoichiometric amounts of water and compositions that contain variable amounts of water. In some embodiments, solvates are excluded.

[0050] The term "prophylaxis" as used herein includes preventing or delaying the appearance of clinical symptoms of a disease, disorder or disability that develops in a patient or subject, particularly a human, who is afflicted with or susceptible to a disease, disorder or disability described herein, but who has not yet experienced or exhibited clinical or subclinical symptoms of the disease, disorder or disability.

[0051] As used herein, the term "about" when referring to a value is meant to encompass variations from the specified amount, for example, in some embodiments, ±20%, in some embodiments, ±10%, in some embodiments, ±5%, in some embodiments, ±1%, in some embodiments, ±0.5%, and in some embodiments, ±0.1%, such variations are appropriate for practicing the disclosed methods or using the disclosed compositions.

[0052] Where a range of values ​​is provided, unless the context clearly dictates otherwise, it is understood that each intervening value, to the tenth of the unit of the lower limit between the upper and lower limits of the range, and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges, which may be independently included in smaller ranges, are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0053] As used herein, numerical ranges may include consecutive integers. For example, a range expressed as "0 to 5" includes 0, 1, 2, 3, 4, and 5.

[0054] A "metabolite" is a product produced by metabolism in the body of the specified compound or salt thereof. Metabolites of a compound can be identified using routine techniques known in the art, and their activity can be determined using tests such as those described herein. Such products can result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of an administered compound. Thus, the invention includes metabolites of compounds of the invention, including compounds produced by a process comprising contacting a compound of the invention with a mammal for a period of time sufficient to yield a metabolic product thereof.

[0055] The term "package insert" is used to refer to instructions customarily included in commercial packaging of therapeutic products which contain information about the indications, usage, dosage, administration, contraindications, and / or warnings concerning the use of such therapeutic product.

[0056] The terms "compound of this invention" and "compounds of the present invention", "compounds of the invention" and "compound of formula (I)" include compounds of formula (I), compounds selected from any of formulas (II), (III), (IV), (V), (VI), and (VII), etc., compounds of Tables 1, 2, etc., stereoisomers, geometric isomers, solvates, pharma- ceutically acceptable salts, tautomers, metabolites, prodrugs, polymorphs; and mixtures thereof.

[0057] The symbols "*", "---" or " [ka] Each " refers to the point of attachment of a functional group or other chemical moiety to the remainder of the molecule of which it is a part. Thus, for example, [ka] means that the substituent is attached to the remainder of the molecule as shown. [ka] A bond drawn into a ring system (as opposed to being attached at a separate vertex) indicates that the bond may be attached to any of the suitable ring atoms.

[0058] As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may occur, but does not necessarily have to occur, and the description includes cases where the event or circumstance occurs and cases where it does not occur. For example, "optionally substituted" means that the optionally substituted moiety may incorporate a hydrogen atom or a substituent. "Optionally substituted" means that the compound may be unsubstituted or substituted as defined herein. The term "optionally substituted" means that the specified group is unsubstituted or substituted by one or more substituents independently selected from a group of possible substituents. When referring to the number of substituents, the term "one or more" means a range from one substituent to the highest number of substitutions possible, i.e., replacement of one hydrogen by a substituent to replacement of all hydrogens.

[0059] The term "independently" is used herein to indicate that a variable applies in any instance regardless of the presence or absence of variables with the same or different definitions within the same compound. Thus, in a compound where R" occurs twice and is defined as "independently carbon or nitrogen," both R"s can be carbon, both R"s can be nitrogen, or one R" can be carbon and the other nitrogen. In addition, for example, R 2 and R 3 Hydrogen and hydroxy C 1~6 In compounds independently selected from alkyl, R 2 and R 3 Both of C can be hydrogen or both are hydroxy C 1~6can be alkyl or R 2 and R 3 One of them is hydrogen and the other is hydroxy C 1~6 It may be alkyl.

[0060] In this application, the units ul, uMol, C etc. mean μl, μMol, °C etc.

[0061] In this application, 50 The term "EC" is defined as one in which the agonist effect of a compound can be determined by testing the compound in an in vitro assay described herein, in which the effect of the compound is measured over a range of compound concentrations. The resulting data is typically plotted as a concentration-response curve that follows a sigmoid function, with the concentration of the compound plotted on the x-axis and the response (agonist effect) plotted on the y-axis. 50 The term "half maximal effective concentration" refers to the maximum response (E) observed for a compound in a given in vitro assay. max ) represents the concentration of a particular compound required to obtain 50% of the

[0062] The compounds of the present invention can exist in one or more stereoisomeric forms (e.g., they contain one or more asymmetric carbon atoms). The individual stereoisomers (enantiomers and diastereomers) and mixtures thereof are included within the scope of the subject matter disclosed herein.

[0063] Similarly, it is understood that a compound or salt may exist in tautomeric forms other than those shown in its formula, and these are also included within the scope of the subject matter disclosed herein. It is understood that the subject matter disclosed herein includes combinations and subsets of the specific groups described herein. The scope of the subject matter disclosed herein includes mixtures of stereoisomers as well as purified enantiomers or enantiomerically / diastereomerically enriched mixtures. It is understood that the subject matter disclosed herein includes combinations and subsets of the specific groups defined herein.

[0064] The compounds of the present invention may contain several asymmetric centers and may exist in the form of optically pure enantiomers, mixtures of enantiomers, e.g. racemates, optically pure diastereoisomers, mixtures of diastereoisomers, racemates of diastereoisomers or racemic mixtures of diastereoisomers.

[0065] According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atom can be of the "R" or "S" configuration.

[0066] The term "chiral" refers to molecules that have the property of not being superimposable on their mirror image partners, whereas the term "achiral" refers to molecules that are superimposable on their mirror image partners. Chiral separation of a racemate and its enantiomeric components can be performed to separate the eutomers and distomers.

[0067] The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0068] "Diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can separate under high resolution analytical procedures such as chromatography.

[0069] "Enantiomers" refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0070] Stereochemical definitions and conventions used herein generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric or chiral centers and therefore may exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers, and mixtures thereof, e.g., racemic mixtures, are intended to form part of the present invention. Any organic compound exists in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center. The prefixes d and l or (+) and (-) are used to designate the indication of the rotation of plane polarized light by a compound, with (-) or l meaning that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer is also called an enantiomer, and a mixture of such isomers may be called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur when there has been no stereoselection or stereospecificity in a chemical reaction or process.

[0071] The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0072] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[0073] It should be understood that the individual enantiomers and diastereomers are included in the table below by compound name, and their corresponding structures can be readily determined therefrom. In some cases, the enantiomers or diastereomers are identified by their respective properties, such as their retention time in chiral HPLC or their biological activity (e.g., as further described in the Examples), and the absolute configuration of one or more chiral centers is arbitrarily assigned (e.g., the stereochemistry of all chiral centers is arbitrarily assigned, or the stereochemistry of one chiral center is known and the remaining chiral centers are arbitrarily assigned, etc.).

[0074] In some embodiments of the invention, only one of the possible enantiomers is used, while in other embodiments, a mixture of the possible enantiomers is used, having different percentages of each component.

[0075] In some embodiments, the compounds of the present invention are isotopically labeled by replacing one or more atoms therein with an atom having a different atomic mass or mass number. Such isotopically labeled (e.g., radiolabeled) compounds of formula (I) or solvates or pharma- ceutically acceptable salts thereof are considered to be within the scope of the present disclosure. Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, including, but not limited to, isotopes of each of: 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 Certain isotopically labeled compounds of the invention, for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e. 3 H and carbon-14, i.e. 14 C are particularly useful for this purpose given their ease of incorporation and ready means of detection. For example, compounds of the invention can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99% of a given isotope.

[0076] In some embodiments, the compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof is 2 H (deuterium), 3 H (tritium), preferably 2 It is specifically envisioned to have one or more hydrogen atoms in the structure replaced by H (deuterium). In this manner, any of the hydrogen atoms in the structure may be replaced.

[0077] 3 H, 11 C. 18 F, 15 O and 13 Substitution with positron emitting isotopes, such as N, can be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described in the Examples set forth below, substituting the appropriate isotopically labeled reagent for the non-isotopically labeled reagent previously used.

[0078] In one embodiment, the present invention provides a pharma- ceutically acceptable salt of a compound of the present invention, in particular a pharma- ceutically acceptable salt selected from hydrochloride, fumarate, lactate (especially derived from L-(+)-lactic acid), tartrate (especially derived from L-(+)-tartaric acid) and trifluoroacetate. In yet a further particular embodiment, the present invention provides a compound of formula (I) as described herein or a solvate or pharma- ceutically acceptable salt thereof (i.e., as the "free base" or "free acid", respectively).

[0079] When a bond in a compound of the present invention is drawn non-stereochemically (e.g., planar), the atom to which the bond is attached includes all stereochemical possibilities. When a bond in a compound formula herein is drawn in a defined stereochemical manner (e.g., bold, bold wedge, dashed line, or dashed wedge), it should be understood that the atom to which the stereochemical bond is attached is enriched in the absolute stereoisomer shown, unless otherwise stated. In one embodiment, the compound may be at least 51% of the absolute stereoisomer depicted. In another embodiment, the compound may be at least 80% of the absolute stereoisomer depicted. In another embodiment, the compound may be at least 90% of the absolute stereoisomer depicted. In another embodiment, the compound may be at least 95% of the absolute stereoisomer depicted. In another embodiment, the compound may be at least 97% of the absolute stereoisomer depicted. In another embodiment, the compound may be at least 98% of the absolute stereoisomer depicted. In another embodiment, the compound may be at least 99% of the absolute stereoisomer depicted.

[0080] The term "alkyl" refers to a monovalent or polyvalent, e.g., monovalent or divalent, linear or branched saturated hydrocarbon group, particularly a hydrocarbon group of 1 to 6 carbon atoms ("C1-6 alkyl"), e.g., 1, 2, 3, 4, 5 or 6 carbon atoms. In some embodiments, an alkyl group contains 1 to 3 carbon atoms, e.g., 1, 2 or 3 carbon atoms. Some non-limiting examples are methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), 2-propyl (isopropyl, (CH3)2CH2-), n-butyl (CH3CH2CH2CH2-), iso-butyl ((CH3)2CH2CH2-), sec-butyl (CH3CH(CH3)CH2-), and tert-butyl ((CH3)3C-). A preferred, but non-limiting example of alkyl is tert-butyl ((CH3)3C-) or methyl (CH3-). A preferred, but non-limiting example of an alkyl is methyl (CH3-). Another preferred, but non-limiting example of an alkyl is tert-butyl ((CH3)3C-).

[0081] The term "alkenyl" refers to an alkyl group having at least one site of unsaturation, i.e., carbon-carbon, sp 2 Alkenyl refers to a straight or branched chain monovalent hydrocarbon group, especially of three to six carbon atoms (C3-C6), having a double bond; alkenyl groups include groups having "cis" and "trans" orientations or "E" and "Z" orientations. Preferably, alkenyl contains one unsaturation. Examples include, but are not limited to, ethylenyl or vinyl (-CH=CH2), allyl (-CH2CH=CH2), and the like.

[0082] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical, preferably of two to eight carbon atoms (C2-C8), having at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond. Preferably, the alkynyl contains one unsaturation as described above. Examples include, but are not limited to, ethynyl, propynyl, propargyl, and the like.

[0083] The term "alkoxy" refers to an alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom. An alkoxy group preferably contains 1-6 carbon atoms ("C1-6 alkoxy"), such as 1, 2, 3, 4, 5 or 6 carbon atoms. In other embodiments, an alkoxy group contains 1-4 carbon atoms. In yet other embodiments, an alkoxy group contains 1-3 carbon atoms. Some non-limiting examples of alkoxy groups include CHO-(methoxy), CHCHO-(ethoxy), CHCHCHO-(n-propoxy), and (CH)CO-(tert-butoxy). A particularly preferred, but non-limiting example of an alkoxy is methoxy (CHO-).

[0084] The term "halogen" or "halo" refers to fluoro (F), chloro (Cl), bromo (Br) or iodo (I). Preferably, the term "halogen" or "halo" refers to fluoro (F), chloro (Cl) or bromo (Br). Particularly preferred, but non-limiting examples of "halogen" or "halo" are fluoro (F) and chloro (Cl).

[0085] The term "cyano" refers to a -CN (nitrile) group.

[0086] The terms "hydroxy" or "hydroxyl" refer to an OH group.

[0087] The term "haloalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by one or more halogen atoms. Preferably, a "haloalkyl" refers to a C alkyl group in which one, two or three hydrogen atoms of the alkyl group are replaced by halogen atoms. 1~6It refers to an alkyl group, i.e., haloalkyl includes monohaloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl, etc. The halogen atom can be fluoro (F), chloro (Cl), or bromo (Br). Particularly preferred but non-limiting examples of "halogen" in haloalkyl are fluoro (F) and chloro (Cl). More preferably, the haloalkyl is substituted with fluoro (F). Preferred but non-limiting examples of haloalkyl are (CH3)2FC-(1-fluoro-isopropyl), CF3CH2-(2,2,2-trifluoroethyl), CH3CF2-(1,1-difluoroethyl), CF3-(trifluoromethyl), CH2F-(fluoromethyl) or CHF2-(difluoromethyl). CH3CF2- and CF3- are particularly preferred.

[0088] As used herein, "haloalkoxy" refers to an alkoxy group in which at least one hydrogen atom is replaced by a halogen atom. Preferably, "haloalkoxy" refers to an alkoxy group in which one, two or three hydrogen atoms of the alkyl group are replaced by halogen atoms, preferably C 1~6 Refers to an alkoxy group, i.e., haloalkoxy includes monohaloalkoxy, dihaloalkoxy, trihaloalkoxy, perhaloalkoxy, etc. The halogen atom may be fluoro (F), chloro (Cl), or bromo (Br). Particularly preferred, but non-limiting examples of "halogen" are fluoro (F) and chloro (Cl). More preferably, the haloalkoxy is substituted with fluoro (F). Preferred, but non-limiting examples of haloalkoxy are CHF2O-, CH2FO-, CF3CHO-, CF2HCHO-, CH3CF2CHO-, and CH3CFHCHO-. Similarly preferred, but non-limiting examples of haloalkoxy are haloC selected from CHF2O-, CH2FO-, CF3O-, FCH2CFHCHO-, CH2FCH2O-, and CF3CHO-. 1~6 Alkoxy. CHF2O-, CF3CH2O-, CF3O-, CH2FO- or FCH2CFHCH2O- is particularly preferred.

[0089] The term "hydroxyalkyl" refers to an alkyl group, preferably having 1 to 6 C atoms, in which at least one hydrogen atom of the alkyl group is replaced by one or more hydroxy. Preferably, "hydroxyalkyl" refers to an alkyl group in which 1, 2 or 3 hydrogen atoms of the alkyl group are replaced by hydroxy, preferably C 1~6 It refers to alkyl, i.e., hydroxyalkyl includes monohydroxyalkyl, dihydroxyalkyl, trihydroxyalkyl, perhydroxyalkyl, etc. More preferably, "hydroxyalkyl" refers to an alkyl group in which one hydrogen atom is replaced by hydroxy. Particularly preferred, but non-limiting examples of hydroxyalkyl are HOCH2-(hydroxymethyl) and HOCH2CH2-(hydroxyethyl).

[0090] The term "heterocycloalkyl" refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic heterocyclic ring system of 4-6 ring atoms containing 1, 2 or 3 ring heteroatoms independently selected from N, O and S, with the remaining ring atoms being carbon. Preferably, "heterocycloalkyl" refers to a saturated monocyclic 4-6 membered heterocycloalkyl containing one O atom, non-limiting examples include oxetanyl, oxolanyl and oxanyl. In some embodiments, two substituents together with the two C atoms to which they are attached may form a bicyclic ring system containing a heterocycloalkyl bonded to the phenyl ring of a compound of formula (I) having the following structure: [ka]

[0091] Heterocycloalkyl can be substituted as described herein, for example with halogen. One specific, non-limiting example is: [ka]

[0092] The term "cycloalkyl" refers to a monocyclic ring having 3 to 12 carbon atoms (C3-C 12 ) or a monovalent non-aromatic saturated or partially unsaturated ring having 7 to 12 carbon atoms as a bicyclic ring. Bicyclic carbocycles having 7 to 12 atoms may be arranged, for example, as bicyclo[4,5], [5,5], [5,6] or [6,6] systems, and bicyclic carbocycles having 9 or 10 ring atoms may be arranged as bicyclo[5,6] or [6,6] systems or as bridged systems such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Preferably, "cycloalkyl" refers to a saturated monocyclic 3- to 6-membered cycloalkyl. More preferably, the saturated monocyclic 3- to 6-membered cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of monocyclic carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.

[0093] "Cyano C 1~6 The term "alkoxy" refers to an alkoxy group, preferably having 1 to 6 C atoms, in which at least one hydrogen atom of the alkoxy group is replaced by one or more cyano. 1~6 "Alkoxy" refers to an alkoxy group in which one, two or three hydrogen atoms are replaced by cyano, preferably C 1~6 More preferably, it refers to "cyano C 1~6 "Alkoxy" is a C alkyl group in which one hydrogen atom is replaced by cyano. 1~6 Refers to an alkoxy group. CyanoC 1~6 Particularly preferred, but non-limiting examples of alkoxy are NC-CH2-, NC-CH2CH2-, and NC-CH2CH2CH2-.

[0094] "Haro C 2~6 The term "alkenyl" refers to an alkenyl group in which at least one hydrogen atom of the alkenyl group is replaced by one or more halogen atoms. Preferably, "haloalkenyl" refers to a C 1 -C 2 -H 2 O group in which one, two or three hydrogen atoms of the alkenyl group are replaced by halogen atoms. 2~6 It refers to an alkyl group, i.e., haloalkenyl includes monohaloalkenyl, dihaloalkenyl, trihaloalkenyl, perhaloalkenyl, etc. The halogen atom can be fluoro (F), chloro (Cl), or bromo (Br). Particularly preferred, but non-limiting examples of "halogen" within haloalkenyl are fluoro (F) and chloro (Cl). More preferably, the haloalkenyl is substituted with fluoro (F). Preferred, but non-limiting examples of haloalkenyl are: [ka]

[0095] "Haro C 1~6 The term "alkyl-thiol" refers to a haloC 1~6 alkyl is as described herein; haloC 1~6 It relates to an organic sulfur substituent of the form alkyl-S-. Preferably, R 1 is a haloC selected from F3C-S-, F3CCH2-S-, and F3CCH2CH2-S- 1~6 A more preferred, but non-limiting example is F3CS-.

[0096] The term "mood disorder" as used herein refers to a mental health problem that primarily affects a person's emotional state. It is a disorder in which a person experiences prolonged periods of extreme happiness, extreme sadness, or both. Two of the most common mood disorders are depression and bipolar disorder.

[0097] The term "depression" as used herein relates to a mood disorder causing persistent feelings of sadness and loss of interest, also known as Major Depressive Disorder (MDD).

[0098] The term "behavioral disorder" refers to a disorder that involves a pattern of disruptive behavior in children that lasts for at least six months and causes problems in school, home and social situations. "Behavioral disorder" involves a pattern of disruptive behavior in children that lasts for at least six months and causes problems in school, home and social situations. The most important behavioral disorder is Attention Deficit Hyperactivity Disorder (ADHD).

[0099] As used herein, the term "attention deficit hyperactivity disorder" (ADHD) refers to a behavioral disorder characterized by inattention or hyperactivity and impulsivity. ADHD occurs more frequently in people with epilepsy than in the general population. Children with ADHD are at increased risk of seizures, with approximately 14% of children with ADHD developing seizures.

[0100] The term "developmental disorder" or "neurodevelopmental disorder" as used herein refers to a group of symptoms caused by impairments in the physical, learning, language, or behavioral domains. These symptoms begin during development, affect daily functioning, and can continue throughout a person's life. Examples of neurodevelopmental disorders include autism spectrum disorders ("ASD") and syndromic developmental disorders.

[0101] The term "Autism Spectrum Disorder (ASD)" as used herein refers to a developmental disorder of variable severity characterized by difficulties in social interaction and communication, and restricted or repetitive patterns of thought and behavior. ASD is primarily idiopathic but also encompasses syndromic forms and is currently diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Version 5 (DSM V).

[0102] The term "syndromic developmental disorder" as used herein refers to a developmental disorder with a clinically defined pattern of somatic abnormalities and a neurobehavioral phenotype that may include ASD. Diagnosis is typically confirmed by targeted genetic testing. Examples of syndromic developmental disorders include Dup15q syndrome (Dup15q), fragile X syndrome (FXS) and Angelman syndrome.

[0103] The term "Dup15q syndrome" or "Duq15q" as used herein refers to the common name for chromosome 15q11.2-q13.1 duplication syndrome, a syndromic developmental disorder caused by a partial duplication of chromosome 15 that confers a strong risk for autism spectrum disorder, epilepsy, and intellectual disability.

[0104] As used herein, the term "Fragile X Syndrome" (FXS) relates to a genetic disorder characterized by mild to moderate intellectual disability. The disorder is typically caused by an expansion of a CGG triplet repeat in the FMR1 (Fragile X Mental Retardation 1) gene on the X chromosome.

[0105] The term "Angelman syndrome" as used herein refers to a genetic disorder that primarily affects the nervous system due to a lack of function of a portion of chromosome 15 inherited from a person's mother. Characteristic features of the condition include developmental delay, intellectual disability, severe speech impairment, and movement and balance problems (ataxia). Most affected children also have recurrent seizures (epilepsy).

[0106] The term "intellectual disability" (ID) as used herein relates to a generalized neurodevelopmental disorder characterized by severely impaired intellectual and adaptive functioning. It is defined by an IQ below 70 in addition to two or more adaptive behavioral deficits that affect daily life. ID is also known as general learning disability and was previously known as mental retardation (MR).

[0107] The term "epilepsy" as used herein refers to a neurological disorder characterized by sudden recurrent episodes of sensory disturbances, loss of consciousness, or convulsions associated with abnormal electrical activity in the brain. Examples of epilepsy include diffuse childhood epilepsy, West syndrome, Ohtahara syndrome, and epileptic encephalopathy.

[0108] The term "neurodegenerative disease" as used herein refers to a disease associated with the progressive loss of neuronal structure or function, including neuronal death. Examples of neurodegenerative diseases include, but are not limited to, Alzheimer's disease and motor neuron disease.

[0109] The term "motor neuron disease" as used herein refers to a group of rare neurodegenerative disorders that selectively affect motor neurons. Examples of motor neuron diseases include, but are not limited to, amyotrophic lateral sclerosis (ALS).

[0110] The term "pain" as used herein relates to an unpleasant sensory and emotional experience associated with actual or potential tissue damage. Examples of pain include, but are not limited to, nociceptive pain, chronic pain (including idiopathic pain), neuropathic pain, including chemotherapy-induced neuropathy, phantom limb pain, and psychogenic pain.

[0111] The term "migraine" as used herein relates to a moderate to severe headache disorder causing throbbing or throbbing pain for hours or days.

[0112] The term "tinnitus" as used herein relates to a condition characterised by the perception of sound in the absence of a corresponding external sound.

[0113] Any disease, disorder or disability referred to herein also includes any condition or symptom associated with such disease, disorder or disability.

[0114] Compounds of the Invention All compound names for compound structures were generated using OpenEye Lexichem, version 1.2.0, OpenEye Scientific Software, Santa Fe, NM, USA; www.eyesopen.com .

[0115] It should be understood that features, integers, characteristics, compounds, chemical moieties or groups described in connection with a particular aspect, embodiment or example of the invention are applicable to any other aspect, embodiment or example described herein, except where inconsistent therewith. All of the features disclosed herein (including any accompanying claims, abstracts and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. The invention is not limited to the details of any of the embodiments described herein. Any of the embodiments described in this application may be combined with any of the other embodiments. For example, any of the embodiments herein relating to the compounds of the invention may be combined with any of the embodiments of pharmaceutical compositions, kits, medical uses, or methods of treatment. The invention extends to any novel one or any novel combination of features disclosed herein (including any accompanying claims, abstracts and drawings), or any novel one or any novel combination of steps of any method or process so disclosed.

[0116] In some embodiments of the present invention, the compound of formula (I) has a structure as shown in any of formulas (II), (III), (IV), (V), (VI), and (VII), etc., described herein.

[0117] The present invention relates to compounds of formula (I): [ka] (In the formula, R 1 is halogen, cyano, haloC 1~6 Alkoxy, C1~6 Alkoxy, C 1~6 Alkyl, C 2~8 Alkynyl, Cyano C 1~6 Alkoxy, HaloC 1~6 Alkyl, SF5, HaloC 2~6 Alkenyl, HaloC 1~6 and 4-6 membered heterocycloalkyl, wherein the heterocycloalkyl is selected from halogen and haloC 1~6 optionally substituted with 1 or 2 substituents independently selected from alkyl; R 2 H, D, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; R 3 H, D, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; or R 2 and R 3 together with the carbon atom to which they are attached form a saturated monocyclic 3- to 6-membered cycloalkyl, which cycloalkyl is free of halogen and haloC 1~6 optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl; R 4 H, halogen, haloC 1~6 Alkyl, C 1~6 Alkoxy and C 1~6 alkyl; R 5 , H, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; or R 1 and R 5 together with the two C atoms to which they are attached form a 4-6 membered heterocycloalkyl ring system, the heterocycloalkyl being halogen or haloC 1~6 optionally substituted with 1 or 2 substituents independently selected from alkyl; R 8 H, halogen, haloC 1~6 Alkyl and haloC 1~6 alkoxy) or A solvate or a pharma- ceutically acceptable salt thereof is provided.

[0118] All of the features disclosed in this specification (including any accompanying claims, abstract and drawings) for any embodiment so disclosed may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. The invention is not limited to the details of any embodiment described herein. Any embodiment described in this application may be combined with any other embodiment.

[0119] In some particularly preferred embodiments, the present invention provides a compound having the structure of formula (II): 8 is H, or a solvate or pharma- ceutically acceptable salt thereof: [ka] (In the formula, R 1 is halogen, cyano, haloC 1~6 Alkoxy, C 1~6 Alkoxy, C 1~6 Alkyl, C 2~8 Alkynyl, Cyano C 1~6 Alkoxy, HaloC 1~6 Alkyl, SF5, HaloC 2~6 Alkenyl, HaloC 1~6 and 4-6 membered heterocycloalkyl, wherein the heterocycloalkyl is selected from halogen and haloC 1~6 optionally substituted with 1 or 2 substituents independently selected from alkyl; R 2 H, D, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; R 3 H, D, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; or R 2 and R 3 together with the carbon atom to which they are attached form a saturated monocyclic 3- to 6-membered cycloalkyl, which cycloalkyl is free of halogen and haloC 1~6 optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl; R 4 H, halogen, haloC 1~6 Alkyl, C 1~6 Alkoxy and C 1~6 alkyl; R 5 , H, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; or R 1 and R 5 together with the two C atoms to which they are attached form a 4-6 membered heterocycloalkyl ring system, the heterocycloalkyl being selected from halogen and haloC 1~6 Optionally substituted with 1 or 2 substituents independently selected from alkyl.

[0120] In some embodiments of the invention, the compound of formula (I) has the structure of formula (II):

[0121] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 1 halogen, cyano, haloC 1~6 Alkoxy, C 1~6 Alkoxy, C 1~6 Alkyl, C 2~8 Alkynyl, Cyano C 1~6 Alkoxy, HaloC 1~6 Alkyl, SF5, HaloC 2~6 Alkenyl, HaloC 1~6alkyl-thiol, and 4-6 membered heterocycloalkyl, wherein the heterocycloalkyl is selected from halogen and haloC 1~6 Provided is a compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof, optionally substituted with one or two substituents independently selected from alkyl.

[0122] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 1 is halogen, halo C 1~6 Alkyl, haloC 1~6 Alkoxy, cyano, and cyanoC 1~6 The present invention provides a compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof, wherein R is selected from the group consisting of alkoxy.

[0123] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 1 is halogen, halo C 1~6 Alkoxy, cyano, and cyanoC 1~6 The present invention provides a compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof, wherein R is selected from the group consisting of alkoxy.

[0124] In one preferred embodiment, the present invention provides a compound comprising: 1 is halogen, halo C 1~6 Alkyl and haloC 1~6 The present invention provides a compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof, wherein R is selected from the group consisting of alkoxy.

[0125] In one preferred embodiment, the present invention provides a compound comprising: 1 is halogen, halo C 1~6 Alkyl and haloC 1~6 The present invention provides a compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof, wherein R is selected from the group consisting of alkoxy.

[0126] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 1 Cyano and Cyano C 1~6 The present invention provides a compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof, wherein R is selected from the group consisting of alkoxy.

[0127] In one particularly preferred embodiment, the present invention provides a compound comprising: 1 is halogen, halo C 1~6 The present invention provides a compound of formula (I), or a solvate or pharma- ceutically acceptable salt thereof, wherein R is selected from the group consisting of alkoxy and cyano.

[0128] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 1 is a halogen selected from F-, Cl-, and Br-, or a solvate or pharma- ceutically acceptable salt thereof.

[0129] In one more preferred embodiment, the present invention provides a compound comprising: 1 is F- or a solvate or pharma- ceutically acceptable salt thereof.

[0130] In one preferred embodiment, the present invention provides a compound comprising: 1 is Cl-, or a solvate or pharma- ceutically acceptable salt thereof.

[0131] In one preferred embodiment, the present invention provides a compound comprising: 1 is Br- or a solvate or pharma- ceutically acceptable salt thereof.

[0132] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 1 C 1~6 The present invention provides a compound of formula (I), or a solvate or pharma- ceutically acceptable salt thereof, which is alkoxy.

[0133] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 1 is selected from CH3O-, CH3CH2O-, CH3CH2CH2O-, and (CH3)3CO- 1~6 The present invention provides a compound of formula (I), or a solvate or pharma- ceutically acceptable salt thereof, which is alkoxy.

[0134] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 1is CH3O-, or a solvate or pharma- ceutically acceptable salt thereof.

[0135] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 1 C 1~6 The present invention provides a compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof, wherein R is alkyl.

[0136] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 1 is selected from CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH2-, CH3CH2CH2CH2-, (CH3)2CH2CH2-, (CH3CH(CH3)CH2-, and (CH3)3C-(tert-butyl). 1~6 The present invention provides a compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof, wherein R is alkyl.

[0137] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 1 is selected from CH3- and (CH3)3C-(tert-butyl); 1~6 The present invention provides a compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof, wherein R is alkyl.

[0138] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 1 is (CH3)3C-(tert-butyl), or a solvate or pharma- ceutically acceptable salt thereof.

[0139] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 1 HaroC 2~6 The present invention provides a compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof, wherein: R is 1, 2, 3, or 4;

[0140] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 1 HaloC having the following structure: 2~6 The present invention provides a compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof, wherein: R is 1, 2, 3, or 4; [ka]

[0141] In one preferred embodiment, the present invention provides a compound comprising: 1 is selected from CHF2O-, CFH2O-, CF3O-, CHF2CH2O-, FCH2CFHCH2O- and CF3CH2O- 1~6 The present invention provides a compound of formula (I), or a solvate or pharma- ceutically acceptable salt thereof, which is alkoxy.

[0142] In one preferred embodiment, the present invention provides a compound comprising: 1 is selected from CHF2O-, CFH2O-, and CF3O- 1~6 The present invention provides a compound of formula (I), or a solvate or pharma- ceutically acceptable salt thereof, which is alkoxy.

[0143] In one preferred embodiment, the present invention provides a compound comprising: 1 is CHF2O- or CF3O-, or a solvate or pharma- ceutically acceptable salt thereof.

[0144] In one particularly preferred embodiment, the present invention provides a compound comprising: 1 is CHF2O-, or a solvate or pharma- ceutically acceptable salt thereof.

[0145] In one particularly preferred embodiment, the present invention provides a compound comprising: 1 is CFH2O- or a solvate or pharma- ceutically acceptable salt thereof.

[0146] In one particularly preferred embodiment, the present invention provides a compound comprising: 1 is CF3O-, or a solvate or pharma- ceutically acceptable salt thereof.

[0147] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 1 HaroC 1~6The present invention provides a compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof, wherein R is alkyl.

[0148] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 1 is selected from the group consisting of CF3-, CHF2-, CH3CF2-, and CFH2- 1~6 The present invention provides a compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof, wherein R is alkyl.

[0149] In one preferred embodiment, the present invention provides a compound comprising: 1 is CHF2- or a solvate or pharma- ceutically acceptable salt thereof.

[0150] In one more preferred embodiment, the present invention provides a compound comprising: 1 is CF3- or a solvate or pharma- ceutically acceptable salt thereof.

[0151] In one particularly preferred embodiment, the present invention provides a compound comprising: 1 is cyano, or a solvate or pharma- ceutically acceptable salt thereof.

[0152] In one preferred embodiment, the present invention provides a compound comprising: 1 is selected from NC-CH2O-, NC-CH2CH2O-, and NC-CH2CH2CH2O-; 1~6 The present invention provides a compound of formula (I), or a solvate or pharma- ceutically acceptable salt thereof, which is alkoxy.

[0153] In one preferred embodiment, the present invention provides a compound comprising: 1 is NC-CHO- or a solvate or pharma- ceutically acceptable salt thereof.

[0154] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 1 is a 4- to 6-membered heterocycloalkyl, and the heterocycloalkyl is halogen and haloC 1~6Provided is a compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof, optionally substituted with one or two substituents independently selected from alkyl.

[0155] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 1 is 4-6 membered heterocycloalkyl, and said heterocycloalkyl is unsubstituted, or a solvate or pharma- ceutically acceptable salt thereof.

[0156] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 1 is a 4-6 membered heterocycloalkyl, said heterocycloalkyl being unsubstituted and containing one O atom, or a solvate or pharma- ceutically acceptable salt thereof.

[0157] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 1 is selected from unsubstituted oxetanyl, oxolanyl, and oxanyl, or a solvate or pharma- ceutically acceptable salt thereof.

[0158] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 1 is unsubstituted oxetanyl, or a solvate or pharma- ceutically acceptable salt thereof.

[0159] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 1 is an unsubstituted oxetanyl having the structure: or a solvate or pharma- ceutically acceptable salt thereof. [ka]

[0160] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 1 C 2~8 Provided is a compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof, which is alkynyl.

[0161] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of:1 C has the following structure 2~8 Provided is a compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof, which is alkynyl. [ka]

[0162] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 1 is SF5, or a solvate or pharma- ceutically acceptable salt thereof.

[0163] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 1 HaroC 1~6 Provided is a compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof, which is an alkyl-thiol.

[0164] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 1 is selected from F3C-S-, F3CCH2-S-, and F3C CH2CH2-S-; 1~6 Provided is a compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof, which is an alkyl-thiol.

[0165] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 1 haloC having the structure F3C-S- 1~6 Provided is a compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof, which is an alkyl-thiol.

[0166] In one more preferred embodiment, the present invention provides a compound comprising: 1 and R 5 together with the two C atoms to which they are attached form a 4-6 membered heterocycloalkyl, the heterocycloalkyl being attached to a phenyl ring, and the heterocycloalkyl being halogen or haloC 1~6 The present invention provides a compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof, optionally substituted with one or two substituents selected from alkyl.

[0167] In one more preferred embodiment, the present invention provides a compound comprising: 1 and R 5 are taken together with the two C atoms to which they are attached to form a 4-6 membered heterocycloalkyl, said heterocycloalkyl being attached to a phenyl ring, and said heterocycloalkyl being optionally substituted with one or two halogens, or a solvate or a pharma- ceutically acceptable salt thereof.

[0168] In one more preferred embodiment, the present invention provides a compound comprising: 1 and R 5 are taken together with the two C atoms to which they are attached to form a 4-6 membered heterocycloalkyl, the heterocycloalkyl being attached to a phenyl ring, and the heterocycloalkyl being optionally substituted with one or two halogens selected from F-, Cl- and Br-, or a solvate or a pharma- ceutically acceptable salt thereof.

[0169] In one more preferred embodiment, the present invention provides a compound comprising: 1 and R 5 are taken together with the two C atoms to which they are attached to form a 4-6 membered heterocycloalkyl, said heterocycloalkyl being attached to a phenyl ring, and said heterocycloalkyl being optionally substituted with one or two F-, or a solvate or a pharma- ceutically acceptable salt thereof.

[0170] In one more preferred embodiment, the present invention provides a compound comprising: 1 and R 5 are taken together with the two C atoms to which they are attached to form a 4-6 membered heterocycloalkyl, said heterocycloalkyl being attached to a phenyl ring, and said heterocycloalkyl being optionally substituted with two F-, or a solvate or a pharma- ceutically acceptable salt thereof.

[0171] In one more preferred embodiment, the present invention provides a compound comprising: 1 and R5 together with the two C atoms to which they are attached form a 4-6 membered heterocycloalkyl, which is attached to a phenyl ring, and the bicyclic ring system has the following structure: [ka] and optionally substituted as described herein, or a solvate or pharma- ceutically acceptable salt thereof.

[0172] In one preferred embodiment, the present invention provides a compound comprising: 1 and R 5 taken together with the two C atoms to which they are attached form a 4-6 membered heterocycloalkyl containing two O atoms, optionally substituted as described herein, or a solvate or pharma- ceutically acceptable salt thereof.

[0173] In one preferred embodiment, the present invention provides a compound comprising: 1 and R 5 taken together with the two C atoms to which they are attached form a 4-6 membered heterocycloalkyl containing two O atoms, optionally substituted with one or two halogens, or a solvate or a pharma- ceutically acceptable salt thereof.

[0174] In one preferred embodiment, the present invention provides a compound comprising: 1 and R 5 taken together with the two C atoms to which they are attached form a 4-6 membered heterocycloalkyl containing two O atoms, optionally substituted with two halogens, or a solvate or a pharma- ceutically acceptable salt thereof.

[0175] In one preferred embodiment, the present invention provides a compound comprising: 1 and R 5taken together with the two C atoms to which they are attached form a 5-membered heterocycloalkyl ring system containing two O atoms, substituted with one or two halogens selected from F-, Cl- and Br-, or a solvate or pharma- ceutically acceptable salt thereof.

[0176] In one preferred embodiment, the present invention provides a compound comprising: 1 and R 5 taken together with the two C atoms to which they are attached form a 5-membered heterocycloalkyl ring system containing two O atoms, substituted with one or two F-, or a solvate or a pharma- ceutically acceptable salt thereof.

[0177] In one preferred embodiment, the present invention provides a compound comprising: 1 and R 5 taken together with the two C atoms to which they are attached form a 5-membered heterocycloalkyl ring system containing two O atoms, which are substituted with two F-, or a solvate or a pharma- ceutically acceptable salt thereof.

[0178] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 1 and R 5 taken together with the two C atoms to which they are attached form a 4-6 membered heterocycloalkyl having the following structure: [ka] (In the formula, X is O or S; R 6 H, halogen, haloC 1~6 Alkyl, and C 1~6 alkyl; R 7 H, halogen, haloC 1~6 Alkyl, and C 1~6 alkyl).

[0179] In one embodiment, the present invention provides a compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof, wherein both X are O.

[0180] In one embodiment, the present invention provides a compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof, wherein both X are S.

[0181] In one embodiment, the present invention provides a method for the preparation of a medicament ... which both X are O and R 6 and R 7 and R are both halogen selected from F-, Cl- and Br-, or a solvate or pharma- ceutically acceptable salt thereof.

[0182] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 6 and R 7 and R are each independently selected from the group consisting of F-, F-, F-(CH2)-(CH3)-(CH4)-(CH2-CH3), and F-(CH2)-(CH3)-(CH4)-(CH2-CH3).

[0183] The present invention relates to 2 H, D, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 The present invention provides a compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof, wherein R is selected from the group consisting of alkoxy.

[0184] The present invention relates to 3 H, D, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 The present invention provides a compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof, wherein R is selected from the group consisting of alkoxy.

[0185] In some embodiments, the present invention provides a method for producing a medicament comprising the steps of: (i) R 2 and R 3 or (ii) R 2 and R 3 and the other is D; or a solvate or pharma- ceutically acceptable salt thereof.

[0186] In some preferred embodiments, the present invention provides 2 and R 3 are both H, or a solvate or pharma- ceutically acceptable salt thereof.

[0187] In some other preferred embodiments, the present invention provides 2 and R 3 and R are each independently selected from the group consisting of aryl, aryl, phenyl ...

[0188] In some embodiments, the present invention provides a method for the preparation of a compound comprising the steps of: 2 Hydroxy C 1~6 is alkyl, R 3 is H, or a solvate or pharma- ceutically acceptable salt thereof.

[0189] In some embodiments, the present invention provides a method for the preparation of a compound comprising the steps of: 2 is selected from HOCH2-, HOCH2CH2-, and HOCH2CH2CH2- 1~6 is alkyl, R 3 is H, or a solvate or pharma- ceutically acceptable salt thereof.

[0190] In some embodiments, the present invention provides a method for the preparation of a compound comprising the steps of: 2 is HOCH2- and R 3 is H, or a solvate or pharma- ceutically acceptable salt thereof.

[0191] In some embodiments, the present invention provides a method for the preparation of a compound comprising the steps of: 2 HOCH2- has a structure selected from the following: [ka] and [ka] and R 3 is H, or a solvate or pharma- ceutically acceptable salt thereof.

[0192] In some preferred embodiments, the present invention provides 2 C 1~6 is alkyl, R 3 is H, or a solvate or pharma- ceutically acceptable salt thereof.

[0193] In some preferred embodiments, the present invention provides 2 is selected from CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH2-, (CH3CH2CH2CH2-), (CH3)2CH2CH2-, CH3CH(CH3)CH2-, and (CH3)3C-(tert-butyl). 1~6 is alkyl, R 3 is H, or a solvate or pharma- ceutically acceptable salt thereof.

[0194] In some preferred embodiments, the present invention provides 2 is CH3- or (CH3)3C-(tert-butyl), and R 3 is H, or a solvate or pharma- ceutically acceptable salt thereof.

[0195] In some preferred embodiments, the present invention provides 2 is CH3- and R 3 is H, or a solvate or pharma- ceutically acceptable salt thereof.

[0196] In some preferred embodiments, the present invention provides 2 has the following structure: [ka] or [ka] and R 3 is H, or a solvate or pharma- ceutically acceptable salt thereof.

[0197] In some preferred embodiments, the present invention provides 1 is halogen, cyano, haloC 1~6 Alkoxy, C 1~6 Alkoxy, C 1~6 Alkyl, C 2~8 Alkynyl, Cyano C 1~6 Alkoxy, HaloC 1~6 Alkyl, SF5, HaloC 2~6 Alkenyl, HaloC 1~6 alkyl-thiol, and 4-6 membered heterocycloalkyl, wherein the heterocycloalkyl is selected from halogen and haloC 1~6 Optionally substituted with one or two substituents independently selected from alkyl, R 2 and R 3 are both H, or a solvate or pharma- ceutically acceptable salt thereof.

[0198] In some more preferred embodiments, the present invention provides 1 is halogen, cyano, haloC 1~6 Alkoxy and cyano C 1~6 alkoxy; R 2 and R 3 are both H, or a solvate or pharma- ceutically acceptable salt thereof.

[0199] In some particularly preferred embodiments, the present invention provides 1 halogen, cyano, and haloC 1~6 alkoxy; R 2 and R 3 are both H, or a solvate or pharma- ceutically acceptable salt thereof.

[0200] In some embodiments, the present invention provides a method for the preparation of a compound comprising the steps of: 1is halogen, cyano, haloC 1~6 Alkoxy, C 1~6 Alkoxy, C 1~6 Alkyl, C 2~8 Alkynyl, Cyano C 1~6 Alkoxy, HaloC 1~6 Alkyl, SF5, HaloC 2~6 Alkenyl, HaloC 1~6 alkyl-thiol, and 4-6 membered heterocycloalkyl, wherein the heterocycloalkyl is selected from halogen and haloC 1~6 Optionally substituted with one or two substituents independently selected from alkyl, R 2 and R 3 and R are each independently selected from the group consisting of aryl, aryl, phenyl ...

[0201] In some more preferred embodiments, the present invention provides 1 is halogen, cyano, haloC 1~6 Alkoxy and cyano C 1~6 alkoxy; R 2 and R 3 and R are each independently selected from the group consisting of aryl, aryl, phenyl ...

[0202] In some more preferred embodiments, the present invention provides 1 halogen, cyano, and haloC 1~6 alkoxy; R 2 and R 3 and R are each independently selected from the group consisting of aryl, aryl, phenyl ...

[0203] In some embodiments, the present invention provides a method for the preparation of a compound comprising the steps of: 1 is halogen, cyano, haloC 1~6 Alkoxy, C 1~6 Alkoxy, C 1~6 Alkyl, C 2~8 Alkynyl, Cyano C 1~6 Alkoxy, HaloC 1~6 Alkyl, SF5, HaloC 2~6 Alkenyl, HaloC1~6 alkyl-thiol, and 4-6 membered heterocycloalkyl, wherein the heterocycloalkyl is selected from halogen and haloC 1~6 Optionally substituted with one or two substituents independently selected from alkyl, R 2 Hydroxy C 1~6 is alkyl, R 3 is H, or a solvate or pharma- ceutically acceptable salt thereof.

[0204] In some embodiments, the present invention provides a method for the preparation of a compound comprising the steps of: 1 is halogen, cyano, haloC 1~6 Alkyl, haloC 1~6 Alkoxy and cyano C 1~6 alkoxy; R 2 Hydroxy C 1~6 is alkyl, R 3 is H, or a solvate or pharma- ceutically acceptable salt thereof.

[0205] In some embodiments, the present invention provides a method for the preparation of a compound comprising the steps of: 1 Halogen and haloC 1~6 alkyl; R 2 Hydroxy C 1~6 is alkyl, R 3 is H, or a solvate or pharma- ceutically acceptable salt thereof.

[0206] In some embodiments, the present invention provides a method for the preparation of a compound comprising the steps of: 1 is halogen, cyano and haloC 1~6 alkoxy; R 2 Hydroxy C 1~6 is alkyl, R 3 is H, or a solvate or pharma- ceutically acceptable salt thereof.

[0207] In some embodiments, the present invention provides a method for the preparation of a compound comprising the steps of: 1 is halogen, cyano, haloC 1~6 Alkoxy, C 1~6 Alkoxy, C1~6 Alkyl, C 2~8 Alkynyl, Cyano C 1~6 Alkoxy, HaloC 1~6 Alkyl, SF5, HaloC 2~6 Alkenyl, HaloC 1~6 alkyl-thiol, and 4-6 membered heterocycloalkyl, wherein the heterocycloalkyl is selected from halogen and haloC 1~6 Optionally substituted with one or two substituents independently selected from alkyl, R 2 is HOCH2- and R 3 is H, or a solvate or pharma- ceutically acceptable salt thereof.

[0208] In some embodiments, the present invention provides a method for the preparation of a compound comprising the steps of: 1 is halogen, cyano, haloC 1~6 Alkyl, haloC 1~6 Alkoxy and cyano C 1~6 alkoxy; R 2 is HOCH2- and R 3 is H, or a solvate or pharma- ceutically acceptable salt thereof.

[0209] In some embodiments, the present invention provides a method for the preparation of a compound comprising the steps of: 1 is halogen, cyano, haloC 1~6 Alkyl and haloC 1~6 alkoxy; R 2 is HOCH2- and R 3 is H, or a solvate or pharma- ceutically acceptable salt thereof.

[0210] In some embodiments, the present invention provides a method for the preparation of a compound comprising the steps of: 1 Halogen and haloC 1~6 alkyl; R 2 is HOCH2- and R 3 is H, or a solvate or pharma- ceutically acceptable salt thereof.

[0211] In some embodiments, the present invention provides a method for the preparation of a compound comprising the steps of:1 is a halogen, and R 2 is HOCH2- and R 3 is H, or a solvate or pharma- ceutically acceptable salt thereof.

[0212] In some embodiments, the present invention provides a method for the preparation of a compound comprising the steps of: 1 is a halogen selected from F-, Cl- and Br-; R 2 is HOCH2- and R 3 is H, or a solvate or pharma- ceutically acceptable salt thereof.

[0213] In some embodiments, the present invention provides a method for the preparation of a compound comprising the steps of: 1 HaroC 1~6 is alkyl, R 2 is HOCH2- and R 3 is H, or a solvate or pharma- ceutically acceptable salt thereof.

[0214] In some embodiments, the present invention provides a method for the preparation of a compound comprising the steps of: 1 is selected from the group consisting of CF3-, CHF2-, CH3CF2-, and CFH2- 1~6 is alkyl, R 2 is HOCH2- and R 3 is H, or a solvate or pharma- ceutically acceptable salt thereof.

[0215] In some embodiments, the present invention provides a method for the preparation of a compound comprising the steps of: 2 HOCH2- has a structure selected from the following: [ka] and [ka] or a solvate or pharma- ceutically acceptable salt thereof.

[0216] In some embodiments, the present invention provides a method for the preparation of a compound comprising the steps of: 1 is halogen, cyano, haloC 1~6 Alkoxy, C 1~6 Alkoxy, C 1~6 Alkyl, C 2~8 Alkynyl, Cyano C 1~6 Alkoxy, HaloC 1~6 alkyl, SF, haloC2-6 alkenyl, haloC1-6 alkyl-thiol, and 4-6 membered heterocycloalkyl, wherein the heterocycloalkyl is selected from halogen and haloC 1~6 Optionally substituted with one or two substituents independently selected from alkyl, R 2 C 1~6 is alkyl, R 3 is H, or a solvate or pharma- ceutically acceptable salt thereof.

[0217] In some embodiments, the present invention provides a method for the preparation of a compound comprising the steps of: 1 is halogen, cyano, haloC 1~6 Alkoxy, C 1~6 Alkoxy, C 1~6 Alkyl, C 2~8 Alkynyl, Cyano C 1~6 Alkoxy, HaloC 1~6 alkyl, SF, haloC2-6 alkenyl, haloC1-6 alkyl-thiol, and 4-6 membered heterocycloalkyl, wherein the heterocycloalkyl is selected from halogen and haloC 1~6 Optionally substituted with one or two substituents independently selected from alkyl, R 2 is selected from CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH2-, CH3CH2CH2CH2-, (CH3)2CH2CH2-, (CH3CH(CH3)CH2-, and (CH3)3C-(tert-butyl). 1~6 is alkyl, R 3 is H, or a solvate or pharma- ceutically acceptable salt thereof.

[0218] In some embodiments, the present invention provides a method for the preparation of a compound comprising the steps of: 1 is halogen, cyano, haloC1~6 Alkoxy, C 1~6 Alkoxy, C 1~6 Alkyl, C 2~8 Alkynyl, Cyano C 1~6 Alkoxy, HaloC 1~6 Alkyl, SF5, HaloC 2~6 Alkenyl, HaloC 1~6 alkyl-thiol, and 4-6 membered heterocycloalkyl, wherein the heterocycloalkyl is selected from halogen and haloC 1~6 Optionally substituted with one or two substituents independently selected from alkyl, R 2 is selected from CH3- and (CH3)3C-(tert-butyl); 1~6 is alkyl, R 3 is H, or a solvate or pharma- ceutically acceptable salt thereof.

[0219] In some embodiments, the present invention provides a method for the preparation of a compound comprising the steps of: 1 is halogen, cyano, haloC 1~6 Alkoxy, C 1~6 Alkoxy, C 1~6 Alkyl, C 2~8 Alkynyl, Cyano C 1~6 Alkoxy, HaloC 1~6 Alkyl, SF5, HaloC 2~6 Alkenyl, HaloC 1~6 alkyl-thiol, and 4-6 membered heterocycloalkyl, wherein the heterocycloalkyl is selected from halogen and haloC 1~6 Optionally substituted with one or two substituents independently selected from alkyl, R 2 is CH3- and R 3 is H, or a solvate or pharma- ceutically acceptable salt thereof.

[0220] In some embodiments, the present invention provides a method for the preparation of a compound comprising the steps of: 1 is halogen, cyano, haloC 1~6 Alkoxy, C 1~6 Alkoxy, C 1~6 Alkyl, C 2~8 Alkynyl, Cyano C 1~6Alkoxy, HaloC 1~6 Alkyl, SF5, HaloC 2~6 Alkenyl, HaloC 1~6 alkyl-thiol, and 4-6 membered heterocycloalkyl, wherein the heterocycloalkyl is selected from halogen and haloC 1~6 Optionally substituted with one or two substituents independently selected from alkyl, R 2 has the following structure: [ka] or [ka] or a solvate or pharma- ceutically acceptable salt thereof.

[0221] In the following embodiments, "formed saturated monocyclic 3- to 6-membered cycloalkyl" refers to unsubstituted cycloalkyl or cycloalkyl substituted as described herein. In particular, the cycloalkyl is unsubstituted.

[0222] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 2 and R 3 are taken together with the carbon atom to which they are attached to form a saturated monocyclic 3- to 6-membered cycloalkyl, or a solvate or pharma- ceutically acceptable salt thereof.

[0223] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl, the cycloalkyl being selected from halogen and haloC 1~6 The present invention provides a compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof, optionally substituted with 1, 2, 3 or 4 substituents independently selected from alkyl.

[0224] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of:2 and R 3 together with the carbon atom to which they are attached form cyclopropyl, wherein said cycloalkyl is unsubstituted; or a solvate or pharma- ceutically acceptable salt thereof.

[0225] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 2 and R 3 taken together with the carbon atom to which they are attached form cyclopropyl, said cycloalkyl being selected from unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, or a solvate or pharma- ceutically acceptable salt thereof.

[0226] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 2 and R 3 taken together with the carbon atom to which they are attached form an unsubstituted cyclopropyl, or a solvate or pharma- ceutically acceptable salt thereof.

[0227] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 2 and R 3 taken together with the carbon atom to which they are attached form a cyclopropyl having the structure: [ka]

[0228] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 1 halogen, cyano, cyanoC 1~6 Alkoxy and haloC 1~6 alkyl; R 2 and R 3 taken together with the carbon atom to which they are attached form a cyclopropyl having the structure: [ka]

[0229] In some embodiments, the present invention provides a method for the preparation of a compound comprising the steps of: 4 H, halogen, haloC 1~6 Alkyl, C 1~6 Alkoxy and C 1~6 or a solvate or pharma- ceutically acceptable salt thereof, wherein R is selected from the group consisting of alkyl, aryl ...

[0230] In some embodiments, the present invention provides a method for the preparation of a compound comprising the steps of: 4 is halogen, halo C 1~6 Alkyl and haloC 1~6 The present invention provides a compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof, wherein R is selected from the group consisting of alkoxy.

[0231] In some particularly preferred embodiments, the present invention provides 4 is a halogen selected from F-, Cl-, and Br-, or a solvate or pharma- ceutically acceptable salt thereof.

[0232] In some particularly preferred embodiments, the present invention provides 4 is F- or a solvate or pharma- ceutically acceptable salt thereof.

[0233] In some embodiments, the present invention provides a method for the preparation of a compound comprising the steps of: 4 C 1~6 The present invention provides a compound of formula (I), or a solvate or pharma- ceutically acceptable salt thereof, which is alkoxy.

[0234] In some embodiments, the present invention provides a method for the preparation of a compound comprising the steps of: 4 is selected from CH3O-, CH3CH2O-, CH3CH2CH2O-, and (CH3)3CO- 1~6 The present invention provides a compound of formula (I), or a solvate or pharma- ceutically acceptable salt thereof, which is alkoxy.

[0235] In some embodiments, the present invention provides a method for the preparation of a compound comprising the steps of: 4 is CH3O-, or a solvate or pharma- ceutically acceptable salt thereof.

[0236] In some more preferred embodiments, the present invention provides 4 (i) a haloC selected from CHF2O-, CFH2O-, CF3O-, CHF2CH2O-, FCH2CFHCH2O-, and CF3CH2O- 1~6 alkoxy or (ii) halo selected from CF3-, CHF2-, CH3CF2-, and CFH2- 1~6 The compound according to the invention relates to the above compound, wherein R is an alkyl group.

[0237] In some more preferred embodiments, the present invention provides 4 is F-, CHF2O- or CF3-.

[0238] In some particularly preferred embodiments, the present invention provides 4 is F- or CF3-.

[0239] In some particularly preferred embodiments, the present invention provides 4 is CF3-.

[0240] In some preferred embodiments, the present invention provides 4 is H, or a solvate or pharma- ceutically acceptable salt thereof.

[0241] In some preferred embodiments, the present invention provides 4 is H and a bicyclo[1.1.1]pentanyl ring having the structure: [ka]

[0242] In some embodiments, the present invention provides a method for the preparation of a compound comprising the steps of: 5H, halogen, haloC 1~6 Alkyl, C 1~6 Alkoxy and C 1~6 or a solvate or pharma- ceutically acceptable salt thereof, wherein R is selected from the group consisting of alkyl, aryl ...

[0243] In some particularly preferred embodiments, the present invention provides 5 is H, or a solvate or pharma- ceutically acceptable salt thereof.

[0244] In some more preferred embodiments, the present invention provides 1 is halogen, halo C 1~6 Alkoxy, cyano, and cyanoC 1~6 alkyl; R 2 and R 3 are both H and R 4 is halogen or haloC 1~6 is alkyl, R 5 is H and R 8 is H, or a solvate or pharma- ceutically acceptable salt thereof.

[0245] In some more preferred embodiments, the present invention provides 1 is F- or CF3O-, and R 2 and R 3 are both H and R 4 is F- or CF3-, and R 5 is H and R 8 is H, or a solvate or pharma- ceutically acceptable salt thereof.

[0246] Exemplary compounds of formula (I) in Table 1 are useful for inhibiting Kv7.2 (EC 50It was made, characterized and tested for <10 micromolar (μM) and % maximal activation of Kv7.2 activation and has the following structure and corresponding name (OpenEye Lexichem, version 1.2.0, OpenEye Scientific Software, Santa Fe, NM, USA; https: / / www.eyesopen.com / lexichem-tk).

[0247] In some embodiments, the compound is selected from Table 1, or a solvate or pharma- ceutically acceptable salt thereof. [Table 1] TIFF2025506201000028.tif240170 TIFF2025506201000029.tif237170 TIFF2025506201000030.tif248170 TIFF2025506201000031.tif237170 TIFF2025506201000032.tif231170 TIFF2025506201000033.tif229170 TIFF2025506201000034.tif142170

[0248] The compounds of the present invention have been shown to be agents acting on Kv7.2 and are therefore useful for the treatment and / or prevention of any of the diseases, disorders, or disabilities described herein. They are particularly useful for the therapeutic and / or prophylactic treatment of Kv7.2-associated disorders, diseases, or disabilities. More particularly, they are useful for the therapeutic and / or prophylactic treatment of Kv7.2-associated disorders, diseases, or disabilities selected from behavioral disorders, mood disorders, neurodevelopmental disorders, intellectual disabilities, epilepsy, neurodegenerative disorders, pain, migraine, and tinnitus. Behavioral disorders are, for example, attention deficit hyperactivity disorder (ADHD). Mood disorders are, for example, depression. Neurodevelopmental disorders are, for example, autism spectrum disorders (ASD) or symptomatic developmental disorders. Symptomatic developmental disorders are, for example, Dup15q syndrome (Dup15q), fragile X syndrome (FXS), and Angelman syndrome. Epilepsy is, for example, diffuse childhood epilepsy, West syndrome, Ohtahara syndrome and epileptic encephalopathy. Neurodegenerative diseases are, for example, Alzheimer's disease or motor neuron diseases.

[0249] Thus, the compounds of the present invention are useful Kv7.2 modulators that offer favorable pharmacological properties such as potency, selectivity and metabolic stability.

[0250] Compounds having one or more of the following combinations of features have particularly beneficial Kv7.2 EC values ​​in the following ranges: 50 These have been found to exhibit: (i) EC 50 or (ii) EC<3 μM and selectivity>10-fold 50 <1 μM and selectivity >30-fold.

[0251] The compounds of the invention, particularly those having a human hepatic microsomal clearance rate of less than 20 μl / min / mg, have been found to exhibit beneficial metabolic stability.

[0252] In some embodiments of the present invention, the compound of formula (I) has a structure as shown in any of formulas (II), (III), (IV), (V), (VI), and (VII), etc., described herein.

[0253] In some embodiments, the present invention provides a compound of formula (III): [ka] (In the formula, R 1 , R 2 , R 3 , and R 4 is as described herein), or A solvate or a pharma- ceutically acceptable salt thereof is provided. In some preferred embodiments, the present invention provides a compound of formula (III): [ka] (In the formula, R 1 is halogen, cyano, haloC 1~6 Alkoxy, Cyano C 1~6 Alkoxy and haloC 1~6 alkyl; R 2 H, D, C 1~6 Alkyl and hydroxy C 1~6 alkyl; R 3 is selected from H and D; R 4 H, halogens, and haloC 1~6 alkyl), or A solvate or a pharma- ceutically acceptable salt thereof is provided. In some embodiments, the present invention provides a compound of formula (IV): [ka] (In the formula, R 1 and R 4is as described herein), or A solvate or a pharma- ceutically acceptable salt thereof is provided. In some embodiments, the present invention provides a compound of formula (IV): [ka] (In the formula, R 1 is halogen, cyano, haloC 1~6 Alkoxy, Cyano C 1~6 Alkoxy and haloC 1~6 alkyl; R 4 H, halogens, and haloC 1~6 alkyl), or A solvate or a pharma- ceutically acceptable salt thereof is provided. In some particularly preferred embodiments, the present invention provides a compound of formula (V): [ka] (In the formula, R 1 and R 4 is as described herein), or A solvate or a pharma- ceutically acceptable salt thereof is provided. In some particularly preferred embodiments, the present invention provides a compound of formula (V): [ka] (In the formula, R 1 is halogen, cyano, haloC 1~6 Alkoxy, Cyano C 1~6 Alkoxy and haloC 1~6 alkyl; R 4 H, halogens, and haloC 1~6 alkyl), or A solvate or a pharma- ceutically acceptable salt thereof is provided. In some particularly preferred embodiments, the present invention provides a compound of formula (VI): [ka] (In the formula, R 1 and R 4 is as described herein), or A solvate or a pharma- ceutically acceptable salt thereof is provided. In some particularly preferred embodiments, the present invention provides a compound of formula (VI): [ka] (In the formula, R 1 is halogen, cyano, haloC 1~6 Alkoxy, Cyano C 1~6 Alkoxy and haloC 1~6 alkyl; R 4 H, halogens, and haloC 1~6 alkyl), or A solvate or a pharma- ceutically acceptable salt thereof is provided. In some particularly preferred embodiments, the present invention provides a compound of formula (VII): [ka] (In the formula, R 4 , R 6 , and R 7 is as described herein), or A solvate or a pharma- ceutically acceptable salt thereof is provided. In some particularly preferred embodiments, the present invention provides a compound of formula (VII): [ka] (In the formula, R 4 H, halogens, and haloC 1~6 alkyl, R 6 and R 7 is H or a halogen, or A solvate or a pharma- ceutically acceptable salt thereof is provided.

[0254] In some preferred embodiments, the compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof is selected from Table 2 (Kv7.2 EC 50 <3μM and; selectivity Kv7.5_7.3 / Kv7.2)>10-fold. [Table 2] TIFF2025506201000046.tif70170

[0255] Compounds of formula (I) having one or more of the following combinations of features have particularly beneficial Kv7.2 EC values ​​in the following ranges: 50 and / or Kv7.5_7.3 / Kv7.2 selectivity ratios: EC 50 <3μM, selectivity >10-fold, EC 50 <1 μM, selectivity >30-fold or EC 50 <1 μM, >30-fold selectivity, and favorable metabolic stability.

[0256] The measurement is carried out by determining whether the compound of formula (I) or a solvate or pharmaceutical salt thereof inhibits Kv7.2 EC 50 <3 μM and a selectivity ratio Kv7.5_7.3 / Kv7.2>10-fold were indicative of favorable pharmacological properties as described herein.

[0257] The measurements also showed that the compounds of formula (I) or solvates or pharmaceutical salts thereof have the favorable pharmacological properties described herein and are therefore preferred if they exhibit one or more of the following properties: a Kv7.5_7.3 / Kv7.2 selectivity ratio >10-fold; and / or A human hepatic microsomal clearance rate of <20 μl / min / mg, and / or Kv7.4 / Kv7.2 selectivity ratio >10-fold.

[0258] In some embodiments of the present invention, in the compounds of the present invention, one or more hydrogen atoms are replaced by deuterium.It has been found that deuteration of the compounds of the present invention provides the advantage of retaining the pharmacological profile of their hydrogen counterparts while positively affecting their metabolic results.Selective replacement of one or more hydrogen atoms in the compounds of the present invention with deuterium improves the pharmaceutical profile of the compounds of the present invention, for example, by reducing the amount of undesirable metabolites when compared with their all-hydrogen counterparts, and by reducing metabolic rate, thus increasing half-life.

[0259] Methods for incorporating deuterium into compounds are well established. Using metabolic studies established in the art, compounds of the present invention can be tested to identify sites for selective placement of deuterium isotopes that are not metabolized or are metabolized at a lower rate. Furthermore, these studies identify metabolic sites as positions where deuterium atoms are placed.

[0260] In some embodiments, the present invention provides a compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof, comprising the following reaction (Scheme 1): [ka]

[0261] In some embodiments, the present invention provides a compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof, comprising the following reaction (Scheme 2): [ka]

[0262] In some embodiments, the present invention provides a compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof, comprising the following reaction (Scheme 3): [ka]

[0263] In some particularly preferred embodiments, the present invention provides compounds of formula (I) or solvates or pharma- ceutically acceptable salts thereof, where urea formation may be achieved by treating the amine (or corresponding salt such as HCl) with an isocyanate (Scheme 1) in DCM or DMF at temperatures between RT and 40°C, or by reacting a first amine with 1,1'-carbonyldiimidazole' (Scheme 2) in a solvent (DCM, AcN, THF) and in the presence of a suitable base (DIPEA, NEt3) to generate an activated urea prior to addition of a second amine (or corresponding salt), or by reacting a first amine with para-nitrophenyl chloroformate (Scheme 3) or phenyl chloroformate in a solvent (AcN, THF) and in the presence of a base (DIPEA, NEt3) to generate a carbamate which can be purified or used in situ with a second amine to obtain the desired urea.

[0264] In some preferred embodiments, the present invention provides a compound of formula (I) or a solvate or pharma-ceutically acceptable salt thereof, wherein the preferred conditions are using CDI with DIPEA as base and DCM as solvent at 0°C for 45 minutes, followed by addition of a second amine and stirring at 40°C for 6-15 hours.

[0265] Pharmaceutical Compositions and Administration In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the invention described herein.

[0266] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the invention described herein and one or more pharma- ceutically acceptable excipients.

[0267] In one embodiment, the present invention provides a pharmaceutical composition further comprising one or more pharmaceutical excipients selected from diluents, fillers, bulking agents, binders, disintegrants, glidants, wetting agents, coatings, emulsifiers or dispersing agents, compression / encapsulation aids, creams or lotions, lubricants, solutions for parenteral administration, materials for chewable tablets, sweeteners or flavoring agents, suspending / gelling agents, and wet granulation agents.

[0268] In a particular embodiment, the present invention provides such pharmaceutical compositions that are particularly useful for the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2.

[0269] More particularly, the pharmaceutical compositions described herein are useful for the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 selected from behavioral disorders, mood disorders, neurodevelopmental disorders, intellectual disabilities, epilepsy, neurodegenerative diseases, pain, migraine, and tinnitus.

[0270] The compounds of the present invention can be used as medicines (e.g., in the form of pharmaceutical preparations). Pharmaceutical preparations can be administered to the body orally (e.g., in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g., in the form of nasal sprays), or rectally (e.g., in the form of suppositories). However, administration can also be carried out parenterally, such as intramuscularly or intravenously (e.g., in the form of injection solutions).

[0271] The compounds of the present invention can be processed with pharma- ceutically inert inorganic or organic adjuvants for the preparation of tablets, coated tablets, sugar-coated tablets, and hard gelatin capsules.Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc., can be used as adjuvants for tablets, sugar-coated tablets, or hard gelatin capsules, for example.

[0272] Suitable adjuvants for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semisolid substances, or liquid polyols etc.

[0273] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar or glucose etc.

[0274] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

[0275] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semisolid or liquid polyols etc.

[0276] In addition, the pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain further therapeutically valuable substances.

[0277] The dosage can vary within a wide range and is of course adapted to the individual requirements in each particular case. In general, for oral administration, a daily dosage of about 0.1 mg to 20 mg per kg of body weight, preferably about 0.5 mg to 4 mg per kg of body weight (for example, about 300 mg per person), is preferably divided into 1 to 3 individual doses, which, if appropriate, can be, for example, of the same amount. However, it is clear that the upper limit given in this specification can be exceeded, if this is indicated.

[0278] Provided herein is a pharmaceutical composition comprising the compound of the present invention.In some embodiments, the pharmaceutical composition comprises one or more pharma-ceutically acceptable excipients.The conventional procedure for selecting and preparing suitable pharmaceutical compositions is described, for example, in "Pharmaceuticals-The Science of Dosage Form Designs", MEAulton, Churchill Livingstone, 1988, the entirety of which is incorporated herein by reference.

[0279] Further provided is a process for preparing a pharmaceutical composition comprising combining one or more compounds of the invention.

[0280] Further provided is a method for preparing a pharmaceutical composition, comprising combining one or more compounds of the present invention with one or more pharma-ceutically acceptable excipients.The pharmaceutical composition can be prepared, for example, by conventional dissolving, mixing, granulating or coating methods, or combinations thereof. Such pharma- ceutically acceptable excipients may include, for example, sugars (e.g., lactose, glucose, sucrose), starches (e.g., corn starch, potato starch); cellulose and its derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose, cellulose acetate); powdered tragacanth; malt; gelatin; talc; cocoa butter and suppository wax; oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil); glycols (e.g., propylene glycol); polyethylene glycol (PEG); esters (e.g., ethyl oleate, ethyl laurate); agar; buffers (e.g., magnesium hydroxide, aluminum hydroxide); alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer; non-toxic compatible lubricants (e.g., sodium lauryl sulfate, magnesium stearate); colorants; release agents; coating agents; sweeteners; flavorings and fragrances. Preservatives and antioxidants can also be present in the pharmaceutical composition, according to the judgment of the formulator.

[0281] Depending on the intended method of administration, the disclosed pharmaceutical compositions can be in solid, semi-solid, or liquid dosage form, such as, for example, injectable solutions, tablets, suppositories, pills, sustained release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, and the like, and in some cases, unit dosage forms consistent with conventional pharmaceutical practice.

[0282] These methods may include systemic or local administration, such as oral, nasal, parenteral (by intravenous (both bolus and infusion), intramuscular, or subcutaneous injection), transdermal, vaginal, buccal, rectal, or topical (by powder, ointment, or drops) routes of administration. These methods may also include intracisternal, intraperitoneal, as an oral or nasal spray, or as a liquid aerosol or dry powder pharmaceutical composition for inhalation. In some embodiments, the pharmaceutical compositions provided herein include one or more of the disclosed compounds, tautomers thereof, and / or pharma- ceutically acceptable salts thereof, and are for oral administration. In other embodiments, the pharmaceutical compositions are for intravenous administration.

[0283] Solid dosage forms for oral administration may include capsules (e.g., soft and hard filled gelatin capsules), tablets, pills, powders and granules. In some embodiments, solid dosage forms may be prepared with one or more coatings and / or shells, such as release-controlling coatings, e.g., enteric coatings. Solid dosage forms may be formulated to release one or more disclosed compounds (or solvates, tautomers or pharma-ceutically acceptable salts thereof) solely, or primarily, or preferentially, in a certain portion of the digestive tract, optionally in a delayed manner. Solid dosage forms may also include, for example, microencapsulated forms.

[0284] Liquid dosage forms for oral administration may include, for example, pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. Such liquid compositions may include, for example, pharma- ceutically acceptable excipients, such as water or other solvents, solubilizers, emulsifiers, oils, polyethylene glycols, and fatty acid esters, adjuvants, sweeteners, flavorings, or aromatics, or any combination thereof. Pharmaceutical compositions for injection may include, for example, sterile injectable aqueous compositions (e.g., solutions, suspensions, or emulsions) or oily suspensions.

[0285] Injectable pharmaceutical compositions, in some embodiments, may include one or more solvents and / or diluents, such as water, Ringer's solution, USP and isotonic sodium chloride solution, sterile fixed oils, fatty acids, or any combination thereof. In some embodiments, injectable pharmaceutical compositions may be prepared as lyophilized powders, e.g., lyophilized powders that are mixed with a liquid diluent prior to injection.

[0286] In some embodiments, it may be desirable to prolong the effect of one or more of the compounds disclosed herein, or its pharmaceutically acceptable salt, from administration by subcutaneous or intramuscular injection.Such delay can be achieved, for example, by using a liquid suspension of crystalline or amorphous material with poor water solubility; or by dissolving or suspending the compound or its solvate, tautomer, or pharmaceutically acceptable salt in an oil vehicle; or via an injectable depot form that includes a microencapsule matrix that includes one or more biodegradable polymers.

[0287] Pharmaceutical compositions for rectal or vaginal administration may include suppositories which may be prepared using suitable non-irritating excipients such as cocoa butter, polyethylene glycol, or a suppository wax, or using fatty emulsions or suspensions.

[0288] Dosage forms for topical or transdermal administration may include, for example, ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. Ophthalmic pharmaceutical compositions and ear drops may also be prepared.

[0289] The pharmaceutical compositions provided herein may be packaged in unit-dose or multi-dose containers, for example sealed ampoules or vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid excipient for injection (e.g., a diluent, carrier, e.g., water) immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, or tablets of the kind described herein. Unit dosage formulations include those containing a daily dose or daily sub-dose, or an appropriate fraction thereof, of an active ingredient.

[0290] The subject matter further provides veterinary compositions comprising at least one active ingredient as defined herein together with a veterinary excipient or carrier for the active ingredient. The veterinary excipient or carrier is a substance useful for the purpose of administering the composition and may be a solid, liquid or gas substance that is otherwise inert or acceptable in the veterinary arts and compatible with the active ingredient.

[0291] These veterinary compositions may be administered parenterally, orally, or by any other desired route.

[0292] medical use The compounds of the present invention described herein or pharmaceutical compositions comprising the same may be useful as medicaments for the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need of such treatment.

[0293] In one embodiment, the present invention provides a method for therapeutic and / or prophylactic treatment of a disorder, disease, or disability associated with Kv7.2 in a subject in need thereof, comprising administering an effective amount of a compound of the present invention as described herein or a pharmaceutical composition thereof.

[0294] In one embodiment, the present invention provides a method for therapeutic and / or prophylactic treatment of a disorder, disease, or disability associated with Kv7.2 in a subject in need thereof, comprising administering an effective amount of a compound of the present invention as described herein or a pharmaceutical composition comprising the same, wherein the pharmaceutical composition further comprises one or more pharma- ceutically acceptable excipients.

[0295] In one embodiment, the present invention provides a method for the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, comprising administering to said subject a compound of formula (I): [ka] (In the formula, R 1 is halogen, cyano, haloC 1~6 Alkoxy, C 1~6 Alkoxy, C 1~6 Alkyl, C 2~8 Alkynyl, Cyano C 1~6 Alkoxy, HaloC 1~6 Alkyl-thiol, SF5, HaloC 2~6 Alkenyl, HaloC 1~6 and thiol, and 4-6 membered heterocycloalkyl, wherein the heterocycloalkyl is selected from halogen and haloC 1~6 optionally substituted with 1 or 2 substituents independently selected from alkyl; R 2 H, D, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; R 3 H, D, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; or R 2 and R 3 together with the carbon atom to which they are attached form a saturated monocyclic 3- to 6-membered cycloalkyl, which cycloalkyl is free of halogen and haloC 1~6 optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl; R 4 H, halogen, haloC 1~6 Alkyl, C 1~6 Alkoxy and C 1~6 alkyl; R 5 , H, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; or R 1 and R 5 together with the two C atoms to which they are attached form a 4-6 membered heterocycloalkyl ring system, the heterocycloalkyl being selected from halogen and haloC 1~6 optionally substituted with 1 or 2 substituents independently selected from alkyl; R 8 H, halogen, haloC 1~6 Alkyl and haloC 1~6 alkoxy) or The method includes the step of forming a compound comprising the compound of formula (I) or a soluble salt thereof.

[0296] In one embodiment, the present invention provides a method for therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, comprising a compound of the present invention as described herein, in particular a compound selected from formulas (I), (II), (III), (IV), (V), (VI), and (VII) or a solvate or pharma- ceutically acceptable salt thereof, any exemplified compound, any embodiment or combination of embodiments.

[0297] In one embodiment, the present invention provides a method for therapeutic and / or prophylactic treatment of a disorder, disease, or disability associated with Kv7.2 in a subject in need thereof, comprising a compound selected from any of the list of compounds described herein, or a solvate or pharmaceutically acceptable salt thereof.

[0298] In one embodiment, the present invention provides a method for therapeutic and / or prophylactic treatment of a Kv7.2 associated disorder, disease, or disability in a subject in need thereof comprising a compound selected from Tables 1 and 2, or a solvate or pharma- ceutically acceptable salt thereof.

[0299] In one embodiment, the present invention provides a method for therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, comprising a compound selected from formulas (I), (II), (III), (IV), (V), (VI), and (VII) or a solvate or pharma- ceutically acceptable salt thereof, wherein the disorder, disease or disability associated with Kv7.2 is selected from behavioral disorders, mood disorders, neurodevelopmental disorders, intellectual disabilities, epilepsy, neurodegenerative diseases, pain, migraine, and tinnitus.

[0300] In one embodiment, the present invention provides a method as described above for therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the behavioral disorder is attention deficit hyperactivity disorder (ADHD).

[0301] In one embodiment, the present invention provides a method for therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need of such treatment, wherein the mood disorder is depression.

[0302] In one embodiment, the present invention provides a method as described above for therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the neurodevelopmental disorder is selected from autism spectrum disorder (ASD) and syndromic developmental disorder.

[0303] In one embodiment, the present invention provides such a method for therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the syndromic developmental disorder is selected from Dup15q syndrome (Dup15q), Fragile X syndrome (FXS) and Angelman syndrome.

[0304] In one embodiment, the present invention provides the above-mentioned method for therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the epilepsy is selected from diffuse childhood epilepsy, West syndrome, Ohtahara syndrome, and epileptic encephalopathy.

[0305] In one embodiment, the present invention provides such a method for therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the neurodegenerative disease is selected from Alzheimer's disease and motor neuron disease.

[0306] In one embodiment, the present invention provides a method for therapeutic and / or prophylactic treatment of a Kv7.2-associated disorder, disease, or disability in a subject in need thereof, comprising administering an effective amount of a pharmaceutical composition described herein.

[0307] Further provided herein is a compound, solvate, pharma- ceutically acceptable salt or pharmaceutical composition thereof as described herein for use as a therapeutically active substance.

[0308] In one embodiment, the present invention provides, as a therapeutically active substance, a compound of formula (I): [ka] (In the formula, R 1 is halogen, cyano, haloC 1~6 Alkoxy, C 1~6 Alkoxy, C 1~6 Alkyl, C 2~8 Alkynyl, Cyano C 1~6 Alkoxy, HaloC 1~6 Alkyl-thiol, SF5, HaloC 2~6 Alkenyl, HaloC 1~6 and thiol, and 4-6 membered heterocycloalkyl, wherein the heterocycloalkyl is selected from halogen and haloC 1~6 optionally substituted with 1 or 2 substituents independently selected from alkyl; R 2 H, D, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; R 3 H, D, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; or R 2 and R 3 together with the carbon atom to which they are attached form a saturated monocyclic 3- to 6-membered cycloalkyl, which cycloalkyl is free of halogen and haloC 1~6 optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl; R 4 H, halogen, haloC 1~6 Alkyl, C 1~6 Alkoxy and C 1~6 alkyl; R 5 , H, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; or R 1 and R 5together with the two C atoms to which they are attached form a 4-6 membered heterocycloalkyl ring system, the heterocycloalkyl being halogen or haloC 1~6 optionally substituted with 1 or 2 substituents independently selected from alkyl; R 8 H, halogen, haloC 1~6 Alkyl and haloC 1~6 alkoxy), or The use of a solvate or a pharma- ceutically acceptable salt thereof is provided.

[0309] In one embodiment, the present invention provides the use of a compound of the invention as described herein, in particular a compound selected from formulas (I), (II), (III), (IV), (V), (VI), and (VII) or a solvate or pharma- ceutically acceptable salt thereof, any exemplified compound, any embodiment, or combination of embodiments, as a therapeutically active substance.

[0310] In one embodiment, the present invention provides the use of a compound selected from Tables 1 and 2, or a solvate or pharma- ceutically acceptable salt thereof, as a therapeutically active substance.

[0311] In one embodiment, the present invention provides the use of a compound selected from any of the list of compounds described herein, or a solvate or pharma- ceutically acceptable salt thereof, as a therapeutically active substance.

[0312] Further provided herein is a compound, solvate, pharma- ceutically acceptable salt or pharmaceutical composition thereof for use in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof.

[0313] In one embodiment, the present invention provides a compound of formula (I) for use in the therapeutic and / or prophylactic treatment of a Kv7.2 associated disorder, disease or disability in a subject in need thereof: [ka] (In the formula, R 1 is halogen, cyano, haloC 1~6 Alkoxy, C 1~6 Alkoxy, C 1~6 Alkyl, C 2~8 Alkynyl, Cyano C 1~6 Alkoxy, HaloC 1~6 Alkyl-thiol, SF5, HaloC 2~6 Alkenyl, HaloC 1~6 and thiol, and 4-6 membered heterocycloalkyl, wherein the heterocycloalkyl is selected from halogen and haloC 1~6 optionally substituted with 1 or 2 substituents independently selected from alkyl; R 2 H, D, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; R 3 H, D, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; or R 2 and R 3 together with the carbon atom to which they are attached form a saturated monocyclic 3- to 6-membered cycloalkyl, which cycloalkyl is free of halogen and haloC 1~6 optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl; R 4 H, halogen, haloC 1~6 Alkyl, C 1~6 Alkoxy and C 1~6 alkyl; R5 , H, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; or R 1 and R 5 together with the two C atoms to which they are attached form a 4-6 membered heterocycloalkyl ring system, the heterocycloalkyl being halogen or haloC 1~6 optionally substituted with 1 or 2 substituents independently selected from alkyl; R 8 H, halogen, haloC 1~6 Alkyl and haloC 1~6 alkoxy), or A solvate or a pharma- ceutically acceptable salt thereof is provided.

[0314] In one embodiment, the present invention provides a compound of the invention as described herein, in particular a compound selected from formulas (I), (II), (III), (IV), (V), (VI), and (VII) or a solvate or pharma- ceutically acceptable salt thereof, any exemplified compound, any embodiment, or combination of embodiments, for use in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof.

[0315] In one embodiment, the present invention provides a compound selected from Tables 1 and 2, or a solvate or pharma- ceutically acceptable salt thereof, for use in the therapeutic and / or prophylactic treatment of a disorder, disease, or disability associated with Kv7.2 in a subject in need thereof.

[0316] In one embodiment, the present invention provides a compound selected from any of the list of compounds of the present invention for use in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof.

[0317] In one embodiment, the present invention provides a compound of the present invention for use in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein such disorder, disease or disability is selected from behavioral disorders, mood disorders, neurodevelopmental disorders, intellectual disabilities, epilepsy, neurodegenerative diseases, pain, migraine, and tinnitus.

[0318] In one embodiment, the present invention provides a compound of the present invention for use in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the behavioral disorder is attention deficit hyperactivity disorder (ADHD).

[0319] In one embodiment, the present invention provides a compound of the present invention for use in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need of such treatment, wherein the mood disorder is depression.

[0320] In one embodiment, the present invention provides a compound of the present invention for use in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the neurodevelopmental disorder is selected from autism spectrum disorder (ASD) and syndromic developmental disorder.

[0321] In one embodiment, the present invention provides a compound of the invention for use in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the syndromic developmental disorder is selected from Dup15q syndrome (Dup15q), Fragile X syndrome (FXS) and Angelman syndrome.

[0322] In one embodiment, the present invention provides a compound of the present invention for use in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the epilepsy is selected from generalized childhood epilepsy, West syndrome, Ohtahara syndrome, and epileptic encephalopathy.

[0323] In one embodiment, the present invention provides a compound of the present invention for use in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the neurodegenerative disease is selected from Alzheimer's disease and motor neuron disease.

[0324] Further provided herein is the use of the compounds of the present invention in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need of such treatment.

[0325] In one embodiment, the present invention provides a compound of formula (I) for the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof: [ka] (In the formula, R 1 is halogen, cyano, haloC1~6 Alkoxy, C 1~6 Alkoxy, C 1~6 Alkyl, C 2~8 Alkynyl, Cyano C 1~6 Alkoxy, HaloC 1~6 Alkyl-thiol, SF5, HaloC 2~6 Alkenyl, HaloC 1~6 and thiol, and 4-6 membered heterocycloalkyl, wherein the heterocycloalkyl is selected from halogen and haloC 1~6 optionally substituted with 1 or 2 substituents independently selected from alkyl; R 2 H, D, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; R 3 H, D, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; or R 2 and R 3 together with the carbon atom to which they are attached form a saturated monocyclic 3- to 6-membered cycloalkyl, which cycloalkyl is free of halogen and haloC 1~6 optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl; R 4 H, halogen, haloC 1~6 Alkyl, C 1~6 Alkoxy and C 1~6 alkyl; R 5 , H, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; or R 1 and R 5 together with the two C atoms to which they are attached form a 4-6 membered heterocycloalkyl ring system, the heterocycloalkyl being halogen or haloC 1~6optionally substituted with 1 or 2 substituents independently selected from alkyl; R 8 H, halogen, haloC 1~6 Alkyl and haloC 1~6 alkoxy), or The use of a solvate or a pharma- ceutically acceptable salt thereof is provided.

[0326] In one embodiment, the present invention provides the use of a compound of the present invention as described herein, in particular a compound selected from formulas (I), (II), (III), (IV), (V), (VI), and (VII) or a solvate or pharma- ceutically acceptable salt thereof, any exemplified compound, any embodiment or combination of embodiments, for the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need of such treatment.

[0327] In one embodiment, the present invention provides the use of a compound selected from Tables 1 and 2, or a solvate or pharma- ceutically acceptable salt thereof, for the therapeutic and / or prophylactic treatment of a disorder, disease, or disability associated with Kv7.2 in a subject in need thereof.

[0328] In one embodiment, the present invention provides the use of a compound selected from any list of compounds described herein, or a solvate or pharma- ceutically acceptable salt thereof, for the therapeutic and / or prophylactic treatment of a disorder, disease, or disability associated with Kv7.2 in a subject in need of such treatment.

[0329] In one embodiment, the present invention provides the use of a compound of the present invention in the therapeutic and / or prophylactic treatment of a Kv7.2 associated disorder, disease or disability in a subject in need thereof, wherein the Kv7.2 associated disorder, disease or disability is selected from behavioral disorders, mood disorders, neurodevelopmental disorders, intellectual disabilities, epilepsy, neurodegenerative diseases, pain, migraine, and tinnitus.

[0330] In one embodiment, the present invention provides the use of a compound of the present invention in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the behavioral disorder is attention deficit hyperactivity disorder (ADHD).

[0331] In one embodiment, the present invention provides the use of a compound of the present invention in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need of such treatment, wherein the mood disorder is depression.

[0332] In one embodiment, the present invention provides the use of a compound of the present invention in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the neurodevelopmental disorder is selected from autism spectrum disorder (ASD) and syndromic developmental disorder.

[0333] In one embodiment, the present invention provides the use of a compound of the present invention in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the syndromic developmental disorder is selected from Dup15q syndrome (Dup15q), Fragile X syndrome (FXS) and Angelman syndrome.

[0334] In one embodiment, the present invention provides the use of a compound of the present invention in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the epilepsy is selected from generalized childhood epilepsy, West syndrome, Ohtahara syndrome, and epileptic encephalopathy.

[0335] In one embodiment, the present invention provides the use of a compound of the present invention in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the neurodegenerative disease is selected from Alzheimer's disease and motor neuron disease.

[0336] Further provided herein is the use of a compound of the present invention or a pharmaceutical composition comprising the same for the manufacture of a medicament for the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof.

[0337] In one embodiment, the present invention provides a compound of formula (I) for the manufacture of a medicament for use in the therapeutic and / or prophylactic treatment of a Kv7.2 associated disorder, disease or disability in a subject in need thereof: [ka] (In the formula, R 1 is halogen, cyano, haloC 1~6 Alkoxy, C 1~6 Alkoxy, C 1~6 Alkyl, C 2~8 Alkynyl, Cyano C 1~6 Alkoxy, HaloC 1~6 Alkyl-thiol, SF5, HaloC 2~6 Alkenyl, HaloC 1~6and thiol, and 4-6 membered heterocycloalkyl, wherein the heterocycloalkyl is selected from halogen and haloC 1~6 optionally substituted with 1 or 2 substituents independently selected from alkyl; R 2 H, D, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; R 3 H, D, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; or R 2 and R 3 together with the carbon atom to which they are attached form a saturated monocyclic 3- to 6-membered cycloalkyl, which cycloalkyl is free of halogen and haloC 1~6 optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl; R 4 H, halogen, haloC 1~6 Alkyl, C 1~6 Alkoxy and C 1~6 alkyl; R 5 , H, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; or R 1 and R 5 together with the two C atoms to which they are attached form a 4-6 membered heterocycloalkyl ring system, the heterocycloalkyl being halogen or haloC 1~6 optionally substituted with 1 or 2 substituents independently selected from alkyl; R 8 H, halogen, haloC 1~6 Alkyl and haloC 1~6 alkoxy), or The use of a solvate or a pharma- ceutically acceptable salt thereof is provided.

[0338] In one embodiment, the invention provides the use of a compound of the invention as described herein, in particular a compound selected from formulas (I), (II), (III), (IV), (V), (VI), and (VII) or a solvate or pharma- ceutically acceptable salt thereof, any exemplified compound, any embodiment or combination of embodiments, for the manufacture of a medicament for use in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof.

[0339] In one embodiment, the present invention provides the use of a compound selected from Tables 1 and 2, or a solvate or pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for use in the therapeutic and / or prophylactic treatment of a Kv7.2-associated disorder, disease, or disability in a subject in need thereof.

[0340] In one embodiment, the present invention provides the use of a compound selected from any list of compounds described herein, or a solvate or pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for use in the therapeutic and / or prophylactic treatment of a disorder, disease, or disability associated with Kv7.2 in a subject in need thereof.

[0341] In one embodiment, the present invention provides the use of a compound of the present invention for the manufacture of a medicament for use in the therapeutic and / or prophylactic treatment of a Kv7.2 associated disorder, disease or disability in a subject in need thereof, wherein the Kv7.2 associated disorder, disease or disability is selected from behavioral disorders, mood disorders, neurodevelopmental disorders, intellectual disabilities, epilepsy, neurodegenerative diseases, pain, migraine, and tinnitus.

[0342] In one embodiment, the present invention provides the use of a compound of the present invention for the manufacture of a medicament for use in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the behavioral disorder is attention deficit hyperactivity disorder (ADHD).

[0343] In one embodiment, the present invention provides the use of a compound of the present invention for the manufacture of a medicament for use in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the mood disorder is depression.

[0344] In one embodiment, the invention provides the use of a compound of the invention for the manufacture of a medicament for use in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the neurodevelopmental disorder is selected from autism spectrum disorder (ASD) and syndromic developmental disorder.

[0345] In one embodiment, the invention provides the use of a compound of the invention for the manufacture of a medicament for use in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the syndromic developmental disorder is selected from Dup15q syndrome (Dup15q), Fragile X syndrome (FXS) and Angelman syndrome.

[0346] In one embodiment, the present invention provides the use of a compound of the present invention for the manufacture of a medicament for use in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the epilepsy is selected from generalized childhood epilepsy, West syndrome, Ohtahara syndrome, and epileptic encephalopathy.

[0347] In one embodiment, the present invention provides the use of a compound of the present invention for the manufacture of a medicament for use in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the neurodegenerative disease is selected from Alzheimer's disease and motor neuron disease.

[0348] Further provided is a pharmaceutical composition comprising a compound described herein, or a solvate or pharma- ceutically acceptable salt thereof.

[0349] Further provided is a pharmaceutical composition comprising a compound described herein, or a solvate or pharma- ceutically acceptable salt thereof, further comprising one or more pharma- ceutically acceptable excipients.

[0350] In one particularly preferred embodiment, the present invention provides a compound of formula (I): [ka] (In the formula, R 1 is halogen, cyano, haloC 1~6 Alkoxy, C 1~6 Alkoxy, C 1~6 Alkyl, C 2~8 Alkynyl, Cyano C 1~6 Alkoxy, HaloC 1~6 Alkyl-thiol, SF5, HaloC 2~6 Alkenyl, HaloC 1~6 and thiol, and 4-6 membered heterocycloalkyl, wherein the heterocycloalkyl is selected from halogen and haloC 1~6 optionally substituted with 1 or 2 substituents independently selected from alkyl; R 2 H, D, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; R3 H, D, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; or R 2 and R 3 together with the carbon atom to which they are attached form a saturated monocyclic 3- to 6-membered cycloalkyl, which cycloalkyl is free of halogen and haloC 1~6 optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl; R 4 H, halogen, haloC 1~6 Alkyl, C 1~6 Alkoxy and C 1~6 alkyl; R 5 , H, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; or R 1 and R 5 together with the two C atoms to which they are attached form a 4-6 membered heterocycloalkyl ring system, the heterocycloalkyl being halogen or haloC 1~6 optionally substituted with 1 or 2 substituents independently selected from alkyl; R 8 H, halogen, haloC 1~6 Alkyl and haloC 1~6 alkoxy) or A pharmaceutical composition comprising a solvate or a pharma- ceutically acceptable salt thereof is provided.

[0351] In one particularly preferred embodiment, the present invention provides a compound of formula (I): [ka] (In the formula, R 1 is halogen, cyano, haloC 1~6 Alkoxy, C 1~6 Alkoxy, C1~6 Alkyl, C 2~8 Alkynyl, Cyano C 1~6 Alkoxy, HaloC 1~6 Alkyl-thiol, SF5, HaloC 2~6 Alkenyl, HaloC 1~6 and thiol, and 4-6 membered heterocycloalkyl, wherein the heterocycloalkyl is selected from halogen and haloC 1~6 optionally substituted with 1 or 2 substituents independently selected from alkyl; R 2 H, D, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; R 3 H, D, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; or R 2 and R 3 together with the carbon atom to which they are attached form a saturated monocyclic 3- to 6-membered cycloalkyl, which cycloalkyl is free of halogen and haloC 1~6 optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl; R 4 H, halogen, haloC 1~6 Alkyl, C 1~6 Alkoxy and C 1~6 alkyl; R 5 , H, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; or R 1 and R 5 together with the two C atoms to which they are attached form a 4-6 membered heterocycloalkyl ring system, the heterocycloalkyl being halogen or haloC 1~6 optionally substituted with 1 or 2 substituents independently selected from alkyl; R 8H, halogen, haloC 1~6 Alkyl and haloC 1~6 alkoxy), or A pharmaceutical composition comprising a solvate or a pharma- ceutically acceptable salt thereof, Pharmaceutical compositions are provided which further comprise one or more pharma- ceutically acceptable excipients.

[0352] In one particularly preferred embodiment, the present invention provides a compound of formula (II): [ka] (In the formula, R 1 is halogen, cyano, haloC 1~6 Alkoxy and cyano C 1~6 alkoxy; R 2 H, D, and hydroxy C 1~6 alkyl; R 3 H, D, and hydroxy C 1~6 alkyl; R 4 H, halogens, and haloC 1~6 alkyl; R 5 is H; or R 1 and R 5 together with the two C atoms to which they are attached form a 4-6 membered heterocycloalkyl ring system, the heterocycloalkyl being halogen or haloC 1~6 optionally substituted with 1 or 2 substituents independently selected from alkyl, A pharmaceutical composition comprising a solvate or a pharma- ceutically acceptable salt thereof is provided.

[0353] In one particularly preferred embodiment, the present invention provides a compound of formula (II): [ka] (In the formula, R 1 is halogen, cyano, haloC 1~6 Alkoxy and cyano C 1~6 alkoxy; R 2 H, D, and hydroxy C 1~6 alkyl; R 3 H, D, and hydroxy C 1~6 alkyl; R 4 H, halogens, and haloC 1~6 alkyl; R 5 is H; or R 1 and R 5 together with the two C atoms to which they are attached form a 4-6 membered heterocycloalkyl ring system, the heterocycloalkyl being halogen or haloC 1~6 optionally substituted with 1 or 2 substituents independently selected from alkyl, A pharmaceutical composition comprising a solvate or a pharma- ceutically acceptable salt thereof is provided.

[0354] Pharmaceutical compositions are provided which further comprise one or more pharma- ceutically acceptable excipients.

[0355] In one particularly preferred embodiment, the present invention provides a pharmaceutical composition comprising a compound of the invention as described herein, in particular a compound selected from formulas (I), (II), (III), (IV), (V), (VI), and (VII) or a solvate or pharma- ceutically acceptable salt thereof, for use in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof.

[0356] In one particularly preferred embodiment, the present invention provides a pharmaceutical composition comprising a compound selected from formulas (I), (II), (III), (IV), (V), (VI), and (VII) as described herein or a solvate or pharma- ceutically acceptable salt thereof, for use in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the disorder, disease or disability is selected from a behavioral disorder, a mood disorder, a neurodevelopmental disorder, an intellectual disability, epilepsy, a neurodegenerative disease, pain, migraine, and tinnitus.

[0357] In one particularly preferred embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention for use in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the behavioral disorder is attention deficit hyperactivity disorder (ADHD).

[0358] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention for use in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the mood disorder is depression.

[0359] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention for use in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the neurodevelopmental disorder is selected from autism spectrum disorder (ASD) and syndromic developmental disorder.

[0360] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention for use in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the syndromic developmental disorder is selected from Dup15q syndrome (Dup15q), Fragile X syndrome (FXS) and Angelman syndrome.

[0361] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention for use in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the epilepsy is selected from generalized childhood epilepsy, West syndrome, Ohtahara syndrome, and epileptic encephalopathy.

[0362] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention for use in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the neurodegenerative disease is selected from Alzheimer's disease and motor neuron disease.

[0363] In one embodiment, the present invention provides a pharmaceutical composition as described above comprising a compound selected from formula (I), (II), (III), (IV), (V), (VI), and (VII) or a solvate or pharma- ceutically acceptable salt thereof, any exemplified compound, any embodiment, or combination of embodiments, as described herein.

[0364] In one embodiment, the present invention provides a pharmaceutical composition as described above comprising a compound selected from Tables 1 and 2, or a solvate or pharma- ceutically acceptable salt thereof.

[0365] In one embodiment, the present invention provides a pharmaceutical composition as described above comprising a compound selected from any of the list of compounds described herein, or a solvate or pharma- ceutically acceptable salt thereof.

[0366] There is further provided a pharmaceutical composition comprising a compound of the invention for use in a method for therapeutic and / or prophylactic treatment of a Kv7.2-associated disorder, disease or disability in a subject in need thereof.

[0367] There is further provided a pharmaceutical composition comprising a compound of the invention and one or more pharma- ceutically acceptable excipients for use in a method for therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof.

[0368] In one embodiment, the present invention provides a compound of formula (I): [ka] (In the formula, R 1 is halogen, cyano, haloC 1~6 Alkoxy, C 1~6 Alkoxy, C 1~6 Alkyl, C 2~8 Alkynyl, Cyano C 1~6 Alkoxy, HaloC 1~6 Alkyl-thiol, SF5, HaloC 2~6 Alkenyl, HaloC 1~6 and thiol, and 4-6 membered heterocycloalkyl, wherein the heterocycloalkyl is selected from halogen or haloC 1~6 optionally substituted with 1 or 2 substituents independently selected from alkyl; R 2 H, D, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; R3 H, D, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; or R 2 and R 3 together with the carbon atom to which they are attached form a saturated monocyclic 3- to 6-membered cycloalkyl, which cycloalkyl is free of halogen and haloC 1~6 optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl; R 4 H, halogen, haloC 1~6 Alkyl, C 1~6 Alkoxy and C 1~6 alkyl; R 5 , H, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; or R 1 and R 5 together with the two C atoms to which they are attached form a 4-6 membered heterocycloalkyl ring system, the heterocycloalkyl being halogen or haloC 1~6 optionally substituted with 1 or 2 substituents independently selected from alkyl; R 8 H, halogen, haloC 1~6 Alkyl and haloC 1~6 alkoxy), or Pharmaceutical compositions for use in the methods of treatment, including solvates or pharma- ceutically acceptable salts thereof, are provided.

[0369] In one embodiment, the present invention provides a compound of formula (I): [ka] (In the formula, R 1 is halogen, cyano, haloC 1~6 Alkoxy, C 1~6Alkoxy, C 1~6 Alkyl, C 2~8 Alkynyl, Cyano C 1~6 Alkoxy, HaloC 1~6 Alkyl-thiol, SF5, HaloC 2~6 Alkenyl, HaloC 1~6 and thiol, and 4-6 membered heterocycloalkyl, wherein the heterocycloalkyl is selected from halogen or haloC 1~6 optionally substituted with 1 or 2 substituents independently selected from alkyl; R 2 H, D, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; R 3 H, D, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; or R 2 and R 3 together with the carbon atom to which they are attached form a saturated monocyclic 3- to 6-membered cycloalkyl, which cycloalkyl is free of halogen and haloC 1~6 optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl; R 4 H, halogen, haloC 1~6 Alkyl, C 1~6 Alkoxy and C 1~6 alkyl; R 5 , H, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; or R 1 and R 5 together with the two C atoms to which they are attached form a 4-6 membered heterocycloalkyl ring system, the heterocycloalkyl being selected from halogen and haloC 1~6 optionally substituted with 1 or 2 substituents independently selected from alkyl; R8 H, halogen, haloC 1~6 Alkyl and haloC 1~6 alkoxy), or 1. A pharmaceutical composition for use in a method of treatment comprising a solvate or pharma- ceutically acceptable salt thereof, comprising: Pharmaceutical compositions are provided which further comprise one or more pharma- ceutically acceptable excipients.

[0370] In one embodiment, the present invention provides a compound of formula (II): [ka] (In the formula, R 1 is halogen, cyano, haloC 1~6 Alkoxy and cyano C 1~6 alkoxy; R 2 H, D, and hydroxy C 1~6 alkyl; R 3 H, D, and hydroxy C 1~6 alkyl; R 4 H, halogens, and haloC 1~6 alkyl; R 5 is H; or R 1 and R 5 together with the two C atoms to which they are attached form a 4-6 membered heterocycloalkyl ring system, the heterocycloalkyl being selected from halogen and haloC 1~6 optionally substituted with 1 or 2 substituents independently selected from alkyl, Pharmaceutical compositions for use in the methods of treatment, including solvates or pharma- ceutically acceptable salts thereof, are provided.

[0371] In one embodiment, the present invention provides a compound of formula (II): [ka] (In the formula, R 1 is halogen, cyano, haloC 1~6 Alkoxy and cyano C 1~6 alkoxy; R 2 H, D, and hydroxy C 1~6 alkyl; R 3 H, D, and hydroxy C 1~6 alkyl; R 4 H, halogens, and haloC 1~6 alkyl; R 5 is H; or R 1 and R 5 together with the two C atoms to which they are attached form a 4-6 membered heterocycloalkyl ring system, the heterocycloalkyl being selected from halogen and haloC 1~6 optionally substituted with 1 or 2 substituents independently selected from alkyl, 1. A pharmaceutical composition for use in a method of treatment comprising a solvate or pharma- ceutically acceptable salt thereof, comprising: Pharmaceutical compositions are provided which further comprise one or more pharma- ceutically acceptable excipients.

[0372] In one embodiment, the present invention provides a pharmaceutical composition for use in a method of treatment comprising a compound of the present invention for therapeutic and / or prophylactic treatment of a Kv7.2 associated disorder, disease or disability in a subject in need thereof.

[0373] In one embodiment, the present invention provides a pharmaceutical composition for use in a method of treatment comprising a compound of the present invention for therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the disorder, disease or disability is selected from behavioral disorders, mood disorders, neurodevelopmental disorders, intellectual disabilities, epilepsy, neurodegenerative disorders, pain, migraine, and tinnitus.

[0374] In one embodiment, the present invention provides a pharmaceutical composition for use in a method of treatment comprising a compound of the present invention for therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the behavioral disorder is attention deficit hyperactivity disorder (ADHD).

[0375] In one embodiment, the present invention provides a pharmaceutical composition for use in a method of treatment comprising a compound of the present invention for therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need of such treatment, wherein the mood disorder is depression.

[0376] In one embodiment, the present invention provides a pharmaceutical composition for use in a method of treatment comprising a compound of the present invention for therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the neurodevelopmental disorder is selected from autism spectrum disorder (ASD) and syndromic developmental disorder.

[0377] In one embodiment, the present invention provides a pharmaceutical composition for use in a method of treatment comprising a compound of the present invention for therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the syndromic developmental disorder is selected from Dup15q syndrome (Dup15q), Fragile X syndrome (FXS) and Angelman syndrome.

[0378] In one embodiment, the present invention provides a pharmaceutical composition for use in a method of treatment comprising a compound of the present invention for therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the epilepsy is selected from generalized childhood epilepsy, West syndrome, Ohtahara syndrome, and epileptic encephalopathy.

[0379] In one embodiment, the present invention provides a pharmaceutical composition for use in a method of treatment comprising a compound of the present invention for therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the neurodegenerative disease is selected from Alzheimer's disease and motor neuron disease.

[0380] In one embodiment, the present invention provides a pharmaceutical composition as described above comprising a compound selected from any of formulas (I), (II), (III), (IV), (V), (VI), and (VII) or a solvate or pharma- ceutically acceptable salt thereof, any exemplified compound, any embodiment, or combination of embodiments, as described herein.

[0381] In one embodiment, the present invention provides a pharmaceutical composition as described above comprising a compound selected from Tables 1 and 2, or a solvate or pharma- ceutically acceptable salt thereof.

[0382] In one embodiment, the present invention provides a pharmaceutical composition as described above comprising a compound selected from any of the list of compounds described herein, or a solvate or pharma- ceutically acceptable salt thereof.

[0383] Further provided is a pharmaceutical composition comprising a compound as described herein, or a solvate or pharma- ceutically acceptable salt thereof, for use in the manufacture of a medicament for the therapeutic and / or prophylactic treatment of a Kv7.2-associated disorder, disease or disability in a subject in need thereof.

[0384] There is further provided a pharmaceutical composition comprising a compound as described herein, or a solvate or pharma- ceutical acceptable salt thereof, for use in the manufacture of a medicament for the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, the pharmaceutical composition further comprising one or more pharma- ceutical acceptable excipients.

[0385] In one embodiment, the present invention provides a pharmaceutical composition for use in the manufacture of a medicament for the therapeutic and / or prophylactic treatment of a disorder, disease, or disability associated with Kv7.2 in a subject in need thereof, comprising a compound of formula (I): [ka] (In the formula, R 1 is halogen, cyano, haloC 1~6 Alkoxy, C 1~6 Alkoxy, C 1~6 Alkyl, C 2~8 Alkynyl, Cyano C 1~6 Alkoxy, HaloC 1~6 Alkyl-thiol, SF5, HaloC 2~6 Alkenyl, HaloC 1~6thiol, and 4- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is selected from one or two halogen or haloC 1~6 optionally substituted with alkyl; R 2 H, D, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; R 3 H, D, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; or R 2 and R 3 together with the carbon atom to which they are attached form a saturated monocyclic 3- to 6-membered cycloalkyl, which cycloalkyl is free of halogen and haloC 1~6 optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl; R 4 H, halogen, haloC 1~6 Alkyl, C 1~6 Alkoxy and C 1~6 alkyl; R 5 , H, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; or R 1 and R 5 together with the two C atoms to which they are attached form a 4-6 membered heterocycloalkyl ring system, the heterocycloalkyl being selected from halogen and haloC 1~6 optionally substituted with 1 or 2 substituents independently selected from alkyl; R 8 H, halogen, haloC 1~6 Alkyl and haloC 1~6 alkoxy), or A pharmaceutical composition comprising a solvate or a pharma- ceutically acceptable salt thereof is provided.

[0386] In one embodiment, the present invention provides a pharmaceutical composition for use in the manufacture of a medicament for the therapeutic and / or prophylactic treatment of a disorder, disease, or disability associated with Kv7.2 in a subject in need thereof, comprising a compound of formula (I): [ka] (In the formula, R 1 is halogen, cyano, haloC 1~6 Alkoxy, C 1~6 Alkoxy, C 1~6 Alkyl, C 2~8 Alkynyl, Cyano C 1~6 Alkoxy, HaloC 1~6 Alkyl-thiol, SF5, HaloC 2~6 Alkenyl, HaloC 1~6 and thiol, and 4-6 membered heterocycloalkyl, wherein the heterocycloalkyl is selected from halogen and haloC 1~6 optionally substituted with 1 or 2 substituents independently selected from alkyl; R 2 H, D, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; R 3 H, D, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; or R 2 and R 3 together with the carbon atom to which they are attached form a saturated monocyclic 3- to 6-membered cycloalkyl, which cycloalkyl is free of halogen and haloC 1~6 optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl; R 4 H, halogen, haloC 1~6 Alkyl, C 1~6 Alkoxy and C1~6 alkyl; R 5 , H, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; or R 1 and R 5 together with the two C atoms to which they are attached form a 4-6 membered heterocycloalkyl ring system, the heterocycloalkyl being selected from halogen and haloC 1~6 optionally substituted with 1 or 2 substituents independently selected from alkyl; R 8 H, halogen, haloC 1~6 Alkyl and haloC 1~6 alkoxy), or including solvates or pharma- ceutically acceptable salts thereof, Pharmaceutical compositions are provided which further comprise one or more pharma- ceutically acceptable excipients.

[0387] In one embodiment, the present invention provides a pharmaceutical composition for use in the manufacture of a medicament for the therapeutic and / or prophylactic treatment of a Kv7.2 associated disorder, disease or disability in a subject in need thereof, comprising a compound of formula (II): [ka] (In the formula, R 1 is halogen, cyano, haloC 1~6 Alkoxy and cyano C 1~6 alkoxy; R 2 H, D, and hydroxy C 1~6 alkyl; R 3 H, D, and hydroxy C 1~6 alkyl; R 4 H, halogens, and haloC 1~6alkyl; R 5 is H; or R 1 and R 5 together with the two C atoms to which they are attached form a 4-6 membered heterocycloalkyl ring system, the heterocycloalkyl being selected from halogen and haloC 1~6 optionally substituted with 1 or 2 substituents independently selected from alkyl, A pharmaceutical composition comprising a solvate or a pharma- ceutically acceptable salt thereof is provided.

[0388] In one embodiment, the present invention provides a pharmaceutical composition for use in the manufacture of a medicament for the therapeutic and / or prophylactic treatment of a Kv7.2 associated disorder, disease or disability in a subject in need thereof, comprising a compound of formula (II): [ka] (In the formula, R 1 is halogen, cyano, haloC 1~6 Alkoxy and cyano C 1~6 alkoxy; R 2 H, D, and hydroxy C 1~6 alkyl; R 3 H, D, and hydroxy C 1~6 alkyl; R 4 H, halogens, and haloC 1~6 alkyl; R 5 is H; or R 1 and R 5 together with the two C atoms to which they are attached form a 4-6 membered heterocycloalkyl ring system, the heterocycloalkyl being selected from halogen and haloC 1~6optionally substituted with 1 or 2 substituents independently selected from alkyl, including solvates or pharma- ceutically acceptable salts thereof, Pharmaceutical compositions are provided which further comprise one or more pharma- ceutically acceptable excipients.

[0389] In one embodiment, the present invention provides a pharmaceutical composition for use in the therapeutic and / or prophylactic treatment of a Kv7.2 associated disorder, disease or disability in a subject in need thereof, for use in the manufacture of a medicament for the therapeutic and / or prophylactic treatment of a Kv7.2 associated disorder, disease or disability in a subject in need thereof, the pharmaceutical composition comprising a compound of formula (I) as described herein or a solvate or pharma- ceutical acceptable salt thereof.

[0390] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention for use in the manufacture of a medicament for the therapeutic and / or prophylactic treatment of a Kv7.2 associated disorder, disease or disability in a subject in need thereof, wherein the disorder, disease or disability is selected from a behavioral disorder, a mood disorder, a neurodevelopmental disorder, an intellectual disability, epilepsy, a neurodegenerative disease, pain, migraine, and tinnitus.

[0391] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention for use in the manufacture of a medicament for the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the behavioral disorder is attention deficit hyperactivity disorder (ADHD).

[0392] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention for use in the manufacture of a medicament for the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the mood disorder is depression.

[0393] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention for use in the manufacture of a medicament for the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the neurodevelopmental disorder is selected from autism spectrum disorder (ASD) and syndromic developmental disorder.

[0394] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention for use in the manufacture of a medicament for the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the syndromic developmental disorder is selected from Dup15q syndrome (Dup15q), Fragile X syndrome (FXS) and Angelman syndrome.

[0395] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention for use in the manufacture of a medicament for the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the epilepsy is selected from generalized childhood epilepsy, West syndrome, Ohtahara syndrome, and epileptic encephalopathy.

[0396] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention for use in the manufacture of a medicament for the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the neurodegenerative disease is selected from Alzheimer's disease and motor neuron disease.

[0397] In one embodiment, the present invention provides a pharmaceutical composition as described above comprising a compound selected from any of formulas (I), (II), (III), (IV), (V), (VI), and (VII) or a solvate or pharma- ceutically acceptable salt thereof, any exemplified compound, any embodiment, or combination of embodiments, as described herein.

[0398] In one embodiment, the present invention provides a pharmaceutical composition as described above comprising a compound selected from Tables 1 and 2, or a solvate or pharma- ceutically acceptable salt thereof.

[0399] In one embodiment, the pharmaceutical composition comprises a compound selected from any of the list of compounds described herein, or a solvate or pharma- ceutically acceptable salt thereof.

[0400] Combination therapy The compounds of the present invention may be combined with one or more other compounds of the present invention or one or more other therapeutic agents in any combination thereof in the treatment of the diseases, disorders, or disabilities provided herein.For example, the compounds of the present invention may be administered simultaneously, sequentially, or separately in combination with other therapeutic agents known to be useful in the treatment of diseases or disorders selected from those listed herein.

[0401] In some embodiments, the compounds of the invention may be combined with another therapeutically active agent that has a synergistic effect in the treatment of any disease, disorder, or disability described herein.

[0402] As used herein, "combination" refers to any mixture or permutation of one or more compounds of the present invention with one or more other compounds of the present invention, or one or more additional therapeutic agents. Unless the context clearly indicates otherwise, "combination" may include simultaneous or sequential delivery of a compound of the present invention with one or more therapeutic agents. Unless the context clearly indicates otherwise, "combination" may include dosage forms of a compound of the present invention with another therapeutic agent. Unless the context clearly indicates otherwise, "combination" may include routes of administration of a compound of the present invention with another therapeutic agent. Unless the context clearly indicates otherwise, "combination" may include formulations of a compound of the present invention with another therapeutic agent. Dosage forms, routes of administration, and pharmaceutical compositions include, but are not limited to, those described herein.

[0403] manufactured goods In one embodiment, the invention provides articles of manufacture or "kits" containing materials useful for the treatment of a disorder, disease or disability described herein.

[0404] In one embodiment of the invention, the kit comprises a container comprising a compound of the invention as described in any embodiment of the invention.

[0405] In one embodiment, the present invention provides a kit comprising a container comprising a compound of the invention described herein or a pharmaceutical composition thereof.

[0406] In one embodiment, the invention provides a kit comprising a compound of the invention described herein, any exemplified compound, any embodiment, or combination of embodiments, or a pharmaceutical composition thereof.

[0407] In one embodiment, the invention provides a kit, wherein the compound is selected from compounds of Formula (I), (II), (III), (IV), (V), (VI) and (VII) as described herein, or a solvate, pharma- ceutically acceptable salt, or pharmaceutical composition thereof.

[0408] In one embodiment, the invention provides a kit, wherein the compound is selected from Tables 1 and 2, or a solvate, a pharma- ceutically acceptable salt, or a pharmaceutical composition described herein. In one embodiment, the invention provides a kit for use in treating a Kv7.2 associated disorder, disease, or disability, comprising: a) a first pharmaceutical composition comprising a compound of the invention; b) Instructions for use and A kit comprising:

[0409] In one embodiment, the invention provides a kit for use in the therapeutic and / or prophylactic treatment of a Kv7.2 associated disorder, disease or disability, comprising: a) a compound of the invention as described herein, or a pharmaceutical composition thereof, or a pharmaceutical composition for use; b) Instructions for use and A kit comprising:

[0410] In one embodiment, the invention relates to a kit for use in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 selected from behavioral disorders, mood disorders, neurodevelopmental disorders, intellectual disabilities, epilepsy, neurodegenerative diseases, pain, migraine, and tinnitus, comprising: a) a compound of formula (I) as described herein: [ka] (In the formula, R 1 is halogen, cyano, haloC 1~6 Alkoxy, C 1~6 Alkoxy, C 1~6 Alkyl, C 2~8 Alkynyl, Cyano C 1~6 Alkoxy, HaloC 1~6 Alkyl-thiol, SF5, HaloC 2~6 Alkenyl, HaloC 1~6 thiol, and 4- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is selected from one or two halogen or haloC 1~6optionally substituted with alkyl; R 2 H, D, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; R 3 H, D, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; or R 2 and R 3 together with the carbon atom to which they are attached form a saturated monocyclic 3- to 6-membered cycloalkyl, which cycloalkyl is free of halogen and haloC 1~6 optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl; R 4 H, halogen, haloC 1~6 Alkyl, C 1~6 Alkoxy and C 1~6 alkyl; R 5 , H, C 1~6 Alkyl, Hydroxy C 1~6 Alkyl, and C 1~6 alkoxy; or R 1 and R 5 together with the two C atoms to which they are attached form a 4-6 membered heterocycloalkyl ring system, the heterocycloalkyl being halogen or haloC 1~6 optionally substituted with 1 or 2 substituents independently selected from alkyl; R 8 H, halogen, haloC 1~6 Alkyl and haloC 1~6 alkoxy), or a first pharmaceutical composition comprising a solvate or a pharma- ceutically acceptable salt, a pharmaceutical composition, or a pharmaceutical composition for use; and b) Instructions for use and A kit comprising:

[0411] In one embodiment, the invention relates to a kit for use in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 selected from behavioral disorders, mood disorders, neurodevelopmental disorders, intellectual disabilities, epilepsy, neurodegenerative diseases, pain, migraine, and tinnitus, comprising: a) a compound of formula (II) as described herein: [ka] (In the formula, R 1 is halogen, cyano, haloC 1~6 Alkoxy and cyano C 1~6 alkoxy; R 2 H, D, and hydroxy C 1~6 alkyl; R 3 H, D, and hydroxy C 1~6 alkyl; R 4 H, halogens, and haloC 1~6 alkyl; R 5 is H; or R 1 and R 5 together with the two C atoms to which they are attached form a 4-6 membered heterocycloalkyl ring system, the heterocycloalkyl being selected from halogen and haloC 1~6 optionally substituted with 1 or 2 substituents independently selected from alkyl, a first pharmaceutical composition comprising a solvate or a pharma- ceutically acceptable salt, a pharmaceutical composition, or a pharmaceutical composition for use; and b) Instructions for use and A kit comprising:

[0412] In one embodiment, the invention provides a kit for use in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2, which may be selected from a behavioral disorder, a mood disorder, a neurodevelopmental disorder, an intellectual disability, epilepsy, a neurodegenerative disease, pain, migraine, and tinnitus.

[0413] In one embodiment, the invention provides a kit for the uses described herein, wherein the behavioral disorder is attention deficit hyperactivity disorder (ADHD).

[0414] In one embodiment, the invention provides a kit for the uses described herein, wherein the mood disorder is depression.

[0415] In one embodiment, the invention provides a kit for use as described herein, wherein the neurodevelopmental disorder is selected from autism spectrum disorder (ASD) and syndromic developmental disorder.

[0416] In one embodiment, the invention provides a kit for use as described herein, wherein the syndromic developmental disorder is selected from Dup15q syndrome (Dup15q), Fragile X syndrome (FXS), and Angelman syndrome.

[0417] In one embodiment, the invention provides a kit for use as described herein, wherein the epilepsy is selected from generalized childhood epilepsy, West syndrome, Ohtahara syndrome, and epileptic encephalopathy.

[0418] In one embodiment, the invention provides a kit for the uses described herein, wherein the neurodegenerative disease is selected from Alzheimer's disease and motor neuron disease.

[0419] In one embodiment, the invention provides a kit for the uses described herein, further comprising a label or package insert on or associated with the container.

[0420] The term "package insert" is used to refer to instructions customarily included in commercial packaging of therapeutic products which contain information about the indications, usage, dosage, administration, contraindications, and / or warnings concerning the use of such therapeutic product.

[0421] Suitable containers include, for example, bottles, vials, syringes, blister packs, etc. The containers may be formed from a variety of materials such as glass or plastic.

[0422] The container may hold a compound of the invention or a formulation thereof that is effective for treating a condition and may have a sterile access port (e.g., the container may be an intravenous solution bag or a vial with a stopper pierceable by a hypodermic needle). At least one active agent in the composition is a compound of the invention. The label or package insert indicates that the composition is used to treat a selected condition, such as cancer. Additionally, the label or package insert may indicate that the patient to be treated is a patient with a disorder, such as a hyperproliferative disorder, neurodegeneration, cardiac hypertrophy, pain, migraine, or neurotraumatic disease or event. In one embodiment, the label or package insert indicates that the composition comprising the compound of the invention can be used to treat a disorder resulting from abnormal cell proliferation. The label or package insert may also indicate that the composition can be used to treat other disorders. Alternatively or additionally, the article of manufacture may further comprise a second container containing a pharma- ceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffered saline, Ringer's solution, and dextrose solution. The article of manufacture may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0423] In one embodiment, the present invention provides a kit for use as described herein, further comprising instructions for administering the compound of the present invention and, if present, the second pharmaceutical formulation.For example, when the kit comprises a first composition comprising the compound of the present invention and a second pharmaceutical formulation, the kit can further comprise instructions for administering the first and second pharmaceutical compositions simultaneously, sequentially, or separately to a patient in need of administration.

[0424] In one embodiment, the present invention provides a kit for use as described herein, suitable for delivery of solid oral forms of the compounds of the present invention, such as tablets or capsules. Such kits preferably include several unit doses. Such kits may include a card with the doses arranged in the order of their intended use. An example of such a kit is a "blister pack". Blister packs are well known in the packaging industry and are widely used to package pharmaceutical unit dosage forms. If desired, a memory aid can be provided, for example in the form of numbers, letters, or other markings, or with a calendar insert, that designates the days in the treatment schedule on which the doses can be administered.

[0425] In one embodiment, the present invention provides a kit for use as described herein, comprising: (a) a first container in which a compound of the present invention is contained; and optionally (b) a second container in which a second pharmaceutical formulation is contained, the second pharmaceutical formulation comprising a second compound having antiproliferative activity. Alternatively, or in addition, the kit may further comprise a third container comprising a pharma- ceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffered saline, Ringer's solution, and dextrose solution. The article of manufacture may further comprise other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0426] In one embodiment, the present invention provides a kit for use as described herein, which comprises a composition of the present invention and a second therapeutic agent, and may comprise a container for containing the separate compositions, such as a divided bottle or a divided foil packet, but the separate compositions may be contained in a single undivided container. Typically, the kit includes instructions for administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.

[0427] Manufacturing method In a further aspect, the present invention provides a compound of formula (I) or a solvate or pharma- ceutically acceptable salt when prepared according to the processes described herein.

[0428] The preparation of the compounds of the present invention, in particular those selected from formulae (I), (II), (III), (IV), (V), (VI), and (VII), may be carried out in sequential or convergent synthetic routes.

[0429] The syntheses of the present invention are depicted in the following general schemes. The skills required to carry out the reactions and purification of the resulting products are known to those skilled in the art. The substituents and indices used in the following process descriptions have the meanings given herein unless otherwise indicated.

[0430] In any of the embodiments with respect to the schemes or examples described in this application relating to the compounds of the invention, any embodiment may be combined with any other embodiment, unless inconsistent.

[0431] If the starting material, intermediate or compound of the invention, in particular one of the compounds selected from formulae (I), (II), (III), (IV), (V), (VI) and (VII), contains one or more functional groups that are not stable or reactive under the reaction conditions of one or more reaction steps, suitable protecting groups (as described in "Protective Groups in Organic Chemistry", TW Greene and PG M Hutts, 5th Edition, 2014, John Wiley & Sons, NY) can be introduced before the critical step by applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature.

[0432] When the starting materials or intermediates contain a stereocenter, the compounds of the present invention, in particular the compounds selected from formulae (I), (II), (III), (IV), (V), (VI), and (VII), are obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art, such as chiral HPLC, chiral SFC, or chiral crystallization. Racemic compounds can be separated into their antipodes via diastereomeric salts, for example, by crystallization with optically pure acids, or by separating the antipodes by specific chromatographic methods using either chiral adsorbents or chiral eluents. It is likewise possible to separate starting materials and intermediates containing a stereocenter to obtain diastereomerically / enantiomerically enriched starting materials and intermediates. The use of such diastereomerically / enantiomerically enriched starting materials and intermediates in the synthesis of the compounds of the present invention typically results in the respective diastereomerically / enantiomerically enriched compounds of the present invention.

[0433] Those skilled in the art will recognize that in the synthesis of the compounds of the present invention, particularly those of formulae (I), (II), (III), (IV), (V), (VI) and (VII), (unless otherwise desired) an "orthogonal protecting group strategy" can be applied to cleave some protecting groups one at a time without affecting other protecting groups in the molecule. The principle of orthogonal protection is well known in the art and has been described in the literature (e.g., Barany and RB Merrifield, J. Am. Chem. Soc. 1977, 99, 7363; H. Waldmann et al., Angew. Chem. Int. Ed. Engl. 1996, 35, 2056).

[0434] One skilled in the art will recognize that the reaction sequence may be varied depending on the reactivity and nature of the intermediates.

[0435] More specifically, the compounds of the present invention, i.e., compounds selected from formulas (I), (II), (III), (IV), (V), (VI), and (VII) or solvates or pharma- ceutically acceptable salts thereof, may be prepared by the methods set forth below, the methods set forth in the Examples, or analogous methods.

[0436] Suitable reaction conditions for each reaction step are known to those skilled in the art. For reaction conditions described in the literature that affect the reactions described, see, for example, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Son, New York, NY, 1999). The reaction could be easily carried out with or without a solvent. There is no particular restriction regarding the nature of the solvent used, as long as it does not adversely affect the reagents also involved in the reaction and it can dissolve the reagents at least to some extent.

[0437] The reactions described can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the reactions described in a temperature range from -78°C to reflux.

[0438] The time required for the reaction may also vary widely depending on many factors, especially the reaction temperature and the nature of the reagents. However, a period of 0.5 hours to several days is usually sufficient to obtain the intermediates and compounds described. The reaction sequence is not limited to the sequence shown in the scheme, but the order of the reaction steps can be freely changed depending on the starting materials and their respective reactivities.

[0439] In cases where starting materials or intermediates are not commercially available or their synthesis has not been described in the literature, they can be prepared by analogy with existing procedures for analogous materials or as outlined in the experimental section.

[0440] Abbreviation AcN is acetonitrile THF is tetrahydrofuran NEt3 is triethylamine DMSO is dimethyl sulfoxide EtOAc is ethyl acetate CDI is 1,1'-carbonyldiimidazole DCM is dichloromethane DIPEA is N,N-diisopropylethylamine DMA is dimethylacetamide DMF is N,N-dimethylformamide HCl is hydrogen chloride HPLC is High Pressure Liquid Chromatography LCMS is liquid chromatography mass spectrometry mCPBA is 3-chloroperoxybenzoic acid NaHCO3 is sodium bicarbonate NaOH is sodium hydroxide NMP is N-methylpyrrolidone MeOH is methanol MgSO4 is magnesium sulfate Pd(dppf)Cl2 is 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride PYBROP is bromotripyrrolidinophosphonium hexafluorophosphate o / n is overnight RT is room temperature TLC is thin layer chromatography CHO is Chinese hamster ovary CMV is a cytomegalovirus FBS is fetal bovine serum NEAAs are non-essential amino acids NaCl is sodium chloride KCl is potassium chloride CaCl2 is calcium chloride MgCl2 is magnesium chloride HEPES is 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid NMDG is N-methyl-D-glucamine diatrizoate EGTA is ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid EDTA is ethylenediaminetetraacetic acid DPBS is Dulbecco's phosphate buffered saline mV is millivolt TEA is tetraethylammonium NADPH is nicotinamide adenine dinucleotide phosphate CL int is the intrinsic clearance.

[0441] The present invention relates to compounds of formula (I): [ka] or a solvate or a pharma- ceutically acceptable salt thereof.

[0442] The synthesis of the compounds of the invention is shown in the following schemes and in the description of 58 specific examples. The skills required to carry out the reactions and purification of the resulting products are known to those skilled in the art.

[0443] More specifically, the compounds of the present invention, for example, compounds selected from formulae (I) to (VII) or solvates or pharma- ceutically acceptable salts thereof, can be prepared by the methods shown in the Examples or by methods analogous thereto. Starting materials are either commercially available or can be prepared by methods analogous to those shown below or known in the art.

[0444] General Procedure For further information regarding the general procedures, please refer to the embodiments regarding the process for preparing a compound of formula (I) or a solvate or pharma- ceutically acceptable salt thereof described herein. Scheme 1: Synthesis of compounds of formula I using isocyanates [ka] Scheme 2: Synthesis of compounds of formula I using CDI [ka] Scheme 3: Synthesis of compounds of formula I using 4-nitrophenyl chloroformate [ka]

[0445] Urea formation can be achieved by treating the amine (or corresponding salt such as HCl) with an isocyanate (Scheme 1) in DCM or DMF and in the presence of a suitable base (DIPEA, NEt3) at temperatures between RT and 40° C., or by reacting the first amine with 1,1′-carbonyldiimidazole′ (Scheme 2) in a solvent (DCM, AcN, THF) and in the presence of a suitable base (DIPEA, NEt3) to generate a reactive intermediate prior to addition of the second amine (or corresponding salt), or by reacting the first amine with para-nitrophenyl chloroformate (Scheme 3) or phenyl chloroformate in a solvent (AcN, THF) and in the presence of a base (DIPEA, NEt3) to generate a carbamate intermediate which can be purified or used in situ with the second amine to give the desired urea.

[0446] Preferred conditions are using CDI with DIPEA as base and DCM as solvent at 0° C. for 45 min, followed by addition of the second amine and stirring at 40° C. for 6-15 h.

[0447] Compound isolation and purification Isolation and purification of the compounds and intermediates described herein, as appropriate, may be carried out by any suitable separation or purification procedure, such as, for example, filtration, extraction, crystallization, column chromatography, thick layer chromatography, preparative low-pressure or high-pressure liquid chromatography, or a combination of these procedures.

[0448] However, other equivalent separation or isolation procedures may of course also be used. Mixtures of chiral compounds of formula (I) may be separated using preparative chiral HPLC purification. EXAMPLES

[0449] Example 1: 1-(3-Methoxy-1-bicyclo[1.1.1]pentanyl)-3-[[3-(trifluoromethoxy)phenyl]methyl]urea [ka] 3-Methoxybicyclo[1.1.1]pentan-1-amine hydrochloride (29.9 mg, 0.2 mmol) was dissolved in AcN (3 mL) and DIPEA (0.3 mL) and the reaction was then cooled to 0° C. 4-Nitrophenyl chloroformate (40.3 mg, 0.2 mmol) was added and the reaction mixture was stirred for 1 h while the temperature was allowed to reach RT. 3-(Trifluoromethoxy)benzylamine (114.69 mg, 0.6 mmol) was then added and the reaction was stirred at RT for a further 4 h. The solvent was removed in vacuo. DMF (2 ml) was added and purification by preparative HPLC afforded the title compound as a white solid (14% yield). MS(m / z): 331.1[M+H]+.

[0450] Example 2: 1-[[3-(trifluoromethoxy)phenyl]methyl]-3-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]urea [ka] To a solution of 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride (310 mg, 1.65 mmol) and DIPEA (0.86 mL, 4.96 mmol) in dry DCM (6.6 mL) in an ice bath was added 1,1'-carbonyldiimidazole (294.76 mg, 1.82 mmol). The reaction was stirred at 0-5°C for 45 min, then 3-(trifluoromethoxy)benzylamine (315.88 mg, 1.65 mmol) was added and the reaction was stirred at 35°C for 15 h. The reaction was concentrated in vacuo, dissolved in 2 mL of DMF, and purified by preparative HPLC to give the title compound (74% yield) as a white solid. MS(m / z):368.9[M+H]+.

[0451] Example 3: 1-[(1R)-1-(3-chlorophenyl)-2-hydroxyethyl]-3-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]urea [ka] The title compound was obtained as in Example 2 as a white solid (yield 56%) using (R)-3-chlorophenylglycinol, 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride and 1,1'-carbonyldiimidazole. MS(m / z):349.1[M+H]+.

[0452] Example 4: 1-(3-Methoxy-1-bicyclo[1.1.1]pentanyl)-3-[[3-(trifluoromethyl)phenyl]methyl]urea [ka] The title compound was obtained as in Example 1 using 3-(trifluoromethyl)benzylamine, 3-methoxybicyclo[1.1.1]pentan-1-amine hydrochloride and 4-nitrophenyl chloroformate as a white solid (yield 30%). MS(m / z): 315.1[M+H]+.

[0453] Example 5: 1-[(3-cyanophenyl)methyl]-3-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]urea [ka] The title compound was obtained as in Example 2 using 3-trifluoromethylbicyclo[1.1.1]pentan-1-amine hydrochloride, 3-(aminomethyl)benzonitrile and 1,1′-carbonyldiimidazole as a white solid (78% yield). MS(m / z):309.9[M+H]+.

[0454] Example 6: 1-(3-Fluoro-1-bicyclo[1.1.1]pentanyl)-3-[[3-(trifluoromethoxy)phenyl]methyl]urea [ka] The title compound was obtained as in Example 1 using 3-(trifluoromethoxy)benzylamine, 3-fluorobicyclo[1.1.1]pentan-1-amine hydrochloride and 4-nitrophenyl chloroformate as a white solid (yield 3%). MS(m / z):319.1[M+H]+.

[0455] Example 7: 1-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-[[3-(trifluoromethyl)phenyl]methyl]urea [ka] The title compound was obtained as in Example 2 using 3-trifluoromethylbicyclo[1.1.1]pentan-1-amine hydrochloride, 3-(trifluoromethyl)benzylamine and 1,1′-carbonyldiimidazole as a white solid (yield 38%). MS(m / z): 353.3[M+H]+.

[0456] Example 8: 1-(3-fluoro-1-bicyclo[1.1.1]pentanyl)-3-[(1S)-1-(3-methoxyphenyl)ethyl]urea [ka] The title compound was obtained as in Example 2 as a white solid (yield 18%) using 3-fluorobicyclo[1.1.1]pentan-1-amine hydrochloride, (S)-1-(3-methoxyphenyl)ethan-1-amine and 1,1′-carbonyldiimidazole. MS(m / z): 279.5[M+H]+.

[0457] Example 9: 1-(3-Fluoro-1-bicyclo[1.1.1]pentanyl)-3-[(1S)-1-[3-(trifluoromethyl)phenyl]ethyl]urea [ka] The title compound was obtained as in Example 2 as a white solid (69% yield) using 3-fluorobicyclo[1.1.1]pentan-1-amine hydrochloride, (S)-1-(3-(trifluoromethyl)phenyl)ethane-1-amine and 1,1′-carbonyldiimidazole. MS(m / z):317.3[M+H]+.

[0458] Example 10: 1-(3-fluoro-1-bicyclo[1.1.1]pentanyl)-3-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]urea [ka] The title compound was obtained as in Example 2 as a white solid (87% yield) using 3-fluorobicyclo[1.1.1]pentan-1-amine hydrochloride, (S)-1-(3-(trifluoromethoxy)phenyl)ethane-1-amine and 1,1′-carbonyldiimidazole. MS(m / z): 333.5[M+H]+.

[0459] Example 11: 1-(3-fluoro-1-bicyclo[1.1.1]pentanyl)-3-[[3-(trifluoromethyl)phenyl]methyl]urea [ka] The title compound was obtained as in Example 2 as a white solid (86% yield) using 3-fluorobicyclo[1.1.1]pentan-1-amine hydrochloride, (3-(trifluoromethyl)phenyl)methanamine and 1,1'-carbonyldiimidazole. MS(m / z): 303.5[M+H]+.

[0460] Example 12: 1-[(1R)-1-(3-bromophenyl)-2-hydroxyethyl]-3-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]urea [ka] The title compound was obtained as in Example 2 using 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride, (R)-2-amino-2-(3-bromophenyl)ethan-1-ol and 1,1'-carbonyldiimidazole as a white solid (32% yield). MS(m / z): 393.1[M+H]+.

[0461] Example 13: 1-[(3-cyanophenyl)methyl]-3-(3-fluoro-1-bicyclo[1.1.1]pentanyl)urea [ka] a) 4-Nitrophenyl N-[(3-cyanophenyl)methyl]carbamate 4-Nitrophenyl chloroformate (1.68 g, 8.32 mmol) was dissolved in dry DCM (40 mL) and then cooled to 0° C. under N2. To this was then slowly added a solution of 3-(aminomethyl)benzonitrile (1 g, 7.57 mmol) and triethylamine (2.11 mL, 15.13 mmol) in dry DCM (15 mL). After the addition was complete, the reaction was stirred at 0° C. for 1 h and then at RT for 1 h. The reaction was diluted with 50 mL of saturated NaHCO3 and extracted with 2×80 mL of DCM. The organic phase was then washed with 50 mL of saturated brine, dried over MgSO4, and concentrated in vacuo. The crude product was dry loaded onto silica and purified by automated column chromatography (Rf=0.33 in 1:1 Hept:EtOAc) to give the product (596 mg, 2 mmol, 26.5% yield) as an off-white solid. b) 1-[(3-cyanophenyl)methyl]-3-(3-fluoro-1-bicyclo[1.1.1]pentanyl)urea To a solution of 3-fluorobicyclo[1.1.1]pentan-1-amine hydrochloride (41.7 mg, 0.303 mmol) in dry DMSO (1.5 ml) containing triethylamine (0.14 mL, 1 mmol) was added 4-nitrophenyl N-[(3-cyanophenyl)methyl]carbamate (75 mg, 0.25 mmol). The reaction was stirred at RT for 1 h and then purified by reverse phase HPLC to give the title product (70% yield) as a white solid. MS(m / z):260.6[M+H]+.

[0462] Example 14: 1-[(3-cyanophenyl)methyl]-3-(3-methyl-1-bicyclo[1.1.1]pentanyl)urea [ka] The title compound was obtained as in Example 13 using 3-methylbicyclo[1.1.1]pentan-1-amine hydrochloride, 3-(aminomethyl)benzonitrile and 4-nitrophenyl chloroformate as a white solid (60% yield). MS(m / z): 256.1[M+H]+.

[0463] Example 15: 1-[(3-cyanophenyl)methyl]-3-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]urea [ka] The title compound was obtained as in Example 13 using 3-(difluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride, 3-(aminomethyl)benzonitrile and 4-nitrophenyl chloroformate as a white solid (75% yield). MS(m / z): 292.1[M+H]+.

[0464] Example 16: 1-[(1S)-1-(3-bromophenyl)ethyl]-3-(3-fluoro-1-bicyclo[1.1.1]pentanyl)urea [ka] The title compound was obtained as in Example 2 using 3-fluorobicyclo[1.1.1]pentan-1-amine hydrochloride, (1S)-1-(3-bromophenyl)ethanamine and 1,1′-carbonyldiimidazole as a white solid (79% yield). MS(m / z):327.1 [M+H]+.

[0465] Example 17: 1-[(1R)-1-(3-bromophenyl)-2-hydroxyethyl]-3-(3-fluoro-1-bicyclo[1.1.1]pentanyl)urea [ka] The title compound was obtained as a white solid (77% yield) in the same manner as in Example 2 using 3-fluorobicyclo[1.1.1]pentan-1-amine hydrochloride, (2R)-2-amino-2-(3-bromophenyl)ethanol hydrochloride and 1,1'-carbonyldiimidazole. MS(m / z):343.1[M+H]+.

[0466] Example 18: 1-[(1S)-1-(3-chlorophenyl)ethyl]-3-(3-fluoro-1-bicyclo[1.1.1]pentanyl)urea [ka] The title compound was obtained as in Example 2 as a white solid (75% yield) using 3-fluorobicyclo[1.1.1]pentan-1-amine hydrochloride, (1S)-1-(3-chlorophenyl)ethanamine hydrochloride and 1,1′-carbonyldiimidazole. MS(m / z): 283.1[M+H]+.

[0467] Example 19: 1-(3-fluoro-1-bicyclo[1.1.1]pentanyl)-3-[(3-fluorophenyl)methyl]urea [ka] The title compound was obtained as in Example 2 using 3-fluorobicyclo[1.1.1]pentan-1-amine hydrochloride, (3-fluorophenyl)methanamine and 1,1′-carbonyldiimidazole as a white solid (79% yield). MS(m / z): 253.1[M+H]+.

[0468] Example 20: 1-(3-methyl-1-bicyclo[1.1.1]pentanyl)-3-[[3-(trifluoromethyl)phenyl]methyl]urea [ka] The title compound was obtained as in Example 2 as a white solid (yield 36%) using 3-methylbicyclo[1.1.1]pentan-1-amine hydrochloride, [3-(trifluoromethyl)phenyl]methanamine and 1,1'-carbonyldiimidazole. MS(m / z): 299.1[M+H]+.

[0469] Example 21: 1-(3-propan-2-yl-1-bicyclo[1.1.1]pentanyl)-3-[[3-(trifluoromethyl)phenyl]methyl]urea [ka] The title compound was obtained as in Example 2 as a white solid (yield 37%) using 3-isopropylbicyclo[1.1.1]pentan-1-amine hydrochloride, [3-(trifluoromethyl)phenyl]methanamine and 1,1'-carbonyldiimidazole. MS(m / z):327.2[M+H]+.

[0470] Example 22: 1-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-[[3-(trifluoromethyl)phenyl]methyl]urea [ka] The title compound was obtained as in Example 2 as a white solid (16% yield) using 3-(difluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride, [3-(trifluoromethyl)phenyl]methanamine and 1,1′-carbonyldiimidazole. MS(m / z): 335.1[M+H]+.

[0471] Example 23: 1-(1-bicyclo[1.1.1]pentanyl)-3-[[3-(trifluoromethyl)phenyl]methyl]urea [ka] The title compound was obtained as in Example 13 as a white solid (78% yield) using bicyclo[1.1.1]pentan-1-amine hydrochloride, [3-(trifluoromethyl)phenyl]methanamine and 4-nitrophenyl chloroformate. MS(m / z):285.1[M+H]+.

[0472] Example 24: 1-(3-fluoro-1-bicyclo[1.1.1]pentanyl)-3-[(1S)-1-(3-fluorophenyl)ethyl]urea [ka] The title compound was obtained as in Example 2 as a white solid (73% yield) using 3-fluorobicyclo[1.1.1]pentan-1-amine hydrochloride, (1S)-1-(3-fluorophenyl)ethanamine and 1,1′-carbonyldiimidazole. MS(m / z):267.1[M+H]+.

[0473] Example 25: 1-(1-bicyclo[1.1.1]pentanyl)-3-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]urea [ka] The title compound was obtained as in Example 2 as a white solid (yield 26%) using bicyclo[1.1.1]pentan-1-amine hydrochloride, (1S)-1-[3-(trifluoromethoxy)phenyl]ethanamine hydrochloride and 1,1′-carbonyldiimidazole. MS(m / z): 315.1[M+H]+.

[0474] Example 26: 1-(3-methyl-1-bicyclo[1.1.1]pentanyl)-3-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]urea [ka] Using 3-methylbicyclo[1.1.1]pentan-1-amine hydrochloride, (1S)-1-[3-(trifluoromethoxy)phenyl]ethanamine hydrochloride and 1,1′-carbonyldiimidazole, the title compound was obtained as a white solid (yield 62%) in the same manner as in Example 2. MS(m / z): 329.1[M+H]+.

[0475] Example 27: 1-(3-propan-2-yl-1-bicyclo[1.1.1]pentanyl)-3-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]urea [ka] The title compound was obtained as a white solid (70% yield) in the same manner as in Example 2 using 3-isopropylbicyclo[1.1.1]pentan-1-amine hydrochloride, (1S)-1-[3-(trifluoromethoxy)phenyl]ethanamine hydrochloride and 1,1'-carbonyldiimidazole. MS(m / z):357.2 [M+H]+.

[0476] Example 28: 1-(1-bicyclo[1.1.1]pentanyl)-3-[[3-(trifluoromethoxy)phenyl]methyl]urea [ka] The title compound was obtained as in Example 13 as a white solid (55% yield) using bicyclo[1.1.1]pentan-1-amine hydrochloride, [3-(trifluoromethoxy)phenyl]methanamine and 4-nitrophenyl chloroformate. MS(m / z):301.1[M+H]+.

[0477] Example 29: 1-[[3-(difluoromethoxy)phenyl]methyl]-3-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]urea [ka] Using 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride, [3-(difluoromethoxy)phenyl]methanamine hydrochloride and 4-nitrophenyl chloroformate, the title compound was obtained as a white solid (46% yield) in the same manner as in Example 13. MS(m / z): 351.1[M+H]+.

[0478] Example 30: 1-[[3-(oxetan-3-yl)phenyl]methyl]-3-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]urea [ka] The title compound was obtained as in Example 2 as a white solid (yield 28%) using 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride, [3-(oxetan-3-yl)phenyl]methanamine and 1,1′-carbonyldiimidazole. MS(m / z):341.1[M+H]+.

[0479] Example 31: 1-[[3-(difluoromethyl)phenyl]methyl]-3-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]urea [ka] The title compound was obtained as in Example 2 as a white solid (yield 39%) using 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride, [3-(difluoromethyl)phenyl]methanamine hydrochloride and 1,1'-carbonyldiimidazole. MS(m / z): 335.1[M+H]+.

[0480] Example 32: 1-[(3-ethynylphenyl)methyl]-3-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]urea [ka] The title compound was obtained as in Example 2 as a white solid (48% yield) using 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride, (3-ethynylphenyl)methanamine hydrochloride and 1,1'-carbonyldiimidazole. MS(m / z):309.1[M+H]+.

[0481] Example 33: 1-[(2,2-difluoro-1,3-benzodioxol-5-yl)methyl]-3-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]urea [ka] The title compound was obtained as in Example 2 as a white solid (yield 38%) using 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride, (2,2-difluoro-1,3-benzodioxol-5-yl)methanamine and 1,1′-carbonyldiimidazole. MS(m / z): 365.1[M+H]+.

[0482] Example 34: 1-[[3-(fluoromethoxy)phenyl]methyl]-3-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]urea [ka] The title compound was obtained as in Example 2 as a white solid (yield 36%) using 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride, [3-(fluoromethoxy)phenyl]methanamine hydrochloride and 1,1'-carbonyldiimidazole. MS(m / z): 333.1[M+H]+.

[0483] Example 35: 1-[dideuterio-[3-(trifluoromethoxy)phenyl]methyl]-3-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]urea [ka] a) [3-(trifluoromethoxy)phenyl](2H2)methanamine 3-(Trifluoromethoxy)benzonitrile (187.12 mg, 1 mmol) was dissolved in dry THF (5 mL) in a dry flask and then cooled to -10 °C under N2. The solution was then treated portionwise with lithium(2H)almanuid (119.64 mg, 2.85 mmol) and the reaction was stirred at 0° C. for 1 h, then at RT for 3 h, then cooled in an ice bath and treated with 75 μL DO, 50 μL 20% NaOD in DO, then 150 μL DO, then stirred at RT for 15 min. The reaction was filtered through a celite pad and the pad was washed with 2×30 ml DCM. The combined filtrates were then concentrated in vacuo to give 170 mg of crude oil. The crude product was dissolved in 3 ml EtO, treated with 1 ml 4M HCl in dioxane and stirred for 15 min, then diluted with 3 ml EtO and the precipitate was filtered off, washed with 2×3 ml EtO and dried in vacuum to give [3-(trifluoromethoxy)phenyl](2H)methanamine (168.2 mg, 73.2% yield) as a white solid. MS(m / z): 194[M+H]+. b) 1-[dideuterio-[3-(trifluoromethoxy)phenyl]methyl]-3-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]urea 3-(Trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride, [3-(trifluoromethoxy)phenyl]( 2 H 2 ) Methanamine hydrochloride and 1,1'-carbonyldiimidazole were used to obtain the title compound as a white solid (34% yield) as in Example 2. MS(m / z): 333.1[M+H]+.

[0484] Example 36: 1-[(3-bromophenyl)methyl]-3-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]urea [ka] The title compound was obtained as in Example 2 as a white solid (yield 32%) using 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride, (3-bromophenyl)methanamine and 1,1'-carbonyldiimidazole. MS(m / z):363.0[M+H]+.

[0485] Example 37: 1-(1-bicyclo[1.1.1]pentanyl)-3-[1-[3-(trifluoromethoxy)phenyl]ethyl]urea [ka] A solution of 1-isocyanatobicyclo[1.1.1]pentane (65.48 mg, 0.6 mmol) in anhydrous DCM (1.0 mL) was added slowly to a solution of 1-[3-(trifluoromethoxy)phenyl]ethylamine (123.11 mg, 0.6 mmol) in anhydrous DCM (1.0 mL) at RT and left stirring overnight.

[0486] The reaction was then concentrated and the crude product was purified by preparative HPLC eluting with 5-95% ACN / 0.1% FA / 0.1% FA in water to give the title product as a white solid (42.4% yield). MS(m / z): 315.1[M+H]+.

[0487] Example 38: 1-[1-[3-(difluoromethoxy)phenyl]ethyl]-3-(3-fluoro-1-bicyclo[1.1.1]pentanyl)urea [ka] The title compound was obtained as in Example 2 using 3-fluorobicyclo[1.1.1]pentan-1-amine hydrochloride, 1-[3-(difluoromethoxy)phenyl]ethanamine hydrochloride and 1,1'-carbonyldiimidazole as a white solid (yield 37%). MS(m / z):363.0[M+H]+.

[0488] Example 39: 1-(1-bicyclo[1.1.1]pentanyl)-3-[[3-(pentafluoro-λ6-sulfanyl)phenyl]methyl]urea [ka] The title compound was obtained as in Example 37 using 1-isocyanatobicyclo[1.1.1]pentane and 3-(pentafluorothio)benzylamine as a white solid (73% yield). MS(m / z):343.1[M+H]+.

[0489] Example 40: 1-(1-bicyclo[1.1.1]pentanyl)-3-[(3-bromophenyl)methyl]urea [ka] The title compound was obtained as in Example 37 using 1-isocyanatobicyclo[1.1.1]pentane and (3-bromophenyl)methanamine hydrochloride as a white solid (62% yield). MS(m / z): 295.0[M+H]+.

[0490] Example 41: 1-(1-bicyclo[1.1.1]pentanyl)-3-[(3-chlorophenyl)methyl]urea [ka] The title compound was obtained as in Example 37 using 1-isocyanatobicyclo[1.1.1]pentane and (3-chlorophenyl)methanamine as a white solid (76% yield). MS(m / z): 251.1[M+H]+.

[0491] Example 42: 1-(1-bicyclo[1.1.1]pentanyl)-3-[(3-tert-butylphenyl)methyl]urea [ka] The title compound was obtained as in Example 37 using 1-isocyanatobicyclo[1.1.1]pentane and (3-tertbutylphenyl)methanamine as a white solid (41% yield). MS(m / z):273.2[M+H]+.

[0492] Example 43: 1-(1-bicyclo[1.1.1]pentanyl)-3-[[3-(difluoromethoxy)phenyl]methyl]urea [ka] Using 1-isocyanatobicyclo[1.1.1]pentane and [3-(difluoromethoxy)phenyl]methanamine hydrochloride, the title compound was obtained as in Example 37 as a white solid (70% yield). MS(m / z): 283.1[M+H]+.

[0493] Example 44: 1-[(1S)-1-(3-bromophenyl)-2-hydroxyethyl]-3-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]urea [ka] The title compound was obtained as a white solid (yield 29%) in the same manner as in Example 2 using 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride, (2S)-2-amino 2-(3-bromophenyl)ethanol hydrochloride and 1,1'-carbonyldiimidazole. MS(m / z):393.0[M+H]+.

[0494] Example 45: 1-[[3-(2,2-difluoroethenyl)phenyl]methyl]-3-(3-fluoro-1-bicyclo[1.1.1]pentanyl)urea [ka] a) N-{[3-(2,2-difluoroethenyl)phenyl]methyl}carbamate tert-Butyl 3-formylbenzylcarbamate (300 mg, 1.28 mmol) and 97% sodium chlorodifluoroacetate (388.8 mg, 2.55 mmol) were added to an oven-dried round-bottom flask and purged under N2. The mixture was dissolved in NMP (5 mL) and heated to 100 °C for 5 min. 97% sodium chlorodifluoroacetate (388.8 mg, 2.55 mmol) was then added in portions over 5 min and the reaction was left stirring at 100 °C for 2 h. After 2 h the reaction was quenched in water and the product was extracted with EtOAc (3x) and the organic layers were combined and washed with 21 mL of 30% H20 then with brine (3x), dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography on silica eluting with EtOAc in heptane to give tert-butyl N-{[3-(2,2-difluoroethenyl)phenyl]methyl}carbamate as a yellow oil (100 mg, 29% yield). b) [3-(2,2-difluoroethenyl)phenyl]methanamine tert-Butyl N-{[3-(2,2-difluoroethenyl)phenyl]methyl}carbamate (100 mg, 0.37 mmol) was dissolved in DCM (1 mL) and trifluoroacetic acid (0.14 mL, 1.86 mmol) was added. The reaction was left stirring at RT for 2 h. The reaction was concentrated and the crude product was loaded onto an SCX cartridge, the cartridge was washed with DCM / MeOH and the product was washed with DCM / 7 N NH3 in MeOH. The basic fraction was isolated and concentrated to give [3-(2,2-difluoroethenyl)phenyl]methanamine as a yellow solid (100 mg). MS(m / z): 170[M+H]+. c) 1-[[3-(2,2-difluoroethenyl)phenyl]methyl]-3-(3-fluoro-1-bicyclo[1.1.1]pentanyl)urea The title compound was obtained as in Example 2 as a white solid (10% yield) using 3-fluorobicyclo[1.1.1]pentan-1-amine hydrochloride, [3-(2,2-difluoroethenyl)phenyl]methanamine and 1,1'-carbonyldiimidazole. MS(m / z): 397.1[M+H]+.

[0495] Example 46: 1-(3-methyl-1-bicyclo[1.1.1]pentanyl)-3-[[3-(trifluoromethoxy)phenyl]methyl]urea [ka] The title compound was obtained as in Example 1 using 3-(trifluoromethoxy)benzylamine, 3-methylbicyclo[1.1.1]pentan-1-amine hydrochloride and 4-nitrophenyl chloroformate as a white solid (78% yield). MS(m / z): 315.1[M+H]+.

[0496] Example 47: 1-[(3-cyano-2-fluorophenyl)methyl]-3-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]urea [ka] The title compound was obtained as in Example 2 using 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride, 3-(aminomethyl)-2-fluorobenzonitrile hydrochloride and 1,1'-carbonyldiimidazole as a white solid (yield 53%). MS(m / z):328.1[M+H]+.

[0497] Example 48: 1-[(1R)-2-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl]-3-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]urea [ka] Using 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride, (2R)-2-amino-2-[3-(trifluoromethyl)phenyl]ethanol and 1,1'-carbonyldiimidazole, the title compound was obtained as a white solid (61% yield) in the same manner as in Example 2. MS(m / z): 383.1[M+H]+.

[0498] Example 49: 1-[[3-(cyanomethoxy)phenyl]methyl]-3-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]urea [ka] The title compound was obtained as a white solid (68% yield) in the same manner as in Example 2 using 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride, 2-[3-(aminomethyl)phenoxy]acetonitrile hydrochloride and 1,1'-carbonyldiimidazole. MS(m / z): 340.1[M+H]+.

[0499] Example 50: 1-(3-fluoro-1-bicyclo[1.1.1]pentanyl)-3-[[3-(trifluoromethylsulfanyl)phenyl]methyl]urea [ka] The title compound was obtained as a white solid (63% yield) in the same manner as in Example 2 using 3-fluorobicyclo[1.1.1]pentan-1-amine hydrochloride, {3-[(trifluoromethyl)sulfanyl]phenyl}methanamine hydrochloride and 1,1'-carbonyldiimidazole. MS(m / z): 335.1[M+H]+.

[0500] Example 51: 1-(1-bicyclo[1.1.1]pentanyl)-3-[(1S)-1-[3-(trifluoromethyl)phenyl]ethyl]urea [ka] The title compound was obtained as in Example 37 using 1-isocyanatobicyclo[1.1.1]pentane and (1S)-1-[3-(trifluoromethyl)phenyl]ethanamine hydrochloride as a white solid (100% yield). MS(m / z): 299.1[M+H]+.

[0501] Example 52: 1-[(3-cyanophenyl)-dideuteriomethyl]-3-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]urea [ka] a) tert-Butyl N-[(3-cyanophenyl)(2H2)methyl]carbamate 3-Bromobenzonitrile (0.12 mL, 1.56 g / mL, 0.99 mmol) was dissolved in dehydrated DMF (10 mL), and then Boc-GlyOH-2,2-d2 (262.85 mg, 1.48 mmol), nickel(II) chloride dimethoxyethane adduct (10.86 mg, 0.05 mmol), (4,4'-di-t-butyl-2,2'-bipyridine)bis[3,5-difluorophenyl]-2,2-dioxo-1,2-diphenyl-2,3-diaminetetraacetate (1,2-dimethylphenyl)-2,4-diaminetetraacetate (1,2-dimethylphenyl)-2,5-diaminetetraacetate (1,2-dimethylphenyl) ... The reaction mixture was treated with 2-[5-trifluoromethyl-2-pyridinyl-κN)phenyl-κC]iridium(III) hexafluorophosphate 99% (11.09 mg, 0.01 mmol), 4,4'-di-tert-butyl-2,2'-dipyridyl (13.27 mg, 0.05 mmol) and cesium carbonate (483.33 mg, 1.48 mmol) and then bubbled with N2. The reaction was sealed, then stirred and irradiated with blue light (450 nm, 30 W with liquid cooling to 25° C.) for 16 hours. The reaction was then diluted with 100 mL of EtOAc and then washed with 100 mL of saturated NaHCO3 and the aqueous phase was extracted with a further 100 mL of EtOAc. The combined organic phase was washed with 100 mL HO, 50 mL saturated brine, dried over MgSO, concentrated onto silica, and purified by silica flash chromatography eluting with 3:1 heptane:EtOAc to give tert-butyl N-[(3-cyanophenyl)(2H)methyl]carbamate (127 mg, 54.8% yield) as a yellow oil. MS(m / z): 179[M-tBu+H]+ b) 3-[amino(2H2)methyl]benzonitrile tert-Butyl N-[(3-cyanophenyl)(2H)methyl]carbamate (127 mg, 0.54 mmol) was dissolved in dry 1,4-dioxane (2.5 mL) then treated with HCl (4M in dioxane) (2.03 mL (4M), 8.13 mmol) and stirred for 16 h. The reaction was treated with an additional 0.5 mL of 4M HCl in dioxane and warmed to 40° C. for 1 h. The reaction was then blown down, treated with 8 mL of Et2O and sonicated to form a fine ppt which was then filtered off, washed with 2×4 mL of Et2O and dried in vacuo to give 3-[amino(2H)methyl]benzonitrile (75.7 mg, 82% yield) as an off-white solid. MS(m / z): 135.1[M+H]+. c) 1-[(3-cyanophenyl)-dideuteriomethyl]-3-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]urea The title compound was obtained as in Example 2 using 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride, 3-[amino(2H2)methyl]benzonitrile hydrochloride and 1,1'-carbonyldiimidazole as a white solid (yield 63%). MS(m / z):312.1[M+H]+.

[0502] Example 53: 1-(1-bicyclo[1.1.1]pentanyl)-3-[1-[3-(trifluoromethyl)phenyl]cyclopropyl]urea [ka] The title compound was obtained as in Example 37 using 1-isocyanatobicyclo[1.1.1]pentane and 1-[3-(trifluoromethyl)phenyl]cyclopropan-1-amine as a white solid (72% yield). MS(m / z):311.1[M+H]+.

[0503] Example 54: 1-(1-bicyclo[1.1.1]pentanyl)-3-[(1R)-2-hydroxy-1-[3-(trifluoromethyl)phenyl]ethyl]urea [ka] The title compound was obtained as in Example 37 using 1-isocyanatobicyclo[1.1.1]pentane and (2R)-2-amino-2-[3-(trifluoromethyl)phenyl]ethanol as a white solid (72% yield). MS(m / z): 315.1[M+H]+.

[0504] Example 55: 1-[(1R)-2-hydroxy-1-[3-(trifluoromethoxy)phenyl]ethyl]-3-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]urea [ka] Using 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride, rel-(2R)-2-amino-2-[3-(trifluoromethoxy)phenyl]ethanol and 1,1'-carbonyldiimidazole, the title compound was obtained as a white solid (yield 26%) in the same manner as in Example 2. MS(m / z): 399.1[M+H]+.

[0505] Example 56: 1-[[3-(difluoromethoxy)-4-fluorophenyl]methyl]-3-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]urea [ka] Using 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride, [3-(difluoromethoxy)-4-fluorophenyl]methanamine hydrochloride and 1,1'-carbonyldiimidazole, the title compound was obtained as a white solid (48% yield) in the same manner as in Example 2. MS(m / z):369.1[M+H]+.

[0506] Example 57: 1-[[3-(trifluoromethoxy)-2-fluorophenyl]methyl]-3-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]urea [ka] The title compound was obtained as in Example 2 as a white solid (yield 26%) using 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride, (3-(2,2,2-trifluoroethoxy)phenyl)methanamine and 1,1'-carbonyldiimidazole. MS(m / z): 387.1[M+H]+.

[0507] Example 58: 1-[[3-(2,2,2-trifluoroethoxy)phenyl]methyl]-3-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]urea [ka] Using 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride, [3-(trifluoromethoxy)-2-fluorophenyl]methanamine and 4-nitrophenyl chloroformate, the title compound was obtained as a white solid (55% yield) in the same manner as in Example 13. MS(m / z): 383.1[M+H]+.

[0508] Biological Experiments The efficacy of Kv7 enhancers was determined using the SyncroPatch 384 (Nanion) high-throughput electrophysiology platform.

[0509] Example 57 Cell Culture CHO cells stably expressing either human Kv7.2, Kv7.4 or Kv7.5 / 7.3 under the constitutive CMV promoter were used for these studies. Cells were maintained in F12 Hams+1 mM L-glutamine (Hyclone) supplemented with 10% FBS (Sigma), 0.3x NEAA (non-essential G amino acids) and 400ug / ml G418 at 37°C, 5% CO2. Cells were cultured in T-225 flasks (Nunc) for 2-3 days to reach 85-95% confluence before electrophysiological recordings were performed.

[0510] Example 58 Solution The solution had the following composition: Earle's Balanced Salt Solution (mM): 135 NaCl, 5.4 KCl, 5 Glucose, 2 CaCl2, 1 MgCl2, 5 HEPES, pH 7.4. Seal Enhancer Solution (mM): 90 NaCl, 3 KCl, 35 CaCl2, 10 MgCl2, 10 HEPES, pH 7.4. Extracellular Recording Solution (mM): 71 NaCl, 70 NMDG, 13 KCl, 5 Glucose, 2 CaCl2, 1 MgCl2, 10 HEPES, pH 7.4. Intracellular Recording Solution (mM): 130 KF, 20 KCl, 4 EGTA, 10 HEPES, 2 EDTA, 0.01 Escin, pH 7.2.

[0511] Example 59 Cell Preparation Once adequate confluence was reached, cells were harvested for electrophysiological recordings. Cells were first washed with DPBS (Hyclone, Cat. No. SH30028.03) and then 2 ml of Accutase (MP Biomedicals No. 1000449) was added at 28°C until approximately 90% of the cells were suspended. F12 HAM medium + 1 mM L-glutamine (Hyclone, SH30026.02) was then added to the flask to dilute the accutase. Cells were then triturated until a single cell suspension was achieved, a cell count was performed, and cells were centrifuged at 1,000 rpm for 2 min. The medium was then aspirated and cells were diluted to 0.75 × 10 6 The cells were resuspended in Earle's Balanced Salt Solution to a concentration of 10 cells / ml and allowed to recover at 10°C for 25 minutes.

[0512] Example 60: SyncroPatch recording At the start of each assay, 20 μl of cell suspension was dispensed into each well of a multihole 384-well SyncroPatch chip by the on-board pipettor. Cell sealing was initiated and seal enhancer solution was added to promote seal formation. Once sealing was complete, cells were washed three times with extracellular recording solution and the assay voltage protocol was started. Human Kv7.2, Kv7.4 or Kv7.5 / 7.3 channels were assessed using a voltage protocol in which cells were voltage clamped at a holding potential of -60 mV. Potassium currents were sequentially activated by a series of three voltage steps to -30 mV for 3 s, 40 mV for 1 s and -90 mV for 4 s with 12 s between successive voltage sweeps. Potassium currents were measured from the -90 mV repolarization step. Baseline currents were assessed for 3.5 min before the addition of 5.6 μM zinc pyrithione (1 μM for Kv7.4). Kv7.2, Kv7.4 or Kv7.5 / 7.3 currents in the presence of zinc pyrithione were acquired over 5 min to allow channels to reach steady-state activity before addition of test agents. Channel activity was monitored for 3 min before addition of 30 μM ML-213 (3 min) to achieve maximal activation. 150 mM TEA containing 10 μM XE-991 was applied for 2 min to measure leak current during maximal inhibition of Kv7.2, Kv7.4 or Kv7.5 / 7.3 channels.

[0513] Example 61 Data Analysis Data were collected on the SyncroPatch platform using PatchControl software (Nanion) and processed and analyzed using DataControl software (Nanion). Activation percentages were calculated from potassium currents as follows: the average current of five sweeps in the presence of zinc pyrithione immediately prior to the addition of test agent was considered as the "control" data. Similarly, for "drug" data, the average potassium current in the presence of test agent of five sweeps immediately prior to the addition of 30 μM ML-213 was determined. For "maximal activation" data, the average potassium current of five sweeps immediately prior to the addition of 150 mM TEA + 10 μM XE-991 was determined, and for "maximal inhibition" data, the average current from five sweeps immediately prior to the addition of TEA was determined. Using Pipeline Pilot (Accelrys), activation percentages for each of the 384 wells of the seal chip were calculated as (("drug" - "maximal inhibition") / ("maximal activation" - "maximal inhibition"))*100. Activation percentages were plotted as a function of concentration, and concentration-response curves were calculated as EC 50 The logistic equation to determine (IDBS ABASE) was fitted: Y is Bottom + (Top-Bottom) / (1 + 10^((LogEC50-X)*HillSlope)). EC50 for human Kv7.2 50 The values ​​are shown in Table 1.

[0514] Example 62 Microsomal Clearance Pooled, gender-mixed human liver microsomes were purchased from BioIVT at a concentration of 20 mg protein / mL and stored at -80°C. Incubations were performed in V-bottom 350 μL polypropylene 96-well plates. Compounds were diluted in phosphate buffer (final concentration 0.5 μM compound, 0.5% DMSO) and mixed with diluted liver microsomes (fc 0.25 mg / mL). This mixture was aliquoted into assay plates (6 wells per compound) and pre-warmed at 37°C for 10 min. The time course was initiated by the addition of NADPH (fc 0.5 mM, final incubation volume 100 μL) to each well. Reactions were stopped at 0.5, 3, 5, 10, 20 and 30 min by the addition of 150 μL of acetonitrile containing the internal standard (IS; 0.125 μg / mL daidzein) and stopped samples were removed to a clean polypropylene plate. At the end of the assay, the plates were refrigerated for 1 hour and then centrifuged at 3000 rpm for 10 minutes at 4°C. Samples of the supernatant were removed to a new plate, diluted 10-fold with 50:50 acetonitrile:water, and then heat sealed. Analysis was by liquid chromatography coupled with tandem mass spectrometry (LC-MS / MS) for analyte and IS levels. For calculation of results, ratios of analyte to IS peak areas were generated (IS ratios). Dextromethorphan and verapamil were included in each experiment as controls for high clearance compounds. IS ratio data were transformed to natural logarithmic values, which were plotted against time, and a linear regression fit was applied. The slope of the line was adjusted by multiplying by -1 to account for the extinction constant (k el ) and converted back to the in vitro CL using the extinction constant. int was calculated as: in vitro CL int (μL / min / mg protein) is k el *(1000 / protein concentration (mg / mL)).

[0515] Example 63 The compound of formula (I), or a solvate or a pharma- ceutically acceptable salt thereof, may be used in a manner known per se as the active ingredient for the manufacture of tablets of the following composition: per tablet Active ingredient: 200mg Microcrystalline cellulose 155mg Cornstarch 25mg Talc 25mg Hydroxypropyl methylcellulose 20mg 425mg

[0516] Example 64 The compound of formula (I) or a solvate or a pharma- ceutically acceptable salt thereof can be used in a manner known per se as an active ingredient to prepare capsules of the following composition: Per capsule Active ingredient 100.0mg Cornstarch 20.0mg Lactose 95.0mg Talc 4.5mg Magnesium stearate 0.5mg 220.0mg

[0517] The foregoing invention has been described in some detail by way of illustration and example for purposes of clarity and understanding. It will be apparent to those skilled in the art that changes and modifications may be practiced within the scope of the appended claims. It is therefore to be understood that the above specification is illustrative and is not intended to be limiting. The scope of the invention should therefore be determined not with reference to the above specification, but instead with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled.

[0518] All patents, patent applications, and publications cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual patent, patent application, or publication was so individually indicated.

Claims

1. A compound selected from the group consisting of: Table 1 or a solvate or pharmaceutically acceptable salt thereof.

2. Use of a compound of claim 1 or a solvate or pharmaceutically acceptable salt thereof in the manufacture of a medicament for the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the disorder, disease or disability is selected from behavioral disorders, mood disorders, neurodevelopmental disorders, intellectual disabilities, epilepsy, neurodegenerative diseases, pain, migraine, and tinnitus.

3. A pharmaceutical composition comprising the compound of claim 1 or a solvate or pharmaceutically acceptable salt thereof for use in the therapeutic and / or prophylactic treatment of a disorder, disease or disability associated with Kv7.2 in a subject in need thereof, wherein the disorder, disease or disability is selected from behavioral disorders, mood disorders, neurodevelopmental disorders, intellectual disabilities, epilepsy, neurodegenerative diseases, pain, migraine, and tinnitus.