Novel carboxamide derivatives

Abstract

The present invention relates to a general formula (I): 【Chemical 1】 JPEG2026517859000271.jpg29151 (wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A 1 , A 2 and X are as defined herein) To provide a novel bicyclopentanyl compound having the same or a solvate or a pharmaceutically acceptable salt thereof, a composition containing this compound, a process for producing this compound, and a method of using this compound.

Description

Technical Field

[0001] Field of the Invention The present invention relates to novel carboxamide compounds useful as Kv7.2 enhancers (or positive modulators), their production, pharmaceutical compositions, kits containing these compounds, and their use as agents for the therapeutic and / or prophylactic treatment of disorders, diseases or impairments associated with Kv7.2. These disorders, diseases or impairments can be selected from behavioral disorders, mood disorders, neurodevelopmental disorders, intellectual disorders, epilepsy, neurodegenerative diseases, pain, migraine and tinnitus.

Background Art

[0002] Background of the Invention Potassium channel family 7 or Q in humans includes five proteins encoded by the genes KCNQ1, KCNQ2, KCNQ3, KCNQ4 and KCNQ5. These KCNQ proteins form homomeric and heteromeric channels that respond to changes in membrane voltage and open to allow potassium ions to flow out of the cell membrane. Homomeric Kv7.2 channels as well as heteromeric Kv7.2 and Kv7.3 channels have been studied for their unique distributions and their potential roles as major regulators of neuronal excitability in many CNS and PNS pathways (Wang et al., 1998). The KCNQ2 channel controls the neuronal resting membrane potential, spike frequency adaptation of neuronal firing and presynaptic release. Dysfunction of this channel destabilizes the network even when lost only in inhibitory neurons (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). Regardless of whether it is primary or secondary EE, seizure activity worsens clinical outcomes and alters normal neurodevelopment (von Deimling, Helbig and Marsh, 2017).

[0004] Childhood epilepsy affects approximately 1 in 200 children (Waaler et al., 2000) and causes cognitive, behavioral, and neurological impairments (Simkin and Kiskinis, 2018). In cases of specific pathogenic KCNQ2 mutations, the majority of patients experience developmental delays, even though most individuals eventually become seizure-free (Kato et al., 2013). Targeting the Kv7 channel provides a genetically validated target for epilepsy due to the different modes of action among antiepileptic drugs (Gunthorpe, Large and Sankar, 2012). Kv7.2 enhancers show potential to alter neurodevelopmental trajectories by addressing the neural network instability that causes epilepsy (Kessi et al., 2020).

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

[0006] Atypical sensory processing (ASP) (Thye et al., 2018), another defining characteristic of ASD, is also driven by convergent genetic features observed in co-twin control studies (Neufeld et al., 2021). The biology involved in increased sensory sensitivity has been studied in preclinical models, where hyperexcitability of multisensory neurons appears independently of genetic manipulation that originally causes pathological neurodevelopment. Some genes that, when manipulated, result in increased sensory sensitivity include CNTNAP2 (Penagarikano et al., 2011), SHANK3 (Holder and Quach, 2016), and GABRB3 (Tanaka et al., 2012). Kv7.2 enhancers have shown potential to modify the neurodevelopmental trajectory in ASD by normalizing network stability, neural information processing, and sensory abnormalities, ultimately contributing to 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] The Kv7.2 enhancer has also shown promise in syndromic neurodevelopmental disorders, partly due to the prevalence and impact of epilepsy (Budisteanu et al., 2020). For example, epilepsy is prevalent in Angelman syndrome (over 80%), with most cases starting before the age of 3 (Fiumara et al., 2010).

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

[0009] In fragile X syndrome, approximately 15% of individuals experience epilepsy (Berry-Kravis, 2002) and also exhibit abnormal sensory processing (McCullagh et al., 2020). KCNQ2 (Kv7.2 gene) is downregulated in rodent models in the absence of fragile X intellectual disability protein (FMRP) (Zhang et al., 2018). Therefore, Kv7.2 enhancers may have a positive effect on fragile X by acting on both epilepsy and sensory processing.

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

[0011] For all of these neurodevelopmental disorders, early diagnosis and identification of the correct anti-epileptic treatment are central to strategies aimed at normalizing the neurodevelopmental trajectory.

[0012] Within behavioral disorders, Kv7.2 enhancers showed promise in attention deficit hyperactivity disorder (ADHD) and major depressive disorder (MDD, depression). Some patients with KCNQ2 mutations and a mild epileptic phenotype exhibit cognitive delay and ADHD (Lee et al., 2019). Kv7.2 enhancers were suggested to address neural network instability and behavioral impulsivity associated with ADHD. In the MDD domain, retigabine (Kv7 opener) demonstrated antidepressant efficacy in patients by acting on the brain's reward centers (Tan et al., 2018). The significant reduction in depressive symptoms observed with retigabine positions Kv7.2 enhancers as a treatment candidate in MDD.

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

[0014] Within the context of sensory abnormalities, abnormal plasticity of the KCNQ2 channel is strongly associated with the induction of tinnitus (Li, Choi and Tzounopoulos, 2013). This association is based on the localization of the Kv7.2 channel in the cochlea (Jin et al., 2009) and how cochlear injury depends on the neuronal excitability driven by Kv7.2 channel closure (Liu, Glowatzki and Fuchs, 2015). Retigabin prevents the development of tinnitus in preclinical models (Li, Choi and Tzounopoulos, 2013). Interestingly, evidence supporting how KCNQ2 pathology is related across indications is the prevalence of tinnitus and hyperacusis in ASD compared to the general population (Danesh et al., 2015).

[0015] In neurodegenerative diseases, unregulated K+ homeostasis in a chronic neuroinflammatory state 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), with axonal hyperexcitability in particular predicting survival (Kanai et al., 2012). Patient-derived motor neurons exhibit membrane hyperexcitability, and the tool compound retigabine (a pan-Kv7 enhancer) rescues this phenotype (Wainger et al., 2014). Motor neuron hyperexcitability has been found early in in vivo systems before the onset of the disease (Kuo et al., 2004), and this is a contributing factor to disease progression. In recent years, clinical trials using retigabine in ALS have demonstrated its effectiveness against functional biomarkers of ALS (Wainger et al., 2021) and its ability to protect against peripheral neuropathy preclinically (Nodera et al., 2011).

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

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

[0018] Therefore, enhancing the activity of Kv7.2 is a promising strategy for the treatment or prevention of diseases related to Kv7.2. These include 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] International Publication No. 2020 / 163268 relates to pyridine urea derivatives as KCNQ enhancers.

[0020] U.S. Patent No. 5,384,330 relates to pharmacologically active 1,2,4-triaminobenzene derivatives that modulate potassium ion channels Kv7.2 - Kv7.5 (KCNQ2 - KCNQ5) for the treatment of drug-resistant epilepsy. This compound has shown tolerance problems and other side effects.

[0021] To date, drugs acting on Kv7.2 have not been approved for the treatment of any of the diseases, disorders or disabilities described herein, and thus there is a need for modulators of Kv7.2 that provide a therapeutic effect. Furthermore, it would be beneficial to have a Kv7 modulator that is more highly selective for Kv7.2 than other Kv7 channels. For example, there is a need for Kv7.2 modulators that provide a combination of favorable pharmacological properties such as potency, selectivity and metabolic stability.

[0022] Therefore, an object of the present invention is to provide a selective Kv7.2 enhancer having favorable pharmacological properties useful as a Kv7.2 enhancer (or positive modulator) for the therapeutic and / or prophylactic treatment of disorders, diseases or disabilities related to Kv7.2.

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Zhao, G. et al. (2020) “Gene4Denovo: an integrated database and analytic platform for de novo mutations in humans,” Nucleic acids research. Oxford Academic, 48 (D1), pp. D913-D926. [Overview of the project] [Means for solving the problem]

[0024] Summary of the present invention In some embodiments, the formula provided herein is (I): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A 1 , A 2 (and X is as defined herein) It is a compound of the same, or its solvate or a pharmaceutically acceptable salt thereof.

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

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

[0027] In a further embodiment, the present invention provides a compound of formula (I) or a solvate or pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for use in the therapeutic and / or preventive treatment of disorders, diseases or impairments related to Kv7.2.

[0028] In a further embodiment, the present invention provides the use of a compound of formula (I) or its solvate or pharmaceutically acceptable salt or a pharmaceutical composition containing the same in therapeutic and / or prophylactic treatment of disorders, diseases or impairments related to Kv7.2.

[0029] In a further embodiment, the present invention provides the use of a compound of formula (I) or its solvate or pharmaceutically acceptable salt or a pharmaceutical composition containing the same for the manufacture of agents for the therapeutic and / or prophylactic treatment of disorders, diseases or impairments related to Kv7.2.

[0030] In a further embodiment, the present invention provides a method for therapeutic and / or prophylactic treatment of a disorder, disease or impairment related to Kv7.2, comprising administering a therapeutically effective amount of a compound of formula (I) or a solvate or pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

[0031] In a further embodiment, the present invention is a kit for use in the therapeutic and / or preventive treatment of disorders, diseases or impairments related to Kv7.2, a) A compound of formula (I) or its solvate or pharmaceutically acceptable salt or a pharmaceutical composition containing the same or a pharmaceutical composition for use, b) Instructions for use and We provide a kit that includes this.

[0032] The compounds of formula (I) described herein, or their solvates or pharmaceutically acceptable salts, offer a combination of beneficial pharmacological properties, such as potency, selectivity, and metabolic stability. Adequate metabolic stability is important to ensure a suitable pharmacological half-life, which is best achieved with compounds having a human liver microsomal clearance of less than 20 μL / min / mg. Selectivity within the Kv7 family is desirable to avoid effects on tissues where the indications described herein are not therapeutically viable. For example, the effects of Kv7.4 and Kv7.5 in skeletal muscle and smooth muscle affect human arterial function, and KCNQ2 expression is minimal or undetectable in these tissues (Ng et al 2011). [Modes for carrying out the invention]

[0033] Detailed description of the present invention definition Features, integers, properties, compounds, chemical parts, or groups described in conjunction with specific aspects, embodiments, or examples of the present invention should be understood to be applicable to any other aspects, embodiments, or examples described herein, unless otherwise adapted. All features and / or steps of any method or process disclosed herein (including the appended claims, abstract, and drawings) may be combined in any combination, except for any combination in which at least some of such features and / or steps are mutually exclusive.

[0034] The present invention is not limited to the details of any embodiments expressly disclosed herein. Any embodiments described herein may be combined with any other embodiments. The present invention extends to any novel one or any novel combination of features disclosed herein (including the appended claims and abstract), or any novel one or any novel combination of any embodiments, or any step of any method or process so as disclosed herein.

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

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

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

[0038] "To administer," "to be administered," or "to administer" means the impartation of the compound of the present invention to a patient or subject by any means (e.g., infusion, inhalation, injection, paste, suppository, or tablet) when used to treat a disorder, disease, or impairment described herein therapeutically and / or prophylactically.

[0039] As used herein, the terms “inclusive,” “contains,” and “includes” are used in their open and unrestricted sense.

[0040] The articles “a” and “an,” when used in this disclosure, may refer to one or more (e.g., at least one) grammatical objects of these articles. For example, “element” may mean one or more elements.

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

[0042] Where described herein, the chemical groups in this disclosure may be “unsubstituted” or “substituted” with one or more substituents (e.g., 1, 2, 3, 4, or 5), may be “substituted” as generally shown herein, or may be “substituted” as exemplified by certain classes, subclasses, and species of this disclosure. Generally, the term “substituted” refers to the replacement of a hydrogen atom in a given structure with a particular substituent. In some embodiments, multiple hydrogen atoms are replaced with a particular substituent (e.g., two hydrogen atoms are replaced with one oxo substituent). The substituent combinations envisioned by this disclosure typically result in the formation of stable or chemically feasible compounds. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In yet another embodiment, an optionally substituted group has three substituents. In yet another embodiment, an optionally substituted group has substituents as described herein. As used herein, the term “unsubstituted” may mean that a particular group has no substituents beyond the enumerated portion (for example, if its valence is filled with hydrogen).

[0043] "Effective dose" or "therapeutic effective dose" refers to an amount of the compound of the present invention, particularly the compound of formula (I) or its solvate or pharmaceutically acceptable salt or the aforementioned pharmaceutical composition, that is sufficient to produce a desired therapeutic outcome, such as a reduction in the severity of the duration of one or more signs, symptoms or causes of a disease, disability or disability, stabilization of such severity or elimination thereof. In therapeutic use, beneficial or desirable results may include, for example, a reduction in one or more symptoms (biochemical, histological and / or behavioral) arising from a disease, disability or disability, including complications and intermediate pathological phenotypes presented during the onset of the disease, disability or disability; an improvement in the quality of life of a person suffering from a disease, disability or disability; a reduction in the dose of other drugs required to treat the disease, disability or disability; an enhancement of the effect of another drug therapy; a delay in the progression of the disease, disability or disability and / or an extension of the patient's survival.

[0044] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological efficacy and properties of a free base or free acid and is not biologically or otherwise undesirable. Such salts are formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, especially hydrochloric acid) and organic acids (e.g., 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 a free acid. Examples of 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, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine resin, trimethylamine resin, diethylamine resin, triethylamine resin, tripropylamine resin, ethanolamine resin, lysine resin, arginine resin, N-ethylpiperidine resin, piperidine resin, polyimine resin, and salts of the same.

[0046] The terms “excipient” or “pharmaceutical excipient,” as used herein, refer to any pharmaceutically acceptable excipient that may be used in the manufacture of a drug or pharmaceutical composition, such as a tablet containing a compound (or tautomer or pharmaceutically acceptable salt) described herein as an active ingredient. The term excipient may include, but is not limited to, any substance used as a diluent, filler, bulking agent, binder, disintegrant, flow enhancer, humectant, coating, emulsifier or dispersant, compression / encapsulation aid, cream or lotion, lubricant, parenteral administration solution, chewable tablet material, sweetener or flavoring agent, suspension / gelling agent or wet granulator. Disintegrants are excipients that swell and dissolve when wet, thereby causing the tablet to disintegrate in the body, releasing the active ingredient for absorption. Examples include cross-linked polymers such as crospovidone and croscarmellose sodium, and modified starches such as sodium starch glycolate. Fillers are excipients that increase the size of a tablet by increasing its bulk volume. Fillers ensure that the final product reaches a volume suitable for patient handling. Examples of fillers include vegetable cellulose, lactose, starch, and mannitol. Specific examples include lactose monohydrate such as Pharmatose 200M, microcrystalline cellulose (MCC) such as Avicel PH101 or Avicel PH102, and spray-dried lactose such as Fast Flo 316™. Binders refer to excipients that hold the components of a tablet together. Binders ensure that tablets and granules can be formed with the required mechanical strength. Examples of binders include polyvinylpyrrolidone (PV), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), cellulose, sugar alcohols such as sorbitol, proteins such as gelatin, and polymers such as PVP, e.g., copovidone (PVP / VA 64), and PEG. Lubricants refer to excipients that prevent components from agglomerating and sticking to tablet punches or capsule filling machines. The lubricant also ensures that the tablet can be formed and ejected with a low ratio of the active ingredient to the wall.Examples of lubricants include minerals such as talc or silica, and fats such as stearin and magnesium stearate. Examples of coatings include cellulose phthalate acetate, ethylcellulose, gellan gum, maltodextrin, and enteric coatings. Examples of compression / encapsulation aids include calcium carbonate, dextrose, fructose dc (dc - "directly compressible"), honey dc, lactose (anhydrous or monohydrate, optionally combined with aspartame, cellulose, or microcrystalline cellulose), starch dc, and sucrose. Examples of creams or lotions include maltodextrin and carrageenan. Examples of chewable tablet materials include dextrose, fructose dc, and lactose (monohydrate, optionally combined with aspartame or cellulose). Examples of suspending / gelling agents include carrageenan, sodium starch glycolate, and xanthan gum. Examples of sweeteners include aspartame, dextrose, fructose dc, sorbitol, and sucrose dc. Examples of wet granulating agents include calcium carbonate, maltodextrin, and microcrystalline cellulose. In some cases, the term "excipient" includes pharmaceutically acceptable carriers. Those skilled in the art know of suitable pharmaceutical compositions for use in the treatment of patients and methods for producing them.

[0047] The terms “patient” or “subject” may include both mammals and non-mammals. Examples of mammals may include, but are not limited to, any member of the following classes of Mammalia: humans, non-human primates such as chimpanzees, monkeys, baboons or rhesus monkeys and other apes and monkey species, domestic animals such as cattle, horses, sheep, goats and pigs, companion animals such as rabbits, dogs and cats, laboratory animals such as rodents such as rats, mice and guinea pigs and similar species. Examples of non-mammals may include, but are not limited to, birds, fish and similar species. “Patient” or “subject” may include both humans and animals. In some preferred embodiments, “patient” or “subject” is human.

[0048] As used herein, the terms “to treat” or “to treat” mean to postpone the onset of one or more diseases, disabilities or impairments, to prevent the onset of one or more diseases, disabilities or impairments, and / or to reduce the severity of one or more symptoms of a disease, disability or impairment that is expected to develop or manifest. Therefore, these terms may include remission of symptoms of one or more existing diseases, disabilities or impairments, prevention of one or more additional symptoms, remission or prevention of the underlying cause of one or more symptoms, inhibition of a disease, disability or impairment, e.g., prevention of the onset of a disease, disability or impairment, mitigation of a disease, disability or impairment, induction of regression of a disease, disability or impairment, mitigation of symptoms caused by a disease, disability or impairment, or cessation or reduction of symptoms of a disease, disability or impairment.

[0049] The compounds of the present invention and disclosure may exist as solvates. The term "solvate" may refer to a variable stoichiometric complex formed by a solute and a solvent. Such a solvent for the purposes of this disclosure cannot interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates in which water is the solvent molecule are typically referred to as hydrates. Examples of hydrates include compositions containing a stoichiometric amount of water and compositions containing a variable amount of water. In some embodiments, solvates are excluded.

[0050] When used herein, the term “prevention” includes: preventing or delaying the onset of clinical symptoms of a disease, disability or disability in a patient or subject (especially a human) who is susceptible to or prone to any of the diseases, disabilities or disabilities described herein, but who has not yet experienced or shown any clinical or subclinical symptoms of such disease, disability or disability.

[0051] Where used herein, the term “about” means, when referring to a value, to include variations from a specified amount of, for example, ±20% in some embodiments, ±10% in some embodiments, ±5% in some embodiments, ±1% in some embodiments, ±0.5% in some embodiments, and ±0.1% in some embodiments, and so the variations are appropriate for carrying out the methods of the Disclosure or using the compositions of the Disclosure.

[0052] Where a range of values ​​is provided, unless the context explicitly indicates otherwise, each value interposing between the upper and lower limits of this range (up to one-tenth of the lower limit) and any other specified or interposing values ​​within that specified range are understood to be included in the invention. The upper and lower limits of these smaller ranges (which may independently be included in smaller ranges) are also included in the invention, subject to any specifically excluded limit values ​​within the specified range. Where a specified range includes one or both of the limit values, a range excluding one or both of these included limit values ​​is also included in the invention.

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

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

[0055] The term “package insert” is used to refer to the instructions that are customarily included in the market packaging of such therapeutic drugs, including information relating to the indications, usage, dosage, administration, contraindications, and / or warnings for the use of such therapeutic drugs.

[0056] The terms "compound of this invention," "compounds of the present invention," and "compounds of the present invention," as well as similar expressions, include stereoisomers, geometric isomers, solvates, pharmaceutically acceptable salts, tautomers, metabolites, prodrugs, polymorphs, and mixtures thereof, including the compound of formula (I), compounds selected from formulas (II) to (XV), the compounds of Table 1, and the compounds shown elsewhere in this application. In some embodiments, solvates are not included.

[0057] "*", "---", or drawn at the end of a bond or through a bond. [ka] The symbols indicate the attachment points of a functional group or other chemical part to the remainder of a molecule. Therefore, for example, [ka] teeth, [ka] As shown, this means that the substituent is attached to the rest of the molecule.

[0058] The bonds depicted in the ring system (as opposed to those linked at separate vertices) indicate that these bonds can attach to any of the suitable ring atoms.

[0059] As used herein, the terms "optional" or "optionally" mean that the subsequently described event or situation may or may not occur and that this description includes both the case where the event or situation occurs and the case 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 a compound may or may not be substituted as defined herein. The term "optionally substituted" means that a particular group is unsubstituted or substituted by one or more substituents independently selected from the group of possible substituents. When indicating the number of substituents, the term "one or more" means from one substituent up to the highest possible number of substitutions, i.e., from replacement of one hydrogen to replacement of all hydrogens by substituents.

[0060] As used herein, the term "independently" is used to indicate that a variable element applies in any one instance, regardless of the presence or absence of variable elements having the same or different definitions within the same compound. Thus, in a compound where R'' appears 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 can be nitrogen. Additionally, for example, in a compound where R 2 and R 3 are independently selected from hydrogen and hydroxyC 1~6 alkyl, both R 2 and R 3 can be hydrogen, or both can be hydroxyC 1~6 alkyl, or one of R 2 and R 3 can be hydrogen and the other can be hydroxyC 1~6 alkyl.

[0061] In this application, units such as ul, uMol, and C mean μL, μMol, and ℃, etc.

[0062] "EC" in this application50 The term "agonist effect" is defined as being determined by testing the compound in an in vitro assay as described herein, thereby measuring the effect of the compound over various compound concentrations. The obtained data are plotted as a concentration-response curve, which typically follows a sigmoid function, with the compound concentration plotted on the x-axis and the response (agonist effect) plotted on the y-axis. 50 The term "maximum half-volume effective concentration" refers to the maximum response (E) observed for a particular compound in a given in vitro assay. max This shows the concentration of this compound required to obtain 50% of the product.

[0063] The compounds of the present invention may exist in one or more stereoisomers (e.g., containing one or more chiral carbon atoms). Individual stereoisomers (enantiomers and diastereomers) and mixtures thereof are within the scope of the subject matter disclosed herein.

[0064] Similarly, compounds or salts may exist in tautomeric forms other than those shown by formulas, and these are also understood to be within the scope of the subject matter disclosed herein. It should be 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 and purified enantiomers or enantiomerically / diastereomerically enriched mixtures. It should be understood that the subject matter disclosed herein includes combinations and subsets of the specific groups defined herein.

[0065] The compounds of the present invention may contain several chiral centers and may exist in the form of optically pure enantiomers, mixtures of enantiomers, such as racemates, optically pure diastereoisomers, mixtures of diastereoisomers, racemates of diastereoisomers, or mixtures of racemates of diastereoisomers.

[0066] According to the Cahn-Ingold-Prelog Convention, an asymmetric carbon atom can have either an "R" or "S" stereoconfiguration.

[0067] The term "chiral" refers to a molecule that cannot be superimposed on its mirror image, while the term "achiral" refers to a molecule that can be superimposed on its mirror image. Chiral separation of a racemate into its enantiomer components can be performed to separate the utemer and distomer.

[0068] The term "stereoisomer" refers to compounds that have the same chemical structure but differ in the arrangement of atoms or groups in space.

[0069] A "diastereomer" refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as different melting points, boiling points, spectral properties, and reactivity. Mixtures of diastereomers can be separated using high-resolution analytical procedures such as chromatography.

[0070] An "enantiomer" refers to two stereoisomers of a compound whose mirror images cannot be superimposed on each other.

[0071] The definitions and conventions of stereochemistry used herein generally follow SP. 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 a chiral or asymmetric center and may therefore exist in various stereoisomers. Diastereomers, enantiomers, and atropisomers, as well as mixtures thereof, such as racemic mixtures, are examples, but are not limited to these; all stereoisomers of the compounds of the present invention are intended to form part of the present invention. Any organic compound may exist in an optically active form, i.e., the organic compound has the ability to rotate the plane of plane-polarized light. In the description of optically active compounds, the prefixes D and L or R and S are used to represent the absolute configuration of the molecule around its chiral center. The prefixes d and l, or (+) and (-), are used to indicate the sign of the rotation of plane-polarized light by the compound, where (-) or 1 means the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. With respect to a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Certain stereoisomers may also be called enantiomers, and mixtures of such isomers are often called enantiomer mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0072] The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantimer species that lack optical activity.

[0073] The term "tautomer" or "tautomer" refers to structural isomers of various energies that can be interconverted across low-energy barriers. For example, proton tautomers (also known as prototropic tautomers) are interconverted via proton transfer, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers are interconverted through partial rearrangement of bonded electrons.

[0074] Individual enantiomers and diastereomers are included in the table below, named by compound name, and it should be understood that their corresponding structures can be easily determined from them. In some examples, enantiomers or diastereomers are identified by their respective properties (e.g., retention time on chiral HPLC) or their biological activity (e.g., biological activity as further described in the examples), and the absolute configurations of one or more chiral centers are 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).

[0075] In some embodiments of the present invention, only one of the possible enantiomers is used. In other embodiments, a mixture of possible enantiomers is used, with different proportions of each component.

[0076] In some embodiments, the compounds of the present invention are isotope-labeled by replacing one or more atoms in the compound with atoms of different atomic mass or mass number. Such isotope-labeled (e.g., radioactively labeled) compounds of formula (I) or their solvates or pharmaceutically acceptable salts are considered to be within the scope of this disclosure. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, for example, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N,15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I and 125 Examples include, but are not limited to, I. Certain isotope-labeled compounds of the present invention (e.g., those incorporating radioactive isotopes) are useful for studying drug and / or substrate tissue distribution. Radioactive isotope tritium, i.e. 3 H and carbon-14, that is 14 C is particularly useful for this purpose in terms of ease of incorporation and easy detection. For example, the compounds of the present invention can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.

[0077] In some embodiments, the compound of formula (I) or its solvate or pharmaceutically acceptable salt has, 2 H (deuterium), 3 H (tritium), preferably 2 It is particularly assumed that the molecule has one or more hydrogen atoms substituted with H (deuterium). Any of the hydrogen atoms in the structure can be substituted in this way.

[0078] 3 H, 11 C, 18 F, 15 O and 13 Substitution with positron-emitting isotopes such as 1N may be useful in positron emission tomography (PET) studies to investigate the acceptor occupancy of a substrate. The isotope-labeled compounds of the present invention can generally be prepared by prior art known to those skilled in the art, or by a process similar to that described in the examples below, using a suitable isotope-labeling reagent instead of an unlabeled reagent already in use.

[0079] In one embodiment, the present invention provides pharmaceutically acceptable salts of the compounds of the present invention, particularly pharmaceutically acceptable salts selected from hydrochloride, fumarate, lactate (particularly derived from L-(+)-lactic acid), tartrate (particularly derived from L-(+)-tartaric acid), and trifluoroacetate. In more specific embodiments, the present invention provides compounds relating to formula (I) as described herein (i.e., described as “free base” or “free acid” respectively), or solvates or pharmaceutically acceptable salts thereof.

[0080] When a bond in a compound of the present invention is depicted non-stereochemically (e.g., flatly), the atom to which this bond is attached includes all stereochemical possibilities. When a bond in a compound formula of this specification is depicted in a defined stereochemical style (e.g., bold, bold wedge, dashed line, or dashed wedge), it should be understood that, unless otherwise specified, the atom to which the stereochemical bond is attached is rich in the indicated absolute stereoisomers. In one embodiment, the compound may be at least 51% of the indicated absolute stereoisomers. In another embodiment, the compound may be at least 80% of the indicated absolute stereoisomers. In another embodiment, the compound may be at least 90% of the indicated absolute stereoisomers. In another embodiment, the compound may be at least 95% of the indicated absolute stereoisomers. In another embodiment, the compound may be at least 97% of the indicated absolute stereoisomers. In another embodiment, the compound may be at least 98% of the indicated absolute stereoisomers. In another embodiment, the compound may be at least 99% of the indicated absolute stereoisomers.

[0081] The term "alkyl" refers to monovalent or polyvalent (e.g., monovalent or divalent) linear or branched saturated hydrocarbon groups, and in particular to hydrocarbon groups with 1 to 6 carbon atoms ("C1-6 alkyl"), e.g., hydrocarbon groups with 1, 2, 3, 4, 5, or 6 carbon atoms. In some embodiments, alkyl groups include 1 to 3 carbon atoms, e.g., 1, 2, or 3 carbon atoms. Some non-limiting examples include 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-). Preferred non-limiting examples of alkyl are tert-butyl ((CH3)3C-) or methyl (CH3-). A preferred non-limiting example of alkyl is methyl(CH3-). Another preferred non-limiting example of alkyl is tert-butyl((CH3)3C-).

[0082] The term "alkoxy" refers to an alkyl group (already defined) attached to the parent molecule via an oxygen atom. The alkoxy group preferably comprises 1 to 6 carbon atoms ("C1-6 alkoxy"), for example, 1, 2, 3, 4, 5, or 6 carbon atoms. In other embodiments, the alkoxy group comprises 1 to 4 carbon atoms. In yet another embodiment, the alkoxy group comprises 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include CH3O- (methoxy), CH3CH2O- (ethoxy), CH3CH2CH2O- (n-propoxy), and (CH3)3CO- (tert-butoxy). A particularly preferred non-limiting example of an alkoxy is methoxy (CH3O-).

[0083] The term "halogen" or "halo" refers to fluoro(F), chloro(Cl), bromo(Br), or iodine(I). Preferably, the term "halogen" or "halo" refers to fluoro(F), chloro(Cl), or bromo(Br). Particularly preferred non-limiting examples of "halogen" or "halo" are fluoro(F) and chloro(Cl).

[0084] The term "cyano" refers to the -CN (nitrile) group.

[0085] The terms "hydroxy" or "hydroxyl" refer to the OH group.

[0086] 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, the "haloalkyl" is a C alkyl group in which one, two, or three hydrogen atoms of the alkyl group are replaced by halogen atoms. 1~6 The term refers to an alkyl group, i.e., haloalkyls include monohaloalkyls, dihaloalkyls, trihaloalkyls, perhaloalkyls, and the like. The halogen atom may be fluoro(F), chloro(Cl), or bromo(Br). Particularly preferred non-limiting examples of the "halogen" in the haloalkyl are fluoro(F) and chloro(Cl). More preferably, the haloalkyl is substituted with fluoro(F). Preferred non-limiting examples of haloalkyls are (CH3)2FC-(1-fluoroisopropyl), CF3CH2-(2,2,2-trifluoroethyl), CH3CF2-(1,1-difluoroethyl), CF3-(trifluoromethyl), CH2F-(fluoromethyl), or CHF2-(difluoromethyl). Particularly preferred are CH3CF2- and CF3-.

[0087] The term "haloalkoxy," as used herein, refers to an alkoxy group in which at least one hydrogen atom is replaced by a halogen atom. Preferably, "haloalkoxy" is an alkoxy group in which one, two, or three hydrogen atoms of the alkyl group are replaced by halogen atoms (preferably C 1~6The term "haloalkoxy" refers to an alkoxy group, and examples of haloalkoxys include monohaloalkoxys, dihaloalkoxys, trihaloalkoxys, perhaloaloxys, and the like. The halogen atom may be fluoro(F), chloro(Cl), or bromo(Br). Particularly preferred non-limiting examples of "halogen" are fluoro(F) and chloro(Cl). More preferably, the haloalkoxy is substituted with fluoro(F). Preferred non-limiting examples of haloalkoxys are CHF2O-, CH2FO-, CF3CH2O-, CF2HCH2O-, CH3CF2CH2O-, and CH3CFHCH2O-. Similarly preferred non-limiting examples of haloalkoxys are selected from CHF2O-, CH2FO-, CF3O-, FCH2CFHCH2O-, CH2FCH2O-, and CF3CH2O-. 1~6 It is an alkoxy compound. Particularly preferred are CHF2O-, CF3CH2O-, CF3O-, CH2FO-, or FCH2CFHCH2O-.

[0088] The term "hydroxyalkyl" preferably refers to an alkyl group having 1 to 6 carbon atoms, wherein at least one of the hydrogen atoms of the alkyl group is replaced by one or more hydroxyls. Preferably, "hydroxyalkyl" is an alkyl group, preferably C 1~6 The term "hydroxyalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms are replaced by hydroxyls, i.e., hydroxyalkyls include monohydroxyalkyls, dihydroxyalkyls, trihydroxyalkyls, perhydroxyalkyls, and the like. More preferably, "hydroxyalkyl" refers to an alkyl group in which one hydrogen atom is replaced by a hydroxyl. Particularly preferred non-limiting examples of hydroxyalkyls are HOCH2-(hydroxymethyl) and HOCH2CH2-(hydroxyethyl).

[0089] The term "heterocycloalkyl" refers to a monovalent, saturated or partially unsaturated monocyclic or bicyclic heterocyclic system of 4 to 6 ring atoms, comprising one, two, or three ring heteroatoms independently selected from N, O, and S, with the remaining ring atom being carbon. Preferably, "heterocycloalkyl" refers to a saturated monocyclic 4 to 6-membered heterocycloalkyl containing one O atom, and non-limiting examples include oxetanyl, oxolanyl, and oxanyl. Heterocycloalkyls may be substituted as described herein, for example, with halogens.

[0090] The term "cycloalkyl" refers to a ring having 3 to 10 carbon atoms (C3-C3). 10) refers to a monovalent non-aromatic saturated or partially unsaturated ring having 7 to 10 carbon atoms as a bicyclic ring. In some embodiments, cycloalkyl is a monocyclic 4 to 6-membered cycloalkenyl group having one non-aromatic double bond. In some embodiments, cycloalkenyl is selected from cyclobutenyl, cyclopentenyl, and cyclohexenyl. Polycyclic and bicyclic cycloalkyl groups may include fused or bridged polycyclic or bicyclic moieties, each ring being a saturated or partially unsaturated non-aromatic hydrocarbon. Cycloalkyl includes bicyclic cycloalkyls, which refer to a 4 to 10-membered bridged cycloalkyl moiety consisting of two saturated carbon rings having two carbon atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms. Bicyclic carbocyclic rings having 7 to 10 atoms may be arranged as, for example, bicyclo[4,5], [5,5], [5,6], or [6,6] systems, and bicyclic carbocyclic rings having 9 or 10 ring atoms may be arranged as bicyclo[5,6] or [6,6] systems, or as bridging 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 carbocyclic compounds include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopenta-1-enyl, 1-cyclopenta-2-enyl, 1-cyclopenta-3-enyl, cyclohexyl, 1-cyclohexa-1-enyl, 1-cyclohexa-2-enyl, 1-cyclohexa-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.

[0091] "Cyano C 1~6The term "alkoxy" preferably refers to an alkoxy group having 1 to 6 carbon atoms, wherein at least one hydrogen atom of the alkoxy group is replaced by one or more cyano atoms. Preferably, "cyanoC 1~6 "Alkoxy" is an alkyl group in which one, two, or three hydrogen atoms of the alkoxy group are replaced by cyano atoms, preferably C 1~6 Refers to an alkoxy. More preferably, "cyanoC 1~6 "Alkoxy" is a C molecule in which one hydrogen atom is replaced by a cyanonucleotide. 1~6 Refers to an alkoxy group. Cyano C 1~6 Particularly preferred non-limiting examples of alkoxys are NC-CH2-O-, NC-CH2CH2-O-, and NC-CH2CH2CH2-O-.

[0092] "C 3~5 Cycloalkyl C 1~6 When used herein, the term "alkoxy" means that at least one hydrogen atom is C 3~5 This refers to an alkoxy group that has been replaced by a cycloalkyl group. Preferably, "C 3~5 Cycloalkyl C 1~6 "Alkoxy" refers to a group where one, two, or three hydrogen atoms of the alkoxy group are C 3~5 This refers to an alkoxy group that has been replaced by a cycloalkyl group. Preferably, "C 3~5 Cycloalkyl C 1~6 "Alkoxy" is a group where one hydrogen atom of the alkoxy group is C 3~5 This refers to an alkoxy group that has been replaced by a cycloalkyl group. Preferably, the alkoxy group contains one carbon atom. Preferred non-limiting examples are 2-cyclopropylmethoxy and 2-cyclobutylmethoxy.

[0093] The term "heteroaryl," as used herein, refers to a five- or six-membered monocyclic aromatic group comprising at least one ring heteroatom. In some embodiments, the heteroatom is independently selected from the group consisting of N, O, and S atoms. The number of ring atoms refers to the total number of carbon atoms and heteroatoms in one ring. In some embodiments, the heteroaryl is a five- or six-membered monocyclic aromatic group having two N atoms. In some embodiments, the heteroaryl is a five- or six-membered monocyclic aromatic group comprising one N atom. In some embodiments, the heteroaryl is a five- or six-membered monocyclic aromatic group comprising one N atom and one O atom. Examples of five-membered heteroaryl groups include, but are not limited to, pyrrolylpyrazolyl, imidazolyl, oxazolyl, triazolyl, or furanyl. In some preferred embodiments, the five-membered heteroaryl is pyrazolyl, imidazolyl, or oxazolyl. In some more preferred embodiments, the five-membered heteroaryl is pyrazolyl or imidazolyl. Examples of six-membered heteroaryl groups include, but are not limited to, pyrimidinyl, pyridinyl, pyrazinyl, or pyridazinyl. In some more preferred embodiments, the six-membered heteroaryl is pyrazinyl, pyridinyl, or pyrimidinyl.

[0094] "Hydroxy C 2~4 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 hydroxyl groups. Preferably, "hydroxyalkenyl" refers to a C group in which one, two, or three hydrogen atoms of the alkenyl group are replaced by hydroxyl groups. 2~4 This refers to an alkenyl group, specifically hydroxyalkenyls such as monohydroxyalkenyls, dihydroxyalkenyls, trihydroxyalkenyls, perhydroxyalkenyls, and the like. A preferred non-limiting example of a hydroxyalkenyl is HO-CH2-CH=CH-.

[0095] The term “7- to 11-membered spirocyclic cycloalkyl” as used herein refers to a bicyclic spirocyclic cycloalkyl having 7, 8, 9, 10, or 11 carbon atoms and two saturated non-aromatic rings. In some embodiments, the spirocyclic cycloalkyl includes a tricyclic spiro-cycloalkyl containing 9- to 11 carbon atoms. In some embodiments, the ring directly attached to this molecule is not a four-membered ring. In some examples, the 7- to 10-membered spirocyclic cycloalkyl is selected from spiro[3.3]heptanyl, spiro[2.3]hexanyl, and spiro[3.4]octanyl, which are optionally substituted as described herein.

[0096] The term “7- to 11-membered oxo-spiro-heterocycloalkyl” as used herein refers to a bicyclic oxa-spiro-heterocycloalkyl comprising 7, 8, 9, 10, or 11 ring atoms, including two saturated monocyclic rings, where one ring contains one oxygen atom. In some embodiments, this oxygen atom is located in a ring directly attached to the molecule. In some embodiments, the ring directly attached to the molecule is not a four-membered ring. In some embodiments, the 7- to 11-membered oxa-spiro-heterocycloalkyl is selected from oxaspiroheptanyl, oxaspirooctanyl, oxaspironanyl, oxaspirodecanyl, and oxaspirowndecanyl. In some preferred embodiments, the oxa-spiro-heterocycloalkyl includes one oxygen atom to form a 9- to 10-membered oxa-spiro-heterocycloalkyl. Non-limiting examples of 9- to 10-membered oxa-spiro-heterocycloalkyl are selected from oxaspironanyl and oxaspirodecanyl. All oxo-spiro-heterocycloalkyl groups may be substituted as described herein.

[0097] The term “mood disorder,” as used herein, primarily relates to mental health problems affecting a person’s emotional state. It is a disorder in which a person experiences prolonged periods of extreme happiness, extreme sadness, or both. The two most common mood disorders are depression and bipolar disorder.

[0098] The term “depression,” as used herein, refers to a mood disorder characterized by a persistent feeling of sadness and loss of interest. This is also known as major depressive disorder (MDD).

[0099] The term "behavioral disorder" refers to a disorder characterized by patterns of disruptive behavior in children that persist for at least six months and cause problems in school, home, and social settings. The most important behavioral disorder is attention deficit hyperactivity disorder (ADHD).

[0100] The term "Attention Deficit Hyperactivity Disorder" (ADHD), as used herein, refers to a behavioral disorder characterized by inattention or excessive activity and impulsivity. ADHD is more common in people with epilepsy than in the general population. Children with ADHD are at higher risk of seizures, with approximately 14% of children with ADHD experiencing seizures.

[0101] The terms “developmental disorder” or “neurodevelopmental disorder,” as used herein, refer to a group of conditions caused by impairments in the physical, learning, language, or behavioral domains. These conditions may begin during development, affect daily functioning, and may persist for life. Examples of neurodevelopmental disorders include autism spectrum disorder ("ASD") and syndrome developmental disorders.

[0102] The term "Autism Spectrum Disorder (ASD)," as used herein, refers to a developmental disorder of varying severity characterized by difficulties in social interaction and communication, as well as restrictive or repetitive patterns of thinking and behavior. ASD encompasses forms that are mostly idiopathic but can also be symptomatic and is currently diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Version 5 (DSM-V).

[0103] The term “syndrome developmental disorder,” as used herein, refers to a developmental disorder having a clinically defined pattern of somatic abnormalities and a neurobehavioral phenotype that may include ASD. Diagnosis is typically confirmed by targeted gene testing. Examples of syndrome developmental disorders include Dup15q syndrome (Dup15q), Fragile X syndrome (FXS), and Angelman syndrome.

[0104] The terms “Dup15q syndrome” or “Duq15q,” as used herein, refer to the common name for chromosome 15q11.2–q13.1 duplication syndrome. This is a syndrome of developmental disorder caused by a partial duplication of chromosome 15, which increases the risk of autism spectrum disorder, epilepsy, and intellectual disability.

[0105] The term “Fragile X Syndrome” (FXS), as used herein, refers to a genetic disorder characterized by mild to moderate intellectual disability. This disorder is typically caused by an expansion of the CGG triplet repeat in the FMR1 (Fragile X Mental Retardation 1) gene on the X chromosome.

[0106] The term "Angelman syndrome," as used herein, refers to a genetic disorder primarily affecting the nervous system, resulting from a functional deficiency of a portion of chromosome 15 inherited from a person's mother. Characteristic features of this condition include developmental delay, intellectual disability, severe speech impairment, and motor and balance problems (ataxia). Most affected children may also experience recurrent seizures (epilepsy).

[0107] As used herein, the term “intellectual disability” (ID) refers to a generalized neurodevelopmental disorder characterized by significantly impaired intellectual and adaptive functioning. It is defined by an IQ below 70, in addition to two or more deficits in adaptive behavior affecting daily living and general life. ID is also known as a common learning disability and was formerly known as intellectual disability (MR).

[0108] As used herein, the term “epilepsy” refers to a neurological disorder characterized by sudden, recurrent episodes of sensory disturbances, loss of consciousness, or seizures associated with abnormal electrical activity in the brain. Examples of epilepsy include a wide range of childhood epilepsy, West syndrome, Ohtahara syndrome, and epileptic encephalopathy.

[0109] As used herein, the term “neurodegenerative disease” refers to diseases that involve the progressive loss of structure or function of neurons, including neuronal death. Examples of neurodegenerative diseases include, but are not limited to, Alzheimer’s disease and motor neuron disease.

[0110] As used herein, the term “motor neuron disease” 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).

[0111] As used herein, the term "pain" refers 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 such as chemotherapy-induced neuropathy, phantom limb pain, and psychogenic pain.

[0112] As used herein, the term "migraine" refers to a moderate to severe headache disorder that causes throbbing or pulsating pain over several hours or days.

[0113] As used herein, the term "tinnitus" refers to a condition characterized by the perception of sound in the absence of a corresponding external sound.

[0114] Any disease, disability, or impairment described herein also includes any condition or pathology associated with such disease, disability, or impairment.

[0115] Compound of the present invention All compound names for the compound structures were generated using OpenEye Lexichem, Version 1.2.0, OpenEye Scientific Software, Santa Fe, NM, USA, www.eyesopen.com.

[0116] Features, integers, properties, compounds, chemical parts, or chemical groups described in conjunction with specific aspects, embodiments, or examples of the present invention should be understood to be applicable to any other aspects, embodiments, or examples described herein, insofar as they do not conflict. All features and / or all steps of any method or process disclosed herein (including the appended claims, abstract, and drawings) may be combined in any combination, except for any combination in which at least some of such features and / or steps are mutually exclusive. The present invention is not limited to the details of any embodiments described herein. Any embodiment described herein may be combined with any other embodiment. For example, any embodiment herein relating to a compound of the present invention may be combined with any embodiment of a pharmaceutical composition, kit, medical use, or treatment method. The present invention extends to any novel one or any novel combination of features or any novel one or any novel combination of steps of any method or process disclosed herein (including the appended claims, abstract, and drawings).

[0117] In some embodiments of the present invention, the compound of formula (I) has a structure represented by any one of the formulas (II) to (XV) described herein.

[0118] The present invention relates to formula (I): [ka] (In the formula, A 1 is N or CR a And, A 2 is N or CR b And, R a is hydrogen or halogen, R b is hydrogen or halogen, R 1 is hydrogen, cyano, haloC 1~6 alkyl, C 1~6 alkoxy, haloC 1~6 alkoxyl and halogen, R 2 and R 3 are independently selected from hydrogen, hydroxy, C 1~6 alkyl, C 1~6 alkoxy, hydroxyC 1~6 alkyl, C 3~5 cycloalkylC 1~6 alkoxy, cyano, cyanoC 1~6 alkoxy, haloC 1~6 alkoxy, hydroxy-C 2~4 alkenyl, or R 2 and R 3 together with the carbon atom to which they are attached, optionally form a 4- to 6-membered heterocycloalkyl or 3- to 6-membered cycloalkyl optionally substituted with 1 to 4 halogens or oxo, or R 3 is absent and R 2 is =CHCH2OH, R 4 is hydrogen, hydroxyC 1~6 alkyl or halogen, R 5 is hydrogen or halogen, X is NH, NHCH2, CH2, CH2CH2, CH2CH2CH2, NHCH2CH2CH2, NHCH2CH2, CH=CH, CH2CH2CH(OH), CH2CH(OH), absent, CHFCH2, and

Chemical formula

[0119] In this application, regarding X [ka] The base means that the bond is not part of X, for example, X is a structure: [ka] This is a cyclopropyl incorporated into the compound of formula (I), as shown in the exemplary compound having the characteristic.

[0120] In one embodiment, the present invention relates to (i) A 1 (ii)A 2 (iii)A 1 and A 2 Both are N, or (iv) A 1 CR a and A 2 CR b The present invention provides a compound of formula (I), or its solvate or pharmaceutically acceptable salt thereof.

[0121] In one embodiment, the present invention is A 1 and A 2Only one of them is N, and the other is CR a or CR b The present invention provides a compound of formula (I), or its solvate or pharmaceutically acceptable salt thereof.

[0122] In one preferred embodiment, the present invention is A 1 CR a and A 2 CR b The present invention provides a compound of formula (I), or its solvate or pharmaceutically acceptable salt thereof.

[0123] In one preferred embodiment, the present invention is R a and R b The present invention provides a compound of formula (I), or a solvate or pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

[0124] In one preferred embodiment, the present invention is R a F is F, and R b The present invention provides a compound of formula (I), or a solvate or pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

[0125] In one embodiment, the present invention is given by formula: [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , X and R 6 (As described herein) The present invention provides a compound of formula (II) having , or a solvate or pharmaceutically acceptable salt thereof.

[0126] In one embodiment, the present invention is R 1 The present invention provides a compound of formula (I), or a solvate or pharmaceutically acceptable salt thereof, wherein is a halogen.

[0127] In one embodiment, the present invention is R 1The present invention provides a compound of formula (I), or a solvate or pharmaceutically acceptable salt thereof, which is a halogen selected from F, Cl, and Br.

[0128] In one embodiment, the present invention is R 1 The present invention provides a compound of formula (I), or a solvate or pharmaceutically acceptable salt thereof, which is a halogen selected from Cl and Br.

[0129] In one preferred embodiment, the present invention is R 1 The present invention provides a compound of formula (I), or its solvate or pharmaceutically acceptable salt, wherein the compound is Cl.

[0130] In one preferred embodiment, the present invention is R 1 is cyano or halo C 1~6 The present invention provides a compound of formula (I) that is an alkoxy, or a solvate or pharmaceutically acceptable salt thereof.

[0131] In one preferred embodiment, the present invention is R 1 The present invention provides a compound of formula (I), or a solvate or pharmaceutically acceptable salt thereof, wherein the compound is cyano.

[0132] In one preferred embodiment, the present invention is R 1 ga HaroC 1~6 The present invention provides a compound of formula (I) that is an alkoxy, or a solvate or pharmaceutically acceptable salt thereof.

[0133] In one preferred embodiment, the present invention is R 1 However, Halo C is selected from CHF2O-, CH2FO-, CF3CH2O-, CF2HCH2O-, CH3CF2CH2O-, and CH3CFHCH2O-. 1~6 The present invention provides a compound of formula (I) that is an alkoxy, or a solvate or pharmaceutically acceptable salt thereof.

[0134] In one preferred embodiment, the present invention is R 1 The present invention provides a compound of formula (I), or its solvate or pharmaceutically acceptable salt, wherein the compound is CHF2O-.

[0135] In one embodiment, the present invention is given by formula: [ka] (In the formula, R 2 , R 3 , R 4 , R 5 , X and R 6 (As described herein) The present invention provides a compound of formula (III) having the above, or a solvate or pharmaceutically acceptable salt thereof.

[0136] In one preferred embodiment, the present invention is given by formula: [ka] (In the formula, R 2 , R 3 , R 4 , R 5 , X and R 6 (As described herein) The present invention provides a compound of formula (IV) having the above, or a solvate or pharmaceutically acceptable salt thereof.

[0137] In one preferred embodiment, the present invention is given by formula: [ka] (In the formula, R 2 , R 3 , R 4 , R 5 , X and R 6 (As described herein) The present invention provides a compound of formula (V) having the above, or a solvate or pharmaceutically acceptable salt thereof.

[0138] In one preferred embodiment, the present invention is R 2 is hydroxy, and R 3 C 1~6 Alkyl or R2 C 1~6 It is an alkoxy, and R 3 C 1~6 The present invention provides a compound of formula (I) that is alkyl, or a solvate or pharmaceutically acceptable salt thereof.

[0139] In one preferred embodiment, the present invention is A 1 CR a A 2 CR b And R a and R b is hydrogen, R 1 R is selected from Cl, cyano and CHF2O-, 2 C 1~6 It is an alkoxy, R 3 C 1~6 The present invention provides a compound of formula (I) that is alkyl, or a solvate or pharmaceutically acceptable salt thereof.

[0140] In one preferred embodiment, the present invention is A 1 CR a A 2 CR b And R a and R b is hydrogen, R 1 Cl is and R 2 C 1~6 It is an alkoxy, R 3 C 1~6 The present invention provides a compound of formula (I) that is alkyl, or a solvate or pharmaceutically acceptable salt thereof.

[0141] In one preferred embodiment, the present invention is A 1 CR a A 2 CR b And R a and R b is hydrogen, R 1 is cyano, R 2 C 1~6 It is an alkoxy, R 3 C 1~6The present invention provides a compound of formula (I) that is alkyl, or a solvate or pharmaceutically acceptable salt thereof.

[0142] In one preferred embodiment, the present invention is A 1 CR a A 2 CR b And R a and R b is hydrogen, R 1 is CHF2O-, and R 2 C 1~6 It is an alkoxy, R 3 C 1~6 The present invention provides a compound of formula (I) that is alkyl, or a solvate or pharmaceutically acceptable salt thereof.

[0143] In one embodiment, the present invention is R 2 C 1~6 The present invention provides a compound of formula (I), or a solvate or pharmaceutically acceptable salt thereof, which is alkyl and in which one or more hydrogen atoms are replaced by D.

[0144] In one embodiment, the present invention is R 2 is -OCD3, and R 3 C 1~6 The present invention provides a compound of formula (I) that is alkyl, or a solvate or pharmaceutically acceptable salt thereof.

[0145] In one embodiment, the present invention is R 2 is hydroxyl or -OCD3, and R 3 The present invention provides a compound of formula (I), or a solvate or pharmaceutically acceptable salt thereof, wherein the compound is methyl.

[0146] In one embodiment, the present invention is R 2 is methoxy, and R 3 The present invention provides a compound of formula (I), or a solvate or pharmaceutically acceptable salt thereof, wherein the compound is methyl.

[0147] In one embodiment, the present invention is given by formula: [ka] (In the formula, X and R 6 (As described herein) The present invention provides a compound of formula (VI) having , or a solvate or pharmaceutically acceptable salt thereof.

[0148] In one embodiment, the present invention is R 2 and R 3 The present invention provides a compound of formula (I) or a solvate or pharmaceutically acceptable salt thereof, wherein, together with the attached C atom, they form a 4-6 membered heterocycloalkyl or a 3-6 membered cycloalkyl, and such heterocycloalkyl or cycloalkyl is optionally substituted with 1-4 halogens or oxos.

[0149] In one embodiment, the present invention is R 2 and R 3 The present invention provides a compound of formula (I) or a solvate or pharmaceutically acceptable salt thereof, wherein these atoms, together with the attached C atom, form a 4-6 membered heterocycloalkyl group, and such heterocycloalkyl groups are optionally substituted with 1-4 halogens or oxos.

[0150] In one embodiment, the present invention provides a compound of formula (I) or a solvate or pharmaceutically acceptable salt thereof, wherein the formed heterocycloalkyl comprises one or two S atoms or O atoms.

[0151] In one embodiment, the present invention provides a compound of formula (I) or a solvate or pharmaceutically acceptable salt thereof, wherein the formed heterocycloalkyl comprises one or two oxygen atoms.

[0152] In one embodiment, the present invention provides a compound of formula (I) or a solvate or pharmaceutically acceptable salt thereof, wherein the formed heterocycloalkyl contains two oxygen atoms.

[0153] In one embodiment, the present invention provides a compound of formula (I) or a solvate or pharmaceutically acceptable salt thereof, wherein the heterocycloalkyl group contains one oxygen atom.

[0154] In one embodiment, the present invention is R 4 and R 5 The present invention provides a compound of formula (I), or its solvate or pharmaceutically acceptable salt, wherein the compound is H.

[0155] In one embodiment, the present invention is R 2 , R 3 , R 4 and R 5 The following structure includes a linker which is optionally replaced as described herein: [ka] The present invention provides a compound of formula (I) or its solvate or pharmaceutically acceptable salt having the above.

[0156] In one embodiment, the present invention is R 2 , R 3 , R 4 and R 5 The following structure includes a linker which is optionally replaced as described herein: [ka] The present invention provides a compound of formula (I) or its solvate or pharmaceutically acceptable salt having the above.

[0157] In one embodiment, the present invention is R 2 , R 3 , R 4 and R 5 The following structure includes a linker which is optionally replaced as described herein: [ka] The present invention provides a compound of formula (I) or its solvate or pharmaceutically acceptable salt having the above.

[0158] In one embodiment, the present invention provides a compound of formula (I) or a solvate or pharmaceutically acceptable salt thereof, wherein the heterocycloalkyl ring is substituted with two F atoms.

[0159] The bond connecting this ring to the molecule is R 2 and R 3 Furthermore, they are not part of the ring formed by these attached carbon atoms.

[0160] In one embodiment, the present invention provides a compound of formula (I) or a solvate or pharmaceutically acceptable salt thereof, wherein the heterocycloalkyl ring is substituted with one oxo.

[0161] In one embodiment, the present invention is given by formula: [ka] (In the formula, X and R 6 (As described herein) The present invention provides a compound of formula (VII) having the heterocycloalkyl ring, or a solvate or pharmaceutically acceptable salt thereof. The heterocycloalkyl ring may be substituted as described herein.

[0162] In one embodiment, the present invention is given by formula: [ka] (In the formula, X and R 6 (As described herein) The present invention provides a compound of formula (VIII) having the , or a solvate or pharmaceutically acceptable salt thereof. The heterocycloalkyl ring may be substituted as described herein.

[0163] In one embodiment, the present invention is R 2 and R 3The present invention provides a compound of formula (I) or a solvate or pharmaceutically acceptable salt thereof, wherein these atoms, together with the attached C atom, form a 3-6 membered cycloalkyl group, and such cycloalkyl groups are optionally substituted with 1-4 halogens or oxos.

[0164] In one embodiment, the present invention provides a compound of formula (I) or a solvate or pharmaceutically acceptable salt thereof, wherein the cycloalkyl formed is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and these are optionally substituted as described above.

[0165] In one embodiment, the present invention provides a compound of formula (I) or a solvate or pharmaceutically acceptable salt thereof, wherein the cycloalkyl formed is selected from cyclopropyl or cyclobutyl, and these are optionally substituted as described above.

[0166] In one embodiment, the present invention is characterized in that the cycloalkyl formed is an unsubstituted cyclopropyl, and the linker is structured as follows: [ka] The present invention provides a compound of formula (I) or its solvate or pharmaceutically acceptable salt having the above.

[0167] The bond connecting the ring to the molecule is R 2 and R 3 Furthermore, they are not part of the ring formed by these attached carbon atoms.

[0168] In one embodiment, the present invention is given by formula: [ka] (In the formula, R 2 , R 3 , X and R 6 (As described herein) The present invention provides a compound of formula (IX) having the above, or a solvate or pharmaceutically acceptable salt thereof.

[0169] In one embodiment, the present invention is given by formula: [ka] (In the formula, X and R 6 (As described herein) The present invention provides a compound of formula (X) having , or a solvate or pharmaceutically acceptable salt thereof.

[0170] In one embodiment, the present invention is given by formula: [ka] (In the formula, R 2 , R 3 , R 4 , R 5 , X and R 6 (As described herein) The present invention provides a compound of formula (XI) having , or a solvate or pharmaceutically acceptable salt thereof.

[0171] In one embodiment, the present invention is given by formula: [ka] (In the formula, R 2 , R 3 , R 4 , R 5 , X and R 6 (As described herein) The present invention provides a compound of formula (XII) having , or a solvate or pharmaceutically acceptable salt thereof.

[0172] In one embodiment, the present invention is given by formula: [ka] (In the formula, R 2 , R3 , X and R 6 (As described herein) The present invention provides a compound of formula (XIII) having , or a solvate or pharmaceutically acceptable salt thereof.

[0173] In one embodiment, the present invention is given by formula: [ka] (In the formula, R 2 , R 3 , X and R 6 (As described herein) The present invention provides a compound of formula (XIV) having , or a solvate or pharmaceutically acceptable salt thereof.

[0174] In one embodiment, the present invention allows X to be NH, CH2, CH2CH2, CH2CH2CH2, non-existent, and [ka] The present invention provides a compound of formula (I), or a solvate or pharmaceutically acceptable salt thereof, selected from the above.

[0175] In one embodiment, the present invention is characterized in that X is CH2, CH2CH2, CH2CH2CH2, absent, and [ka] The present invention provides a compound of formula (I), or a solvate or pharmaceutically acceptable salt thereof, selected from the above.

[0176] In this application, regarding X [ka] The base is X, structure: [ka] This means that the compound of formula (I), as shown by the exemplary compound having the characteristic, is a cyclopropyl compound.

[0177] In one embodiment, the present invention is characterized in that X is CH2, CH2CH2, CH2CH2CH2, absent, and [ka] The present invention provides a compound of formula (I), or a solvate or pharmaceutically acceptable salt thereof, selected from the above.

[0178] In one embodiment, the present invention provides a compound of formula (I) or a solvate or pharmaceutically acceptable salt thereof, wherein X is NH.

[0179] In one embodiment, the present invention provides a compound of formula (I) or a solvate or pharmaceutically acceptable salt thereof, wherein X is CH2.

[0180] In one embodiment, the present invention provides a compound of formula (I) or a solvate or pharmaceutically acceptable salt thereof, in which X is absent.

[0181] In one embodiment, the present invention is that X is [ka] The present invention provides a compound of formula (I), or its solvate or pharmaceutically acceptable salt thereof.

[0182] In one embodiment, the present invention is R 6 C 1~6 Alkyl, Halo C 1~6 Selected from alkyl, heterocycloalkyl and heteroaryl, where heterocycloalkyl and heteroaryl are halogens, halo C 1~6 Alkyl, C 1~6 Alkyl, C 1~6 Alkoxy and Halo C 1~6The present invention provides a compound of formula (I), or a solvate or pharmaceutically acceptable salt thereof, which is optionally substituted with one, two, or three substituents independently selected from the alkoxy.

[0183] In one embodiment, the present invention is R 6 The saturated monocyclic cycloalkyl group is selected from 3-6 member saturated monocyclic cycloalkyl groups, 7-11 member spiro-cycloalkyl groups, or phenyl groups, and the saturated monocyclic cycloalkyl group, spiro-cycloalkyl group, or phenyl group is a halogen, halo C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkoxy and Halo C 1~6 The present invention provides a compound of formula (I), or a solvate or pharmaceutically acceptable salt thereof, which is optionally substituted with one, two, or three substituents independently selected from the alkoxy.

[0184] In one preferred embodiment, the present invention is R 6 However, halogen, Halo C 1~6 Alkyl, C 1~6 Alkyl, C 1~6 Alkoxy and Halo C 1~6 The present invention provides a compound of formula (I), or a solvate or pharmaceutically acceptable salt thereof, which is a 7-11 member spirocycloalkyl group optionally substituted with one, two, or three substituents independently selected from the alkoxy.

[0185] In one preferred embodiment, the present invention provides a compound of formula (I) or a solvate or pharmaceutically acceptable salt thereof, wherein the spirocycloalkyl group is unsubstituted.

[0186] In a preferred embodiment, the present invention provides a compound of formula (I) or a solvate or pharmaceutically acceptable salt thereof, wherein the 7-11 membered spirosiloalkyl is a bicyclic spirocycloalkyl having two saturated non-aromatic rings and containing 7, 8, 9, 10, or 11 carbon atoms.

[0187] In a preferred embodiment, the present invention provides a compound of formula (I) or a solvate or pharmaceutically acceptable salt thereof, wherein the 7-11 membered spirosiloalkyl is a tricyclic spirocycloalkyl having two saturated non-aromatic rings and containing 7, 8, 9, 10, or 11 carbon atoms.

[0188] In one preferred embodiment, the present invention relates to a 7-11 member spirocycloalkyl group, structured as follows: [ka] The present invention provides a compound of formula (I), or a solvate or pharmaceutically acceptable salt thereof, which is a tricyclic spirocycloalkyl containing 9 to 11 carbon atoms and having three saturated non-aromatic rings.

[0189] In a preferred embodiment, the present invention provides a compound of formula (I) or a solvate or pharmaceutically acceptable salt thereof, wherein the ring directly attached to the molecule is not a four-membered ring.

[0190] In a preferred embodiment, the present invention provides a compound of formula (I) or a solvate or pharmaceutically acceptable salt thereof, in which a 7- to 11-membered spirocycloalkyl is optionally substituted as described herein, selected from spiro[3.3]heptanyl, spiro[2.3]hexanyl, and spiro[3.4]octanyl.

[0191] In one preferred embodiment, the present invention is R 6 The present invention provides a compound of formula (I), or a solvate or pharmaceutically acceptable salt thereof, wherein is a 7-11 member spirocycloalkyl and X is absent.

[0192] In a preferred embodiment, the present invention provides an oxo-spiro-heterocycloalkyl group with a halogen, halo C 1~6 Alkyl, C 1~6 Alkyl, C 1~6 Alkoxy and Halo C 1~6The present invention provides a compound of formula (I), or a solvate or pharmaceutically acceptable salt thereof, which is optionally substituted with one, two, or three substituents independently selected from the alkoxy.

[0193] In a preferred embodiment, the present invention provides a compound of formula (I) or a solvate or pharmaceutically acceptable salt thereof, wherein the oxo-spiro-heterocycloalkyl group is unsubstituted.

[0194] In a preferred embodiment, the present invention provides a compound of formula (I) or a solvate or pharmaceutically acceptable salt thereof, wherein the 7-11 member oxo-spiro-heterocycloalkyl is a bicyclic oxa-spiro-heterocycloalkyl containing 7, 8, 9, 10, or 11 ring atoms, each ring comprising two saturated monocyclic rings, and one ring comprising one O-atom.

[0195] In a preferred embodiment, the present invention provides a compound of formula (I), or a solvate or pharmaceutically acceptable salt thereof, wherein the oxygen atom is present in a ring directly attached to the molecule.

[0196] In a preferred embodiment, the present invention provides a compound of formula (I) or a solvate or pharmaceutically acceptable salt thereof, wherein the ring directly attached to the molecule is not a four-membered ring.

[0197] In a preferred embodiment, the present invention provides a compound of formula (I) or a solvate or pharmaceutically acceptable salt thereof, wherein the 7- to 11-membered oxa-spiro-heterocycloalkyl is selected from oxaspiroheptanil, oxaspirooctanil, oxaspironanil, oxaspirodecanil, and oxaspirodecanil.

[0198] In a preferred embodiment, the present invention provides a compound of formula (I) or a solvate or pharmaceutically acceptable salt thereof, wherein the oxa-spiro-heterocycloalkyl contains one oxygen atom to form a 9- to 10-membered oxa-spiro-heterocycloalkyl.

[0199] In a preferred embodiment, the present invention provides a compound of formula (I) or a solvate or pharmaceutically acceptable salt thereof, wherein the 9-10 membered oxa-spiro-heterocycloalkyl is selected from oxaspirononanyl and oxaspirodecanyl.

[0200] In one preferred embodiment, the present invention is R 6 The present invention provides a compound of formula (I) or a solvate or pharmaceutically acceptable salt thereof, wherein is a 7-11 member oxa-spirocycloalkyl and X is absent.

[0201] In one embodiment, the present invention is R 6 This is a 3-10 member cycloalkyl group, and this cycloalkyl group is a halogen, halo C 1~6 Alkyl, C 1~6 Alkyl, C 1~6 Alkoxy and Halo C 1~6 The present invention provides a compound of formula (I), or a solvate or pharmaceutically acceptable salt thereof, which is optionally substituted with one, two, or three substituents independently selected from the alkoxy.

[0202] In one embodiment, the present invention is R 6 However, halogen, Halo C 1~6 Alkyl, C 1~6 Alkyl, C 1~6 Alkoxy and Halo C 1~6 The present invention provides a compound of formula (I), or a solvate or pharmaceutically acceptable salt thereof, which is a 3-10 membered cycloalkyl selected from saturated monocyclic 4-6 membered cycloalkyls, monocyclic 4-6 membered cycloalkenyls, and 4-10 membered bridged cycloalkyls, which are optionally substituted with one, two, or three substituents independently selected from the alkoxy.

[0203] In one preferred embodiment, the present invention is R 6 This is a saturated monocyclic cycloalkyl with 4 to 6 members, and this cycloalkyl is a halogen, halo C 1~6 Alkyl, C 1~6 Alkyl, C 1~6 Alkoxy and Halo C 1~6The present invention provides a compound of formula (I), or a solvate or pharmaceutically acceptable salt thereof, which is optionally substituted with one, two, or three substituents independently selected from the alkoxy.

[0204] In one preferred embodiment, the present invention is R 6 This is a saturated monocyclic cycloalkyl with 4 to 6 members, and this saturated monocyclic cycloalkyl is a halogen, halo C 1~6 Alkyl, C 1~6 Alkyl, C 1~6 Alkoxy and Halo C 1~6 The present invention provides a compound of formula (I), or a solvate or pharmaceutically acceptable salt thereof, which is optionally substituted with one, two, or three substituents independently selected from the alkoxy.

[0205] In one preferred embodiment, the present invention is R 6 The present invention provides a compound of formula (I), or a solvate or pharmaceutically acceptable salt thereof, wherein the saturated monocyclic cycloalkyl group is a 4-6 member saturated monocyclic cycloalkyl group, and this saturated monocyclic cycloalkyl group is optionally substituted with one or two halogens.

[0206] In one preferred embodiment, the present invention is R 6 The present invention provides a compound of formula (I), or a solvate or pharmaceutically acceptable salt thereof, wherein is a saturated monocyclic cycloalkyl group with 4 to 6 members, and this saturated monocyclic cycloalkyl group is unsubstituted.

[0207] In one preferred embodiment, the present invention is R 6 The present invention provides a compound of formula (I), or a solvate or pharmaceutically acceptable salt thereof, wherein is a saturated monocyclic 4-6 member cycloalkyl group, and this saturated monocyclic cycloalkyl group is optionally substituted with one halogen.

[0208] In one embodiment, the present invention is R 6 The present invention provides a compound of formula (I), or a solvate or pharmaceutically acceptable salt thereof, wherein is a saturated monocyclic cycloalkyl group with 4 to 6 members, and this saturated monocyclic cycloalkyl group is optionally substituted with one F.

[0209] In one embodiment, the present invention is R 6 The present invention provides a compound of formula (I) or a solvate or pharmaceutically acceptable salt thereof, which is a 4- to 10-membered crosslinked cycloalkyl group optionally substituted as described herein.

[0210] In one embodiment, the present invention is R 6 However, halogen, Halo C 1~6 Alkyl, C 1~6 Alkyl, C 1~6 Alkoxy and Halo C 1~6 The present invention provides a compound of formula (I), or a solvate or pharmaceutically acceptable salt thereof, which is a cycloalkyl compound optionally substituted with one, two, or three substituents independently selected from the alkoxy.

[0211] In one embodiment, the present invention is R 6 The present invention provides a compound of formula (I), or a solvate or pharmaceutically acceptable salt thereof, wherein is unsubstituted bicyclo[2.2.1]heptanyl.

[0212] In one embodiment, the present invention is R 6 However, it is a monocyclic 4-6 membered cycloalkenyl having one non-aromatic double bond, and is a halogen, halo C 1~6 Alkyl, C 1~6 Alkyl, C 1~6 Alkoxy and Halo C 1~6 The present invention provides a compound of formula (I), or a solvate or pharmaceutically acceptable salt thereof, which is a cycloalkenyl optionally substituted with one, two, or three substituents independently selected from the alkoxy.

[0213] In one embodiment, the present invention is R 6 The present invention provides a compound of formula (I), or a solvate or pharmaceutically acceptable salt thereof, which is an unsubstituted monocyclic 4-6 member cycloalkenyl having one non-aromatic double bond.

[0214] In one preferred embodiment, the present invention is R 6However, halogen, Halo C 1~6 Alkyl, C 1~6 Alkyl, C 1~6 Alkoxy and Halo C 1~6 The present invention provides a compound of formula (I), or a solvate or pharmaceutically acceptable salt thereof, which is a phenyl compound optionally substituted with one, two, or three substituents independently selected from the alkoxy.

[0215] In one preferred embodiment, the present invention is R 6 The present invention provides a compound of formula (I), or a solvate or pharmaceutically acceptable salt thereof, wherein is an unsubstituted phenyl.

[0216] In one preferred embodiment, the present invention is R 6 The present invention provides a compound of formula (I), or a solvate or pharmaceutically acceptable salt thereof, which is a phenyl compound substituted with Cl.

[0217] In one preferred embodiment, the present invention relates to formula (I): [ka] (In the formula, A 1 CR a And, A 2 CR b And, R a It is hydrogen, R b It is hydrogen, R 1 It is selected from Cl, cyano and CHF2O-, R 2 and R 3 C 1~6 Alkyl, C 1~6 It is alkoxy, or R 2 and R 3 These, together with the carbon atoms to which they are attached, form a 4- to 6-membered heterocycloalkyl group, and such heterocycloalkyl groups are optionally substituted with one or two F- or oxo atoms. R4 and R 5 It is hydrogen, X is [ka] Selected from NHCH2, absent, CH2, and CH2CH2, R 6 These are saturated monocyclic cycloalkyl groups with 3 to 6 members, spiro-cycloalkyl groups with 7 to 11 members, or phenyl groups. Saturated monocyclic cycloalkyl groups, spiro-cycloalkyl groups, or phenyl groups are halogens, halo C 1~6 Alkyl, C 1~6 Alkyl, C 1~6 Alkoxy and Halo C 1~6 (Optionally substituted with one, two, or three substituents independently selected from the alkoxy) The present invention provides compounds, solvates thereof, or pharmaceutically acceptable salts thereof.

[0218] In one embodiment, the present application relates to the following formula: [ka] The present invention provides compounds having the following properties.

[0219] In one preferred embodiment, the present invention has a structure: [ka] The present invention provides compounds having the following properties.

[0220] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a solvate or pharmaceutically acceptable salt thereof, wherein such a compound of formula (I) exhibits a Kv7.2 EC50 value and / or a Kv7.5-7.3 / Kv7.2 selectivity ratio in the range of (i) EC50 < 3 μM, Select > 10x, or (ii) EC50 < 1 μM, Select > 30x.

[0221] All features disclosed herein (including the appended claims, abstract, and drawings) relating to any such embodiment may be combined in any combination, except for any combination in which at least some of such features and / or processes are mutually exclusive. The present invention is not limited to the details of any embodiment described herein. Any embodiment described herein may be combined with any other embodiment.

[0222] Compounds of exemplary formula (I) in Table 1 were prepared according to the method of the present invention, characterized, and activated at Kv7.2 (EC2 concentration less than 10 micromolars). 50 Tests were conducted for maximum activation percentage (μM) and Kv7.2, and these compounds have the following structures and corresponding names (OpenEye Lexichem, Version 1.2.0, OpenEye Scientific Software, Santa Fe, NM, USA, https: / / www.eyesopen.com / lexichem-tk).

[0223] In some embodiments, the compound is selected from Table 1 or its solvates or pharmaceutically acceptable salts.

[0224] [Table 1]

[0225] [Table 2]

[0226] [Table 3]

[0227] [Table 4]

[0228] Table 5

[0229] Table 6

[0230] Table 7

[0231] Table 8

[0232] Table 9

[0233] Table 10

[0234] Table 11

[0235] Table 12

[0236] Table 13

[0237] Table 14

[0238] Table 15

[0239] [Table 16]

[0240] [Table 17]

[0241] [Table 18]

[0242] [Table 19]

[0243] The compounds of the present invention have been shown to act on Kv7.2 and are therefore useful for the treatment and / or prevention of any of the diseases, disorders, or impairments described herein. The compounds of the present invention are particularly useful for the therapeutic and / or preventive treatment of disorders, diseases, or impairments associated with Kv7.2. More specifically, the compounds of the present invention are useful for the therapeutic and / or preventive treatment of disorders, diseases, or impairments associated with Kv7.2, which are selected from behavioral disorders, mood disorders, neurodevelopmental disorders, intellectual disabilities, epilepsy, neurodegenerative diseases, pain, migraines, and tinnitus. Behavioral disorders include, for example, attention deficit hyperactivity disorder (ADHD). Mood disorders include, for example, depression. Neurodevelopmental disorders include, for example, autism spectrum disorder (ASD) or symptomatic developmental disorders. Symptomatic developmental disorders include, for example, Dup15q syndrome (Dup15q), fragile X syndrome (FXS), and Angelman syndrome. Epilepsy includes, for example, broad childhood epilepsy, West syndrome, Ohtahara syndrome, and epileptic encephalopathy. Neurodegenerative diseases include, for example, Alzheimer's disease or motor neuron disease.

[0244] Therefore, the compounds of the present invention are useful Kv7.2 modulators that provide desirable pharmacological properties such as potency and selectivity.

[0245] Compounds having one or more of the following combinations of characteristics are particularly useful within the range of Kv7.2 EC. 50 It has been found that the values ​​and / or the Kv7.5_7.3 / Kv7.2 selectivity ratio are shown: (i)EC 50 <3 μM and selectivity> 10x, or (ii) EC 50 <1 μM and selectivity> 30x.

[0246] In some embodiments of the present invention, the compound of formula (I) has a structure represented by any of the formulas (II) to (XV) described herein.

[0247] Measurements show Kv7.2 EC 50 When the concentration is less than 3 μM and the selectivity ratio Kv7.5_7.3 / Kv7.2 is greater than 10 times, the compound of formula (I) or its solvate or pharmaceutically acceptable salt has been shown to have the preferred pharmacological properties described herein.

[0248] In some embodiments of the present invention, one or more hydrogen atoms in the compound of the present invention are replaced with deuterium. Deuteration of the compound of the present invention has been found to confer the advantage of retaining the pharmacological profile of the hydrogen counterpart of the compound while positively affecting the metabolic outcomes of the compound. Selective replacement of one or more hydrogens with deuterium in the compound of the present invention improves the pharmaceutically profile of the compound of the present invention, for example, by reducing the amount of undesirable metabolites compared to all of its hydrogen counterparts, and by slowing the metabolic rate and thus increasing the half-life.

[0249] Methods for incorporating deuterium into compounds are well-established. Using established metabolic studies in the art, the compounds of the present invention can be tested to identify sites for the selective placement of deuterium isotopes, which are either not metabolized or are metabolized at a lower rate.

[0250] Pharmaceutical composition and administration In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention as described herein.

[0251] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention as described herein and one or more pharmaceutically acceptable excipients.

[0252] In one embodiment, the present invention provides a pharmaceutical composition further comprising one or more pharmaceutically active ingredients selected from diluents, fillers, bulking agents, binders, disintegrants, flow enhancers, humectants, coatings, emulsifiers or dispersants, compression / encapsulation aids, creams or lotions, lubricants, solutions for parenteral administration, materials for chewable tablets, sweeteners or flavorings, suspension / gelling agents, and wet granulators.

[0253] In certain embodiments, the present invention provides the above-mentioned pharmaceutical compositions which are particularly useful for the therapeutic and / or preventive treatment of disorders, diseases or impairments related to Kv7.2.

[0254] More specifically, the pharmaceutical compositions described herein are useful for the therapeutic and / or preventive treatment of disorders, diseases or impairments related to Kv7.2, the diseases, disorders or impairments being selected from behavioral disorders, mood disorders, neurodevelopmental disorders, intellectual disabilities, epilepsy, neurodegenerative diseases, pain, migraines and tinnitus.

[0255] The compounds of the present invention may be used as pharmaceuticals (e.g., in the form of pharmaceutical formulations). These pharmaceutical formulations may be administered orally (e.g., in the form of tablets, coated tablets, sugar-coated tablets, hard and soft gelatin capsules, solutions, emulsions, or suspensions), intranasally (e.g., in the form of nasal sprays), or rectally (e.g., in the form of suppositories). However, administration may also be parenterally, such as intramuscularly or intravenously (e.g., in the form of injections).

[0256] The compounds of the present invention may be treated with pharmaceutically inert inorganic or organic adjuvants for the production of tablets, coated tablets, sugar-coated tablets, and hard gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof, for example, can be used as such adjuvants for tablets, sugar-coated tablets, or hard gelatin capsules.

[0257] Suitable adjuvants for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid substances, or liquid polyols.

[0258] Suitable adjuvants for the production of solutions and syrups include, for example, water, polyols, sucrose, invert sugar, or glucose.

[0259] Suitable adjuvants for injection solutions include, for example, water, alcohol, polyol, glycerol, or vegetable oil.

[0260] Suitable adjuvants for suppositories include, for example, natural or solidified oils, waxes, fats, semi-solid or liquid polyols.

[0261] Furthermore, this pharmaceutical formulation may contain preservatives, solubilizers, viscosity-enhancing agents, stabilizers, humectants, emulsifiers, sweeteners, colorants, flavorings, salts to alter osmotic pressure, buffers, masking agents, or antioxidants. This pharmaceutical formulation may also contain other therapeutically valuable substances.

[0262] Dosages can vary over a wide range and, naturally, can be adapted to the individual requirements of each specific case. Generally, for oral administration, a daily dose of approximately 0.1 mg to 20 mg per kg of body weight, preferably approximately 0.5 mg to 4 mg per kg of body weight (e.g., approximately 300 mg per person), (e.g., divided into 1 to 3 individual doses, which may consist of the same amount) should be appropriate. However, it will be clear that the upper limits specified herein can be exceeded where indicated.

[0263] Provided herein are pharmaceutical compositions comprising the compounds of the present invention. In some embodiments, the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients. Conventional procedures for selecting and preparing suitable pharmaceutical compositions are described, for example, in “Pharmaceuticals - The Science of Dosage Form Designs,” ME Aulton, Churchill Livingstone, 1988, which is incorporated herein by reference in its entirety.

[0264] Furthermore, a method for preparing a pharmaceutical composition is provided, which includes combining one or more compounds of the present invention.

[0265] Further provided is a method for preparing a pharmaceutical composition, comprising combining one or more compounds of the present invention with one or more pharmaceutically acceptable excipients. The pharmaceutical composition may be prepared, for example, by conventional dissolution, mixing, granulation, or coating methods or combinations thereof. Examples of such pharmaceutically acceptable excipients include: sugars (e.g., lactose, glucose, sucrose), starches (e.g., corn starch, potato starch), cellulose and its derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose, cellulose acetate), tragacanth powder, malt, gelatin, talc, cocoa butter and suppository waxes, 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 solution, non-toxic compatible lubricants (e.g., sodium lauryl sulfate, magnesium stearate), colorants, release agents, coatings, sweeteners and flavorings and fragrances. Preservatives and antioxidants may also be present in this pharmaceutical composition at the discretion of the formulation manufacturer.

[0266] Depending on the intended mode of administration, the pharmaceutical compositions of this disclosure may be in solid, semi-solid, or liquid dosage forms, such as injections, tablets, suppositories, pills, sustained-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or similar, and may be in unit doses and may be consistent with conventional pharmaceutical practices.

[0267] These modes of administration may include systemic or topical administration, such as oral, nasal, parenteral (by intravenous injection (both bolus and infusion), intramuscular or subcutaneous injection), percutaneous, vaginal, buccal, rectal, or topical (by powder, ointment, or droplet). These modes may also include intracisional, intraperitoneal, oral or nasal spray, or liquid aerosol or dry powder pharmaceutical composition for inhalation. In some embodiments, the pharmaceutical composition provided herein comprises one or more disclosed compounds, their tautomers, and / or pharmaceutically acceptable salts thereof, and is for oral administration. In other embodiments, the pharmaceutical composition is for intravenous administration.

[0268] 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 using one or more coatings and / or shells, such as release-controlled coatings (e.g., enteric coatings). Solid dosage forms may be formulated to selectively release one or more disclosed compounds (or their solvates, tautomers, or pharmaceutically acceptable salts) in a delayed manner only in specific parts of the gastrointestinal tract, or release in most of these parts, or preferentially in these parts. Microencapsulated forms may also be included as solid dosage forms, for example.

[0269] Examples of liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. Examples of such liquid compositions include pharmaceutically acceptable excipients such as water or other solvents, solubilizers, emulsifiers, oils, polyethylene glycol and fatty acid esters, adjuvants, sweeteners, flavorings or fragrances, or any combination thereof. Examples of pharmaceutical compositions for injection include sterile aqueous compositions for injection (e.g., solutions, suspensions or emulsions) or oily suspensions.

[0270] In some embodiments, the pharmaceutical composition for injection may contain one or more solvents and / or diluents, such as water, Ringer's solution, USP and isotonic sodium chloride solution, sterile fixative oil, fatty acids, or any combination thereof. In some embodiments, the pharmaceutical composition for injection may be prepared as a lyophilized powder, for example, as a lyophilized powder that is mixed with a liquid diluent before injection.

[0271] In some embodiments, it may be desirable to extend the effect of one or more of the compounds disclosed herein or their pharmaceutically acceptable salts from administration by subcutaneous or intramuscular injection. Such delays can be achieved, for example, by using a liquid suspension of a crystalline or amorphous material with low water solubility, or by dissolving or suspending the compound or its solvate, tautomer, or pharmaceutically acceptable salt in an oil vehicle, or by an injectable depot form comprising a microcapsule matrix containing one or more biodegradable polymers.

[0272] Examples of pharmaceutical compositions for rectal or vaginal administration include suppositories that can be prepared using suitable non-irritating excipients such as cocoa butter, polyethylene glycol, or suppository wax, or suppositories that can be prepared using a lipid emulsion or suspension.

[0273] 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.

[0274] The pharmaceutical compositions provided herein may be packaged in unit dose or multi-dose containers (e.g., sealed ampoules or vials) and may be stored under freeze-dried (lyophilized) conditions requiring only the addition of sterile liquid excipients for injection (e.g., diluents, carriers, e.g., water) immediately before use. Immediate injection solutions and suspensions may be prepared from sterile powders, granules, or tablets of the types described herein. Unit dose formulations may include a daily dose or a unit daily partial dose of the active ingredient or an appropriate proportion thereof.

[0275] This subject further provides veterinary compositions comprising at least one active ingredient as defined herein, together with a veterinary excipient or carrier. The veterinary excipient or carrier may be a solid, liquid, or gaseous material that is useful for administering the composition, is otherwise inert or acceptable in the veterinary field, and is compatible with the active ingredient.

[0276] This veterinary composition may be administered parenterally, orally, or by any other desired route.

[0277] medical use The compounds of the present invention described herein, or pharmaceutical compositions containing the same, may be useful as pharmaceuticals for therapeutic and / or preventive treatment of disorders, diseases, or impairments related to Kv7.2 in subjects in need.

[0278] In one embodiment, the present invention provides a method for providing therapeutic and / or prophylactic treatment for a disorder, disease or impairment related to Kv7.2 in a subject in need thereof, comprising administering an effective amount of a compound or pharmaceutical composition thereof as described herein.

[0279] In one embodiment, the present invention provides a method for providing therapeutic and / or prophylactic treatment for a disorder, disease or impairment related to 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, the pharmaceutical composition further comprising one or more pharmaceutically acceptable excipients.

[0280] In one embodiment, a method for providing therapeutic and / or preventive treatment for a disability, disease, or disability related to Kv7.2 to a person in need thereof, comprising formula (I): [ka] (In the formula, A 1 is N or CR a And, A 2 is N or CR b And, R a is hydrogen or halogen, R b is hydrogen or halogen, R 1 This is hydrogen, cyano, halo C 1~6 Alkyl, C 1~6 Alkoxy, Halo C 1~6 Selected from alkoxy and halogen, R 2 and R 3 is hydrogen, hydroxyl, C 1~6 Alkyl, C 1~6 Alkoxy, Hydroxy C 1~6 Alkyl, C 3~6 Cycloalkoxy, cyano, -OCD3, cyano C 1~6 Alkoxy, Halo C 1~6 Alkoxy, hydroxy-C 2~4 Selected independently of Alkenil, or R 2 and R 3They form a 4-6 member heterocycloalkyl or 3-6 member cycloalkyl group that is optionally substituted with 1-4 halogens or oxos, together with the carbon atoms to which they are attached, or R 3 It does not exist, and R 2 is =CHCH2OH, R 4 is hydrogen, hydroxyl C 1~6 It is an alkyl or halogen, R 5 is hydrogen or halogen, X is NH, NHCH2, CH2, CH2CH2, CH2CH2CH2, NHCH2CH2CH2, NHCH2CH2, CH=CH, CH2CH2CH(OH), CH2CH(OH), non-existent, CHFCH2, and [ka] Selected from, R 6 These include 3-10 member cycloalkyl groups, 7-11 member spiro-cycloalkyl groups, 7-11 member oxo-spiro-heterocycloalkyl groups, aryl groups, heteroaryl groups, and C groups. 1~6 Alkyl, -C≡CCH3, 4-10 member heterocycloalkyl and halo C 1~6 Selected from alkyl, cycloalkyl, spiro-cycloalkyl, oxa-spiro-cycloalkyl, aryl, heteroaryl or heterocycloalkyl, halogen, halo C 1~6 Alkyl, C 1~6 Alkyl, C 1~6 Alkoxy and Halo C 1~6 (Optionally substituted with one, two, or three substituents independently selected from the alkoxy) The present invention provides a method comprising the compound or its solvate or pharmaceutically acceptable salt.

[0281] In one embodiment, the present invention provides a method for providing therapeutic and / or prophylactic treatment for a disorder, disease or impairment related to Kv7.2 in a subject in need thereof, comprising the compounds of the present invention described herein, in particular compounds selected from formulas (I) and (II) to (XV) or solvates or pharmaceutically acceptable salts thereof, any exemplary compounds, any embodiment or combination of embodiments.

[0282] In one embodiment, the present invention provides a method for providing therapeutic and / or prophylactic treatment for a disorder, disease or disability related to Kv7.2 in a subject in need thereof, comprising a compound selected from any list of compounds described herein, or a solvate or pharmaceutically acceptable salt thereof.

[0283] In one embodiment, the present invention provides a method for providing therapeutic and / or prophylactic treatment for a disorder, disease or disability related to Kv7.2 in a subject in need thereof, comprising a compound selected from Table 1 or shown elsewhere in this application, or a solvate or pharmaceutically acceptable salt thereof.

[0284] In one embodiment, the present invention provides a method for providing therapeutic and / or prophylactic treatment for a disorder, disease, or disability related to Kv7.2 in a subject in need thereof, comprising a compound selected from formulas (I) and (II) to (XV) or a solvate or pharmaceutically acceptable salt thereof, wherein the disorder, disease, or disability related to Kv7.2 is selected from behavioral disorders, mood disorders, neurodevelopmental disorders, intellectual disabilities, epilepsy, neurodegenerative diseases, pain, migraines, and tinnitus.

[0285] In one embodiment, the present invention provides a method for performing therapeutic and / or preventive measures for a disorder, disease or impairment related to Kv7.2 in a person in need thereof, wherein the behavioral disorder is attention deficit hyperactivity disorder (ADHD).

[0286] In one embodiment, the present invention provides a method for performing therapeutic and / or preventive measures for disorders, diseases or impairments related to Kv7.2 in a person in need thereof, wherein the mood disorder is depression.

[0287] In one embodiment, the present invention provides a method for performing therapeutic and / or preventive measures for disorders, diseases or impairments related to Kv7.2 in a subject in need thereof, wherein the neurodevelopmental disorder is selected from autism spectrum disorder (ASD) and symptomatic developmental disorders.

[0288] In one embodiment, the present invention provides a method for performing therapeutic and / or preventive treatment for a disorder, disease or impairment related to Kv7.2 in a person in need thereof, wherein the symptomatic developmental disorder is selected from Dup15q syndrome (Dup15q), Fragile X syndrome (FXS), and Angelman syndrome.

[0289] In one embodiment, the present invention provides a method for performing therapeutic and / or prophylactic treatment for a disorder, disease or disability related to Kv7.2 in a person in need thereof, wherein the epilepsy is selected from a wide range of childhood epilepsy, West syndrome, Ohtahara syndrome and epileptic encephalopathy.

[0290] In one embodiment, the present invention provides a method for performing therapeutic and / or prophylactic treatment for a disability, disease or impairment related to Kv7.2 in a person in need thereof, wherein the neurodegenerative disease is selected from Alzheimer's disease and motor neuron disease.

[0291] In one embodiment, the present invention provides a method for providing therapeutic and / or prophylactic treatment for a disorder, disease or impairment related to Kv7.2 in a person in need thereof, comprising administering an effective amount of a pharmaceutical composition described herein.

[0292] Further provided herein are compounds, solvates, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, as described herein, for use as therapeutic active substances.

[0293] In one embodiment, the present invention provides a therapeutically active substance with formula (I): [ka] (In the formula, A 1 is N or CR a And, A 2 is N or CR b And, R a is hydrogen or halogen, R b is hydrogen or halogen, R 1 This is hydrogen, cyano, halo C 1~6 Alkyl, C 1~6 Alkoxy, Halo C 1~6 Selected from alkoxy and halogen, R 2 and R 3 is hydrogen, hydroxyl, C 1~6 Alkyl, C 1~6 Alkoxy, Hydroxy C 1~6 Alkyl, C 3~6 Cycloalkoxy, cyano, -OCD3, cyano C 1~6 Alkoxy, Halo C 1~6 Alkoxy, hydroxy-C 2~4 Selected independently of Alkenil, or R 2 and R 3 They form a 4-6 member heterocycloalkyl or 3-6 member cycloalkyl group that is optionally substituted with 1-4 halogens or oxos, together with the carbon atoms to which they are attached, or R 3 It does not exist, and R 2 is =CHCH2OH, R 4 is hydrogen, hydroxyl C1~6 It is an alkyl or halogen, R 5 is hydrogen or halogen, X is NH, NHCH2, CH2, CH2CH2, CH2CH2CH2, NHCH2CH2CH2, NHCH2CH2, CH=CH, CH2CH2CH(OH), CH2CH(OH), non-existent, CHFCH2, and [ka] Selected from, R 6 These include 3-10 member cycloalkyl groups, 7-11 member spiro-cycloalkyl groups, 7-11 member oxo-spiro-heterocycloalkyl groups, aryl groups, heteroaryl groups, and C groups. 1~6 Alkyl, -C≡CCH3, 4-10 member heterocycloalkyl and halo C 1~6 Selected from alkyl, cycloalkyl, spiro-cycloalkyl, oxa-spiro-cycloalkyl, aryl, heteroaryl or heterocycloalkyl, halogen, halo C 1~6 Alkyl, C 1~6 Alkyl, C 1~6 Alkoxy and Halo C 1~6 (Optionally substituted with one, two, or three substituents independently selected from the alkoxy) The present invention provides the use of the compound or its solvate or pharmaceutically acceptable salt.

[0294] In one embodiment, the present invention provides the use of the compounds of the present invention described herein, particularly compounds selected from formulas (I) and (II) to (XV), or solvates or pharmaceutically acceptable salts thereof, any exemplary compounds, any embodiment, or any combination of embodiments as therapeutic active substances.

[0295] In one embodiment, the present invention provides the use of a compound selected from Table 1 or shown elsewhere in this application, or a solvate or pharmaceutically acceptable salt thereof, as a therapeutically active substance.

[0296] In one embodiment, the present invention provides the use of a compound selected from any list of the compounds described herein, or a solvate or pharmaceutically acceptable salt thereof, as a therapeutically active substance.

[0297] Further provided herein are compounds, solvates thereof, pharmaceutically acceptable salts, or pharmaceutical compositions for use in providing therapeutic and / or preventive treatment for disorders, diseases, or impairments related to Kv7.2 in subjects requiring such treatment.

[0298] In one embodiment, the present invention relates to a therapeutic and / or preventive measure for a disability, disease, or disability related to Kv7.2, used in a person in need thereof, using formula (I): [ka] (In the formula, A 1 is N or CR a And, A 2 is N or CR b And, R a is hydrogen or halogen, R b is hydrogen or halogen, R 1 This is hydrogen, cyano, halo C 1~6 Alkyl, C 1~6 Alkoxy, Halo C 1~6 Selected from alkoxy and halogen, R 2 and R 3 is hydrogen, hydroxyl, C 1~6 Alkyl, C 1~6 Alkoxy, Hydroxy C 1~6 Alkyl, C 3~6 Cycloalkoxy, cyano, -OCD3, cyano C 1~6 Alkoxy, Halo C 1~6 Alkoxy, hydroxy-C 2~4 Selected independently of Alkenil, or R 2 and R3 They form a 4-6 member heterocycloalkyl or 3-6 member cycloalkyl group that is optionally substituted with 1-4 halogens or oxos, together with the carbon atoms to which they are attached, or R 3 It does not exist, and R 2 is =CHCH2OH, R 4 is hydrogen, hydroxyl C 1~6 It is an alkyl or halogen, R 5 is hydrogen or halogen, X is NH, NHCH2, CH2, CH2CH2, CH2CH2CH2, NHCH2CH2CH2, NHCH2CH2, CH=CH, CH2CH2CH(OH), CH2CH(OH), non-existent, CHFCH2, and [ka] Selected from, R 6 These include 3-10 member cycloalkyl groups, 7-11 member spiro-cycloalkyl groups, 7-11 member oxo-spiro-heterocycloalkyl groups, aryl groups, heteroaryl groups, and C groups. 1~6 Alkyl, -C≡CCH3, 4-10 member heterocycloalkyl and halo C 1~6 Selected from alkyl, cycloalkyl, spiro-cycloalkyl, oxa-spiro-cycloalkyl, aryl, heteroaryl or heterocycloalkyl, halogen, halo C 1~6 Alkyl, C 1~6 Alkyl, C 1~6 Alkoxy and Halo C 1~6 (Optionally substituted with one, two, or three substituents independently selected from the alkoxy) The present invention provides compounds, solvates thereof, or pharmaceutically acceptable salts thereof.

[0299] In one embodiment, the present invention provides compounds of the present invention as described herein, particularly compounds selected from formulas (I) and (II) to (XV), or solvates or pharmaceutically acceptable salts thereof, any exemplary compounds, any embodiment, or combination of embodiments, for use in providing therapeutic and / or prophylactic treatment for disorders, diseases or impairments related to Kv7.2 in subjects requiring such treatment.

[0300] In one embodiment, the present invention provides compounds selected from Table 1 or shown elsewhere in this application, or solvates or pharmaceutically acceptable salts thereof, for use in providing therapeutic and / or prophylactic treatment for disorders, diseases or impairments related to Kv7.2 in subjects in need thereof.

[0301] In one embodiment, the present invention provides compounds selected from any list of the present invention for use in providing therapeutic and / or preventive treatment for disorders, diseases or impairments related to Kv7.2 in subjects in need thereof.

[0302] In one embodiment, the present invention provides compounds for use in providing therapeutic and / or preventive treatment for disorders, diseases or impairments related to Kv7.2 in subjects requiring such treatment, wherein such disorders, diseases or impairments are selected from behavioral disorders, mood disorders, neurodevelopmental disorders, intellectual disabilities, epilepsy, neurodegenerative diseases, pain, migraines and tinnitus.

[0303] In one embodiment, the present invention provides a compound for use in providing therapeutic and / or preventive treatment for a disorder, disease or impairment related to Kv7.2 in a subject in need thereof, wherein the behavioral disorder is attention deficit hyperactivity disorder (ADHD).

[0304] In one embodiment, the present invention provides compounds for use in providing therapeutic and / or preventive treatment for disorders, diseases or impairments related to Kv7.2 in subjects in need thereof, wherein the mood disorder is depression.

[0305] In one embodiment, the present invention provides compounds for use in providing therapeutic and / or preventive treatment for disorders, diseases or impairments related to Kv7.2 in subjects requiring such treatment, wherein the neurodevelopmental disorder is selected from autism spectrum disorder (ASD) and symptomatic developmental disorders.

[0306] In one embodiment, the present invention provides compounds for use in providing therapeutic and / or preventive treatment for disorders, diseases or impairments related to Kv7.2 in subjects in need thereof, wherein the symptomatic developmental disorder is selected from Dup15q syndrome (Dup15q), Fragile X syndrome (FXS), and Angelman syndrome.

[0307] In one embodiment, the present invention provides compounds for use in providing therapeutic and / or prophylactic treatment for disorders, diseases or impairments related to Kv7.2 in subjects requiring such treatment, wherein the compounds are selected from a wide range of childhood epilepsy, West syndrome, Ohtahara syndrome and epileptic encephalopathy.

[0308] In one embodiment, the present invention provides compounds for use in providing therapeutic and / or prophylactic treatment for impairments, diseases or disabilities related to Kv7.2 in subjects requiring such treatment, wherein the neurodegenerative disease is selected from Alzheimer's disease and motor neuron disease.

[0309] Further provided herein are the uses of the compounds of the present invention in providing therapeutic and / or preventive treatment for disorders, diseases, or impairments related to Kv7.2 in subjects in need thereof.

[0310] In one embodiment, the present invention provides a therapeutic and / or preventive measure for a disability, disease or disability related to Kv7.2, in a person in need thereof, using formula (I): [ka] (In the formula, A 1 is N or CR a And, A 2 is N or CR b And, R a is hydrogen or halogen, R b is hydrogen or halogen, R 1 This is hydrogen, cyano, halo C 1~6 Alkyl, C 1~6 Alkoxy, Halo C 1~6 Selected from alkoxy and halogen, R 2 and R 3 is hydrogen, hydroxyl, C 1~6 Alkyl, C 1~6 Alkoxy, Hydroxy C 1~6 Alkyl, C 3~6 Cycloalkoxy, cyano, -OCD3, cyano C 1~6 Alkoxy, Halo C 1~6 Alkoxy, hydroxy-C 2~4 Selected independently of Alkenil, or R 2 and R 3 They form a 4-6 member heterocycloalkyl or 3-6 member cycloalkyl group that is optionally substituted with 1-4 halogens or oxos, together with the carbon atoms to which they are attached, or R 3 It does not exist, and R 2 is =CHCH2OH, R 4 is hydrogen, hydroxyl C 1~6 It is an alkyl or halogen, R 5 is hydrogen or halogen, X is NH, NHCH2, CH2, CH2CH2, CH2CH2CH2, NHCH2CH2CH2, NHCH2CH2, CH=CH, CH2CH2CH(OH), CH2CH(OH), non-existent, CHFCH2, and [ka] Selected from, R 6 These include 3-10 member cycloalkyl groups, 7-11 member spiro-cycloalkyl groups, 7-11 member oxo-spiro-heterocycloalkyl groups, aryl groups, heteroaryl groups, and C groups. 1~6 Alkyl, -C≡CCH3, 4-10 member heterocycloalkyl and halo C 1~6 Selected from alkyl, cycloalkyl, spiro-cycloalkyl, oxa-spiro-cycloalkyl, aryl, heteroaryl or heterocycloalkyl, halogen, halo C 1~6 Alkyl, C 1~6 Alkyl, C 1~6 Alkoxy and Halo C 1~6 (Optionally substituted with one, two, or three substituents independently selected from the alkoxy) The present invention provides the use of the compound or its solvate or pharmaceutically acceptable salt.

[0311] In one embodiment, the present invention provides the use of the compounds of the present invention described herein, particularly compounds selected from formulas (I) and (II) to (XV) or their solvates or pharmaceutically acceptable salts, any exemplary compounds, any embodiment or combination of embodiments, for therapeutic and / or preventive treatment of disorders, diseases or impairments related to Kv7.2 in subjects in need thereof.

[0312] In one embodiment, the present invention provides the use of compounds selected from Table 1 or shown elsewhere in this application, or their solvates or pharmaceutically acceptable salts, for therapeutic and / or preventive treatment of disorders, diseases or impairments related to Kv7.2 in subjects in need thereof.

[0313] In one embodiment, the present invention provides the use of a compound selected from any list of compounds described herein, or a solvate or pharmaceutically acceptable salt thereof, for therapeutic and / or preventive treatment of disorders, diseases or impairments related to Kv7.2 in subjects in need thereof.

[0314] In one embodiment, the present invention provides a use of the compounds of the present invention in providing therapeutic and / or preventive treatment for a disorder, disease or impairment related to Kv7.2 in a subject in need thereof, wherein the disorder, disease or impairment related to Kv7.2 is selected from behavioral disorders, mood disorders, neurodevelopmental disorders, intellectual disabilities, epilepsy, neurodegenerative diseases, pain, migraines and tinnitus.

[0315] In one embodiment, the present invention provides a use of the compound in providing therapeutic and / or preventive treatment for a disorder, disease or impairment related to Kv7.2 in a subject in need thereof, wherein the behavioral disorder is attention deficit hyperactivity disorder (ADHD).

[0316] In one embodiment, the present invention provides a use of the compound in providing therapeutic and / or preventive treatment for disorders, diseases or impairments related to Kv7.2 in subjects in need thereof, wherein mood disorders are depression.

[0317] In one embodiment, the present invention provides a use of the compounds of the present invention in providing therapeutic and / or preventive treatment for disorders, diseases or impairments related to Kv7.2 in subjects in need thereof, wherein the neurodevelopmental disorders are selected from autism spectrum disorder (ASD) and symptomatic developmental disorders.

[0318] In one embodiment, the present invention provides the use of the compounds of the present invention in providing therapeutic and / or preventive treatment for disorders, diseases or impairments related to Kv7.2 in subjects in need thereof, wherein the symptomatic developmental disorders are selected from Dup15q syndrome (Dup15q), Fragile X syndrome (FXS), and Angelman syndrome.

[0319] In one embodiment, the present invention provides a use of the compounds of the present invention in providing therapeutic and / or prophylactic treatment for a disorder, disease or impairment related to Kv7.2 in a subject in need thereof, wherein the epilepsy is selected from a wide range of childhood epilepsy, West syndrome, Ohtahara syndrome and epileptic encephalopathy.

[0320] In one embodiment, the present invention provides a use of the compounds of the present invention in providing therapeutic and / or prophylactic treatment for impairment, disease or disability related to Kv7.2 in a subject in need thereof, wherein the neurodegenerative disease is selected from Alzheimer's disease and motor neuron disease.

[0321] Further provided herein are the use of the compounds of the present invention or pharmaceutical compositions containing them for producing agents for therapeutic and / or preventive treatment of disorders, diseases or impairments related to Kv7.2 in subjects in need thereof.

[0322] In one embodiment, the present invention relates to a method for manufacturing a drug for use in providing therapeutic and / or preventive treatment for disorders, diseases or impairments related to Kv7.2 in subjects in need thereof, using formula (I): [ka] (In the formula, A 1 is N or CR a And, A 2 is N or CR b And, R ais hydrogen or halogen, R b is hydrogen or halogen, R 1 This is hydrogen, cyano, halo C 1~6 Alkyl, C 1~6 Alkoxy, Halo C 1~6 Selected from alkoxy and halogen, R 2 and R 3 is hydrogen, hydroxyl, C 1~6 Alkyl, C 1~6 Alkoxy, Hydroxy C 1~6 Alkyl, C 3~6 Cycloalkoxy, cyano, -OCD3, cyano C 1~6 Alkoxy, Halo C 1~6 Alkoxy, hydroxy-C 2~4 Selected independently of Alkenil, or R 2 and R 3 They form a 4-6 member heterocycloalkyl or 3-6 member cycloalkyl group that is optionally substituted with 1-4 halogens or oxos, together with the carbon atoms to which they are attached, or R 3 It does not exist, and R 2 is =CHCH2OH, R 4 is hydrogen, hydroxyl C 1~6 It is an alkyl or halogen, R 5 is hydrogen or halogen, X is NH, NHCH2, CH2, CH2CH2, CH2CH2CH2, NHCH2CH2CH2NHCH2CH2, CH=CH, CH2CH2CH(OH), CH2CH(OH), non-existent, CHFCH2, and [ka] Selected from, R 6These include 3-10 member cycloalkyl groups, 7-11 member spiro-cycloalkyl groups, 7-11 member oxo-spiro-heterocycloalkyl groups, aryl groups, heteroaryl groups, and C groups. 1~6 Alkyl, -C≡CCH3, 4-10 member heterocycloalkyl and halo C 1~6 Selected from alkyl, cycloalkyl, spiro-cycloalkyl, oxa-spiro-cycloalkyl, aryl, heteroaryl or heterocycloalkyl, halogen, halo C 1~6 Alkyl, C 1~6 Alkyl, C 1~6 Alkoxy and Halo C 1~6 (Optionally substituted with one, two, or three substituents independently selected from the alkoxy) The present invention provides the use of the compound or its solvate or pharmaceutically acceptable salt.

[0323] In one embodiment, the present invention provides the use of the compounds of the present invention described herein, particularly compounds selected from formulas (I) and (II) to (XV) or their solvates or pharmaceutically acceptable salts, any exemplary compounds, any embodiment or combination of embodiments, for the production of agents for use in providing therapeutic and / or prophylactic treatment for disorders, diseases or impairments related to Kv7.2 in subjects in need thereof.

[0324] In one embodiment, the present invention provides the use of compounds selected from Table 1 or shown elsewhere in this application, or their solvates or pharmaceutically acceptable salts, for the manufacture of agents for use in administering therapeutic and / or prophylactic treatment for disorders, diseases or impairments related to Kv7.2 in subjects in need thereof.

[0325] In one embodiment, the present invention provides the use of a compound selected from any list of compounds described herein, or a solvate or pharmaceutically acceptable salt thereof, for the manufacture of a pharmacopoeia for use in administering therapeutic and / or prophylactic treatment for disorders, diseases or impairments related to Kv7.2 in subjects in need thereof.

[0326] In one embodiment, the present invention provides a use of the compounds of the present invention for producing agents for use in providing therapeutic and / or preventive treatment for disorders, diseases or impairments related to Kv7.2 in subjects in need thereof, wherein the disorders, diseases or impairments related to Kv7.2 are selected from behavioral disorders, mood disorders, neurodevelopmental disorders, intellectual disabilities, epilepsy, neurodegenerative diseases, pain, migraines and tinnitus.

[0327] In one embodiment, the present invention provides a use of the compounds of the present invention for producing agents for use in providing therapeutic and / or preventive treatment for a disorder, disease or impairment related to Kv7.2 in a subject in need thereof, wherein the behavioral disorder is attention deficit hyperactivity disorder (ADHD).

[0328] In one embodiment, the present invention provides a use of the compounds of the present invention for producing agents for use in providing therapeutic and / or preventive treatment for disorders, diseases or impairments related to Kv7.2 in subjects in need thereof, wherein mood disorders are depression.

[0329] In one embodiment, the present invention provides a use of the compounds of the present invention for producing agents for use in providing therapeutic and / or preventive treatment for disorders, diseases or impairments related to Kv7.2 in subjects in need thereof, wherein the neurodevelopmental disorders are selected from autism spectrum disorder (ASD) and symptomatic developmental disorders.

[0330] In one embodiment, the present invention provides a use of the compounds of the present invention for producing agents for use in providing therapeutic and / or prophylactic treatment for disorders, diseases or impairments related to Kv7.2 in subjects in need thereof, wherein the symptomatic developmental disorder is selected from Dup15q syndrome (Dup15q), Fragile X syndrome (FXS), and Angelman syndrome.

[0331] In one embodiment, the present invention provides a use of the compounds of the present invention for producing agents for use in providing therapeutic and / or prophylactic treatment for disorders, diseases or impairments related to Kv7.2 in subjects in need thereof, wherein the use is selected from a wide range of childhood epilepsy, West syndrome, Ohtahara syndrome and epileptic encephalopathy.

[0332] In one embodiment, the present invention provides a use of the compounds of the present invention for producing agents for use in providing therapeutic and / or prophylactic treatment for impairments, diseases or disabilities related to Kv7.2 in subjects in need thereof, wherein the neurodegenerative disease is selected from Alzheimer's disease and motor neuron disease.

[0333] Also provided are pharmaceutical compositions comprising the compounds described herein, or their solvates or pharmaceutically acceptable salts.

[0334] Further provided are pharmaceutical compositions comprising a compound described herein or a solvate or pharmaceutically acceptable salt thereof, further comprising one or more pharmaceutically acceptable excipients.

[0335] In one particularly preferred embodiment, the present invention relates to formula (I): [ka] (In the formula, A 1 is N or CR a And, A 2 is N or CR b And, R a is hydrogen or halogen, R b is hydrogen or halogen, R 1 This is hydrogen, cyano, halo C 1~6 Alkyl, C 1~6 Alkoxy, Halo C 1~6Selected from alkoxy and halogen, R 2 and R 3 is hydrogen, hydroxyl, C 1~6 Alkyl, C 1~6 Alkoxy, Hydroxy C 1~6 Alkyl, C 3~6 Cycloalkoxy, cyano, -OCD3, cyano C 1~6 Alkoxy, Halo C 1~6 Alkoxy, hydroxy-C 2~4 Selected independently of Alkenil, or R 2 and R 3 They form a 4-6 member heterocycloalkyl or 3-6 member cycloalkyl group that is optionally substituted with 1-4 halogens or oxos, together with the carbon atoms to which they are attached, or R 3 It does not exist, and R 2 is =CHCH2OH, R 4 is hydrogen, hydroxyl C 1~6 It is an alkyl or halogen, R 5 is hydrogen or halogen, X is NH, NHCH2, CH2, CH2CH2, CH2CH2CH2, NHCH2CH2CH2, NHCH2CH2, CH=CH, CH2CH2CH(OH), CH2CH(OH), non-existent, CHFCH2, and [ka] Selected from, R 6 These include 3-10 member cycloalkyl groups, 7-11 member spiro-cycloalkyl groups, 7-11 member oxo-spiro-heterocycloalkyl groups, aryl groups, heteroaryl groups, and C groups. 1~6 Alkyl, -C≡CCH3, 4-10 member heterocycloalkyl and halo C 1~6 Selected from alkyl, cycloalkyl, spiro-cycloalkyl, oxa-spiro-cycloalkyl, aryl, heteroaryl or heterocycloalkyl, halogen, halo C1~6 Alkyl, C 1~6 Alkyl, C 1~6 Alkoxy and Halo C 1~6 (Optionally substituted with one, two, or three substituents independently selected from the alkoxy) The present invention provides a pharmaceutical composition comprising the compound, its solvate, or a pharmaceutically acceptable salt thereof.

[0336] In one particularly preferred embodiment, the present invention relates to formula (I): [ka] (In the formula, A 1 is N or CR a And, A 2 is N or CR b And, R a is hydrogen or halogen, R b is hydrogen or halogen, R 1 This is hydrogen, cyano, halo C 1~6 Alkyl, C 1~6 Alkoxy, Halo C 1~6 Selected from alkoxy and halogen, R 2 and R 3 is hydrogen, hydroxyl, C 1~6 Alkyl, C 1~6 Alkoxy, Hydroxy C 1~6 Alkyl, C 3~6 Cycloalkoxy, cyano, -OCD3, cyano C 1~6 Alkoxy, Halo C 1~6 Alkoxy, hydroxy-C 2~4 Selected independently of Alkenil, or R 2 and R 3 They form a 4-6 member heterocycloalkyl or 3-6 member cycloalkyl group that is optionally substituted with 1-4 halogens or oxos, together with the carbon atoms to which they are attached, or R3 It does not exist, and R 2 is =CHCH2OH, R 4 is hydrogen, hydroxyl C 1~6 It is an alkyl or halogen, R 5 is hydrogen or halogen, X is NH, NHCH2, CH2, CH2CH2, CH2CH2CH2, NHCH2CH2CH2, NHCH2CH2, CH=CH, CH2CH2CH(OH), CH2CH(OH), non-existent, CHFCH2, and [ka] Selected from, R 6 These include 3-10 member cycloalkyl groups, 7-11 member spiro-cycloalkyl groups, 7-11 member oxo-spiro-heterocycloalkyl groups, aryl groups, heteroaryl groups, and C groups. 1~6 Alkyl, -C≡CCH3, 4-10 member heterocycloalkyl and halo C 1~6 Selected from alkyl, cycloalkyl, spiro-cycloalkyl, oxa-spiro-cycloalkyl, aryl, heteroaryl or heterocycloalkyl, halogen, halo C 1~6 Alkyl, C 1~6 Alkyl, C 1~6 Alkoxy and Halo C 1~6 The alkoxy is optionally substituted with one, two, or three substituents independently selected, and the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients. The present invention provides a pharmaceutical composition comprising the compound, its solvate, or a pharmaceutically acceptable salt thereof.

[0337] In one particularly preferred embodiment, the present invention provides a pharmaceutical composition comprising compounds of the present invention as described herein, particularly compounds selected from formulas (I) and (II) to (XV), or solvates or pharmaceutically acceptable salts thereof, for use in providing therapeutic and / or prophylactic treatment for disorders, diseases or impairments related to Kv7.2 in subjects requiring such treatment.

[0338] In one particularly preferred embodiment, the present invention provides a pharmaceutical composition comprising a compound selected from formulas (I) and (II) to (XV) described herein, or a solvate or pharmaceutically acceptable salt thereof, for use in providing therapeutic and / or prophylactic treatment for a disorder, disease or disability related to 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, migraines and tinnitus.

[0339] In one particularly preferred embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention for use in providing therapeutic and / or preventive treatment for a disorder, disease or impairment related to Kv7.2 in a subject in need thereof, wherein the behavioral disorder is attention deficit hyperactivity disorder (ADHD).

[0340] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention for use in providing therapeutic and / or preventive treatment for a disorder, disease or impairment related to Kv7.2 in a subject in need thereof, wherein the mood disorder is depression.

[0341] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention for use in providing therapeutic and / or preventive treatment for a disorder, disease or impairment related to Kv7.2 in a subject in need thereof, wherein the neurodevelopmental disorder is selected from autism spectrum disorder (ASD) and symptomatic developmental disorders.

[0342] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention for use in providing therapeutic and / or preventive treatment for a disorder, disease or impairment related to Kv7.2 in a subject in need thereof, wherein the symptomatic developmental disorder is selected from Dup15q syndrome (Dup15q), Fragile X syndrome (FXS), and Angelman syndrome.

[0343] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention for use in providing therapeutic and / or prophylactic treatment for a disorder, disease or impairment related to Kv7.2 in a subject in need thereof, wherein the epilepsy is selected from a wide range of childhood epilepsy, West syndrome, Ohtahara syndrome and epileptic encephalopathy.

[0344] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention for use in providing therapeutic and / or preventive treatment for disorders, diseases or impairments related to Kv7.2 in a subject in need thereof, wherein the neurodegenerative disease is selected from Alzheimer's disease and motor neuron disease.

[0345] In one embodiment, the present invention provides the above-mentioned pharmaceutical composition comprising a compound selected from formulas (I) and (II) to (XV) described herein, or a solvate or pharmaceutically acceptable salt thereof, any exemplary compound, any embodiment, or any combination of embodiments.

[0346] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound selected from Table 1 or shown elsewhere in this application, or a solvate or pharmaceutically acceptable salt thereof.

[0347] In one embodiment, the present invention provides the above-mentioned pharmaceutical composition comprising a compound selected from any list of compounds described herein, or a solvate or pharmaceutically acceptable salt thereof.

[0348] Also provided are pharmaceutical compositions comprising the compounds of the present invention for use in a manner that provides therapeutic and / or preventive treatment for disorders, diseases or impairments related to Kv7.2 in subjects requiring such treatment.

[0349] Also provided are pharmaceutical compositions comprising the compounds of the present invention and one or more pharmaceutically acceptable excipients for use in a manner that provides therapeutic and / or prophylactic treatment for disorders, diseases or impairments related to Kv7.2 in subjects requiring such treatment.

[0350] In one embodiment, the present invention relates to formula (I): [ka] (In the formula, A 1 is N or CR a And, A 2 is N or CR b And, R a is hydrogen or halogen, R b is hydrogen or halogen, R 1 This is hydrogen, cyano, halo C 1~6 Alkyl, C 1~6 Alkoxy, Halo C 1~6 Selected from alkoxy and halogen, R 2 and R 3 is hydrogen, hydroxyl, C 1~6 Alkyl, C 1~6 Alkoxy, Hydroxy C 1~6 Alkyl, C 3~6 Cycloalkoxy, cyano, -OCD3, cyano C 1~6 Alkoxy, Halo C 1~6 Alkoxy, hydroxy-C 2~4 Selected independently of Alkenil, or R 2 and R 3 They form a 4-6 member heterocycloalkyl or 3-6 member cycloalkyl group that is optionally substituted with 1-4 halogens or oxos, together with the carbon atoms to which they are attached, or R 3 It does not exist, and R 2 is =CHCH2OH, R 4 is hydrogen, hydroxyl C 1~6 It is an alkyl or halogen, R 5 is hydrogen or halogen, X is NH, NHCH2, CH2, CH2CH2, CH2CH2CH2, NHCH2CH2CH2, NHCH2CH2, CH=CH, CH2CH2CH(OH), CH2CH(OH), non-existence, and CHFCH2, and [ka] Selected from, R 6 These include 3-10 member cycloalkyl groups, 7-11 member spiro-cycloalkyl groups, 7-11 member oxo-spiro-heterocycloalkyl groups, aryl groups, heteroaryl groups, and C groups. 1~6 Alkyl, -C≡CCH3, 4-10 member heterocycloalkyl and halo C 1~6 Selected from alkyl, cycloalkyl, spiro-cycloalkyl, oxa-spiro-cycloalkyl, aryl, heteroaryl or heterocycloalkyl, halogen, halo C 1~6 Alkyl, C 1~6 Alkyl, C 1~6 Alkoxy and Halo C 1~6 (Optionally substituted with one, two, or three substituents independently selected from the alkoxy) The present invention provides a pharmaceutical composition for use in a treatment method, comprising the compound or its solvate or a pharmaceutically acceptable salt thereof.

[0351] In one embodiment, the present invention relates to formula (I): [ka] (In the formula, A 1 is N or CR a And, A 2 is N or CR b And, R a is hydrogen or halogen, R b is hydrogen or halogen, R 1 This is hydrogen, cyano, halo C 1~6 Alkyl, C 1~6 Alkoxy, Halo C 1~6 Selected from alkoxy and halogen, R 2 and R 3 is hydrogen, hydroxyl, C 1~6 Alkyl, C 1~6 Alkoxy, Hydroxy C 1~6 Alkyl, C 3~6 Cycloalkoxy, cyano, -OCD3, cyano C 1~6 Alkoxy, Halo C 1~6 Alkoxy, hydroxy-C 2~4 Selected independently of Alkenil, or R 2 and R 3 They form a 4-6 member heterocycloalkyl or 3-6 member cycloalkyl group that is optionally substituted with 1-4 halogens or oxos, together with the carbon atoms to which they are attached, or R 3 It does not exist, and R 2 is =CHCH2OH, R 4 is hydrogen, hydroxyl C 1~6 It is an alkyl or halogen, R 5 is hydrogen or halogen, X is NH, NHCH2, CH2, CH2CH2, CH2CH2CH2, NHCH2CH2CH2, NHCH2CH2, CH=CH, CH2CH2CH(OH), CH2CH(OH), non-existence, and CHFCH2, and [ka] Selected from, R 6 These include 3-10 member cycloalkyl groups, 7-11 member spiro-cycloalkyl groups, 7-11 member oxo-spiro-heterocycloalkyl groups, aryl groups, heteroaryl groups, and C groups. 1~6Alkyl, -C≡CCH3, 4-10 member heterocycloalkyl and halo C 1~6 Selected from alkyl, cycloalkyl, spiro-cycloalkyl, oxa-spiro-cycloalkyl, aryl, heteroaryl or heterocycloalkyl, halogen, halo C 1~6 Alkyl, C 1~6 Alkyl, C 1~6 Alkoxy and Halo C 1~6 (Optionally substituted with one, two, or three substituents independently selected from the alkoxy) The present invention provides a pharmaceutical composition for use in a treatment method, comprising a compound or a solvate or pharmaceutically acceptable salt thereof, further comprising one or more pharmaceutically acceptable excipients.

[0352] In one embodiment, the present invention is represented by formula (II): [ka] (In the formula, A 1 is N or CR a And, A 2 is N or CR b And, R a is hydrogen or halogen, R b is hydrogen or halogen, R 1 This is hydrogen, cyano, halo C 1~6 Alkyl, C 1~6 Alkoxy, Halo C 1~6 Selected from alkoxy and halogen, R 2 and R 3 is hydrogen, hydroxyl, C 1~6 Alkyl, C 1~6 Alkoxy, Hydroxy C 1~6 Alkyl, C 3~6 Cycloalkoxy, cyano, -OCD3, cyano C 1~6 Alkoxy, Halo C 1~6 Alkoxy, hydroxy-C 2~4Selected independently of Alkenil, or R 2 and R 3 They form a 4-6 member heterocycloalkyl or 3-6 member cycloalkyl group that is optionally substituted with 1-4 halogens or oxos, together with the carbon atoms to which they are attached, or R 3 It does not exist, and R 2 is =CHCH2OH, R 4 is hydrogen, hydroxyl C 1~6 It is an alkyl or halogen, R 5 is hydrogen or halogen, X is NH, NHCH2, CH2, CH2CH2, CH2CH2CH2, NHCH2CH2CH2, NHCH2CH2, CH=CH, CH2CH2CH(OH), CH2CH(OH), non-existence, and CHFCH2, and [ka] Selected from, R 6 These include 3-10 member cycloalkyl groups, 7-11 member spiro-cycloalkyl groups, 7-11 member oxo-spiro-heterocycloalkyl groups, aryl groups, heteroaryl groups, and C groups. 1~6 Alkyl, -C≡CCH3, 4-10 member heterocycloalkyl and halo C 1~6 Selected from alkyl, cycloalkyl, spiro-cycloalkyl, oxa-spiro-cycloalkyl, aryl, heteroaryl or heterocycloalkyl, halogen, halo C 1~6 Alkyl, C 1~6 Alkyl, C 1~6 Alkoxy and Halo C 1~6 (Optionally substituted with one, two, or three substituents independently selected from the alkoxy) The present invention provides a pharmaceutical composition for use in a treatment method, comprising the compound or its solvate or a pharmaceutically acceptable salt thereof.

[0353] In one embodiment, the present invention is represented by formula (II): [ka] (In the formula, A 1 is N or CR a And, A 2 is N or CR b And, R a is hydrogen or halogen, R b is hydrogen or halogen, R 1 This is hydrogen, cyano, halo C 1~6 Alkyl, C 1~6 Alkoxy, Halo C 1~6 Selected from alkoxy and halogen, R 2 and R 3 is hydrogen, hydroxyl, C 1~6 Alkyl, C 1~6 Alkoxy, Hydroxy C 1~6 Alkyl, C 3~6 Cycloalkoxy, cyano, -OCD3, cyano C 1~6 Alkoxy, Halo C 1~6 Alkoxy, hydroxy-C 2~4 Selected independently of Alkenil, or R 2 and R 3 They form a 4-6 member heterocycloalkyl or 3-6 member cycloalkyl group that is optionally substituted with 1-4 halogens or oxos, together with the carbon atoms to which they are attached, or R 3 It does not exist, and R 2 is =CHCH2OH, R 4 is hydrogen, hydroxyl C 1~6 It is an alkyl or halogen, R 5 is hydrogen or halogen, X is NH, NHCH2, CH2, CH2CH2, CH2CH2CH2, NHCH2CH2CH2, NHCH2CH2, CH=CH, CH2CH2CH(OH), CH2CH(OH), non-existence, and CHFCH2, and [ka] Selected from, R 6 These include 3-10 member cycloalkyl groups, 7-11 member spiro-cycloalkyl groups, 7-11 member oxo-spiro-heterocycloalkyl groups, aryl groups, heteroaryl groups, and C groups. 1~6 Alkyl, -C≡CCH3, 4-10 member heterocycloalkyl and halo C 1~6 Selected from alkyl, cycloalkyl, spiro-cycloalkyl, oxa-spiro-cycloalkyl, aryl, heteroaryl or heterocycloalkyl, halogen, halo C 1~6 Alkyl, C 1~6 Alkyl, C 1~6 Alkoxy and Halo C 1~6 (Optionally substituted with one, two, or three substituents independently selected from the alkoxy) The present invention provides a pharmaceutical composition for use in a treatment method, comprising a compound or a solvate or pharmaceutically acceptable salt thereof, further comprising one or more pharmaceutically acceptable excipients.

[0354] In one embodiment, the present invention provides a pharmaceutical composition for use in a treatment method comprising the compound of the present invention for therapeutic and / or preventive treatment of disorders, diseases or impairments related to Kv7.2 in a subject in need thereof.

[0355] In one embodiment, the present invention provides a pharmaceutical composition for use in a treatment method comprising a compound of the present invention for therapeutic and / or preventive treatment of a disorder, disease or disability related to Kv7.2 in a subject requiring such treatment, wherein the disorder, disease or disability is selected from behavioral disorders, mood disorders, neurodevelopmental disorders, intellectual disabilities, epilepsy, neurodegenerative diseases, pain, migraines and tinnitus.

[0356] In one embodiment, the present invention provides a pharmaceutical composition for use in a treatment method comprising the compound of the present invention for therapeutic and / or preventive treatment of a disorder, disease or impairment related to Kv7.2 in a subject requiring such treatment, wherein the behavioral disorder is attention deficit hyperactivity disorder (ADHD).

[0357] In one embodiment, the present invention provides a pharmaceutical composition for use in a treatment method comprising the compound of the present invention for therapeutic and / or preventive treatment of a disorder, disease or impairment related to Kv7.2 in a subject in need thereof, wherein the mood disorder is depression.

[0358] In one embodiment, the present invention provides a pharmaceutical composition for use in a treatment method comprising a compound of the present invention for therapeutic and / or preventive treatment of a disorder, disease or impairment related to Kv7.2 in a subject in need thereof, wherein the neurodevelopmental disorder is selected from autism spectrum disorder (ASD) and symptomatic developmental disorders.

[0359] In one embodiment, the present invention provides a pharmaceutical composition for use in a treatment method comprising a compound of the present invention for therapeutic and / or preventive treatment of a disorder, disease or disability related to Kv7.2 in a subject requiring such treatment, wherein the symptomatic developmental disorder is selected from Dup15q syndrome (Dup15q), Fragile X syndrome (FXS), and Angelman syndrome.

[0360] In one embodiment, the present invention provides a pharmaceutical composition for use in a treatment method comprising a compound of the present invention for therapeutic and / or prophylactic treatment of a disorder, disease or disability related to Kv7.2 in a subject in need thereof, wherein the epilepsy is selected from a wide range of childhood epilepsy, West syndrome, Ohtahara syndrome and epileptic encephalopathy.

[0361] In one embodiment, the present invention provides a pharmaceutical composition for use in a treatment method comprising a compound of the present invention for therapeutic and / or preventive treatment of a disorder, disease or impairment related to Kv7.2 in a subject in need thereof, wherein the neurodegenerative disease is selected from Alzheimer's disease and motor neuron disease.

[0362] In one embodiment, the present invention provides the above-mentioned pharmaceutical composition comprising a compound selected from any of formulas (I) and (II) to (XV) described herein, or a solvate or pharmaceutically acceptable salt thereof, any exemplary compound, any embodiment, or any combination of embodiments.

[0363] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound selected from Table 1 or described elsewhere in this application, or a solvate or pharmaceutically acceptable salt thereof.

[0364] In one embodiment, the present invention provides the above-mentioned pharmaceutical composition comprising a compound selected from any list of compounds described herein, or a solvate or pharmaceutically acceptable salt thereof.

[0365] Also provided are pharmaceutical compositions comprising the compounds described herein or their solvates or pharmaceutically acceptable salts, for use in the manufacture of agents for therapeutic and / or preventive treatment of disorders, diseases or impairments related to Kv7.2 in subjects in need thereof.

[0366] Also provided are pharmaceutical compositions for use in the manufacture of agents for therapeutic and / or preventive treatment of disorders, diseases or impairments related to Kv7.2 in subjects in need thereof, comprising the compounds described herein or their solvates or pharmaceutically acceptable salts, further comprising one or more pharmaceutically acceptable excipients.

[0367] In one embodiment, the present invention relates to a pharmaceutical composition for use in the manufacture of a drug for therapeutic and / or preventive treatment of a disorder, disease or disability related to Kv7.2 in a person in need thereof, comprising formula (I): [ka] (In the formula, A 1 is N or CR a And, A 2 is N or CR b And, R a is hydrogen or halogen, R b is hydrogen or halogen, R 1 This is hydrogen, cyano, halo C 1~6 Alkyl, C 1~6 Alkoxy, Halo C 1~6 Selected from alkoxy and halogen, R 2 and R 3 is hydrogen, hydroxyl, C 1~6 Alkyl, C 1~6 Alkoxy, Hydroxy C 1~6 Alkyl, C 3~6 Cycloalkoxy, cyano, -OCD3, cyano C 1~6 Alkoxy, Halo C 1~6 Alkoxy, hydroxy-C 2~4 Selected independently of Alkenil, or R 2 and R 3They form a 4-6 member heterocycloalkyl or 3-6 member cycloalkyl group that is optionally substituted with 1-4 halogens or oxos, together with the carbon atoms to which they are attached, or R 3 It does not exist, and R 2 is =CHCH2OH, R 4 is hydrogen, hydroxyl C 1~6 It is an alkyl or halogen, R 5 is hydrogen or halogen, X is NH, NHCH2, CH2, CH2CH2, CH2CH2CH2, NHCH2CH2CH2, NHCH2CH2, CH=CH, CH2CH2CH(OH), CH2CH(OH), non-existence, and CHFCH2, and [ka] Selected from, R 6 These include 3-10 member cycloalkyl groups, 7-11 member spiro-cycloalkyl groups, 7-11 member oxo-spiro-heterocycloalkyl groups, aryl groups, heteroaryl groups, and C groups. 1~6 Alkyl, -C≡CCH3, 4-10 member heterocycloalkyl and halo C 1~6 Selected from alkyl, cycloalkyl, spiro-cycloalkyl, oxa-spiro-cycloalkyl, aryl, heteroaryl or heterocycloalkyl, halogen, halo C 1~6 Alkyl, C 1~6 Alkyl, C 1~6 Alkoxy and Halo C 1~6 (Optionally substituted with one, two, or three substituents independently selected from the alkoxy) The present invention provides a pharmaceutical composition comprising the compound, its solvate, or a pharmaceutically acceptable salt thereof.

[0368] In one embodiment, the present invention relates to a pharmaceutical composition for use in the manufacture of a drug for therapeutic and / or preventive treatment of a disorder, disease or disability related to Kv7.2 in a person in need thereof, comprising formula (I): [ka] (In the formula, A 1 is N or CR a And, A 2 is N or CR b And, R a is hydrogen or halogen, R b is hydrogen or halogen, R 1 This is hydrogen, cyano, halo C 1~6 Alkyl, C 1~6 Alkoxy, Halo C 1~6 Selected from alkoxy and halogen, R 2 and R 3 is hydrogen, hydroxyl, C 1~6 Alkyl, C 1~6 Alkoxy, Hydroxy C 1~6 Alkyl, C 3~6 Cycloalkoxy, cyano, -OCD3, cyano C 1~6 Alkoxy, Halo C 1~6 Alkoxy, hydroxy-C 2~4 Selected independently of Alkenil, or R 2 and R 3 They form a 4-6 member heterocycloalkyl or 3-6 member cycloalkyl group that is optionally substituted with 1-4 halogens or oxos, together with the carbon atoms to which they are attached, or R 3 It does not exist, and R 2 is =CHCH2OH, R 4 is hydrogen, hydroxyl C 1~6 It is an alkyl or halogen, R5 is hydrogen or halogen, X is NH, NHCH2, CH2, CH2CH2, CH2CH2CH2, NHCH2CH2CH2, NHCH2CH2, CH=CH, CH2CH2CH(OH), CH2CH(OH), non-existence, and CHFCH2, and [ka] Selected from, R 6 These include 3-10 member cycloalkyl groups, 7-11 member spiro-cycloalkyl groups, 7-11 member oxo-spiro-heterocycloalkyl groups, aryl groups, heteroaryl groups, and C groups. 1~6 Alkyl, -C≡CCH3, 4-10 member heterocycloalkyl and halo C 1~6 Selected from alkyl, cycloalkyl, spiro-cycloalkyl, oxa-spiro-cycloalkyl, aryl, heteroaryl or heterocycloalkyl, halogen, halo C 1~6 Alkyl, C 1~6 Alkyl, C 1~6 Alkoxy and Halo C 1~6 (Optionally substituted with one, two, or three substituents independently selected from the alkoxy) The present invention provides a pharmaceutical composition comprising a compound or a solvate or pharmaceutically acceptable salt thereof, and further comprising one or more pharmaceutically acceptable excipients.

[0369] In one embodiment, the present invention provides a pharmaceutical composition for use in the manufacture of a drug for therapeutic and / or prophylactic treatment of a disorder, disease or impairment related to Kv7.2 in a subject in need thereof, comprising a compound of any one of formulas (II) to (XV) or a solvate or pharmaceutically acceptable salt thereof.

[0370] In one embodiment, the present invention provides a pharmaceutical composition for use in the manufacture of a drug for therapeutic and / or prophylactic treatment of a disorder, disease or impairment related to Kv7.2 in a subject in need thereof, comprising a compound of any one of formulas (II) to (XV) or a solvate or pharmaceutically acceptable salt thereof, and further comprising one or more pharmaceutically acceptable excipients.

[0371] In one embodiment, the present invention provides a pharmaceutical composition for use in the manufacture of a drug for therapeutic and / or preventive treatment of a disorder, disease or disability related to Kv7.2 in a subject in need thereof, comprising a compound of formula (I) as described herein, or a solvate or pharmaceutically acceptable salt thereof, for use in therapeutic and / or preventive treatment of a disorder, disease or disability related to Kv7.2 in a subject in need thereof.

[0372] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention for use in the manufacture of a drug for therapeutic and / or preventive treatment of a disorder, disease or impairment related to Kv7.2 in a subject in need thereof, wherein the disorder, disease or impairment is selected from behavioral disorders, mood disorders, neurodevelopmental disorders, intellectual disabilities, epilepsy, neurodegenerative diseases, pain, migraines and tinnitus.

[0373] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention for use in the manufacture of a drug for therapeutic and / or preventive treatment of a disorder, disease or impairment related to Kv7.2 in a subject in need thereof, wherein the behavioral disorder is attention deficit hyperactivity disorder (ADHD).

[0374] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention for use in the manufacture of a drug for therapeutic and / or preventive treatment of a disorder, disease or impairment related to Kv7.2 in a subject in need thereof, wherein the mood disorder is depression.

[0375] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention for use in the manufacture of a drug for therapeutic and / or preventive treatment of a disorder, disease or impairment related to Kv7.2 in a subject in need thereof, wherein the neurodevelopmental disorder is selected from autism spectrum disorder (ASD) and symptomatic developmental disorders.

[0376] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention for use in the manufacture of a drug for therapeutic and / or preventive treatment of a disorder, disease or disability related to Kv7.2 in a subject in need thereof, wherein the symptomatic developmental disorder is selected from Dup15q syndrome (Dup15q), Fragile X syndrome (FXS), and Angelman syndrome.

[0377] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention for use in the manufacture of a drug for therapeutic and / or prophylactic treatment of a disorder, disease or impairment related to Kv7.2 in a subject in need thereof, wherein the epilepsy is selected from a wide range of childhood epilepsy, West syndrome, Ohtahara syndrome and epileptic encephalopathy.

[0378] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention for use in the manufacture of a drug for therapeutic and / or prophylactic treatment of a disorder, disease or impairment related to Kv7.2 in a subject in need thereof, wherein the neurodegenerative disease is selected from Alzheimer's disease and motor neuron disease.

[0379] In one embodiment, the present invention provides the above-described pharmaceutical composition comprising a compound selected from any of formulas (I) and (II) to (XV) described herein, or a solvate or pharmaceutically acceptable salt thereof, any exemplary compound, any embodiment, or any combination of embodiments.

[0380] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound selected from Table 1 or shown elsewhere in this application, or a solvate or pharmaceutically acceptable salt thereof.

[0381] In one embodiment, the pharmaceutical composition comprises a compound selected from any list of compounds described herein, or a solvate or pharmaceutically acceptable salt thereof.

[0382] Combination therapy The compounds of the present invention may be combined in any combination with one or more other compounds of the present invention or one or more other therapeutic agents in the treatment of diseases, disorders or impairments described 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.

[0383] In some embodiments, the compounds of the present invention may be combined with other therapeutic agents that have a synergistic effect in the treatment of any disease, disorder or disability described herein.

[0384] As used herein, “combination” refers to any mixture or arrangement 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 otherwise specified, “combination” may include the simultaneous or sequential delivery of a compound of the present invention with one or more therapeutic agents. Unless otherwise specified, “combination” may include dosage forms of a compound of the present invention with another therapeutic agent. Unless otherwise specified, “combination” may include routes of administration of a compound of the present invention with another therapeutic agent. Unless otherwise specified, “combination” may include formulations of a compound of the present invention with another therapeutic agent. Dosage forms, routes of administration, and pharmaceutical compositions are, but are not limited to, those described herein.

[0385] product In one embodiment, the present invention provides a product or "kit" comprising materials useful for treating a disability, disease, or disability as described herein.

[0386] In one embodiment of the present invention, the kit includes a container in which a compound of the present invention, as described in any embodiment of the present invention, is contained.

[0387] In one embodiment, the present invention provides a kit comprising a container for containing a compound or pharmaceutical composition thereof as described herein.

[0388] In one embodiment, the present invention provides a kit comprising the compounds of the present invention described herein, any exemplary compounds, any embodiment or combination of embodiments, or pharmaceutical compositions thereof.

[0389] In one embodiment, the present invention provides a kit in which the compound is selected from formulas (I) and (II) to (XV) described herein, or solvates, pharmaceutically acceptable salts, or pharmaceutical compositions thereof.

[0390] In one embodiment, the present invention provides a kit in which a compound is selected from Table 1 as described herein or shown elsewhere in this application, is a solvate, a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

[0391] In one embodiment, the present invention is a kit for use in the treatment of a disability, disease, or disability related to Kv7.2, a) A first pharmaceutical composition comprising the compound of the present invention, b) Instructions for use and We provide a kit that includes this.

[0392] In one embodiment, the present invention is a kit for use in the therapeutic and / or preventive treatment of disorders, diseases or impairments related to Kv7.2, a) A compound of the present invention as described herein, or a pharmaceutical composition thereof, or a pharmaceutical composition for use thereof, b) Instructions for use and We provide a kit that includes this.

[0393] In one embodiment, the present invention is 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, migraines, and tinnitus. a) Formula (I) as described herein: [ka] (In the formula, A 1 is N or CR a And, A 2 is N or CR b And, R a is hydrogen or halogen, R b is hydrogen or halogen, R 1 This is hydrogen, cyano, halo C 1~6 Alkyl, C 1~6 Alkoxy, Halo C 1~6 Selected from alkoxy and halogen, R 2 and R 3 is hydrogen, hydroxyl, C 1~6 Alkyl, C 1~6 Alkoxy, Hydroxy C 1~6 Alkyl, C 3~6 Cycloalkoxy, cyano, -OCD3, cyano C 1~6 Alkoxy, Halo C 1~6 Alkoxy, hydroxy-C 2~4 Selected independently of Alkenil, or R 2 and R 3 They form a 4-6 member heterocycloalkyl or 3-6 member cycloalkyl group that is optionally substituted with 1-4 halogens or oxos, together with the carbon atoms to which they are attached, or R3 It does not exist, and R 2 is =CHCH2OH, R 4 is hydrogen, hydroxyl C 1~6 It is an alkyl or halogen, R 5 is hydrogen or halogen, X is NH, NHCH2, CH2, CH2CH2, CH2CH2CH2, NHCH2CH2CH2, NHCH2CH2, CH=CH, CH2CH2CH(OH), CH2CH(OH), non-existence, and CHFCH2, and [ka] Selected from, R 6 These include 3-10 member cycloalkyl groups, 7-11 member spiro-cycloalkyl groups, 7-11 member oxo-spiro-heterocycloalkyl groups, aryl groups, heteroaryl groups, and C groups. 1~6 Alkyl, -C≡CCH3, 4-10 member heterocycloalkyl and halo C 1~6 Selected from alkyl, cycloalkyl, spiro-cycloalkyl, oxa-spiro-cycloalkyl, aryl, heteroaryl or heterocycloalkyl, halogen, halo C 1~6 Alkyl, C 1~6 Alkyl, C 1~6 Alkoxy and Halo C 1~6 (Optionally substituted with one, two, or three substituents independently selected from the alkoxy) A first pharmaceutical composition comprising a compound or solvate or pharmaceutically acceptable salt, a pharmaceutical composition or a pharmaceutical composition for use, b) Instructions for use and We provide a kit that includes this.

[0394] In one embodiment, the present invention provides a kit for use in the therapeutic and / or preventive treatment of disorders, diseases, or impairments related to Kv7.2. These disorders, diseases, or impairments may be selected from behavioral disorders, mood disorders, neurodevelopmental disorders, intellectual disabilities, epilepsy, neurodegenerative diseases, pain, migraines, and tinnitus, and include compounds, pharmaceutical compositions, or pharmaceutical compositions for use thereof as described herein.

[0395] In one embodiment, the present invention provides a kit for use as described herein, wherein the behavioral disorder is attention deficit hyperactivity disorder (ADHD).

[0396] In one embodiment, the present invention provides a kit for use as described herein, wherein the mood disorder is depression.

[0397] In one embodiment, the present invention provides a kit for use as described herein, wherein the neurodevelopmental disorder is selected from autism spectrum disorder (ASD) and symptomatic developmental disorders.

[0398] In one embodiment, the present invention provides a kit for use as described herein, wherein the symptomatic developmental disorder is selected from Dup15q syndrome (Dup15q), Fragile X syndrome (FXS), and Angelman syndrome.

[0399] In one embodiment, the present invention provides a kit for use as described herein, wherein the epilepsy is selected from a wide range of childhood epilepsy, West syndrome, Ohtahara syndrome, and epileptic encephalopathy.

[0400] In one embodiment, the present invention provides a kit for use as described herein, wherein the neurodegenerative disease is selected from Alzheimer's disease and motor neuron disease.

[0401] In one embodiment, the present invention provides a kit for use as described herein, further comprising a label or accompanying documentation on or attached to the container.

[0402] The term “package insert” is used to refer to the instructions that are customarily included in the market packaging of such therapeutic drugs, including information relating to the indications, use, dosage, administration, contraindications, and / or warnings for the use of such therapeutic drugs.

[0403] Suitable containers include, for example, bottles, vials, syringes, and blister packs. Containers can be made from various materials such as glass or plastic.

[0404] The container may hold a compound or formulation thereof of the present invention that is effective in treating a disease condition and may have a sterile access port (for example, the container may be a bag or vial for intravenous injection solution having a stopper that can be punctured by a subcutaneous needle). At least one activator in the composition is a compound of the present invention. The label or accompanying information indicates that the composition is used to treat a selected disease condition such as cancer. In addition, the label or accompanying information may indicate that the patient being treated is a patient with a disorder such as hyperproliferative disorder, neurodegeneration, cardiac hypertrophy, pain, migraine, or neurotraumatic disease or event. In one embodiment, the label or accompanying information indicates that a composition containing a compound of the present invention may be used to treat a disorder resulting from abnormal cell proliferation. The label or accompanying information may also indicate that the composition may be used to treat other disorders. Alternatively or in addition, the product may further include a second container that contains a pharmaceutically acceptable buffer such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and dextrose solution. The second container may further contain other materials desirable from a commercial and user perspective, such as other buffers, diluents, filters, needles, and syringes.

[0405] 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, a second pharmaceutical formulation. For example, if the kit comprises a first composition comprising the compound of the present invention and a second pharmaceutical formulation, the kit may further comprise instructions for simultaneous, sequential, or separate administration of the first and second pharmaceutical compositions to the patient in need.

[0406] In one embodiment, the present invention provides a kit for use as described herein, which is suitable for the delivery of solid oral forms of the compounds of the present invention, such as tablets or capsules. Such a kit preferably comprises several unit doses. Such a kit may include cards having doses oriented in the order of their intended use. An example of such a kit is a "blister pack," which is well known in the packaging industry and is widely used for packaging pharmaceutical unit dosage forms. If necessary, memory aids may be provided, for example, in the form of numbers, letters or other markings, or with a calendar insert indicating the number of days in a treatment schedule in which the doses may be administered.

[0407] In one embodiment, the present invention provides a kit for use as described herein, comprising (a) a first container containing a compound of the present invention, and optionally, (b) a second container containing a second pharmaceutical formulation, the second pharmaceutical formulation comprising a second compound having anti-overgrowth activity. Alternatively or in addition, the kit may further comprise a third container containing a pharmaceutically acceptable buffer such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and dextrose solution. The third container may further comprise other materials desirable from a commercial and user perspective, such as other buffers, diluents, filters, needles, and syringes.

[0408] In one embodiment, the present invention provides a kit for use as described herein, comprising the composition of the present invention and a second therapeutic agent, and including a container for housing separate compositions, such as a divided bottle or a divided metal foil bag, although these separate compositions may also be housed in a single, undivided container. Typically, the kit includes instructions for the administration of the separate components. The kit form is particularly advantageous when the individual components are preferably administered in different dosage forms (e.g., orally and parenterally), at different dosing intervals, or when titration of the individual components of the combination is desired by the prescribing physician.

[0409] Embodiment I-1. Formula (I): [ka] (In the formula, A 1 is N or CR a And, A 2 is N or CR b And, R a is hydrogen or halogen, R b is hydrogen or halogen, R 1 This is hydrogen, cyano, halo C 1~6 Alkyl, C 1~6 Alkoxy, Halo C 1~6 Selected from alkoxy and halogen, R 2 and R 3 is hydrogen, hydroxyl, C 1~6 Alkyl, C 1~6 Alkoxy, Hydroxy C 1~6 Alkyl, C 3~5 Cycloalkyl C 1~6 Alkoxy, cyano, -OCD3, cyano C 1~6 Alkoxy, Halo C 1~6 Alkoxy, hydroxy-C 2~4 Selected independently of Alkenil, or R2 and R 3 They form a 4-6 member heterocycloalkyl or 3-6 member cycloalkyl group that is optionally substituted with 1-4 halogens or oxos, together with the carbon atoms to which they are attached, or R 3 It does not exist, and R 2 is =CHCH2OH, R 4 is hydrogen, hydroxyl C 1~6 It is an alkyl or halogen, R 5 is hydrogen or halogen, X is NH, NHCH2, CH2, CH2CH2, CH2CH2CH2, NHCH2CH2CH2, NHCH2CH2, CH=CH, CH2CH2CH(OH), CH2CH(OH), non-existent, CHFCH2, and [ka] Selected from, R 6 These include 3-10 member cycloalkyl groups, 7-11 member spiro-cycloalkyl groups, 7-11 member oxo-spiro-heterocycloalkyl groups, aryl groups, heteroaryl groups, and C groups. 1~6 Alkyl, -C≡CCH3, 4-10 member heterocycloalkyl and halo C 1~6 Selected from alkyl, cycloalkyl, spiro-cycloalkyl, oxa-spiro-cycloalkyl, aryl, heteroaryl or heterocycloalkyl, halogen, halo C 1~6 Alkyl, C 1~6 Alkyl, C 1~6 Alkoxy and Halo C 1~6 (Optionally substituted with one, two, or three substituents independently selected from the alkoxy) A compound thereof, or its solvate or pharmaceutically acceptable salt.

[0410] Embodiment I-2.(i)A 1 (ii)A 2 (iii)A 1 and A2 Both are either N or (iv)A 1 CR a and A 2 CR b The compound described in Embodiment I-1.

[0411] Embodiment I-3.A 1 Only N or A 2 The compound according to Embodiment I-2, wherein only N is present.

[0412] Embodiment I-4.A 1 CR a and A 2 CR b The compound described in Embodiment I-1.

[0413] Embodiment I-5.R a and R b The compound described in Embodiment I-4, wherein the compound is hydrogen.

[0414] Embodiment I-6.R 1 The compound is a halogen, as described in any one of Embodiments I-1 to I-5.

[0415] Embodiment I-7.R 1 The compound described in Embodiment I-6, wherein the compound is Cl.

[0416] Embodiment I-8.R 1 The compound is one of the embodiments I-1 to I-5, wherein the compound is cyano or CHF2O-.

[0417] Embodiment I-9.R 2 is hydroxy, and R 3 C 1~6 Alkyl or R 2 C 1~6 It is an alkoxy, and R 3 C 1~6 A compound according to any one of embodiments I-1 to I-8, which is alkyl.

[0418] Embodiment I-10.R 2 is hydroxy, and R 3 The compound described in Embodiment I-9 is methyl.

[0419] Embodiment I-11.R 2 is methoxy, and R 3 The compound described in Embodiment I-9 is methyl.

[0420] Embodiment I-12.R 2 and R 3 The compound according to any one of Embodiments I-1 to I-8, wherein the C atoms to which they are attached form a 4-6 member heterocycloalkyl group that is optionally substituted with one or two halogens.

[0421] Embodiment I-13.R 2 and R 3 These, together with the C atoms to which they are attached, form a 4-6 membered heterocycloalkyl group, and the heterocycloalkyl group is optionally substituted with two F atoms. [ka] The compound described in Embodiment I-12.

[0422] Embodiment I-14.R 4 and R 5 The compound according to any one of embodiments I-1 to I-13, wherein is H.

[0423] Embodiment I-15.X includes CH2, CH2CH2, CH2CH2CH2, non-existence, and [ka] A compound according to any one of embodiments I-1 to I-14, selected from the above.

[0424] Embodiment I-16.X is, [ka] The compound described in Embodiment I-15.

[0425] Embodiment I-17.R 6 The compound is selected from 3-10 membered cycloalkyl, aryl, 7-11 membered spiro-cycloalkyl, and 7-11 membered oxa-spiro-cycloalkyl, as described in any one of Embodiments I-1 to I-16.

[0426] Embodiment I-18.R 6 The compound according to Embodiment I-17, wherein is an aryl, phenyl, and a 3-10 membered cycloalkyl is a 4-6 membered saturated monocyclic cycloalkyl or a 7-10 membered crosslinked cycloalkyl, and such phenyl, cycloalkyl or crosslinked cycloalkyl is optionally substituted with one or two halogens or oxos.

[0427] Embodiment I-19. A compound according to any one of Embodiments I-1 to I-18, selected from the group consisting of the following.

[0428] [Table 20]

[0429] [Table 21]

[0430] [Table 22]

[0431] [Table 23]

[0432] [Table 24]

[0433] Table 25

[0434] Table 26

[0435] Table 27

[0436] Table 28

[0437] Table 29

[0438] Table 30

[0439] Table 31

[0440] Table 32

[0441] Table 33

[0442] Table 34

[0443] [Table 35]

[0444] [Table 36]

[0445] [Table 37]

[0446] Embodiment I-20. A compound of formula (I) exhibiting a Kv7.2 EC50 value and / or Kv7.5-7.3 Kv7.2 selectivity ratio in the range of (i) EC50 < 3 μM, Select. > 10x, or (ii) EC50 < 1 μM, Select. > 30x, as described in any one of Embodiments I-1 to I-19, or a solvate or pharmaceutically acceptable salt thereof.

[0447] Embodiment I-21. A pharmaceutical composition comprising a compound of formula (I) described in any one of Embodiments I-1 to I-20, or a solvate or pharmaceutically acceptable salt thereof.

[0448] A compound of formula (I) described in any one of Embodiments I-1 to I-20, or a solvate or pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in Embodiment I-21, for use in providing therapeutic and / or prophylactic treatment for a disorder, disease or disability related to Embodiment I-22.Kv7.2 in a subject requiring such treatment, wherein the disorder, disease or disability is selected from behavioral disorders, mood disorders, neurodevelopmental disorders, intellectual disabilities, epilepsy, neurodegenerative diseases, pain, migraines and tinnitus.

[0449] Embodiment I-23. A compound or pharmaceutical composition for use as described in Embodiment I-22, wherein the disorder, disease, or impairment is a behavioral disorder, such as attention deficit hyperactivity disorder (ADHD).

[0450] Embodiment I-24. A compound or pharmaceutical composition for use as described in Embodiment I-22, wherein the impairment, disease, or disability is a mood disorder that is depressive.

[0451] Embodiment I-25. The compound or pharmaceutical composition for use according to Embodiment I-22, wherein the disability, disorder, or impairment is a neurodevelopmental disorder selected from autism spectrum disorder (ASD) and symptomatic developmental disorders.

[0452] Embodiment I-26. The compound or pharmaceutical composition for use according to Embodiment I-22, wherein the impairment, disease, or disability is a symptomatic developmental disorder selected from Dup15q syndrome (Dup15q), Fragile X syndrome (FXS), and Angelman syndrome.

[0453] Embodiment I-27. The compound or pharmaceutical composition for use according to Embodiment I-22, wherein the impairment, disease, or disability is epilepsy selected from a wide range of childhood epilepsy, West syndrome, Ohtahara syndrome, and epileptic encephalopathy.

[0454] Embodiment I-28. The compound or pharmaceutical composition for use according to Embodiment I-22, wherein the impairment, disease, or disability is a neurodegenerative disease selected from Alzheimer's disease and motor neuron disease.

[0455] Embodiment I-29. Compounds or pharmaceutical compositions for use according to any one of Embodiments I-21 to I-28 for systemic or local administration, such as orally, nasally, parenterally (as intravenous (both bolus and injection), intramuscular or subcutaneous injection), percutaneously, vaginally, buccal, rectally or topically, as intracisional, intraperitoneal, oral or nasal spray, or as a liquid aerosol or dry powder for inhalation.

[0456] Embodiment I-30. A compound according to any one of Embodiments I-1 to I-20 or a pharmaceutical composition according to Embodiment I-21, for use in therapeutic treatment.

[0457] A compound according to any one of Embodiments I-1 to I-20, or a pharmaceutical composition according to Embodiment I-21, or a compound or pharmaceutical composition for use according to any one of Embodiments I-22 to I-29, for the manufacture of a pharmaceutical for use in therapeutic and / or preventive treatment of disorders, diseases or impairments related to Embodiment I-31.Kv7.2.

[0458] A method for therapeutic and / or prophylactic treatment of a disorder, disease or disability related to Embodiment I-32.Kv7.2, comprising administering a therapeutically effective amount of a compound described in any one of Embodiments I-1 to I-20, or a pharmaceutical composition described in Embodiment I-21, or a pharmaceutical composition for use described in any one of Embodiments I-22 to I-29.

[0459] A kit for use in the therapeutic and / or preventive treatment of disorders, diseases or impairments related to Embodiment I-33.Kv7.2, a) A compound described in any one of Embodiments I-1 to I-20, or a pharmaceutical composition described in Embodiment I-21, or a pharmaceutical composition for use described in any one of Embodiments I-22 to I-29, b) Instructions for use and A kit that includes this.

[0460] Embodiment I-34. The present invention as described herein.

[0461] Manufacturing method In further embodiments, the present invention provides a compound or solvate or pharmaceutically acceptable salt of formula (I) when produced according to the processes described herein.

[0462] The compounds of the present invention (particularly compounds selected from formulas (I) and (II) to (XV)) can be prepared via sequential or convergent synthetic routes.

[0463] The synthesis of the present invention is shown in the schematic scheme below. The skills required to carry out the reaction and purification of the resulting product are known to those skilled in the art. Substituents and subscripts used in the following description of this process have the meanings conferred herein unless otherwise indicated.

[0464] In any embodiment relating to the schemes or examples described herein with respect to the compounds of the present invention, any embodiment may be combined with any other embodiment, insofar as it does not conflict with the other embodiment. If one of the starting materials, intermediates, or compounds of the present invention (in particular compounds selected from formulas (I) and (II) to (XV)) contains one or more functional groups that are unstable and reactive under the reaction conditions of one or more reaction steps, methods known in the art may be applied to introduce an appropriate protecting group (e.g., as described in “Protective Groups in Organic Chemistry” by TW Greene and PGM Wutts, 5th Ed., 2014, John Wiley & Sons, NY) before a critical step. Such protecting groups may be removed at a later step of synthesis using standard methods described in the literature.

[0465] If the starting material or intermediate contains a chiral center, the compounds of the present invention (particularly compounds selected from formulas (I) and (II) to (XV)) can be obtained as a mixture of diastereomers or enantiomers, which can be separated by methods known in the art, for example, by chiral HPLC, chiral SFC, or chiral crystallization. Racemic compounds can be separated into opposing groups via diastereomer salts, for example, by crystallization with an optically pure acid or by separation of opposing groups by a specific chromatographic method using either a chiral adsorbent or a chiral eluent. It is also possible to separate starting materials and intermediates containing a chiral center to obtain diastereomerically / enantiomerically enriched starting materials and intermediates. By using such diastereomerically / enantiomerically enriched starting materials and intermediates in the synthesis of the compounds of the present invention, typically the respective diastereomerically / enantiomerically enriched compounds of the present invention can be obtained.

[0466] Those skilled in the art will recognize that in the synthesis of the compounds of the present invention (particularly compounds of formulas (I) and (II) to (XV)), unless otherwise desired, the "orthogonal protecting strategy" is applied, allowing for the cleavage of several 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).

[0467] Those skilled in the art will recognize that the order of reactions may change depending on the reactivity and properties of the intermediates.

[0468] More specifically, the compounds of the present invention (i.e., compounds selected from any one of formulas (I) and (II) to (XV)) or their solvates or pharmaceutically acceptable salts may be produced by the methods shown below, the methods shown in the examples, or similar methods.

[0469] Appropriate 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 & Sons, New York, NY. 1999). It has been found that it is advantageous to carry out the reactions in or without a solvent. There are no particular restrictions on the properties of the solvent used, provided that the solvent does not adversely affect the reagents involved in the reaction and can dissolve the reagents at least to some extent.

[0470] The described reaction can be carried out over a wide range of temperatures, and the exact reaction temperature is not important to the present invention. It is preferable to carry out the described reaction in the temperature range of -78°C to reflux.

[0471] The time required for the reaction can vary widely depending on many factors, particularly the reaction temperature and the properties of the reagents. However, to obtain the intermediates and compounds described, a period of 0.5 hours to several days is usually sufficient. The reaction sequence is not limited to that shown in the scheme, but the order of the reaction steps can be freely changed depending on the starting materials and their respective reactivity.

[0472] If the starting materials or intermediates are not commercially available or their synthesis is not described in the literature, they may be prepared in a manner similar to existing procedures for analogues, or as outlined in the experimental section.

[0473] Abbreviation ACN is acetonitrile. THF stands for tetrahydrofuran. Net3 is triethylamine. DMSO is dimethyl sulfoxide. HCl is ethyl acetate. CDI is 1,1'-carbonyldiimidazole. DCM is dichloromethane. DIPEA is N,N-diisopropylethylamine. DMA stands for dimethylacetamide. DMF is N,N-dimethylformamide. HCl is hydrogen chloride. HPLC is a form of high-pressure liquid chromatography. LCMS is liquid chromatography-mass spectrometry. mCPBA is 3-chloroperoxybenzoic acid. NaHCO3 is sodium bicarbonate. NaOH is sodium hydroxide. NMI stands for N-methylimidazole. NMP is N-methylpyrrolidone. MeOH is methanol. MgSO4 is magnesium sulfate. Pd(dppf)Cl2 is 1,1'-bis(di-tert-butylphosphin)ferrocenepalladium dichloride. PYBROP is bromotripyrrolidinophosphonium hexafluorophosphate. o / n means overnight. RT is room temperature. TCFH is chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate. TLC is a thin-layer chromatography technique. CHO stands for Chinese hamster ovary. CMV is 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 stands for millivolt. TEA stands for tetraethylammonium. NADPH is nicotinamide adenine dinucleotide phosphate. CL int This is the inherent clearance.

[0474] The present invention relates to formula (I): [ka] The present invention provides compounds, solvates thereof, or pharmaceutically acceptable salts thereof.

[0475] The synthesis of the compounds of the present invention is shown in the following scheme and in the description of 137 specific examples. The skills required to carry out the reaction and purification of the resulting products are known to those skilled in the art.

[0476] More specifically, the compounds of the present invention (e.g., compounds selected from formulas (I) to (VII)) or their solvates or pharmaceutically acceptable salts may be prepared by the methods shown in the examples or by similar methods. The starting materials may be commercially available or prepared by methods similar to those shown below or by methods known in the art.

[0477] Outline of the procedure For further information regarding the general procedure, see the embodiments relating to the process for preparing the compound of formula (I) or its solvate or pharmaceutically acceptable salt as described herein.

[0478] [ka] Amine 1 (or its corresponding salt, e.g., HCl) can be reacted with a carboxylic acid in the presence of a base (e.g., DIPEA, TEA) along with a coupling reagent such as HATU or HBTU, or with TCFH and NMI (Scheme 1).

[0479] The preferred conditions involve using TFCH together with NMI in acetonitrile at room temperature.

[0480] [ka] Urea analogs can be synthesized by reacting amine 2 with isocyanate 3 in a solvent such as DMF, DCM, or ACN. Alternatively, amine 4 (or 2) can be reacted with an activating reagent such as CDI, 2-nitrophenyl chloroformate, triphosgene, or phenyl chloroformate in a solvent such as DMF, DCM, or AcN and in the presence of a suitable base such as DIPEA or Net3 to produce an activated intermediate, which can then be reacted in situ with a second amine 2 (or 4) (or the corresponding HCl salt) to obtain a urea compound. When 4-nitrophenyl chloroformate is used as the activating agent, a carbamate intermediate can be isolated and then reacted with an amine (or the corresponding HCl salt) in a solvent such as DCM or THF to obtain a urea product (Scheme 2).

[0481] The preferred conditions are to use CDI with DIPEA as a base and DCM as a solvent for 45 minutes at 0°C, then add the amine 2 and stir at 35°C for 2 to 6 hours.

[0482] Isolation and purification of compounds The isolation and purification of the compounds and intermediates described herein may be carried out by any suitable separation or purification procedure, as necessary, such as filtration, extraction, crystallization, column chromatography, thick-layer chromatography, preparative low-pressure or high-pressure liquid chromatography, or a combination thereof.

[0483] However, naturally, other equivalent separation or isolation procedures can also be used. A mixture of chiral compounds of formula (I) can be separated using preparative chiral HPLC purification. [Examples]

[0484] Example 1: rac-(1S,2S)-N-[2-(3-chlorophenyl)-2-methoxypropyl]-2-phenyl-cyclopropanecarboxamide [ka] HATU (49.5 mg, 0.13 mmol) was added to a solution of 2(3-chlorophenyl)-2-methoxypropan-1-amine (20 mg, 0.1 mmol) and rac-(1S,2S)-2-phenylcyclopropane-1-carboxylic acid (19.5 mg, 0.12 mmol) in DMF (0.3 mL) and DIPEA (53 μL, 0.30 mmol). The reaction mixture was stirred at RT for 2 hours and directly purified by reverse-phase HPLC (YMC C18 column 25 × 250, water and acetonitrile, 0.1% TFA buffer, 5–100% gradient) to obtain the title product as a white solid (23 mg, yield 66.8%).

[0485] MS(m / z):344.3[M+H]+.

[0486] Example 2 (1S,2S)-N-[(2R)-2-(3-chlorophenyl)-2-methoxypropyl]-2-phenyl-cyclopropanecarboxamide [ka] The compound in question was obtained as a white powder (70% yield) using (R)-2-(3-chlorophenyl)-2-methoxypropan-1-amine, (1S,2S)-2-phenylcyclopropane-1-carboxylic acid and HATU, in the same manner as in Example 1.

[0487] MS(m / z):342.2[M+H]+.

[0488] Example 3: 1-[2-(3-chlorophenyl)-2-methoxypropyl]-3-cyclopentyl urea [ka] This compound can be prepared by a method similar to that described herein.

[0489] MS(m / z):311.5[M+H]+.

[0490] Example 4: 1-[2-(3-chlorophenyl)-2-methoxyethyl]-3-norbornan-2-ylurea [ka] To a solution of norbornane-2-amine (22.2 mg, 0.2 mmol) in DCM (2.0 mL) in an ice batch, DIPEA (200 μL) and N,N'-carbonyldiimidazole (32.4 mg, 0.2 mmol) were added. The reaction mixture was stirred at 0°C for 1 hour, and then (2(3-chlorophenyl)-2-methoxyethane-1-amine hydrochloride (20.5 mg, 0.12 mmol) was added. The reaction mixture was stirred at 35°C for 15 hours. The solvent was removed under vacuum. DMF (2 ml) was added, and the mixture was purified by reverse-phase HPLC (YMC C18 column, 25 × 250, water and acetonitrile, 0.1% TFA buffer, 5-100% gradient) to obtain the title compound as a white solid (39 mg, yield 64%).

[0491] MS(m / z):323.3[M+H]+.

[0492] Example 5: 1-[2-(3-chlorophenyl)-2-methoxypropyl]-3-(3-methoxyphenyl)urea [ka] This compound can be prepared by a method similar to that described herein.

[0493] MS(m / z):340.1[M+H]+.

[0494] Example 6: 1-[2-(3-chlorophenyl)-2-methoxypropyl]-3-(m-tolyl)urea [ka] A solution of 2-(3-chlorophenyl)-2-methoxypropan-1-amine (20 mg, 0.1 mmol) and m-tolyl isocyanate (26.7 mg, 0.2 mmol) in DMF (2 mL) was heated at 50°C for 1 hour. The reaction product was directly purified by reverse-phase HPLC (YMC C18 column 25 × 250, water and acetonitrile, 0.1% TFA buffer, 5–100% gradient) to obtain the title product (11 mg, yield 33%) as a white solid.

[0495] MS(m / z):332.9[M+H]+.

[0496] Example 7: 1-[[1-(3-chlorophenyl)cyclopropyl]methyl]-3-cyclopentyl urea [ka] The compound in question was obtained as a white powder (yield 53%) using (1-(3-chlorophenyl)cyclopropyl)methaneamine and isocyanatocyclopentane, in the same manner as in Example 6.

[0497] MS(m / z):293.5[M+H]+.

[0498] Example 8: 1-Butyl-3-[2-(3-chlorophenyl)-2-methoxypropyl]urea [ka] The compound in question was obtained as a white powder (yield 67%) using 2-(3-chlorophenyl)-2-methoxypropan-1-amine and 1-isocyanatobutane, in the same manner as in Example 6.

[0499] MS(m / z):299.5[M+H]+.

[0500] Example 9: 1-[2-(3-chlorophenyl)-2-methoxypropyl]-3-(2-furylmethyl)urea [ka] The compound in question was obtained as a white powder (45% yield) using 2-(3-chlorophenyl)-2-methoxypropan-1-amine and 2-(isocyanatomethyl)furan, in the same manner as in Example 6.

[0501] MS(m / z):323.5[M+H]+.

[0502] Example 10: 1-[2-(3-chlorophenyl)-2-methoxypropyl]-3-[(3-fluorophenyl)methyl]urea [ka] The compound in question was obtained as a white powder (yield 49%) using 2-(3-chlorophenyl)-2-methoxypropan-1-amine and 1-fluoro-3-(isocyanatomethyl)benzene, in the same manner as in Example 6.

[0503] MS(m / z):351.6[M+H]+.

[0504] Example 11: 1-[2-(3-chlorophenyl)-2-methoxypropyl]-3-(m-tolylmethyl)urea [ka] The compound in question was obtained as a white powder (yield 53%) using 2-(3-chlorophenyl)-2-methoxypropan-1-amine and 1-(isocyanatomethyl)-3-methylbenzene, in the same manner as in Example 6.

[0505] MS(m / z):347.5[M+H]+.

[0506] Example 12: 1-[[1-(3-chlorophenyl)cyclopropyl]methyl]-3-(1-oxaspiro[4,4]nonan-3-yl)urea [ka] (1-(3-chlorophenyl)cyclopropyl)methaneamine (36.3 mg, 0.2 mmol) was added to (1-(3-chlorophenyl)cyclopropyl)methaneamine (36.3 mg, 0.2 mmol) in DCM (0.5 ml) in an ice bath, followed by the addition of DIPEA (70 uL, 0.4 mmol). The reaction mixture was stirred at approximately 0°C for 45 minutes. Next, 1-oxaspiro[4,4]nonane-3-amine (28.2 mg, 0.2 mmol) was added, and the reaction mixture was stirred at 40°C for 3 hours. The solvent was removed under vacuum. DMF (2 ml) was added, and the mixture was purified by reverse-phase HPLC (YMC C18 column 25 × 250, water and acetonitrile, 0.1% TFA buffer, 5-100% gradient) to obtain the title compound as a white solid (yield 41%).

[0507] MS(m / z):349.3[M+H]+.

[0508] Example 13: 1-[2-(3-chlorophenyl)-2-methoxypropyl]-3-(1-oxaspiro[4,4]nonan-3-yl)urea [ka] The compound in question was obtained as a white powder (yield 32%) using 2-(3-chlorophenyl)-2-methoxypropan-1-amine, 1-oxaspiro[4.4]nonane-3-amine, and phenyl chloroformate, in the same manner as in Example 12.

[0509] MS(m / z):367.3[M+H]+.

[0510] Example 14: 1-[2-(3-chlorophenyl)-2-methoxypropyl]-3-(3-ethoxyphenyl)urea [ka] The compound in question was obtained as a white powder (yield 32%) using 2-(3-chlorophenyl)-2-methoxypropan-1-amine, 3-ethoxyaniline, and phenyl chloroformate, in the same manner as in Example 12.

[0511] MS(m / z):363.5[M+H]+.

[0512] Example 15: 1-[[1-(3-chlorophenyl)cyclopropyl]methyl]-3-(tetrahydropyran-2-ylmethyl)urea [ka] The compound in question was obtained as a white powder (yield 19%) using (1-(3-chlorophenyl)cyclopropyl)methaneamine, (tetrahydro-2H-pyran-2-yl)methaneamine, and phenyl chloroformate, in the same manner as in Example 12.

[0513] MS(m / z):323.5[M+H]+.

[0514] Example 16: 1-[(2R)-2-(3-chlorophenyl)-2-methoxypropyl]-3-cyclopentyl urea [ka] The compound in question was obtained as a white powder (yield 76%) using (R)-2-(3-chlorophenyl)-2-methoxypropan-1-amine and isocyanatocyclopentane, in the same manner as in Example 6.

[0515] MS(m / z):311.3[M+H]+.

[0516] Example 17: 1-[(2R)-2-(3-chlorophenyl)-2-methoxypropyl]-3-(3-methoxyphenyl)urea [ka] The compound in question was obtained as a white powder (yield 66%) using (R)-2-(3-chlorophenyl)-2-methoxypropan-1-amine and 1-isocyanato-3-methoxybenzene, in the same manner as in Example 6.

[0517] MS(m / z):349.3[M+H]+.

[0518] Example 18: 1-[2-(3-chlorophenyl)-2-(cyclopropoxy)ethyl]-3-cyclopentyl-urea [ka] a) 1-(2-(3-chlorophenyl)-2-hydroxyethyl)-3-cyclopentylurea The compound in question was obtained as a white powder (yield 86%) using 2-amino-1-(3-chlorophenyl)ethane-1-ol and isocyanatocyclopentane, in the same manner as in Example 6.

[0519] b) 1-[2-(3-chlorophenyl)-2-(cyclopropoxy)ethyl]-3-cyclopentyl urea 1-(2-(3-chlorophenyl)-2-hydroxyethyl)-3-cyclopentylurea (32 mg, 0.11 mmol) was dissolved in DMSO (2 mL), and NaH (60%, 20 mg) was added. The reaction mixture was sonicated under RT for 2 minutes. Then, iodocyclopropane (30.4 mg, 0.18 mmol) was added under nitrogen, and the reaction mixture was stirred at 55°C for 2 hours. Saturated aq.NH4Cl (10 ml) was added. Extraction was performed using AcOEt (2 times × 20 ml). The organic phase was collected, dehydrated with MgSO4, and concentrated. Purification by reverse-phase HPLC (YMC-Pack-ODS-AM column, 250 mm × 20 mm ID, S-5 μm, 12 nm, water and acetonitrile, 0.1% TFA buffer, 0-60% gradient) yielded the title compound as a white solid (yield 7%).

[0520] MS(m / z):322.9[M+H]+.

[0521] Example 19: N-[2-(3-chlorophenyl)-2-methoxypropyl]-2-cyclohexylacetamide [ka] The compound in question was obtained as a white powder (yield 92%) using 2-(3-chlorophenyl)-2-methoxypropan-1-amine, 2-cyclohexylacetic acid, and HATU, in the same manner as in Example 1.

[0522] MS(m / z):324.1[M+H]+.

[0523] Example 20: rac-(1R,2R)-N-[2-(3-chlorophenyl)-2-methoxy-ethyl]-2-phenyl-cyclopropanecarboxamide [ka] The compound in question was obtained as a white powder (yield 76%) using 2-(3-chlorophenyl)-2-methoxyethane-1-amine hydrochloride, rac-(1R,2R)-2-phenylcyclopropanecarboxylic acid and HATU, in the same manner as in Example 1.

[0524] MS(m / z):330.2[M+H]+.

[0525] Example 21: 1-[2-(3-chlorophenyl)-2-methoxypropyl]-3-(cyclopentylmethyl)urea [ka] The compound in question was obtained as a white powder (yield 42%) using 2-(3-chlorophenyl)-2-methoxypropan-1-amine, 1-cyclopentylmethaneamine, and phenyl chloroformate, in the same manner as in Example 12.

[0526] MS(m / z):325.3[M+H]+.

[0527] Example 22: 1-[2-(3-chlorophenyl)-2-methoxyethyl]-3-(m-tolyl)urea [ka] The compound in question was obtained as a white powder (yield 83%) using 2-(3-chlorophenyl)-2-methoxyethane-1-amine hydrochloride and m-tolyl isocyanate, in the same manner as in Example 6.

[0528] MS(m / z):319.3[M+H]+.

[0529] Example 23: 1-[2-(3-chlorophenyl)-2-methoxypropyl]-3-(cyclopropylmethyl)urea [ka] The compound in question was obtained as a white powder (yield 32%) using 2-(3-chlorophenyl)-2-methoxypropan-1-amine, cyclopropanemethylamine, and phenyl chloroformate, in the same manner as in Example 12.

[0530] MS(m / z):297.3[M+H]+.

[0531] Example 24: 1-[2-(3-bromophenyl)-2-isopropoxyethyl]-3-cyclopentyl urea [ka] The compound in question was obtained in the same manner as in Example 18, using 1-(2-(3-bromophenyl)-2-hydroxyethyl)-3-cyclopentylurea, 2-iodopropane, and sodium hydride (yield 6.2%).

[0532] MS(m / z):371.0[M+H]+.

[0533] Example 25: 1-[2-(3-chlorophenyl)-2-methoxypropyl]-3-[rac-(1S,2S,4R)-norbornan-2-yl]urea [ka] The compound of the title was obtained in the same manner as in Example 4, using 2-(3-chlorophenyl)-2-methoxypropan-1-amine, rac-(1R,2R,4S)-bicyclo[2.2.1]heptan-2-amine and N,N'-carbonyldiimidazole (yield 41%).

[0534] MS(m / z):337.3[M+H]+.

[0535] Example 26: 1-[2-(3-chlorophenyl)-2-(triduteriomethoxy)propyl]-3-cyclopentyl-urea [ka] The compound of the title was obtained in the same manner as in Example 18, using 1-(2-(3-chlorophenyl)-2-hydroxypropyl)-3-cyclopentylurea, iodomethane-d3, and sodium hydride (yield 4.6%).

[0536] MS(m / z):314.3[M+H]+.

[0537] Example 27: 1-(3-methoxyphenyl)-3-[[2-(m-tolyl)-1,3-dioxolan-2-yl]methyl]urea [ka] The compound in question was obtained as a white powder (yield 77%) using [2-(3-methylphenyl)-1,3-dioxolan-2-yl]methaneamine and 3-methoxyphenyl isocyanate, similar to Example 6.

[0538] MS(m / z):343.5[M+H]+.

[0539] Example 28: 1-[2-(3-bromophenyl)-2-ethoxyethyl]-3-cyclopentyl urea [ka] The compound in question was obtained in the same manner as in Example 18, using 1-(2-(3-bromophenyl)-2-hydroxyethyl)-3-cyclopentylurea, iodoethane, and sodium hydride (yield 6.2%).

[0540] MS(m / z):356.9[M+H]+.

[0541] Example 29: 1-[2-(3-chlorophenyl)-2-methoxypropyl]-3-[3-(trifluoromethoxy)phenyl]urea [ka] The compound in question was obtained as a white powder (yield 31%) using 2-(3-chlorophenyl)-2-methoxypropan-1-amine, 3-(trifluoromethoxy)aniline, and phenyl chloroformate, in the same manner as in Example 12.

[0542] MS(m / z):400.3[M+H]+.

[0543] Example 30: 1-[2-(3-chlorophenyl)-2-methoxypropyl]-3-cyclopenta-3-en-1-ylurea [ka] The compound of the title was obtained in the same manner as in Example 4, using 2-(3-chlorophenyl)-2-methoxypropan-1-amine, 1-amino-3-cyclopentene, and N,N'-carbonyldiimidazole (yield 59%).

[0544] MS(m / z):309.3[M+H]+.

[0545] Example 31: rac-(1S,2S)-N-[2-cyano-2-[3-(trifluoromethyl)phenyl]propyl]-2-phenyl-cyclopropanecarboxamide [ka] a) 2-(3-(trifluoromethyl)phenyl)propanenitrile 2-[3-(trifluoromethyl)phenyl]acetonitrile (1.851 g, 10 mmol), benzyltriethylammonium chloride (2.28 g, 10 mmol), and a solution of sodium hydroxide (2 g, 50 mmol) in water (10 mL) were combined and vigorously shaken for 30 minutes. Methyl iodide (0.75 mL, 12 mmol) was added, and the mixture was shaken at 45°C for 12 hours. The reaction mixture was diluted with H2O (300 ml) and HCl (400 ml), and the organic layer was separated. The aqueous layer was extracted with HCl (once), the organic layer was collected, dehydrated with MgSO4, filtered, and evaporated. The product (320 mg, yield 16%) was obtained by flash chromatography with silica (hexane / HCl, eluting with HCl at a gradient of 0-30%).

[0546] b) 3-Bromo-2-methyl-2-(3-(trifluoromethyl)phenyl)propanenitrile 2-[3-(trifluoromethyl)phenyl]propanenitrile (320 mg, 1.61 mmol) was dissolved in anhydrous THF (2 mL), cooled to 0°C, and potassium tert-butoxide (234.37 mg, 2.09 mmol) was added. The reaction mixture was stirred at 0°C for 1 hour, and dibromomethane (0.45 mL, 6.43 mmol) was added. The reaction mixture was stirred at RT for 3 hours. Water (50 mL) and EtOAC (100 mL) were added, and the layers were separated. The organic layer was washed with water and brine, dehydrated with MgSO4, and then filtered and evaporated. Crude product was obtained (403 mg, yield 86%) and used directly in the next step.

[0547] c) 3-(1,3-dioxoisoindolin-2-yl)-2-methyl-2-(3-(trifluoromethyl)phenyl)propanenitrile 3-Bromo-2-methyl-2-[3-(trifluoromethyl)phenyl]propanenitrile (403 mg, 1.38 mmol) was dissolved in NMP (5 mL), and potassium phthalimide (332.2 mg, 1.79 mmol) was added. The reaction mixture was stirred overnight at 120°C. The reaction product was then diluted with toluene, extracted with water and brine, dehydrated with MgSO4, filtered, and evaporated. The product was purified by silica flash chromatography (hexane / toluene, eluting with toluene gradient of 0-5%) to obtain the product (282 mg, yield 57%).

[0548] d) 3-amino-2-methyl-2-(3-(trifluoromethyl)phenyl)propanenitrile 3-(1,3-dioxoisoindolin-2-yl)-2-methyl-2-[3-(trifluoromethyl)phenyl]propanenitrile (282 mg, 0.79 mmol) was suspended in EtOH (8 mL), and hydrazine monohydrate (394 mg, 7.87 mmol) was added. The reaction mixture was stirred at 60°C for 1 hour. A precipitate formed. The reaction mixture was concentrated under vacuum, the residue was dissolved in water, and extracted with SiO2. The organic layer was dehydrated with MgSO4, filtered, and concentrated to obtain a yellowish oily product (141.5 mg, yield 78.8%), which was used in the next step without further purification.

[0549] d)rac-(1S,2S)-N-[2-cyano-2-[3-(trifluoromethyl)phenyl]propyl]-2-phenyl-cyclopropanecarboxamide The compound in question was obtained as a white powder (yield 37%) using 3-amino-2-methyl-2-(3-(trifluoromethyl)phenyl)propanenitrile, rac-(1R,2R)-2-phenylcyclopropanecarboxylic acid and HATU, in the same manner as in Example 1.

[0550] MS(m / z):373.4[M+H]+.

[0551] Example 32: 1-[2-(3-chlorophenyl)-2-methoxypropyl]-3-(3-phenylpropyl)urea [ka] This compound can be prepared by a method similar to that described herein.

[0552] MS(m / z):360.9[M+H]+.

[0553] Example 33: 1-[2-(3-chlorophenyl)-2-methoxypropyl]-3-(2-thienylmethyl)urea [ka] This compound can be prepared by a method similar to that described herein.

[0554] MS(m / z):338.9[M+H]+.

[0555] Example 34: 1-[2-(3-chlorophenyl)-2-methoxypropyl]-3-[2-(4-methoxyphenyl)ethyl]urea [ka] This compound can be prepared by a method similar to that described herein.

[0556] MS(m / z):376.9[M+H]+.

[0557] Example 35: 1-[2-(3-chlorophenyl)-2-methoxypropyl]-3-[rac-(1S,4R)-norbornan-2-yl]urea [ka] The compound of the title was obtained in the same manner as in Example 4, using 2-(3-chlorophenyl)-2-methoxypropan-1-amine, rac-(1S,2R,4R)-bicyclo[2.2.1]heptan-2-amine and N,N'-carbonyldiimidazole (yield 65%).

[0558] MS(m / z):337.3[M+H]+.

[0559] Example 36: N-[2-(2-chlorophenyl)-2-methoxyethyl]-2-(1-naphthyl)acetamide [ka] This compound can be prepared by a method similar to that described herein.

[0560] MS(m / z):354.5[M+H]+.

[0561] Example 37: rac-(1S,2S)-N-[2-(3-chlorophenyl)-2-cyanopropyl]-2-phenylcyclopropanecarboxamide [ka] The compound of the title was obtained in the same manner as in Example 31, using 2-(3-chlorophenyl)acetonitrile, rac-(1R,2R)-2-phenylcyclopropanecarboxylic acid and HATU.

[0562] MS(m / z):339.2[M+H]+.

[0563] Example 38: 1-[3-(1r,3r)-(3-chlorophenyl)cyclobutyl]-3-[(1SR,2SR,4RS)-norbornan-2-yl]urea [ka] a) 4-Nitrophenyl N-[(1r,3r)-3-(3-chlorophenyl)cyclobutyl]carbamate 4-nitrophenyl chloroformate (485.1 mg, 2.41 mmol) was stirred in 10 mL of DCM under N2 at 0°C. (1r,3r)-3-(3-chlorophenyl)cyclobutane-1-amine hydrochloride (500 mg, 2.29 mmol) and DIPEA (0.88 mL, 5.04 mmol) were combined in 5 mL of DCM to form a suspension. This was added dropwise to the chloroformate solution. The resulting mixture was stirred under N2 at 0°C for 1 hour, and then heated to RT for 1 hour. The reaction product was diluted in 30 mL of DCM and washed with saturated aq. NaHCO3 (30 mL). The organic layer was washed with brine (30 mL), dehydrated with MgSO4, and concentrated under vacuum to obtain a yellow solid (900 mg). The desired product was obtained as a white solid (370 mg, 46.6%) by purification using silica flash chromatography (eluting with a heptane-60% siRNA / heptane gradient).

[0564] b) 1-[3-(1r,3r)-(3-chlorophenyl)cyclobutyl]-3-[(1SR,2SR,4RS)-norbornan-2-yl]urea A mixture of exo-norbornylamine hydrochloride (46.8 mg, 0.32 mmol) and DIPEA (0.11 mL, 0.63 mmol) in DMF (2 mL) was slowly added to an ice-cold solution of 4-nitrophenyl N-[(1r,3r)-3(3-chlorophenyl)cyclobutyl]carbamate (100 mg, 0.29 mmol) in DMF (2 mL). After 5 minutes, the mixture was heated to RT. The reaction mixture was stirred at RT for 2 hours. The mixture was then partitioned between  (2 × 20 ml) and water (20 ml). The combined organic layer was washed with brine (3 × 20 ml), dehydrated (MgSO4), and evaporated under vacuum to obtain a crude oil (150 mg). The crude oil was purified by silica flash chromatography (eluting on a heptane-50%  gradient) to obtain the desired product as a white solid (75 mg, 81.6%).

[0565] MS(m / z):319.2[M+H]+.

[0566] Example 39: (1S,2S)-N-[[(2R)-2-(3-chlorophenyl)oxetan-2-yl]methyl]-2-phenyl-cyclopropanecarboxamide [ka] The compound of the title was obtained as a white solid using [(2R)-2-(3-chlorophenyl)oxetan-2-yl]methaneamine, (1S,2S)-2-phenylcyclopropanecarboxylic acid and HATU, in the same manner as in Example 1.

[0567] MS(m / z):341.9[M+H]+.

[0568] Example 40: (1S,2S)-N-[[(2S)-2-(3-chlorophenyl)oxetan-2-yl]methyl]-2-phenyl-cyclopropanecarboxamide [ka] The compound of the title was obtained as a white solid using [(2S)-2-(3-chlorophenyl)oxetan-2-yl]methaneamine, (1S,2S)-2-phenylcyclopropanecarboxylic acid and HATU, similar to Example 1. This is the diastereoisomer of Example 39, isolated by purification by reverse-phase HPLC.

[0569] MS(m / z):341.9[M+H]+.

[0570] Example 41: (1S,2S)-N-[[(2R)-2-(3-chlorophenyl)-3,3-difluoro-oxetane-2-yl]methyl]-2-phenyl-cyclopropanecarboxamide [ka] a) ((1-(3,4-chlorophenyl)ethenyl)oxy)trimethylsilane To a solution of diisopropylamine (5.45 mL, 0.72 g / mL, 38.81 mmol) in THF (125 mL), n-butyllithium (14.23 mL (2.5 M), 35.58 mmol) was added under N2 conditions at -78 °C, followed by the dropwise addition of a solution of 3'-chloroacetophenone (4.17 mL, 1.2 g / mL, 32.34 mmol) in THF (25 mL). After 20 minutes, trimethylchlorosilane (6.16 mL, 0.86 g / mL, 48.51 mmol) dissolved in THF (25 mL) was slowly added. After 10 minutes, the cooling bath was removed, and the reaction mixture was stirred at RT for 15 minutes. After recooling, aq. NaHCO3 sol. (100 ml) was added. The mixture was then heated to RT. Water (100 ml) and Et2O (100 ml) were added and partitioned. The organic extract was washed with brine (50 ml), dehydrated (MgSO4), and concentrated under vacuum to obtain a crude liquid. The crude liquid was purified by flash chromatography with silica eluted with heptane-2% SiO / heptane (gradient) to obtain the desired product as a colorless liquid (4.5 g, 61.4%).

[0571] b) 3-Bromo-1-(3-chlorophenyl)-2,2-difluoropropane-1-one To a solution of ((1-(3-chlorophenyl)ethenyl)oxy)trimethylsilane (2.01 g, 8.86 mmol) in acetonitrile (9 mL), [bromo(difluoro)methyl]trimethylsilane (2.07 mL, 1.31 g / mL, 13.3 mmol) was added under N2 conditions, followed by the addition of tetrabutylammonium bromide (571.5 mg, 1.77 mmol). This reaction mixture was heated at 80°C for 1.5 hours and then cooled to RT. Next, N-bromosuccinimide (2.05 g, 11.52 mmol, 1.3 eq) was added and the mixture was stirred for 10 minutes. Water (80 mL) was added, and the mixture was extracted with heptane (3 times × 50 mL). The collected organic matter was dehydrated (MgSO4) and evaporated under vacuum to obtain a yellow oily substance (2.5 g). The product was purified by flash chromatography using silica eluted with heptane-3% HCl / heptane (gradient) to obtain the desired product as a pale yellow liquid (1.15 g, 45.8%).

[0572] c) 2-(3-chlorophenyl)-3,3-difluorooxetane 2-carbonitrile Potassium cyanide (258.4 mg, 3.97 mmol) was added to a solution of 3-bromo-1-(3-chlorophenyl)2,2-difluoropropane-1-one (750 mg, 2.65 mmol) in DMF (15 mL) under N2 conditions. The reaction product turned purple and was stirred overnight. The reaction mixture was partitioned between HCl (2 times × 40 ml) and brine / water (15 ml). The combined organic matter was washed with brine (3 times × 30 ml), dehydrated (MgSO4), and evaporated under vacuum to obtain a crude oily substance (approximately 750 mg). Purification by flash chromatography with silica eluted with heptane-8% HCl (gradient) yielded the desired oxetane product as a colorless liquid (440 mg, 72.4%).

[0573] d) [2-(3-chlorophenyl)-3,3-difluorooxetane2-yl]methaneamine Cobalt(II) chloride hexahydrate (155.4 mg, 0.65 mmol) was added to a solution of 2-(3-chlorophenyl)-3,3-difluorooxetane 2-carbonitrile (300 mg, 1.31 mmol) in THF (6 mL) and water (3 mL) cooled in a salt / ice bath. As the CoCl2 dissolved, the mixture gradually turned purple. Sodium borohydride (494.3 mg, 13.07 mmol) was then added in five portions over 20 minutes. A black precipitate immediately formed, and gas was generated. Due to the large amount of gas generated, the reaction mixture was left open to the atmosphere and then slowly heated to RT in a cooling bath. It was left to stir overnight. To this reaction mixture, aq.NH3 solution (3 mL) and water (5 mL) were added and vigorously stirred for 10 minutes. Â (approximately 20 mL) was added, and the mixture was passed through a Celite plug. Further washing with pharmaceutically acceptable ammonium compounds and water was performed. The layers were separated, and the aqueous layer was washed with an additional ammonium compound (20 ml). The combined organic matter was dehydrated (MgSO4) and evaporated under vacuum to obtain a crude yellow oily substance (255 mg). Purification by flash chromatography using silica eluted with DCM-5% MeOH / DCM (gradient) yielded the desired product as a yellow oily substance (53 mg, 17.4%).

[0574] e)(1S,2S)-N-((2(3-chlorophenyl)-3,3-difluorooxetan2-yl)methyl)-2-phenylcyclopropane1-carboxamide The compound of the title was obtained in the same manner as in Example 1, using [2-(3-chlorophenyl)-3,3-difluorooxetane 2-yl]methaneamine, (1S,2S)-2-phenylcyclopropane 1-carboxylic acid and HATU (yield 65%).

[0575] MS(m / z):378[M+H]+.

[0576] f)(1S,2S)-N-[[(2R)-2-(3-chlorophenyl)-3,3-difluoro-oxetane-2-yl]methyl]-2-phenyl-cyclopropanecarboxamide The compound in question was obtained as a white solid (first isomer eluted in cellulose-4 column, water:MeCN 48:52, in chiral separation of (1S,2S)-N-((2-(3-chlorophenyl)-3,3-difluorooxetane2-yl)methyl)-2-phenylcyclopropane-1-carboxamide) (100% de, yield 46.7%).

[0577] MS(m / z):378.1[M+H]+.

[0578] Example 42: (1S,2S)-N-[[(2S)-2-(3-chlorophenyl)-3,3-difluoro-oxetane-2-yl]methyl]-2-phenyl-cyclopropanecarboxamide [ka] The compound in the title is another diastereomer of Example 41, obtained as a white solid (second isomer eluted in cellulose-4 column, water:MeCN 48:52) by chiral separation of (1S,2S)-N-((2-(3-chlorophenyl)-3,3-difluorooxetane2-yl)methyl)-2-phenylcyclopropane-1-carboxamide (99.5% de, yield 50.0%).

[0579] MS(m / z):378.1[M+H]+.

[0580] Example 43: N-[2-(3-chlorophenyl)-2-methoxypropyl]-2-(2-fluorophenyl)cyclopropanecarboxamide [ka] The compound in question was obtained as a white solid (25% yield) using 2-(3-chlorophenyl)-2-methoxypropan-1-amine, 2-(2-fluorophenyl)cyclopropanecarboxylic acid, and HATU, in the same manner as in Example 1.

[0581] MS(m / z):362.5[M+H]+.

[0582] Example 44: 2-(4-chlorophenyl)-N-[2-(3-chlorophenyl)-2-methoxypropyl]cyclopropanecarboxamide [ka] The compound of the title was obtained as a white solid (12% yield) using 2-(3-chlorophenyl)-2-methoxypropan-1-amine, 2-(4-chlorophenyl)cyclopropanecarboxylic acid, and HATU, in the same manner as in Example 1.

[0583] MS(m / z):378.4[M+H]+.

[0584] Example 45: 1-[2-(3-chlorophenyl)-2-(2,2,2-trifluoroethoxy)ethyl]-3-[rac-(1R,4S)-norbornan-2-yl]urea [ka] The compound of the title was obtained as a white solid (yield 11%) using 2-(3-chlorophenyl)-2-(2,2,2-trifluoroethoxy)ethane-1-amine, exo-2-aminonorbornane, and 4-nitrophenyl chloroformate, in the same manner as in Example 38.

[0585] MS(m / z):391.3[M+H]+.

[0586] Example 46: 1-[2-(3-chlorophenyl)-2-(cyclobutoxy)ethyl]-3-[rac-(1R,4S)-norbornan-2-yl]urea [ka] The compound in question was obtained as a white solid (36% yield) using 1-(2-amino-1-cyclobutoxyethyl)-3-chlorobenzene, exo-2-aminorbornane, and 4-nitrophenyl chloroformate, in the same manner as in Example 38.

[0587] MS(m / z):363.4[M+H]+.

[0588] Example 47: (E)-N-[2-(3-chlorophenyl)-2-methoxypropyl]-3-(2-fluorophenyl)propa-2-enamide [ka] The compound in question was obtained as a white solid (5% yield) using 2-(3-chlorophenyl)-2-methoxypropan-1-amine, 2-fluorocinnamic acid, and HATU, in the same manner as in Example 1.

[0589] MS(m / z):348.4[M+H]+.

[0590] Example 48: (1SR,2SR)-N-[(2R)-2-(3-chlorophenyl)-2-methoxypropyl]-2-(3-pyridyl)cyclopropanecarboxamide [ka] The compound in question was obtained as a white solid (21% yield) using (S)-2-(3-chlorophenyl)-2-methoxypropan-1-amine, rac-(1R,2R)-2-(pyridine-3-yl)cyclopropan-1-carboxylic acid and HATU, in the same manner as in Example 1.

[0591] MS(m / z):344.9[M+H]+.

[0592] Example 49: (1S,2S)-N-[[(2S)-2-(3-cyanophenyl)oxetan-2-yl]methyl]-2-phenyl-cyclopropanecarboxamide [ka] The compound in question was obtained as a white solid (42% yield) using 3-[(2S)-2-(aminomethyl)oxetane-2-yl]benzonitrile, (1S,2S)-2-phenylcyclopropane-1-carboxylic acid, and HATU, in the same manner as in Example 1. This white solid was purified by flash chromatography with silica eluted in hexane at a gradient of 10-30% AcOEt.

[0593] MS(m / z):332.9[M+H]+.

[0594] Example 50: 1-[[2-(3-chlorophenyl)oxetane-2-yl]methyl]-3-(3-methoxyphenyl)urea [ka] The compound of the title was obtained in the same manner as in Example 4, using [2-(3-chlorophenyl)oxetan-2-yl]methaneamine, m-anisidine, and N,N'-carbonyldiimidazole (yield 42%).

[0595] MS(m / z):346.9[M+H]+.

[0596] Example 51: (1S,2S)-N-[2-(2-chloro-4-pyridyl)-2-methoxypropyl]-2-phenyl-cyclopropanecarboxamide [ka] The compound of the title was obtained as a white solid (76% yield) using 2-(2-chloropyridine-4-yl)-2-methoxypropan-1-amine, (1S,2S)-2-phenylcyclopropan-1-carboxylic acid and HATU, in the same manner as in Example 1.

[0597] MS(m / z):344.9[M+H]+.

[0598] Example 52: (1S,2S)-N-[2-Methoxy-2-(2-Methoxy-4-pyridyl)propyl]-2-phenyl-cyclopropanecarboxamide [ka] The compound of the title was obtained as a white solid (82% yield) using 2-methoxy-2-(2-methoxypyridine-4-yl)propan-1-amine, (1S,2S)-2-phenylcyclopropane-1-carboxylic acid and HATU, in the same manner as in Example 1.

[0599] MS(m / z):340.9[M+H]+.

[0600] Example 53: N-[2-(3-chlorophenyl)-2-methoxypropyl]-3-cyclopentyl-propanamide [ka] The compound of the title was obtained as a white solid (10% yield) using 2-(3-chlorophenyl)-2-methoxypropan-1-amine, 3-cyclopentylpropionic acid, and HATU, in the same manner as in Example 1.

[0601] MS(m / z):324.5[M+H]+.

[0602] Example 54: 1-[[2-(3-chlorophenyl)oxetane-2-yl]methyl]-3-[rac-(1S,2S,4R)-norbornan-2-yl]urea [ka] The compound of the title was obtained in the same manner as in Example 4, using [2-(3-chlorophenyl)oxetan-2-yl]methaneamine, exo-2-aminonorbornane, and N,N'-carbonyldiimidazole (yield 39%).

[0603] MS(m / z):335.2[M+H]+.

[0604] Example 55: (1S,2S)-N-[[(2R)-2-(3-cyanophenyl)oxetan-2-yl]methyl]-2-phenyl-cyclopropanecarboxamide [ka] The compound in the title is the second diastereoisomer (yield 32%) isolated from the purification in Example 49 as a white solid after silica gel chromatography purification eluting 10-30% AcOEt (gradient) in hexane.

[0605] MS(m / z):332.9[M+H]+.

[0606] Example 56: N-[3-(1r,3r)-(3-chlorophenyl)cyclobutyl]-2-cyclohexyl-acetamide [ka] The compound in question was obtained as a white solid (84% yield) using (1r,3r)-3-(3-chlorophenyl)cyclobutane 1-amine hydrochloride, 3-cyclopentylpropionic acid, and HATU, in the same manner as in Example 1.

[0607] MS(m / z):306.2[M+H]+.

[0608] Example 57: N-[[2-(3-chlorophenyl)oxetan-2-yl]methyl]-2-cyclohexyl-acetamide [ka] The compound of the title was obtained as a white solid (85% yield) using [2-(3-chlorophenyl)oxetane 2-yl]methaneamine, cyclohexylacetic acid, and HATU, in the same manner as in Example 1.

[0609] MS(m / z):322.2[M+H]+.

[0610] Example 58: 1-(3-chlorophenyl)-3-[[2-(3-chlorophenyl)oxetane-2-yl]methyl]urea [ka] The compound of the title was obtained in the same manner as in Example 4, using [2-(3-chlorophenyl)oxetan-2-yl]methaneamine, 3-chloroaniline, and N,N'-carbonyldiimidazole (yield 15%).

[0611] MS(m / z):351.1[M+H]+.

[0612] Example 59: 1-[[2-(3-chlorophenyl)oxetane-2-yl]methyl]-3-(cyclopentylmethyl)urea [ka] The compound of the title was obtained in the same manner as in Example 6, using [2-(3-chlorophenyl)oxetan-2-yl]methaneamine and (isocyanatomethyl)cyclopentane (yield 77%).

[0613] MS(m / z):323.2[M+H]+.

[0614] Example 60: 1-[[2-(3-chlorophenyl)oxetane-2-yl]methyl]-3-(2,2-dimethylpropyl)urea [ka] The compound of the title was obtained in the same manner as in Example 6, using [2-(3-chlorophenyl)oxetan-2-yl]methaneamine and 1-isocyanato-2,2-dimethylpropane (yield 84%).

[0615] MS(m / z):311.2[M+H]+.

[0616] Example 61: N-[[2-(3-chlorophenyl)oxetan-2-yl]methyl]cyclohexanecarboxamide [ka] The compound of the title was obtained as a white solid (39% yield) using [2-(3-chlorophenyl)oxetane 2-yl]methaneamine, cyclohexanoic acid, and HATU, in the same manner as in Example 1.

[0617] MS(m / z):308.1[M+H]+.

[0618] Example 62: 1-[(3-chlorophenyl)methyl]-3-[[2-(3-chlorophenyl)oxetan-2-yl]methyl]urea [ka] The compound in question was obtained as a colorless, rubbery substance (yield 38%) using [2-(3-chlorophenyl)oxetan-2-yl]methaneamine and 1-chloro-3-(isocyanatomethyl)benzene, similar to Example 6.

[0619] MS(m / z):365.1[M+H]+.

[0620] Example 63: 2-(1-bicyclo[1.1.1]pentanyl)-N-[[2-(3-chlorophenyl)oxetan-2-yl]methyl]acetamide [ka] The compound of the title was obtained as a white solid (75% yield) using [2-(3-chlorophenyl)oxetane 2-yl]methaneamine, bicyclo[1.1.1]pentane 1-ylacetic acid, and HATU, in the same manner as in Example 1.

[0621] MS(m / z):306.1[M+H]+.

[0622] Example 64: N-[[2-(3-chlorophenyl)oxetan-2-yl]methyl]spiro[3,3]heptan-2-carboxamide [ka] The compound of the title was obtained as a white solid (77% yield) using [2-(3-chlorophenyl)oxetane 2-yl]methaneamine, spiro[3.3]heptane 2-carboxylic acid, and HATU, in the same manner as in Example 1.

[0623] MS(m / z):320.1[M+H]+.

[0624] Example 65: N-[[2-(3-chlorophenyl)oxetan-2-yl]methyl]-2-(4,4-difluorocyclohexyl)acetamide [ka] The compound of the title was obtained as a white solid (81% yield) using [2-(3-chlorophenyl)oxetane 2-yl]methaneamine, (4,4-difluorocyclohexyl)acetic acid and HATU, in the same manner as in Example 1.

[0625] MS(m / z):358.1[M+H]+.

[0626] Example 66: (1S,2S)-N-[[2-(3-chlorophenyl)-5-oxotetrahydrofuran-2-yl]methyl]-2-phenyl-cyclopropanecarboxamide [ka] a) Ethyl 4-bromopenta-4-enoate LDA (4.02 g, 37.52 mmol) was added dropwise to a stirred solution of 2,3-dibromo-1-propene (5 g, 25.016 mmol) and CuI (5.72 g, 30.02 mmol) in THF (50 mL) under an N2 atmosphere at -78 °C for 1 hour. Then, ethyl acetate (2.64 g, 30.019 mmol) was added and the mixture was stirred for 1 hour. Upon completion of the reaction, the resulting solution was extracted with ethyl acetate. The organic layer was collected, washed with brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (ethyl acetate:petroleum ether = 1:4) to obtain ethyl 4-bromopenta-4-enoate as a yellow oil (3 g, yield 57.9%).

[0627] b) 4-(3-chlorophenyl)pento-4-enoate 3-chlorophenylboronic acid (3.40 g, 21.73 mmol) was added dropwise to a stirred solution of ethyl 4-bromopenta-4-enoate (3 g, 14.49 mmol), Pd(PPh3)4 (3.35 g, 2.90 mmol), and Cs2CO3 (14.16 g, 43.46 mmol) in dioxane (20 mL), EtOH (20 mL), and H2O (20 mL) over 2 hours at 80°C under an N2 atmosphere. Upon completion of the reaction, the resulting solution was extracted with ethyl acetate (3 times × 30 ml). The organic layer was collected, washed with brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (ethyl acetate:petroleum ether = 1:4) to obtain ethyl 4-(3-chlorophenyl)penta-4-enoate as a yellow oil (2.2 g, yield 63.6%).

[0628] c) 4-(3-chlorophenyl)pento-4-enoic acid LiOH (1.10 g, 46.08 mmol) was added dropwise to a stirred solution of ethyl 4-(3-chlorophenyl)penta-2-enoate (2.2 g, 9.22 mmol) in MeOH (20 mL) and H2O (5 mL) under an N2 atmosphere at 0°C for 2 hours. Upon completion of the reaction, the resulting solution was extracted with ethyl acetate (3 times × 30 ml). The organic layer was collected, washed with brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (ethyl acetate:petroleum ether = 1:4) to obtain 4-(3-chlorophenyl)penta-4-enoic acid as a pale yellow oil (1.5 g, yield 77.3%).

[0629] d) 5-(3-chlorophenyl)-5-(iodomethyl)oxolan-2-one To a stirred solution of 4-(3-chlorophenyl)penta-4-enoic acid (1.5 g, 7.12 mmol) and DMAP (0.17 g, 1.42 mmol) in DCM (20 mL, 314.601 mmol), NIS (3.20 g, 14.24 mmol) was added dropwise over 2 hours at 20°C under an N2 atmosphere. Upon completion of the reaction, the resulting solution was extracted with ethyl acetate (3 times × 30 ml). The organic layer was collected, washed with brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (ethyl acetate:petroleum ether = 1:4) to obtain 5-(3-chlorophenyl)-5-(iodomethyl)oxolan-2-one as a pale yellow oil (1.5 g, yield 62.6%).

[0630] e) 5-(azidomethyl)-5-(3-chlorophenyl)oxolan2-one To a stirred solution of 5-(3-chlorophenyl)-5-(iodomethyl)oxolan-2-one (1.5 g, 4.457 mmol) in DMF (20 mL), NaN3 (1.45 g, 22.29 mmol) was added dropwise overnight at 80°C under an N2 atmosphere. Upon completion of the reaction, the resulting solution was extracted with ethyl acetate (3 times × 30 ml). The organic layer was collected, washed with brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product 5-(azidomethyl)-5-(3-chlorophenyl)oxolan-2-one as a yellow oil (700 mg, yield 62.4%).

[0631] f) 5-(aminomethyl)-5-(3-chlorophenyl)oxolan-2-one A stirred solution of 5-(azidomethyl)-5-(3-chlorophenyl)oxolan-2-one (700 mg, 2.78 mmol), Pd / C (1.48 g, 13.91 mmol), and ZnCl2 (568.7 mg, 4.17 mmol) in THF (5 mL) was incubated overnight at 20 °C under an H2 atmosphere with HCl (0.1 mL, 3.29 mmol). Upon completion of the reaction, the resulting mixture was filtered and washed with THF (3 times × 30 mL). The filtrate was concentrated under vacuum to obtain the crude product, 5-(aminomethyl)-5-(3-chlorophenyl)oxolan-2-one, as a pale yellow oily substance (420 mg, yield 66.9%).

[0632] g)(1S,2S)-N-[[2-(3-chlorophenyl)-5-oxotetrahydrofuran-2-yl]methyl]-2-phenyl-cyclopropanecarboxamide To a stirred mixture of 5-(aminomethyl)-5-(3-chlorophenyl)oxolan-2-one (400 mg, 1.77 mmol), (1S,2S)-2-phenylcyclopropane-1-carboxylic acid (287.5 mg, 1.77 mmol), and TCFH (596.8 mg, 2.13 mmol) in ACN (5 mL), NMI (218.3 mg, 2.66 mmol) was added dropwise at room temperature under an N2 atmosphere. The resulting mixture was stirred for a further 3 hours. The mixture was then purified by reverse-phase chromatography using MeCN in water (10% to 50% gradient over 10 minutes) to obtain (1S,2S)-N-{[2-(3-chlorophenyl)-5-oxooxolan-2-yl]methyl}-2-phenylcyclopropane-1-carboxamide as a white solid (8 mg, yield 1.1%).

[0633] MS(m / z):370.1[M+H]+.

[0634] Example 67: (1S,2S)-N-[[2-[2-(difluoromethoxy)-4-pyridyl]oxetan-2-yl]methyl]-2-phenyl-cyclopropanecarboxamide [ka] a) 4-bromo-2-(difluoromethoxy)pyridine To a stirred solution of 4-bromopyridine-2-ol (20 g, 114.95 mmol) in ACN (200 mL), chlorodifluoroacetate (29.8 g, 229.9 mmol) was added in small increments under a N2 atmosphere at 80°C, and the reaction mixture was stirred overnight at 80°C. Water was added, and the resulting solution was extracted with toluene (3 times). The organic layer was collected, washed with brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether:toluene = 3:1) to obtain the product 4-bromo-2-(difluoromethoxy)pyridine as a pale yellow oil (15 g, yield 58.3%).

[0635] b) 1-tert-butyl3-methyl2-[2-(difluoromethoxy)pyridine-4-yl]propanediate To a stirred solution of 4-bromo-2-(difluoromethoxy)pyridine (15 g, 66.96 mmol) in DMSO (300 mL), CuI (1.28 g, 6.7 mmol), K3PO4 (42.64 g, 200.9 mmol), benzoxazole (1.60 g, 13.39 mmol), and tert-butylmethylmalonate (17.50 g, 100.44 mmol) were added overnight at 80°C under an N2 atmosphere. Upon completion of the reaction, water was added, and the resulting solution was extracted with RINKAN (3 times). The organic layer was collected, washed with brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether: SiO = 3:1) to obtain the product 1-tert-butyl 3-methyl 2-[2-(difluoromethoxy)pyridine-4-yl]propanediate as a pale yellow oily substance (10%, 47.1%).

[0636] c) Methyl 2-[2-(difluoromethoxy)pyridine-4-yl]acetate To a stirred solution of 1-tert-butyl 3-methyl 2-[2-(difluoromethoxy)pyridine-4-yl]propanedioate (15 g, 47.28 mmol) in DCM (20 mL), TFA (20 mL) was added, and the reaction mixture was stirred at 20 °C under an N2 atmosphere for 2 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by silica gel chromatography (petroleum ether: SiO=3:1) to obtain the product, methyl 2-[2-(difluoromethoxy)pyridine-4-yl]acetate, as a yellowish oily substance (10 g, 97.4%).

[0637] d) Methyl 2-diazo-2-[2-(difluoromethoxy)pyridine-4-yl]acetate To a stirred solution of methyl 2-[2-(difluoromethoxy)pyridine-4-yl]acetate (10 g, 46.05 mmol) in ACN (50 mL), tosyl azide (10.90 g, 55.26 mmol) and DBU (10.51 g, 69.07 mmol) were added under N2 conditions at -30 °C. The reaction mixture was stirred at -30 °C for 2 hours. Water was then added, and the resulting solution was extracted with ELISA (3 times). The organic layer was collected, washed with brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether: ELISA = 3:1) to obtain methyl 2-diazo-2-[2-(difluoromethoxy)pyridine-4-yl]acetate as a yellowish oil (11 g, 98.2%).

[0638] e) Methyl 2-(2-bromoethoxy)-2[2-(difluoromethoxy)pyridine-4-yl]acetate Methyl 2-diazo-2-[2-(difluoromethoxy)pyridine-4-yl]acetate (11 g, 45.24 mmol) was added to a stirred solution of 2-bromoethanol (4.52 g, 36.19 mmol) and rhodium(II) acetate dimer (0.40 g, 0.91 mmol) in toluene (50 mL) under a N2 atmosphere at 80 °C. The reaction mixture was stirred at 80 °C for 2 hours and then cooled to RT. Water was added, and the resulting solution was extracted with ELISA (3 times). The organic layer was collected, washed with brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether: ELISA = 3:1) to obtain the product, methyl 2-(2-bromoethoxy)-2-[2-(difluoromethoxy)pyridine-4-yl]acetate, as a pale yellow oily substance (7 g, 45.5%).

[0639] f) Methyl 2-[2-(difluoromethoxy)pyridine-4-yl]oxetane-2-carboxylate LiHMDS (5.17 g, 30.87 mmol) was added to a stirred solution of methyl 2-(2-bromoethoxy)-2-[2-(difluoromethoxy)pyridine-4-yl]acetate (7 g, 20.58 mmol) in THF (800 mL) under an N2 atmosphere at 0°C. The reaction mixture was stirred at 0°C for 1 hour. A saturated ammonium chloride solution was added, and the resulting solution was extracted with RINKAN (3 times). The organic layer was collected, washed with brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether:RINKAN = 3:1) to obtain methyl 2-[2-(difluoromethoxy)pyridine-4-yl]oxetane-2-carboxylate as a pale yellow oil (3 g, 56.2%).

[0640] g) {2-[2-(difluoromethoxy)pyridine-4-yl]oxetan-2-yl}methanol To a stirred solution of methyl 2-[2-(difluoromethoxy)pyridine-4-yl]oxetane-2-carboxylate (3 g, 11.57 mmol) in THF (30 mL), NaBH4 (2.19 g, 57.87 mmol) was added in small increments under an N2 atmosphere at 0°C. The reaction mixture was stirred for 2 hours. A saturated ammonium chloride solution was added, and the resulting solution was extracted with siRNA (3×). The organic layer was collected, washed with brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether:siRNA = 3:1) to obtain the product {2-[2-(difluoromethoxy)pyridine-4-yl]oxetane-2-yl}methanol as a pale yellow oil (2 g, 74.7%).

[0641] h){2-[2-(difluoromethoxy)pyridine-4-yl]oxetan-2-yl}methyl-4-methylbenzenesulfonate To a stirred solution of {2-[2-(difluoromethoxy)pyridine-4-yl]oxetan-2-yl}methanol (2 g, 8.65 mmol), Et3N (2.63 g, 25.95 mmol), and DMAP (0.21 g, 1.73 mmol) in DCM (30 mL), TsCl (2.47 g, 12.98 mmol) was added under a N2 atmosphere at 0°C. The reaction mixture was stirred for 2 hours. Water was added, and the resulting solution was extracted by DCM (3 times). The organic layer was collected, washed with brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether: siRNA = 3:1) to obtain {2-[2-(difluoromethoxy)pyridine-4-yl]oxetan-2-yl}methyl 4-methylbenzenesulfonate (3 g, 90%) as a pale yellow oil.

[0642] i) 4-[2-(azidomethyl)oxetan-2-yl]-2-(difluoromethoxy)pyridine To a stirred solution of {2-[2-(difluoromethoxy)pyridine-4-yl]oxetan-2-yl}methyl 4-methylbenzenesulfonate (3 g, 7.79 mmol) in DMF (50 mL), NaN3 (2.53 g, 38.93 mmol) was added at 80°C under an N2 atmosphere. The reaction mixture was stirred overnight. Water was added, and the resulting solution was extracted with RINKAN (3 times). The organic layer was collected, washed with brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the product 4-[2-(azidomethyl)oxetan-2-yl]-2-(difluoromethoxy)pyridine as a pale yellow oil (1.5 g, 75.2%).

[0643] j)1-{2-[2-(difluoromethoxy)pyridine-4-yl]oxetan-2-yl}methaneamine To a stirred solution of 4-[2-(azidomethyl)oxetan-2-yl]-2-(difluoromethoxy)pyridine (1.5 g, 5.86 mmol) in THF (20 mL) and H2O (5 mL), PPh3 (7.68 g, 29.28 mmol) was added under an N2 atmosphere at 20 °C. The reaction mixture was stirred for 2 hours. Water was added, and the resulting solution was extracted with RINKAN (3 times). The organic layer was collected, washed with brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by reverse-phase chromatography eluting with MeCN in water (10% to 50% gradient over 10 minutes) to obtain 1-{2-[2-(difluoromethoxy)pyridine-4-yl]oxetan-2-yl}methaneamine (500 mg, 37.1%) as a pale yellow oil.

[0644] k)(1S,2S)-N-[[2-[2-(difluoromethoxy)-4-pyridyl]oxetan-2-yl]methyl]-2-phenyl-cyclopropanecarboxamide NMI (71.33 mg, 0.868 mmol) was added to a stirred solution of 1-{2-[2-(difluoromethoxy)pyridine-4-yl]oxetan-2-yl}methaneamine (100 mg, 0.43 mmol), (1S,2S)-2-phenylcyclopropane-1-carboxylic acid (84.54 mg, 0.52 mmol), and TCFH (243.75 mg, 0.87 mmol) in ACN (2 mL) under a N2 atmosphere at 20 °C. The reaction mixture was stirred at RT for 2 hours. The reaction mixture was concentrated under vacuum. The residue was purified by reverse-phase chromatography using MeCN in water (10% to 50% gradient over 10 minutes) to obtain the product (1S,2S)-N-[[2-[2-(difluoromethoxy)-4-pyridyl]oxetan-2-yl]methyl]-2-phenyl-cyclopropanecarboxamide as a reddish-brown solid (7.8 mg, yield 4.5%).

[0645] MS(m / z):375.1[M+H]+.

[0646] Example 68: (1S,2S)-N-[[3-(3-chlorophenyl)oxetan-3-yl]methyl]-2-phenyl-cyclopropanecarboxamide [ka] a) 3-(nitromethyl)oxetan-3-ol Et3N (8.43 g, 83.26 mmol) was added dropwise to a stirred solution of 3-oxetanone (2 g, 27.75 mmol) and nitromethane (2.54 g, 41.63 mmol) in DCM (30 mL) under an N2 atmosphere at 0°C. The reaction mixture was stirred for 1.5 hours. The resulting solution was extracted with DCM (3 times × 30 ml). The organic layer was collected, washed with brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product 3-(nitromethyl)oxetan-3-ol as a yellowish oil (2.9 g, 78.5%).

[0647] b) 3-(nitromethylidene)oxetane To a stirred solution of 3-(nitromethyl)oxetane-3-ol (2.9 g, 21.79 mmol) and Et3N (6.61 g, 65.36 mmol) in DCM (30 mL), MsCl (3.74 g, 32.68 mmol) was added dropwise at 0°C under a N2 atmosphere. The reaction mixture was stirred for 1.5 hours. The resulting solution was extracted using DCM (3 times × 30 mL). The organic layer was collected, washed with brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (siRNA:petroleum ether = 1:4) to obtain the product, 3-(nitromethylidene)oxetane, as a pale yellow solid (1.4 g, 55.8%).

[0648] c) 3-(3-chlorophenyl)-3-(nitromethyl)oxetane To a stirred solution of 1-bromo-3-chlorobenzene (11.65 g, 60.83 mmol) in THF (50 mL), BuLi (24.33 mL, 60.83 mmol, 2.5 M) was added dropwise at -78 °C under an N2 atmosphere. After 30 minutes, a solution of 3-(nitromethylidene)oxetane (1.4 g, 12.17 mmol) in THF (3 mL) was added. Upon completion of the reaction, the resulting solution was poured into a beaker containing ice. The mixture was then extracted with HCl (3 times × 80 mL). The organic layer was collected, washed with brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (HCl:petroleum ether = 1:4) to obtain the product 3-(3-chlorophenyl)-3-(nitromethyl)oxetane as a pale yellow oily substance (400 mg, 14.4%).

[0649] d) 1-[3-(3-chlorophenyl)oxetan-3-yl]methaneamine ZnCl2 (479.05 mg, 3.51 mmol) was added to a stirred solution of 3-(3-chlorophenyl)-3-(nitromethyl)oxetane (400 mg, 1.76 mmol) and Pd / C (935 mg, 8.79 mmol) in i-PrOH (20 mL) under an H2 atmosphere at 25 °C. The reaction mixture was stirred overnight. The suspension was then filtered. The filtrate was concentrated under vacuum to obtain the residual product, 1-[3-(3-chlorophenyl)oxetane-3-yl]methaneamine, as a pale yellow oily substance (120 mg, 34.6%).

[0650] e) (1S,2S)-N-[[3-(3-chlorophenyl)oxetane-3-yl]methyl]-2-phenyl-cyclopropanecarboxamide A stirred mixture of 1-[3-(3-chlorophenyl)oxetan-3-yl]methaneamine (100 mg, 0.51 mmol), (1S,2S)-2-phenylcyclopropane-1-carboxylic acid (82.05 mg, 0.51 mmol), and TCFH (170.34 mg, 0.61 mmol) in ACN (2 mL) was mixed with NMI (62.31 mg, 0.76 mmol) under a N2 atmosphere at RT. The resulting mixture was stirred for 3 hours. This mixture was purified by reverse-phase flash chromatography eluting with MeCN in water (10-50% gradient over 10 minutes) to obtain (1S,2S)-N-{[3-(3-chlorophenyl)oxetan-3-yl]methyl}-2-phenylcyclopropane-1-carboxamide as a reddish-brown solid (16.8 mg, 9.3%).

[0651] MS(m / z):342.1[M+H]+.

[0652] Example 69: N-[(2R)-2-(3-chlorophenyl)-2-methoxypropyl]-4-hydroxy-5,5-dimethyl-hexaneamide [ka] The compound of the title was obtained as a white solid (51% yield) using (R)-2-(3-chlorophenyl)-2-methoxypropan-1-amine, lithio-4-hydroxy-5,5-dimethylhexanoate and HATU, in the same manner as in Example 1.

[0653] MS(m / z):342.2[M+H]+.

[0654] Example 70: (1S,2S)-N-[(2S)-2-(3-chlorophenyl)-2-(cyanomethoxy)ethyl]-2-phenyl-cyclopropanecarboxamide [ka] a) (1S,2S)-N-[(2S)-2-(3-chlorophenyl)-2-hydroxyethyl]-2-phenylcyclopropane 1-carboxamide This compound was obtained as a white solid (74% yield) using (1S)-2-amino-1-(3-chlorophenyl)ethanol hydrochloride, (1S,2S)-2-phenylcyclopropane 1-carboxylic acid, and HATU, in the same manner as in Example 1.

[0655] b) (1S,2S)-N-[(2S)-2-(3-chlorophenyl)-2-(cyanomethoxy)ethyl]-2-phenyl-cyclopropanecarboxamide A flask containing (1S,2S)-N-[(2S)-2-(3-chlorophenyl)-2-hydroxyethyl]-2-phenylcyclopropane-1-carboxamide (83 mg, 0.26 mmol) was filled with a 4 A.mol sieve, flushed with N2 and DCM (4.5 mL), and then bromoacetonitrile (73.23 μL, 1.72 g / mL, 1.05 mmol) was added. The reaction mixture was stirred at RT for 1 hour. Then, tetrabutylammonium iodide (0.05 mL, 0.26 mmol, 1 equivalent) and silver(I) oxide (243.63 mg, 1.05 mmol) were added. The flask was wrapped in foil and stirred overnight under N2. Diluted with DCM and passed through a Celite plug. The filtrate was concentrated, and the residue was purified by silica gel chromatography eluting with heptane-40% siRNA / heptane (gradient) to obtain an impure substance (66 mg). This was dissolved in DMSO (2 ml) and purified by reverse-phase HPL to obtain the title product as a colorless, rubbery substance (47 mg, yield 50.4%).

[0656] MS(m / z):355.1[M+H]+.

[0657] Example 71: 1-(cyclopentylmethyl)-3-[rel-(2S)-2-(3-chlorophenyl)-2-methoxypropyl]urea [ka] The compound in question was obtained as a white solid by chiral separation of 1-(2-(3-chlorophenyl)-2-methoxypropyl)-3-(cyclopentylmethyl)urea in Example 21 (Cellulose-4 column, water:MeCN 48:52) (yield 30%).

[0658] MS(m / z):325.2[M+H]+.

[0659] Example 72: 1-[[3-(3-chlorophenyl)oxetane-3-yl]methyl]-3-(cyclopentylmethyl)urea [ka] 1-[3-(3-chlorophenyl)oxetane-3-yl]methaneamine (300 mg, 1.52 mmol) was added to a stirred mixture of 1-cyclopentylmethanamine (180.6 mg, 1.82 mmol), triphosgene (180.16 mg, 0.61 mmol), and DIPEA (980.8 mg, 7.59 mmol) in DCM (5 mL) under a N2 atmosphere at room temperature. The resulting mixture was stirred for 3 hours and then concentrated under vacuum. The crude product was purified by reverse-phase chromatography using MeCN in water (10% to 50% gradient over 10 minutes) to obtain the title product as a white solid (12.5 mg, 2.5%).

[0660] MS(m / z):323.2[M+H]+.

[0661] Example 73: N-[2-(3-chlorophenyl)-2-(cyanomethoxy)ethyl]-2-cyclopentyl-acetamide [ka] a) 2-3-chlorophenyl)-2-hydroxyacetate TMSCHN2 (6.12 g, 53.59 mmol) was added to a stirred solution of (3-chlorophenyl)(hydroxy)acetic acid (10 g, 53.59 mmol) in DCM (25 mL) and MeOH (25 mL) under an N2 atmosphere at 0°C. The reaction mixture was stirred for 1 hour. Upon completion of the reaction, the mixture was concentrated under vacuum. The residue was purified by silica gel chromatography and eluted with petroleum ether:EtOA = 5:1 to obtain methyl 2-(3-chlorophenyl)-2-hydroxyacetate (10 g, 93%) as a white solid.

[0662] b) 1-(3-chlorophenyl)ethane-1,2-diol NaBH4 (9.43 g, 249.23 mmol) was added to a stirred solution of methyl 2-(3-chlorophenyl)-2-hydroxyacetate (10 g, 49.85 mmol) in THF (50 mL) under an N2 atmosphere at 0°C. The reaction mixture was stirred for 1 hour. A saturated ammonium chloride solution was added, and the resulting solution was extracted with RINKAN (3 times). The organic layer was collected, washed with brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography and eluted with petroleum ether:RINKAN = 5:1 to obtain 1-(3-chlorophenyl)ethane-1,2-diol as a pale yellow oily substance (8 g, 93%).

[0663] c) 2-[(tert-butyldimethylsilyl)oxy]-1-(3-chlorophenyl)ethanol A stirred solution of 1-(3-chlorophenyl)ethane-1,2-diol (8 g, 46.35 mmol) and DMAP (1.13 g, 9.27 mmol) in DCM (40 mL) was mixed with DIPEA (17.97 g, 139.041 mmol) and TBDMSCl (10.48 g, 69.52 mmol) at 0°C. The reaction mixture was stirred for 1 hour. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with petroleum ether:SiO = 5:1 to obtain 2-[(tert-butyldimethylsilyl)oxy]-1-(3-chlorophenyl)ethanol as a pale yellow oil (10 g, 75.2%).

[0664] d) 2-{2-[(tert-butyldimethylsilyl)oxy]-1-(3-chlorophenyl)ethoxy}acetamide To a stirred solution of 2-[(tert-butyldimethylsilyl)oxy]-1-(3-chlorophenyl)ethanol (10 g, 34.86 mmol) in THF (50 mL), t-BuOK (7.82 g, 69.72 mmol) was added under an N2 atmosphere at 0°C. The reaction mixture was stirred for 30 minutes, then 2-bromoacetamide (7.21 g, 52.29 mmol) was added, and the resulting mixture was stirred for a further 2 hours. Upon completion of the reaction, the mixture was concentrated under vacuum. The residue was purified by silica gel chromatography and eluted with DCM:MeOH = 10:1 to obtain 2-{2-[(tert-butyldimethylsilyl)oxy]-1-(3-chlorophenyl)ethoxy}acetamide as a pale yellow oily substance (4 g, 33.4%).

[0665] e) 2-{2-[(tert-butyldimethylsilyl)oxy]-1-(3-chlorophenyl)ethoxy}acetonitrile TFAA (4.89 g, 23.26 mmol) was added at 20°C to a stirred solution of 2-{2-[(tert-butyldimethylsilyl)oxy]-1-(3-chlorophenyl)ethoxy}acetamide (4 g, 11.63 mmol) and pyridine (1.38 g, 17.45 mmol) in THF (30 mL). After 1 hour, the reaction mixture was concentrated under vacuum. The residue was purified by silica gel chromatography and eluted with DCM:MeOH = 10:1 to obtain 2-{2-[(tert-butyldimethylsilyl)oxy]-1-(3-chlorophenyl)ethoxy}acetonitrile as a pale yellow oily substance (3 g, 79.1%).

[0666] f) 2-[1-(3-chlorophenyl)-2-hydroxyethoxy]acetonitrile TBAF (4.81 g, 18.41 mmol) was added at 20°C to a stirred solution of 2-{2-[(tert-butyldimethylsilyl)oxy]-1-(3-chlorophenyl)ethoxy}acetonitrile (3 g, 9.21 mmol) in THF (20 mL). The reaction mixture was stirred for 1 hour. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with DCM:MeOH = 10:1 to obtain 2-[1-(3-chlorophenyl)-2-hydroxyethoxy]acetonitrile as a pale yellow oil (1.8 g, 92.4%).

[0667] g) 2-[1-(3-chlorophenyl)-2-[(4-methylbenzenesulfonyl)oxy]ethoxy]acetonitrile To a stirred solution of 2-[1-(3-chlorophenyl)-2-hydroxyethoxy]acetonitrile (1.8 g, 8.51 mmol) and DMAP (0.21 g, 1.7 mmol) in DCM (10 mL), DIPEA (3.30 g, 25.52 mmol) and TsCl (2.43 g, 12.76 mmol) were added at 0°C, and the reaction mixture was stirred for 1 hour. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, and eluted with DCM:MeOH = 10:1 to obtain 2-[1-(3-chlorophenyl)-2-[(4-methylbenzenesulfonyl)oxy]ethoxy]acetonitrile as a pale yellow oily substance (2 g, 64.3%).

[0668] h)2-[2-azido-1-(3-chlorophenyl)ethoxy]acetonitrile To a stirred solution of 2-[1-(3-chlorophenyl)-2-[(4-methylbenzenesulfonyl)oxy]ethoxy]acetonitrile (2 g, 5.47 mmol) in DMF (20 mL), NaN3 (1.78 g, 27.34 mmol) was added in small amounts at 80°C under an N2 atmosphere. The reaction mixture was stirred overnight. Water was added, and the resulting solution was extracted with RINKAN (3 times). The organic layer was collected, washed with brine, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the product 2-[2-azido-1-(3-chlorophenyl)ethoxy]acetonitrile as a pale yellow oil (1 g, 77.3%).

[0669] i) 2-[2-amino-1-(3-chlorophenyl)ethoxy]acetonitrile To a stirred solution of 2-[2-azido-1-(3-chlorophenyl)ethoxy]acetonitrile (1 g, 4.23 mmol) in THF (8 mL) and H2O (2 mL), PPh3 (5.54 g, 21.13 mmol) was added in small increments under an N2 atmosphere at 20°C. The reaction mixture was stirred for 2 hours. The reaction mixture was concentrated under vacuum. The residue was purified by reverse-phase chromatography using MeCN in water (10% to 50% gradient) to obtain 2-[2-amino-1-(3-chlorophenyl)ethoxy]acetonitrile as a pale yellow oily substance (200 mg, 26.2%).

[0670] j)N-[2-(3-chlorophenyl)-2-(cyanomethoxy)ethyl]-2-cyclopentyl-acetamide This compound was obtained as a white solid (12% yield) using 2-[2-amino-1-(3-chlorophenyl)ethoxy]acetonitrile, cyclopentanoacetic acid, and HATU, in the same manner as in Example 1.

[0671] MS(m / z):321.1[M+H]+.

[0672] Example 74: (1S,2S)-N-[2-(3-chlorophenyl)-3-hydroxypropyl]-2-phenyl-cyclopropanecarboxamide [ka] a) 3-amino-2-(3-chlorophenyl)propan-1-ol A solution of 2-(3-chlorophenyl)acetonitrile (2.34 g, 15.44 mmol) and ethyl formate (1.72 g, 23.22 mmol) in THF (150 mL) was mixed with NaH (0.48 g, 20.0 mmol) in an ice bath. The resulting mixture was stirred at 0°C for 30 minutes, then carefully acidified with dilute HCl and extracted with ethyl acetate. The extract was washed with water and saturated NaCl solution, dehydrated (MgSO4), and concentrated to obtain 3-amino-2-(3-chlorophenyl)propan-1-ol as a white solid (2.0 g, 69.8%).

[0673] b) 3-amino-2-(3-chlorophenyl)propan-1-ol NaBH4 (8.33 g, 220.18 mmol) was added in an ice bath to a solution of 2-(3-chlorophenyl)-3-hydroxypropanenitrile (5 g, 27.53 mmol) and cobalt chloride hexahydrate (9.83 g, 41.32 mmol) in THF (300 mL). The resulting mixture was stirred at 0°C for 30 minutes. Dilute NH4Cl was carefully added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated NaCl solution, dehydrated (MgSO4), and concentrated under vacuum to obtain 3-amino-2-(3-chlorophenyl)propan-1-ol as a white solid (2.5 g, 48.9%).

[0674] c) (1S,2S)-N-[2-(3-chlorophenyl)-3-hydroxypropyl]-2-phenyl-cyclopropanecarboxamide To a stirred mixture of 3-amino-2-(3-chlorophenyl)propan-1-ol (80 mg, 0.43 mmol), (1S,2S)-2-phenylcyclopropane-1-carboxylic acid (69.89 mg, 0.43 mmol), and TCFH (241.81 mg, 0.86 mmol) in ACN (20 mL), NMI (70.76 mg, 0.86 mmol) was added dropwise at 0°C under an N2 atmosphere. The residue was purified by reverse-phase HPLC eluting with MeCN in water (10% to 50% gradient over 20 minutes) to obtain (1S,2S)-N-[2-(3-chlorophenyl)-3-hydroxypropyl]-2-phenylcyclopropane-1-carboxamide as a white solid (61.8 mg, 43.5%).

[0675] MS(m / z):330.1[M+H]+.

[0676] Example 75: 1-[[2-(3-chlorophenyl)-5-oxotetrahydrofuran-2-yl]methyl]-3-(cyclopentylmethyl)urea [ka] This compound was obtained as a white solid (yield 0.6%) using 5-(aminomethyl)-5-(3-chlorophenyl)oxolan-2-one (Example 66), 1-cyclopentylmethaneamine, and triphosgene, similar to Example 72.

[0677] MS(m / z):351.1[M+H]+.

[0678] Example 76: (1S,2S)-N-[[2-(6-chloro-2-pyridyl)oxetan-2-yl]methyl]-2-phenyl-cyclopropanecarboxamide [ka] This compound was obtained as a yellowish solid using 2-bromo-6-chloropyridine, (1S,2S)-2-phenylcyclopropane-1-carboxylic acid and TCFH / NMI, similar to Example 67.

[0679] MS(m / z):343.1[M+H]+.

[0680] Example 77: (1S,2S)-N-[(E)-2-(3-chlorophenyl)-4-hydroxy-buta-2-enyl]-2-phenyl-cyclopropanecarboxamide [ka] a) Ethyl 4-[(tert-butoxycarbonyl)amino]-3-oxobutanoate A solution of [(tert-butoxycarbonyl)amino]acetic acid (10 g, 57.08 mmol) and CDI (13.88 g, 85.62 mmol) in THF (200 mL) was stirred at RT under an N2 atmosphere for 3 hours. MgCl2 (10.87 g, 114.17 mmol) and potassium 3-ethoxy-3-oxopropanoate (19.43 g, 114.17 mmol) were added to this solution at RT. The reaction mixture was stirred at 50 under an N2 atmosphere for 18 hours. The precipitated solid was collected by filtration and washed with THF (200 mL). The organic layer was washed with NH4Cl (300 mL), NaHCO3 (100 mL), and brine (100 mL), dehydrated (MgSO4), and concentrated. The residue was purified by silica gel chromatography and eluted with petroleum ether:toluene (3:7) to obtain ethyl 4-[(tert-butoxycarbonyl)amino]-3-oxobutanoate as a green oily substance (8.1 g, 57.9%).

[0681] b) Ethyl(2Z)-4-[(tert-butoxycarbonyl)amino]-3-[(4-methylbenzenesulfonyl)oxy]buta-2-enoate A solution of ethyl 4-[(tert-butoxycarbonyl)amino]-3-oxobutanoate (8.1 g, 33.02 mmol) and LDA (7.08 g, 66.05 mmol) in THF (100 mL) was stirred at -50°C under an N2 atmosphere for 3 hours. 4-methylbenzenesulfonyl 4-methylbenzenesulfonate (14.01 g, 42.93 mmol) was added, and the reaction mixture was stirred at -50°C for 1 hour. The temperature was returned to RT and the mixture was stirred for 12 hours. Water (100 ml) was added, and the mixture was extracted with SiO2 (100 ml). The organic layer was washed with NaHCO3 (100 ml), 1N NaOH (twice × 100 ml), and brine (twice × 100 ml), dehydrated (MgSO4), and concentrated. The residue was purified by silica gel chromatography and eluted with petroleum ether / ethyl (3:7) to obtain ethyl(2Z)-4-[(tert-butoxycarbonyl)amino]-3-[(4-methylbenzenesulfonyl)oxy]buta-2-enoate as a yellowish solid (7.7g, 58.4%).

[0682] c) Ethyl(2E)-4-[(tert-butoxycarbonyl)amino]-3-(3-chlorophenyl)buta-2-enoate A solution of ethyl(2Z)-4-[(tert-butoxycarbonyl)amino]-3-[(4-methylbenzenesulfonyl)oxy]buta-2-enoate (7.7g, 19.28 mmol), 3-chlorophenylboronic acid (4.52g, 28.91 mmol), Na2CO3 (6.13g, 57.83 mmol), and PdCl2(PPh3)2 (1.353g, 1.93 mmol) in THF (100 mL) and H2O (20 mL) was stirred overnight at 40°C under an N2 atmosphere. The aqueous layer was extracted with SiO2 (100 mL), and the resulting organic layer was washed with aq.NaHCO3 (50 mL) and H2O (50 mL), dehydrated (MgSO4), and concentrated. The residue was purified by silica gel chromatography and eluted with petroleum ether / ethyl (2:3) to obtain ethyl(2E)-4-[(tert-butoxycarbonyl)amino]-3-(3-chlorophenyl)buta-2-enoate (3.6 g, 55.0%) as a red solid.

[0683] d) tert-butyl N-[(2E)-2-(3-chlorophenyl)-4-hydroxybuta-2-en-1-yl]carbamate A solution of ethyl(2E)-4-[(tert-butoxycarbonyl)amino]-3-(3-chlorophenyl)buta-2-enoate (3.6 g, 10.59 mmol) and LiAlH4 (1.21 g, 31.78 mmol) in THF (20 mL) was stirred for 10 minutes under an N2 atmosphere at 0. The reaction product was quenched with sodium sulfate decahydrate at 0. The residual product was purified by reverse-phase chromatography (eluting at H2O:ACN=3:7) to obtain tert-butyl N-[(2E)-2-(3-chlorophenyl)-4-hydroxybuta-2-en-1-yl]carbamate as a white solid (1.54 g, 48.8%).

[0684] e)(2E)4-amino-3-(3-chlorophenyl)buta-2-en-1-ol A solution of tert-butyl N-[(2E)-2-(3-chlorophenyl)-4-hydroxybuta-2-en-1-yl]carbamate (1.5 g, 5.04 mmol) and TFA (15 mL) in DCM (40 mL) was stirred at room temperature for 1 hour. The mixture was concentrated, and the residual product was purified by reverse-phase chromatography (eluting with H2O:ACN = 2:3) to obtain (2E)-4-amino-3-(3-chlorophenyl)buta-2-en-1-ol as a white oil (0.76 g, 76.3%).

[0685] f)(1S,2S)-N-[(E)-2-(3-chlorophenyl)-4-hydroxy-buta-2-enyl]-2-phenyl-cyclopropanecarboxamide A solution of (2E)-4-amino-3-(3-chlorophenyl)buta-2-en-1-ol (100 mg, 0.51 mmol), (1S,2S)-2-phenylcyclopropane-1-carboxylic acid (123.08 mg, 0.76 mmol), TCFH (283.90 mg, 1.01 mmol), and NMI (124.61 mg, 1.52 mmol) in ACN (5 mL) was stirred at room temperature under an N2 atmosphere for 1 hour. The reaction mixture was concentrated, and the residual product was purified by reverse-phase chromatography (eluting with water:ACN = 3:7) to obtain (1S,2S)-N-[(2E)-2-(3-chlorophenyl)-4-hydroxybuta-2-en-1-yl]-2-phenylcyclopropane-1-carboxamide as a white solid (6 mg, 3.5%).

[0686] MS(m / z):342.1[M+H]+.

[0687] Example 78: 1-[(E)-2-(3-chlorophenyl)-4-hydroxy-buta-2-enyl]-3-(cyclopentylmethyl)urea [ka] This compound was obtained as a white solid (47% yield) using (2E)-4-amino-3-(3-chlorophenyl)buta-2-en-1-ol (Example 77), 1-cyclopentylmethaneamine, and triphosgene, similar to Example 72.

[0688] MS(m / z):323.1[M+H]+.

[0689] Example 79: (1RS,2SR)-N-[(2R)-2-(3-chlorophenyl)-2-methoxypropyl]-2-cyclopropyl-cyclopropanecarboxamide [ka] The compound in question was obtained as a colorless, rubbery substance (86% yield) using (R)-2-(3-chlorophenyl)-2-methoxypropan-1-amine, rac-(1R,2S)-2-cyclopropylcyclopropane-1-carboxylic acid and HATU, in the same manner as in Example 1.

[0690] MS(m / z):308.1[M+H]+.

[0691] Example 80: (1RS,2SR)-N-[(2R)-2-(3-chlorophenyl)-2-methoxypropyl]-2-cyclopentyl-cyclopropanecarboxamide [ka] The compound in question was obtained as a colorless, rubbery substance (42% yield) using (R)-2-(3-chlorophenyl)-2-methoxypropan-1-amine, 2-cyclopentylcyclopropane-1-carboxylic acid, and HATU, in the same manner as in Example 1.

[0692] MS(m / z):336.2[M+H]+.

[0693] Example 81: (1SR,2SR)-N-[(2R)-2-(3-chlorophenyl)-2-methoxypropyl]-2-cyclopentyl-cyclopropanecarboxamide [ka] The compound in the title is a mixture of cis-diastereomers obtained from the purification of Example 80 (yield 33%).

[0694] MS(m / z):336.2[M+H]+.

[0695] Example 82: N-[(2R)-2-(3-chlorophenyl)-2-methoxypropyl]spiro[2.5]octane-2-carboxamide [ka] The compound of the title was obtained as a colorless, rubbery substance (yield 92%) using (R)-2-(3-chlorophenyl)-2-methoxypropan-1-amine, spiro[2.5]octane-1-carboxylic acid, and HATU, in the same manner as in Example 1.

[0696] MS(m / z):336.2[M+H]+.

[0697] Example 83: N-[(2R)-2-(3-chlorophenyl)-2-methoxypropyl]-6,6-difluorospiro[2.5]octane-2-carboxamide [ka] The compound of the title was obtained as a colorless rubbery substance (yield 63%) using (R)-2-(3-chlorophenyl)-2-methoxypropan-1-amine, 6,6-difluorospiro[2.5]octane-1-carboxylic acid and HATU, in the same manner as in Example 1.

[0698] MS(m / z):372.2[M+H]+.

[0699] Example 84: N-[(2R)-2-(3-chlorophenyl)-2-methoxypropyl]-6-oxaspiro[2.5]octane-2-carboxamide [ka] The compound of the title was obtained as a colorless, rubbery substance (52% yield) using (R)-2-(3-chlorophenyl)-2-methoxypropan-1-amine, 6-oxaspiro[2.5]octane-1-carboxylic acid and HATU, in the same manner as in Example 1.

[0700] MS(m / z):338.1[M+H]+.

[0701] Example 85: (1S,2S)-N-[[3-(3-cyanophenyl)oxetan-3-yl]methyl]-2-phenyl-cyclopropanecarboxamide [ka] The compound of the title was obtained in the same manner as in Example 68, using 3-bromobenzonitrile, (1S,2S)-2-phenylcyclopropane-1-carboxylic acid and TCFH / NMI.

[0702] MS(m / z):333.2[M+H]+.

[0703] Example 86: (1S,2S)-N-[1-[1-(3-chlorophenyl)cyclopropyl]-2-hydroxy-ethyl]-2-phenyl-cyclopropanecarboxamide [ka] To a solution of 2-amino-2-[1-(3-chlorophenyl)cyclopropyl]ethanol (100 mg, 0.472 mmol, 1.00 equivalent) in ACN (2 mL), (1S,2S)-2-phenylcyclopropane-1-carboxylic acid (76.6 mg, 0.472 mmol) and TCFH (397.6 mg, 1.416 mmol, 3 equivalents) were added, followed by the dropwise addition of NMI (38.8 mg, 0.472 mmol). The mixture was stirred at 25°C for 2 hours until the reaction was complete. The reaction mixture was evaporated under vacuum, and the residue was purified by reverse flash chromatography using MeCN in water (20% to 50% gradient over 30 minutes) to obtain the desired product as a white solid (31.8 mg, 18.9%).

[0704] MS(m / z):356.1[M+H]+.

[0705] Example 87: (1S,2S)-N-[[2-(3-cyanophenyl)-3,3-difluoro-oxetan-2-yl]methyl]-2-phenyl-cyclopropanecarboxamide [ka] a) ((1-(3-bromophenyl)ethenyl)oxy)trimethylsilane A mixture of m-bromoacetophenone (15 g, 75.36 mmol) and NaI (13.56 g, 90.43 mmol) in ACN (20 mL) was stirred at room temperature under a N2 atmosphere for 5 minutes. To this stirred mixture, Et3N (9.15 g, 90.43 mmol) and TMSCl (9.82 g, 90.43 mmol) were added in small amounts under a N2 atmosphere. The resulting mixture was stirred overnight and then concentrated under vacuum. The residue was purified by silica gel chromatography and eluted with petroleum ether / dimethyl = 2:3 to obtain ((1-(3-bromophenyl)ethenyl)oxy)trimethylsilane (7.8 g, 38.2%) as a white oil.

[0706] b) 3-Bromo-1-(3-bromophenyl)-2,2-difluoropropan-1-one A solution of ((1-(3-bromophenyl)ethenyl)oxy)trimethylsilane (7.8 g, 28.76 mmol), (bromodifluoromethyl)trimethylsilane (8.76 g, 43.14 mmol), NBS (6.65 g, 37.39 mmol), and TBAB (1.85 g, 5.75 mmol) in ACN (10 mL) was stirred at 80°C under an N2 atmosphere for 2 hours. The solvent was removed under vacuum, and the residue was purified by silica gel chromatography. Elution with petroleum ether / SiO7 (3:7) yielded 3-bromo-1-(3-bromophenyl)-2,2-difluoropropan-1-one (6.9 g, 73.2%) as a colorless oil.

[0707] c) 2-(3-bromophenyl)-3,3-difluorooxetane-2-carbonitrile A solution of 3-bromo-1-(3-bromophenyl)-2,2-difluoropropan-1-one (6.9 g, 21.04 mmol) and KCN (2.06 g, 31.56 mmol) in DMF (5 mL) was stirred overnight at air temperature under an N2 atmosphere. The resulting mixture was extracted with ethyl acetate (3 times × 20 ml). The collected organic layer was washed with brine (3 times × 20 ml), dehydrated with anhydrous sodium 2 SO4, and concentrated. The residue was purified by silica gel chromatography and eluted with petroleum ether / ethyl acetate = 2:3 to obtain 2-(3-bromophenyl)-3,3-difluorooxetane-2-carbonitrile (2.2 g, 38.2%) as a yellowish oil.

[0708] d) 1-[2-(3-bromophenyl)-3,3-difluorooxetane-2-yl]methaneamine A mixture of 2-(3-bromophenyl)-3,3-difluorooxetane-2-carbonitrile (2.2 g, 8.03 mmol), CoCl2.6H2O (2.86 g, 12.04 mmol), and NaBH4 (2.43 g, 64.22 mmol) in MeOH (15 mL) was stirred at RT under an N2 atmosphere for 40 minutes. The solvent was removed under vacuum, and the residue was purified by silica gel chromatography. Elution was performed at a DCM / MeOH ratio of 10:1 to obtain 1-[2-(3-bromophenyl)-3,3-difluorooxetane-2-yl]methaneamine (376 mg, 16.8%) as a colorless oil.

[0709] e) (1S,2S)-N-[[2-(3-cyanophenyl)-3,3-difluoro-oxetane-2-yl]methyl]-2-phenyl-cyclopropanecarboxamide The compound in question was obtained as a colorless oil (33% yield) using 1-[2-(3-bromophenyl)-3,3-difluorooxetane-2-yl]methaneamine, (1S,2S)-2-phenylcyclopropane-1-carboxylic acid and TCFH / NMI, in the same manner as in Example 86.

[0710] MS(m / z):369.1[M+H]+.

[0711] Example 88: (1S,2S)-N-[[2-(3-cyanophenyl)-5-oxotetrahydrofuran-2-yl]methyl]-2-phenyl-cyclopropanecarboxamide [ka] The compound of the title was obtained as a white solid using 3-cyanophenylboronic acid, (1S,2S)-2-phenylcyclopropane-1-carboxylic acid and TCFH / NMI, in the same manner as in Example 66.

[0712] MS(m / z):361.2[M+H]+.

[0713] Example 89: N-[[3-(3-cyanophenyl)oxetane-3-yl]methyl]-2-cyclohexyl-acetamide [ka] The compound of the title was obtained in the same manner as in Example 85, using 3-[3-(aminomethyl)oxetan-3-yl]benzonitrile, cyclohexaneacetic acid, and TCFH / NMI (yield 6%).

[0714] MS(m / z):313.2[M+H]+.

[0715] Example 90: N-[[2-(3-cyanophenyl)-5-oxotetrahydrofuran-2-yl]methyl]-2-cyclohexyl-acetamide [ka] The compound of the title was obtained in the same manner as in Example 86, using 3-[2-(aminomethyl)-5-oxooxolan-2-yl]benzonitrile, cyclohexaneacetic acid, and TCFH / NMI (yield 3.2%).

[0716] MS(m / z):341.2[M+H]+.

[0717] Example 91: N-[[2-(3-cyanophenyl)-3,3-difluoro-oxetane-3-yl]methyl]-2-cyclohexyl-acetamide [ka] The compound of the title was obtained in the same manner as in Example 87, using 1-[2-(3-bromophenyl)-3,3-difluorooxetan-2-yl]methaneamine, cyclohexaneacetic acid, and TCFH / NMI (yield 26%).

[0718] MS(m / z):349.2[M+H]+.

[0719] Example 92: (1S,2S)-N-[2-(3-chlorophenyl)-4-hydroxy-butyl]-2-phenyl-cyclopropanecarboxamide [ka] a) Methyl 3-(3-chlorophenyl)-3-cyanopropanoate To a stirred mixture of 2-(3-chlorophenyl)acetonitrile (10 g, 65.97 mmol) in DMF (100 ml), NaH (2.37 g, 98.95 mmol) was added in small amounts at 0°C. To the above mixture, 2-methyl bromoacetate (15.14 g, 98.95 mmol) was added in small amounts at 0°C over 30 minutes. The resulting mixture was stirred at 0°C for a further 1 hour. The resulting mixture was extracted with ELISA (3 times × 200 mL). The collected organic layer was washed with water (3 times × 200 mL), dehydrated with anhydrous Na₂SO₄, and concentrated under vacuum. The residue was purified by silica gel chromatography and eluted with petroleum ether / ELISA (5:1) to obtain methyl 3-(3-chlorophenyl)-3-cyanopropanoate (2 g, 13.6%) as a yellowish oil.

[0720] b) 4-amino-3-(3-chlorophenyl)butan-1-ol To a solution of methyl 3-(3-chlorophenyl)-3-cyanopropanoate (2.9 g, 12.97 mmol) in THF (50 mL), LAH (1.23 g, 32.42 mmol) was added in an ice bath at 0°C. The resulting mixture was stirred at 0°C for 30 minutes. This reaction was quenched at 0°C with Na2SO4·10H2O. The resulting mixture was filtered, and the filter cake was washed with THF (3 times × 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (MeOH:DCM = 1:10) to obtain 4-amino-3-(3-chlorophenyl)butan-1-ol as a colorless oil (550 mg, 21.2%).

[0721] c) (1S,2S)-N-[2-(3-chlorophenyl)-4-hydroxy-butyl]-2-phenyl-cyclopropanecarboxamide To a stirred mixture of 4-amino-3-(3-chlorophenyl)butan-1-ol (200 mg, 1.0 mmol) and (1S,2S)-2-phenylcyclopropane-1-carboxylic acid (178.69 mg, 1.1 mmol) in DMF, TCFH (562.06 mg, 2.0 mmol) was added in small amounts at room temperature. NMI (205.59 mg, 2.51 mmol) was added dropwise to the mixture under a nitrogen atmosphere at 0°C. The resulting mixture was further stirred at room temperature for 60 minutes. The residue was purified by reverse-phase HPLC (eluting with 50%-75% MeOH:water over 8 minutes) to obtain (1S,2S)-N-[2-(3-chlorophenyl)-4-hydroxy-butyl]-2-phenyl-cyclopropanecarboxamide as a white solid (38.5 mg, 11.2%).

[0722] MS(m / z):344.1[M+H]+.

[0723] Example 93: N-[[(2S)-2-(3-cyanophenyl)oxetane-2-yl]methyl]-2-cyclohexyl-acetamide [ka] The compound of the title was obtained as a white solid (48% yield) using 3-[(2S)-2-(aminomethyl)oxetan-2-yl]benzonitrile, cyclohexaneacetic acid, and TCFH / NMI, in the same manner as in Example 86.

[0724] MS(m / z):313.2[M+H]+.

[0725] Example 94: N-[[(2R)-2-(3-cyanophenyl)oxetane-2-yl]methyl]-2-cycloheptyl-acetamide [ka] The compound of the title was obtained as a white solid (36% yield) using 3-[(2R)-2-(aminomethyl)oxetan-2-yl]benzonitrile, cycloheptylacetic acid, and TCFH / NMI, in the same manner as in Example 86.

[0726] MS(m / z):337.2[M+H]+.

[0727] Example 95: (1S,2S)-N-[[(2S)-2-(3-cyanophenyl)oxetan-2-yl]methyl]-2-(trifluoromethyl)cyclopropanecarboxamide [ka] The compound of the title was obtained as a white solid (36% yield) using 3-[(2S)-2-(aminomethyl)oxetane-2-yl]benzonitrile, (1S,2S)-2-(trifluoromethyl)cyclopropane-1-carboxylic acid and TCFH / NMI, in the same manner as in Example 86.

[0728] MS(m / z):325.1[M+H]+.

[0729] Example 96: N-[[(2S)-2-(3-cyanophenyl)oxetane-2-yl]methyl]-2,2-difluoro-spiro[2,3]hexane-1-carboxamide [ka] The compound of the title was obtained as a white oil (51% yield) using 3-[(2S)-2-(aminomethyl)oxetane-2-yl]benzonitrile, 2,2-difluorospiro[2.3]hexane-1-carboxylic acid, and TCFH / NMI, in the same manner as in Example 86.

[0730] MS(m / z):333.1[M+H]+.

[0731] Example 97: N-[[(2R)-2-(3-cyanophenyl)oxetane-2-yl]methyl]-2-norbornan-2-ylacetamide [ka] The compound of the title was obtained as a white oil (42% yield) using 3-[(2R)-2-(aminomethyl)oxetane-2-yl]benzonitrile, bicyclo[2.2.1]heptan-2-ylacetic acid and TCFH / NMI, in the same manner as in Example 86.

[0732] MS(m / z):325.2[M+H]+.

[0733] Example 98: N-[[(2R)-2-(3-cyanophenyl)oxetane-2-yl]methyl]bicyclo[2.2.2]octane-2-carboxamide [ka] The compound of the title was obtained as a white oil (20% yield) using 3-[(2R)-2-(aminomethyl)oxetane-2-yl]benzonitrile, bicyclo[2.2.2]octane-2-carboxylic acid and TCFH / NMI, in the same manner as in Example 86.

[0734] MS(m / z):325.2[M+H]+.

[0735] Example 99: (1S,2S)-N-[[2-[6-(difluoromethoxy)-2-pyridyl]oxetan-2-yl]methyl]-2-phenyl-cyclopropanecarboxamide [ka] Starting from 6-bromopyridine-2-ol, 1-(2-(6-(difluoromethoxy)pyridine-2-yl)oxetan-2-yl)methaneamine was obtained in the same manner as in Example 67. The title compound was obtained as a pale yellow oil (18% yield) using 1-(2-[6-(difluoromethoxy)pyridine-2-yl)oxetan-2-yl)methaneamine, (1S,2S)-2-phenylcyclopropane-1-carboxylic acid and TCFH / NMI in the same manner as in Example 86.

[0736] MS(m / z):375.2[M+H]+.

[0737] Example 100: N-[[(2S)-2-(3-cyanophenyl)oxetan-2-yl]methyl]spiro[3,3]heptan-3-carboxamide [ka] The compound of the title was obtained as a white solid (yield 9.4%) using 3-[(2S)-2-(aminomethyl)oxetane-2-yl]benzonitrile, spiro[3.3]heptane-1-carboxylic acid, and TCFH / NMI, in the same manner as in Example 86.

[0738] MS(m / z):311.2[M+H]+.

[0739] Example 101: (1SR,2RS)-N-[[(2S)-2-(3-cyanophenyl)oxetan-2-yl]methyl]-2-cyclobutyl-cyclopropanecarboxamide [ka] The compound of the title was obtained as a white solid (yield 23%) using 3-[(2S)-2(aminomethyl)oxetane-2-yl]benzonitrile, rac-(1R,2S)-2-cyclobutylcyclopropane-1-carboxylic acid and TCFH / NMI, in the same manner as in Example 86.

[0740] MS(m / z):311.2[M+H]+.

[0741] Example 102: N-[[(2S)-2-(3-cyanophenyl)oxetan-2-yl]methyl]spiro[3,4]octane-7-carboxamide [ka] The compound of the title was obtained as a white solid (44% yield) using 3-[(2S)-2-(aminomethyl)oxetane-2-yl]benzonitrile, spiro[3.4]octane-6-carboxylic acid, and TCFH / NMI, in the same manner as in Example 86.

[0742] MS(m / z):325.2[M+H]+.

[0743] Example 103: N-[[(2S)-2-(3-cyanophenyl)oxetane-2-yl]methyl]-3-cyclopentyl-2-fluoropropanamide [ka] The compound of the title was obtained as a white solid (46% yield) using 3-[(2S)-2-(aminomethyl)oxetan-2-yl]benzonitrile, 3-cyclopentyl-2-fluoropropanoic acid, and TCFH / NMI, in the same manner as in Example 86.

[0744] MS(m / z):331.2[M+H]+.

[0745] Example 104: N-[[(2S)-2-(3-cyanophenyl)oxetane-2-yl]methyl]spiro[3,4]octane-8-carboxamide [ka] The compound of the title was obtained as a white solid (yield 23%) using 3-[(2S)-2-(aminomethyl)oxetane-2-yl]benzonitrile, spiro[3.4]octane-5-carboxylic acid, and TCFH / NMI, in the same manner as in Example 86.

[0746] MS(m / z):325.2[M+H]+.

[0747] Example 105: N-[[(2S)-2-(3-cyanophenyl)oxetan-2-yl]methyl]dispiro[3.0.3 5 .1 4 Nonane-7-carboxamide [ka] The compound in the title was prepared in the same manner as in Example 86 as 3-[(2S)-2-(aminomethyl)oxetan-2-yl]benzonitrile, dispiro[3.0.3 5 .1 4 It was obtained as a pale yellow oily substance using nonane-2-carboxylic acid and TCFH / NMI (yield 38%).

[0748] MS(m / z):337.2[M+H]+.

[0749] Example 106: N-[[(2S)-2-(3-cyanophenyl)oxetane-2-yl]methyl]-6-oxaspiro[2.5]octane-2-carboxamide [ka] The compound of the title was obtained as a white solid (yield 34%) using 3-[(2S)-2-(aminomethyl)oxetane-2-yl]benzonitrile, 6-oxaspiro[2.5]octane-1-carboxylic acid, and TCFH / NMI, in the same manner as in Example 86.

[0750] MS(m / z):327.2[M+H]+.

[0751] Example 107: (1SR,2SR)-N-[[(2S)-2-(3-cyanophenyl)oxetan-2-yl]methyl]-2-(4-fluorophenyl)cyclopropanecarboxamide [ka] The compound of the title was obtained as a white solid (35% yield) using 3-[(2S)-2-(aminomethyl)oxetane-2-yl]benzonitrile, (1S,2S)-2-(4-fluorophenyl)cyclopropane-1-carboxylic acid and TCFH / NMI, in the same manner as in Example 86.

[0752] MS(m / z):351.2[M+H]+.

[0753] Example 108: N-[[(2S)-2-(3-cyanophenyl)oxetane-2-yl]methyl]-2-norbornan-2-ylacetamide [ka] The compound of the title was obtained as a white solid (39% yield) using 3-[(2S)-2-(aminomethyl)oxetane-2-yl]benzonitrile, 2-(bicyclo[2.2.1]heptan-2-yl)acetic acid and TCFH / NMI, in the same manner as in Example 86.

[0754] MS(m / z):325.2[M+H]+.

[0755] Example 109: N-[[(2S)-2-(3-cyanophenyl)oxetane-2-yl]methyl]-2-norbornan-1-ylacetamide [ka] The compound of the title was obtained as a white oil (yield 5.8%) using 3-[(2S)-2-(aminomethyl)oxetane-2-yl]benzonitrile, 2-(bicyclo[2.2.1]heptan-1-yl)acetic acid and TCFH / NMI, in the same manner as in Example 86.

[0756] MS(m / z):325.2[M+H]+.

[0757] Example 110: (1RS,2RS)-2-tert-butyl-N-[[(2S)-2-(3-cyanophenyl)oxetan-2-yl]methyl]cyclopropanecarboxamide [ka] The compound of the title was obtained as a white solid (38% yield) using 3-[(2S)-2-(aminomethyl)oxetane-2-yl]benzonitrile, rac-(1S,2S)-2-tert-butylcyclopropane-1-carboxylic acid and TCFH / NMI, in the same manner as in Example 86.

[0758] MS(m / z):313.2[M+H]+.

[0759] Example 111: N-[[(2S)-2-(3-cyanophenyl)oxetane-2-yl]methyl]-2-(2-hydroxynorbornan-2-yl)acetamide [ka] The compound of the title was obtained as a white solid (yield 21%) using 3-[(2S)-2-(aminomethyl)oxetane-2-yl]benzonitrile, 2-(2-hydroxybicyclo[2.2.1]heptan-2-yl)acetic acid and TCFH / NMI, in the same manner as in Example 86.

[0760] MS(m / z):341.2[M+H]+.

[0761] Example 112: (1S,2R)-N-[[(2S)-2-(3-cyanophenyl)oxetan-2-yl]methyl]-2-cyclopentyl-cyclopropanecarboxamide [ka] The compound of the title was obtained as a white solid (20% yield) using 3-[(2S)-2-(aminomethyl)oxetane-2-yl]benzonitrile, (1S,2R)-2-cyclopentylcyclopropane-1-carboxylic acid and TCFH / NMI, in the same manner as in Example 86.

[0762] MS(m / z):325.2[M+H]+.

[0763] Example 113: (1SR,2SR)-N-[[(2S)-2-(3-cyanophenyl)oxetane-2-yl]methyl]-2-(1,1-difluoroethyl)cyclopropanecarboxamide [ka] The compound of the title was obtained as a white solid (20% yield) using 3-[(2S)-2-(aminomethyl)oxetane-2-yl]benzonitrile, 2-(1,1-difluoroethyl)cyclopropane-1-carboxylic acid, and TCFH / NMI, in the same manner as in Example 86.

[0764] MS(m / z):321.1[M+H]+.

[0765] Example 114: (1SR,2SR)-2-tert-butoxy-N-[[(2S)-2-(3-cyanophenyl)oxetan-2-yl]methyl]cyclopropanecarboxamide [ka] The compound of the title was obtained as a white solid (20% yield) using 3-[(2S)-2-(aminomethyl)oxetane-2-yl]benzonitrile, rac-(1S,2S)-2-(tert-butoxy)cyclopropane-1-carboxylic acid and TCFH / NMI, in the same manner as in Example 86.

[0766] MS(m / z):329.2[M+H]+.

[0767] Example 115: N-[[2-[6-(difluoromethoxy)-2-pyridyl]oxetan-2-yl]methyl]-6-oxaspiro[2.5]octane-2-carboxamide [ka] The compound of the title was obtained as a pale yellow oil (40% yield) using 1-{2-[6-(difluoromethoxy)pyridine-2-yl]oxetan-2-yl}methaneamine, 6-oxaspiro[2.5]octane-1-carboxylic acid, and TCFH / NMI, in the same manner as in Example 86.

[0768] MS(m / z):369.2[M+H]+.

[0769] Example 116: N-[[(2S)-2-(3-cyanophenyl)oxetane-2-yl]methyl]-2-spiro[3.3]heptan-2-ylacetamide [ka] The compound of the title was obtained as a white oil (13% yield) using 3-[(2S)-2-(aminomethyl)oxetane-2-yl]benzonitrile, 2-(spiro[3.3]heptan-2-yl)acetic acid and TCFH / NMI, in the same manner as in Example 86.

[0770] MS(m / z):325.2[M+H]+.

[0771] Example 117: 2-Cyclohexyl-N-[[2-[2-(difluoromethoxy)-4-pyridyl]oxetan-2-yl]methyl]acetamide [ka] The compound of the title was obtained as a white solid (28% yield) using 1-{2-[2-(difluoromethoxy)pyridine-4-yl]oxetan-2-yl}methaneamine, cyclohexaneacetic acid, and TCFH / NMI, in the same manner as in Example 86.

[0772] MS(m / z):355.2[M+H]+.

[0773] Example 118: N-[[2-[2-(difluoromethoxy)-4-pyridyl]oxetan-2-yl]methyl]-6,6-difluoro-spiro[2.5]octane-2-carboxamide [ka] The compound of the title was obtained as a white solid (yield 27%) using 1-{2-[2-(difluoromethoxy)pyridine-4-yl]oxetan-2-yl}methaneamine, 6,6-difluorospiro[2.5]octane-1-carboxylic acid and TCFH / NMI, in the same manner as in Example 86.

[0774] MS(m / z):403.2[M+H]+.

[0775] Example 119: 2-Cyclohexyl-N-[[2-[6-(difluoromethoxy)-2-pyridyl]oxetan-2-yl]methyl]acetamide [ka] The compound of the title was obtained as a white solid (42% yield) using 1-{2-[6-(difluoromethoxy)pyridine-2-yl]oxetan-2-yl}methaneamine, 2-cyclohexylacetic acid, and TCFH / NMI, in the same manner as in Example 86.

[0776] MS(m / z):355.2[M+H]+.

[0777] Example 120: N-[[2-[6-(difluoromethoxy)-2-pyridyl]oxetan-2-yl]methyl]-6,6-difluoro-spiro[2.5]octane-2-carboxamide [ka] The compound of the title was obtained as a white solid (yield 61%) using 1-{2-[6-(difluoromethoxy)pyridine-2-yl]oxetan-2-yl}methaneamine, 6,6-difluorospiro[2.5]octane-1-carboxylic acid and TCFH / NMI, in the same manner as in Example 86.

[0778] MS(m / z):403.2[M+H]+.

[0779] Example 121: (1S,2S)-N-[[2-(2-ethyl-4-pyridyl)oxetan-2-yl]methyl]-2-phenyl-cyclopropanecarboxamide [ka] The compound of the title was obtained as a white solid (yield 22%) using 1-[2-(2-ethylpyridine-4-yl)oxetane-2-yl]methaneamine, (1S,2S)-2-phenylcyclopropane-1-carboxylic acid and TCFH / NMI, in the same manner as in Example 86.

[0780] MS(m / z):337.2[M+H]+.

[0781] Example 122: N-[[2-[2-(difluoromethoxy)-4-pyridyl]oxetan-2-yl]methyl]spiro[2.5]octane-2-carboxamide [ka] The compound of the title was obtained as a white solid (7% yield) using 1-{2-[2-(difluoromethoxy)pyridine-4-yl]oxetan-2-yl}methaneamine, spiro[2.5]octane-1-carboxylic acid, and TCFH / NMI, in the same manner as in Example 86.

[0782] MS(m / z):367.2[M+H]+.

[0783] Example 123: N-[[2-[6-(difluoromethoxy)-2-pyridyl]oxetan-2-yl]methyl]spiro[2.5]octan-2-carboxamide [ka] The compound of the title was obtained as a pale yellow oil (yield 53%) using 1-{2-[6-(difluoromethoxy)pyridine-2-yl]oxetan-2-yl}methaneamine, spiro[2.5]octane-1-carboxylic acid, and TCFH / NMI, in the same manner as in Example 86.

[0784] MS(m / z):367.2[M+H]+.

[0785] Example 124: (1SR,2SR)-N-[[(2S)-2-(3-cyanophenyl)oxetan-2-yl]methyl]-2-(2-pyridyl)cyclopropanecarboxamide [ka] The compound of the title was obtained as a white oil (yield 27%) using 3-[(2S)-2-(aminomethyl)oxetane-2-yl]benzonitrile, rac-(1S,2S)-2-(pyridine-2-yl)cyclopropane-1-carboxylic acid and TCFH / NMI, in the same manner as in Example 86.

[0786] MS(m / z):334.2[M+H]+.

[0787] Example 125: (1S,2S)-N-[[2-(3-cyano-4-fluorophenyl)oxetan-2-yl]methyl]-2-phenyl-cyclopropanecarboxamide [ka] The compound of the title was obtained as a white solid (7% yield) using 5-[2-(aminomethyl)oxetane-2-yl]-2-fluorobenzonitrile, (1S,2S)-2-phenylcyclopropane-1-carboxylic acid and TCFH / NMI, in the same manner as in Example 86.

[0788] MS(m / z):351.1[M+H]+.

[0789] Example 126: (1SR,2SR)-N-[[(2S)-2-(3-cyanophenyl)oxetan-2-yl]methyl]-2-ethyl-cyclopropanecarboxamide [ka] The compound of the title was obtained as a white oil (19% yield) using 3-[(2S)-2-(aminomethyl)oxetane-2-yl]benzonitrile, rac-trans-2-ethylcyclopropane-1-carboxylic acid and TCFH / NMI, in the same manner as in Example 86.

[0790] MS(m / z):285.2[M+H]+.

[0791] Example 127: (1SR,2RS)-N-[[(2S)-2-(3-cyanophenyl)oxetan-2-yl]methyl]-2-(3,3-difluorocyclobutyl)cyclopropanecarboxamide [ka] The compound of the title was obtained as a white solid (17% yield) using 3-[(2S)-2-(aminomethyl)oxetane-2-yl]benzonitrile, 2-(3,3-difluorocyclobutyl)cyclopropane-1-carboxylic acid, and TCFH / NMI, in the same manner as in Example 86.

[0792] MS(m / z):347.2[M+H]+.

[0793] Example 128: (1S,2S)-2-(4-bromophenyl)-N-[[(2S)-2-(3-cyanophenyl)oxetan-2-yl]methyl]cyclopropanecarboxamide [ka] The compound of the title was obtained as a white solid (yield 24%) using 3-[(2S)-2-(aminomethyl)oxetane-2-yl]benzonitrile, (1S,2S)-2-(4-bromophenyl)cyclopropane-1-carboxylic acid and TCFH / NMI, in the same manner as in Example 86.

[0794] MS(m / z):411.2[M+H]+.

[0795] Example 129: (1S,2S)-N-[[2-[2-(difluoromethoxy)-4-pyridyl]oxetan-2-yl]methyl]-2-(trifluoromethyl)cyclopropanecarboxamide [ka] The compound of the title was obtained as a white solid (yield 54%) using 1-{2-[2-(difluoromethoxy)pyridine-4-yl]oxetan-2-yl}methaneamine, (1S,2S)-2-(trifluoromethyl)cyclopropane-1-carboxylic acid and TCFH / NMI, in the same manner as in Example 86.

[0796] MS(m / z):367.2[M+H]+.

[0797] Example 130: (1S,2S)-N-[[2-[6-(difluoromethoxy)-2-pyridyl]oxetan-2-yl]methyl]-2-(trifluoromethyl)cyclopropanecarboxamide [ka] The compound of the title was obtained as a pale yellow oil (64% yield) using 1-{2-[6-(difluoromethoxy)pyridine-2-yl]oxetan-2-yl}methaneamine, (1S,2S)-2-(trifluoromethyl)cyclopropane-1-carboxylic acid and TCFH / NMI, in the same manner as in Example 86.

[0798] MS(m / z):367.2[M+H]+.

[0799] Example 131: N-[[(2S)-2-(3-cyanophenyl)oxetane-2-yl]methyl]-2-fluoro-2-norbornan-2-ylacetamide [ka] a) Methyl 2-[(2E)-bicyclo[2.2.1]heptane-2-ylidene]acetate To a stirred solut...

Claims

1. Equation (I): 【Chemistry 1】 (In the formula, A １ is N or CR ａ And, A ２ is N or CR ｂ And, R ａ is hydrogen or halogen, R ｂ is hydrogen or halogen, R １ is selected from hydrogen, cyano, halo C １～６ alkyl, C １～６ alkoxy, halo C １～６ alkoxy and halogen, and R ２ and R ３ is hydrogen, hydroxyl, C １～６ Alkyl, C １～６ Alkoxy, hydroxy C １～６ Alkyl, C ３～５ Cycloalkyl C １～６ Alkoxy, cyano, -OCD ３ Cyano C １～６ Alkoxy, Halo C １～６ Alkoxy, hydroxy-C ２～４ Selected independently of Alkenil, or R ２ and R ３ They form a 4-6 member heterocycloalkyl or 3-6 member cycloalkyl group that is optionally substituted with 1-4 halogens or oxos, together with the carbon atoms to which they are attached, or R ３ It does not exist, and R ２ is, =CHCH ２ OH, R ４ is hydrogen, hydroxyl C １～６ It is an alkyl or halogen, R ５ is hydrogen or halogen, X is NH, NHCH ２ ,CH ２ ,CH ２ CH ２ ,CH ２ CH ２ CH ２ , NHCH ２ CH ２ CH ２ , NHCH ２ CH ２ CH=CH, CH ２ CH ２ CH(OH), CH ２ CH(OH), absent, CHFCH ２ , and 【Chemistry 2】 Selected from, R ６ These include 3-10 member cycloalkyl groups, 7-11 member spirocycloalkyl groups, 7-11 member oxo-spiro-heterocycloalkyl groups, aryl groups, heteroaryl groups, and C2. １～６ Alkyl, -C≡CCH ３ , 4-10 member heterocycloalkyl and halo C １～６ Selected from alkyl, cycloalkyl, spirocycloalkyl, oxa-spirocycloalkyl, aryl, heteroaryl or heterocycloalkyl, halogen, halo C １～６ Alkyl, C １～６ Alkyl, C １～６ Alkoxy and Halo C １～６ (Optionally substituted with one, two, or three substituents independently selected from the alkoxy) A compound thereof, or its solvate or pharmaceutically acceptable salt.

2. (i) A １ only, (ii) A ２ Only, (iii) A １ and ２ Both are either N or (iv) A １ CR ａ and A ２ CR ｂ The compound according to claim 1.

3. A １ Only N or A ２ The compound according to claim 2, wherein only N is present.

4. A １ CR ａ and A ２ CR ｂ The compound according to claim 1.

5. R ａ and R ｂ The compound according to claim 4, wherein is hydrogen.

6. R １ The compound according to any one of claims 1 to 5, wherein is a halogen.

7. R １ The compound according to claim 6, wherein is Cl.

8. R １ is cyano or CHF ２ The compound according to any one of claims 1 to 5, wherein it is O-.

9. R ２ is hydroxy, and R ３ C １～６ Alkyl or R ２ C １～６ It is an alkoxy, and R ３ C １～６ A compound according to any one of claims 1 to 8, wherein it is alkyl.

10. R ２ is hydroxy, and R ３ The compound according to claim 9, wherein is methyl.

11. R ２ is methoxy, and R ３ The compound according to claim 9, wherein is methyl.

12. R ２ and R ３ The compound according to any one of claims 1 to 8, wherein the C atoms to which they are attached form a 4- to 6-membered heterocycloalkyl group that is optionally substituted with one or two halogens.

13. R ２ and R ３ Together with the C atoms to which they are attached, they form a 4-6 membered heterocycloalkyl group, and the heterocycloalkyl group is optionally substituted with two F atoms. 【Transformation 3】 The compound according to claim 12.

14. R ４ and R ５ is H, a compound according to any one of claims 1 to 13.

15. X is CH ２ ,CH ２ CH ２ ,CH ２ CH ２ CH ２ , non-existence, and 【Chemistry 4】 A compound according to any one of claims 1 to 14, selected from the above.

16. X is, 【Transformation 5】 The compound according to claim 15.

17. R ６ is a compound according to any one of claims 1 to 16, selected from C3-C10 cycloalkyl, aryl, C7-C11 spiro-cycloalkyl and C7-C11 oxa-spiro-cycloalkyl.

18. R ６ The compound according to claim 17, wherein is an aryl and a phenyl, and the 3-10 membered cycloalkyl is a 4-6 membered saturated monocyclic cycloalkyl or a 7-10 membered crosslinked cycloalkyl, and the phenyl, cycloalkyl or crosslinked cycloalkyl is optionally substituted with one or two halogens or oxos.

19. A compound according to any one of claims 1 to 18, selected from the group consisting of the following: Table 1 Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 Table 15 Table 16 Table 17 Table 18

20. The compound of formula (I) is a compound of formula (I) according to any one of claims 1 to 19, or a solvate or pharmaceutically acceptable salt thereof, exhibiting a Kv7.2 EC50 value and / or a Kv7.5-7.3 / Kv7.2 selectivity ratio in the range of (i) EC50 < 3 μM, Select. > 10x, or (ii) EC50 < 1 μM, Select. > 30x.

21. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 20, or a solvate or pharmaceutically acceptable salt thereof.

22. A compound of formula (I) according to any one of claims 1 to 20, or a solvate or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21, for use in providing therapeutic and / or preventive treatment for disorders, diseases or impairments related to Kv7.2 in a subject in need thereof, wherein the disorder, disease or impairment is selected from behavioral disorders, mood disorders, neurodevelopmental disorders, intellectual disabilities, epilepsy, neurodegenerative diseases, pain, migraines and tinnitus.

23. The compound or pharmaceutical composition for use according to claim 22, wherein the impairment, disease or impairment is a behavioral disorder that is attention deficit hyperactivity disorder (ADHD).

24. The compound or pharmaceutical composition for use according to claim 22, wherein the impairment, disease or disability is a mood disorder that is depressive.

25. The compound or pharmaceutical composition for use according to claim 22, wherein the impairment, disease or disability is a neurodevelopmental disorder selected from autism spectrum disorder (ASD) and symptomatic developmental disorders.

26. The compound or pharmaceutical composition for use according to claim 22, wherein the impairment, disease, or disability is a symptomatic developmental disorder selected from Dup15q syndrome (Dup15q), Fragile X syndrome (FXS), and Angelman syndrome.

27. The compound or pharmaceutical composition for use according to claim 22, wherein the impairment, disease or disability is epilepsy selected from a wide range of childhood epilepsy, West syndrome, Ohtahara syndrome and epileptic encephalopathy.

28. The compound or pharmaceutical composition for use according to claim 22, wherein the impairment, disease or disability is a neurodegenerative disease selected from Alzheimer's disease and motor neuron disease.

29. Compounds or pharmaceutical compositions for use according to any one of claims 21 to 28, for systemic or local administration, such as orally, nasally, parenterally (by intravenous injection (both bolus and infusion), intramuscular or subcutaneous injection), percutaneously, vaginally, buccal, rectally or topically, as intracisional, intraperitoneal, oral or nasal spray, or as a liquid aerosol or dry powder for inhalation.

30. A compound according to any one of claims 1 to 20 or a pharmaceutical composition according to claim 21, for use in treatment.

31. A compound according to any one of claims 1 to 20, or a pharmaceutical composition according to claim 21, or a compound or pharmaceutical composition for use according to any one of claims 22 to 29, for manufacturing a pharmacopoeia for use in therapeutic and / or preventive treatment of disorders, diseases or impairments related to Kv7.

2.

32. A method for the therapeutic and / or preventive treatment of a disorder, disease or impairment related to Kv7.2, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 20, or a pharmaceutical composition according to claim 21, or a pharmaceutical composition for use according to any one of claims 22 to 29.

33. A kit for use in the therapeutic and / or preventive treatment of disorders, diseases or impairments related to Kv7.2, b) A compound according to any one of claims 1 to 20, or a pharmaceutical composition according to claim 21, or a pharmaceutical composition for use according to any one of claims 22 to 29, b) Instructions for use and A kit that includes this.

34. The present invention as described herein.

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