Novel dioxane derivatives

Abstract

The present invention relates to substituted dioxane derivatives, pharmaceutical compositions containing them, and their use in the treatment, particularly in the treatment and / or prevention of neurological and non-neurological conditions related to mGluR4 function.

Description

[Technical Field]

[0001] The present invention relates to substituted dioxane derivatives, pharmaceutical compositions containing them, and their use in the treatment, particularly in the treatment and / or prevention of neurological and non-neurological conditions related to mGluR4 function. [Background technology]

[0002] L-glutamate (hereinafter referred to as glutamate) is one of the most abundant excitatory neurotransmitters in the vertebrate brain. Dysfunction of the brain's glutamatergic system often leads to neurological or psychiatric disorders. Therefore, modulation of the glutamatergic system is considered an attractive therapeutic approach. Glutamate acts through different types of glutamate receptors located on the cell surface. These include AMPA receptors, kainate receptors, NMDA receptors, and metabotropic glutamate receptors. Metabotropic glutamate receptors (mGluRs) exert their effects through coupling to G proteins and activation of a second messenger system. mGluR subtypes are classified into three groups (based on sequence homology, pharmacology, and a second messenger system), with Group III being the largest group (mGluR4, mGluR6, mGluR7, mGluR8) [Conn and Pin, Annu Rev Pharmacol Toxicol, 1997, 37: 205-237]. Group III mGlu receptors primarily share presynaptic expression (Schoepp, Pharmacol Exp Ther, 2001, 299: 12-20), where they regulate glutamic and GABAic transmission. Activation of Group III receptors (including mGluR4) reduces neurotransmitter release due to its activation of Gαi / o, which leads to attenuated adenylyl cyclase activity.

[0003] mGluR4 receptors are primarily located in the presynaptic terminals of nerve endings. mGluR4 expression is evident in multiple brain regions, with particularly high expression rates in the basal ganglia and cerebellum. Due to its role in regulating mGluR4 expression and neurotransmitter release within related brain circuits, mGluR4 modulators are thought to influence the regulation of excitation / inhibition balance, which is crucial for behavioral control (including Parkinson's disease), impulse control, learning and memory, cognition, anxiety, pain, cerebellar function, epilepsy, and information processing (Marino et al. Ann NY Acad Sci, 2003, 1003: 435-437; Isherwood et al. Neuropharmacology 2017, 123: 249-260; Makoff et al. Mol Brain Res, 1996, 37: 239-248; Davis et al. Neuropharmacology 2013, 66: 365-372; Iscru et al. Genes Brain Behav. 2013, 12: 615-625; Szczurowska and Mares, (Physiol Res, 2012, 61: 619-628) are not the only effects of this drug. Since mGluR4 has been reported to be expressed in peripheral tissues such as the islets of Langerhans, it is thought that antagonists of mGluR4 function may also have therapeutic effects in disorders including metabolic disorders, gastrointestinal disorders, and cancer, but not limited to these (Chang et al. Clin Cancer Res. 2005, 11: 3288-3295; Uhera et al. Diabetes 2004, 53: 998-1006; Nunez-Salces et al. Neurogastroenterol Motil 2020, 32).

[0004] Since mGluR4 has also been reported to be expressed, albeit not exclusively, in vagal afferent pathways, as well as in central satiety pathways and brain circuits, it is thought that antagonists of mGluR4 function may also have therapeutic effects in disorders including, but not limited to, overweight and obesity (Blackshow et al. Front Neurosci 2011, 5: 40; 1-7; Page et al. Br J Pharmacol. 2012, 166: 1537-1558). WO21028512 describes aryl sulfonamides as mGluR4 NAM. However, the activity of these compounds appears to be too low to be applicable as pharmaceuticals, and in particular, the activity of acidic aryl sulfonamides appears to be too low because they may be further exposed to the blood-brain barrier, which limits brain exposure for CNS applications. [Modes for carrying out the invention]

[0005] This invention provides a novel substituted dioxane derivative, which is an unexpectedly potent mGluR4 negative modulator. The compounds of the present invention are effective mGluR4 negative modulators that inhibit the function of mGluR4, thereby blocking glutamate-induced intracellular cAMP reduction. Thus, the present invention provides compounds for use in the treatment of mGluR4-mediated disorders. The present invention further provides a method for treating mGluR4-mediated disorders in human subjects, comprising administering to a subject a compound, a composition of the compound, or a pharmaceutically acceptable salt thereof of the present invention.

[0006] In one aspect, the present invention thus relates to a method of treating a condition, which can reduce the severity of the condition, by administering a compound that inhibits mGluR4 activity, for example a compound described herein that inhibits glutamate-induced intracellular cAMP decrease. As described herein, the measured IC for the inhibition of mGluR4 is 100 nanometers, preferably 50 nM or less. 50 A compound which is an antagonist of mGluR4 function and has. In another aspect, the compounds described herein that are antagonists of mGluR4 function can be used to inhibit the function of mGluR4, such as mGluR4-mediated glutamate-induced intracellular cAMP decrease. In some embodiments, the compounds described herein can be used to inhibit mGluR4-mediated glutamate-induced intracellular cAMP decrease in vitro, for example in cells in a medium. In other embodiments, the compounds described herein can be used to inhibit mGluR4-mediated glutamate-induced intracellular cAMP decrease in vivo.

[0007] Definitions Terms not specifically defined herein should be given the meaning that would be ascribed to them by those of ordinary skill in the art in light of the present disclosure and context. The terms "negative modulator", "antagonist" and "inhibitor" are used interchangeably and refer to an agent that reduces or suppresses a biological activity, such as a decrease in the activity of a receptor, and includes a negative allosteric modulator (NAM). The mGluR4 receptor described herein includes homo-oligomeric and hetero-oligomeric structures (e.g., homomeric mGluR4 and heteromeric mGluR4-mGluR2). Inhibitors of mGluR4 function include inhibitors having any combination of the structural and / or functional properties disclosed herein.

[0008] In terms of methods of inhibition or treatment of the subject matter, the “effective dose” of an (mGluR4) antagonist refers to the amount of antagonist in a preparation that, when applied as part of a desired dosage regimen, produces the desired clinical or functional outcome. While not wishing to be bound by theory, an effective dose of an mGluR4 antagonist for use in the methods of the present invention would be the amount of mGluR4 antagonist effective in reducing the in vitro or in vivo function of one or more mGluR4 receptors. Illustrative functions include, but are not limited to, changes in intracellular cAMP, or the release of synaptic neurotransmitters, or changes in neuronal activity or modulation of impulsive behavior. Compounds that antagonize mGluR4 function include compounds that antagonize the in vitro or in vivo functional activity of mGluR4. When a particular functional activity can be immediately observed only in an in vitro assay, the ability of a compound to inhibit mGluR4 function in that in vitro assay acts as a reasonable substitute for the activity of that compound. In certain embodiments, the effective dose is sufficient to inhibit mGluR4-mediated cellular function.

[0009] mGluR4 antagonists for use in the methods of the present invention may be characterized according to their action or lack of action on one or more receptors. When other receptors are referred to, inhibition of the function of such other receptors is similarly defined. For example, receptor inhibition or receptor activation means that the antagonist inhibits the functional activity of one or more of the other receptors. Such functions include, for example, transmembrane signaling, and / or changes in the intracellular concentration of intracellular substances such as cAMP mediated by a particular receptor, and subsequent functions such as neurotransmitter release. The terms "compound" and "agent" are interchangeable and used to refer to the negative modulator of the present invention.

[0010] In the groups, radicals, or subgroups defined below, the number of carbon atoms is often specified before the group; for example, C1-6-alkyl means an alkyl group or radical having 1 to 6 carbon atoms. Generally, for groups containing two or more subgroups, the last designated subgroup is the chemical bond site of the group; for example, the substituent "aryl-C1-3-alkyl-" means an aryl group bonded to a C1-3-alkyl- group, the latter of which is bonded to the core or the group to which the substituent is chemically bonded. If the compounds of the present invention are described in terms of their chemical names and formulas, in the event of any discrepancy, the formula shall prevail. An asterisk can be used in a sub-formula to indicate a bond connected to the defined core molecule.

[0011] Stereochemistry / solvates / hydrates The compounds described herein may be chiral (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise specified. Compounds of the present invention containing asymmetrically substituted carbon atoms may be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, for example, by the resolution of racemic mixtures or by stereoselective synthesis.

[0012] The separation of racemic mixtures of compounds can be carried out by any of the many methods known in the art. An example of such a method is fractional crystallization using a “chiral resolving agent” which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional crystallization are, for example, optically active acids, such as D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or a variety of optically active camphorsulfonic acids, such as β-camphorsulfonic acid. Other suitable resolving agents for fractional crystallization include stereoisomerically pure forms of α-methylbenzylamine (e.g., S- and R- forms, or diastereomerically pure forms), 2-phenylglycinol, norefedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, and 1,2-diaminocyclohexane. The separation of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by those skilled in the art. The compounds of the present invention also include tautomers, such as keto-enol tautomers.

[0013] Unless otherwise indicated, throughout this specification and the accompanying "Claims," ​​a given chemical formula or name will encompass tautomers and all stereoisomers, optical isomers and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers) and racemic compounds thereof, as well as mixtures of different enantiomers in different proportions, mixtures of diastereomers, or mixtures of any of the aforementioned forms in which such isomers and enantiomers exist. The compounds of the present invention may also include all isotopes of atoms generated in the intermediate or final compound. For example, the compounds of the present invention may include radioactive isotopes, such as tritium. 3 H) or carbon-14 ( 14 C) may be radiolabeled. All variations of the isotope, whether radioactive or not, are intended to be included within the scope of this invention.

[0014] salt The phrase “medically acceptable” is used herein to mean a compound, material, composition and / or dosage form that is within the bounds of sound medical judgment, suitable for use without excessive toxicity, irritation, allergic reactions, or other problems or complications, and has a reasonable benefit / risk ratio of equivalent value. As used herein, “medically acceptable salt” means a derivative of the disclosed compound, wherein the parent compound forms a salt with an acid or a base. Examples of acids that form pharmaceutically acceptable salts with parent compounds containing a basic moiety include mineral acids or organic acids, such as benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methylbenzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, and tartaric acid. Also included are salts of amino acids such as alginates, and salts of organic acids such as glucuronic acid and galacturonic acid (see, for example, Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19).

[0015] The neutralized form of the compound of the present invention is preferably regenerated by contacting the salt with a base or acid in a conventional method to isolate the parent compound. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents; otherwise, the salt is equivalent to the parent form of the compound for the purposes of the present invention. The terms “mGluR4,” “mGluR4 protein,” and “mGluR4 receptor” are used interchangeably throughout this application. Unless expressly stated otherwise, the term “mGluR4” includes homomultimeric structures (e.g., homomultimeric mGluR4) and heteromultimeric structures (e.g., heteromultimeric mGluR4-mGluR2).

[0016] Biological assays The biological activity of the compound is determined by the following method: In vitro study of the efficacy of A. mGluR4 The in vitro activity of the compounds according to the present invention can be studied as follows: HEK293 cells overexpressing human metabolic glutamate receptor 4 are thawed at 37°C and immediately diluted in cell culture medium. After centrifugation, the cell pellet is resuspended in culture medium and then distributed from a stirred spinner flask into the wells of an assay plate. The plate is incubated at room temperature for 1 hour, and then incubated at 37°C / 5% CO2 for 24 hours. The cells are washed three times in the plate with 80 μL of HBSS / HEPES buffer (10 μL of buffer remaining in the wells after washing), and then 5 μL of the compound per well, diluted in HBSS / HEPES buffer containing 0.2% BSA (final concentration: 0.1%), and 1 mM IBMX (final concentration: 0.5 mM) are added to the wells of the assay plate. Subsequently, 1 mM IBMX (final concentration: 0.5 mM) dissolved in HBSS / HEPES buffer containing 5 μL of L-glutamic acid (final concentration: 10 μM), forskolin (final concentration: 1 μM), and 0.2% BSA (final concentration: 0.1%) per well is added to the assay plate (final DMSO concentration: 1%). Several wells of the assay plate are used for either a positive or negative control, or for the cAMP standard curve. The assay plate is incubated at room temperature for 30 minutes. Then, 5 μL of anti-cAMP-antibody-d2 solution and 5 μL of cAMP-europium cryptochloride dilution per well are added to all wells of the plate, and the plate is photoprotected at room temperature and incubated for a further 60 minutes. Emissions at 615 nm and 665 nm (excitation wavelength: 320 nm) are measured using an EnVision® reader (PerkinElmer). The ratio between emissions at 665 nm and emissions at 615 nm is calculated using a reader. The entire assay is performed in a dark room or under green light.

[0017] cAMP standards are prepared by diluting the cAMP stock solution with HBSS / Hepes buffer: 5 μl / well of cAMP dilution (in HBSS / Hepes buffer containing 1 mM IBMX and 0.2% BSA - final concentration: 0.5 mM IBMX and 0.1% BSA) is added to the wells of the assay plate, along with 10 μl / well of HBSS / Hepes buffer containing 0.2% BSA + 5 μl / well of 4% DMSO (final DMSO concentration: 1% - as in the well containing the compound). The final cAMP concentrations in the assay plate are 0, 0.17, 0.69, 2.78, 11.1, 44.5, 178, and 712 nM (two wells / cAMP concentration).

[0018] The microtiter plates for each assay also contained a well with a vehicle control (negative control; 100% CTL; 10 μM L-glutamate + 1 μM forskolin + 0.5 mM IBMX + 1% DMSO) instead of the compound as a control for L-glutamate-induced signaling, and a well with a vehicle control without L-glutamate (positive control; 0% CTL; 0 μM L-glutamate + 1 μM forskolin + 0.5 mM IBMX + 1% DMSO) as a control for non-specific changes in the signal. The data analysis is performed by calculating the ratio of emissions at 665 nm to emissions at 615 nm (Em665 / Em615 ratio). Then, the compound signal is normalized using positive and negative controls according to the following formula: PoC = 100 × ((Signal sample - Positive control) / (Negative control - Positive control))

[0019] B. Evaluation of metabolic stability in human liver microsomes (human MSTs) The metabolic stability of the compounds according to the present invention can be studied as follows: The metabolic degeneration of the test compound is assayed at 37°C using stored human liver microsomes. Each time point contains a final incubation volume of 100 μL, consisting of TRIS buffer (0.1 M), MgCl2 (5 mM), microsomal protein (1 mg / mL), and the test compound at a final concentration of 1 μM at pH 7.6 at room temperature. Following a short preliminary incubation period at 37°C, the reaction is initiated by adding beta-nicotinamide adenine dinucleotide phosphate in its reduced form (NADPH, 1 mM) and terminated by transferring aliquots to the solvent after different time points. After centrifugation (10000 g, 5 min), aliquots of the supernatant are assayed by LC-MS / MS for the amount of the parent compound. Half-life (t 1 / 2 This is determined by the slope of the semi-logarithmic plot of the concentration-time profile.

[0020] Evaluation of efflux in Madin Darby canine kidney (MDCK) cells into which the human MDR1 gene has been introduced. The apparent permeability coefficient (PE) of compounds across the MDCK-MDR1 cell monolayer is measured in the apical-to-basal (AB) and basal-to-apical (BA) transport directions (pH 7.4, 37°C). AB permeability (PEAB) represents drug absorption from the blood into the brain, while BA permeability (PEBA) represents drug efflux from the brain back into the bloodstream via both passive permeability and active transport mechanisms mediated by efflux and uptake transporters expressed on MDCK-MDR1 cells, mostly by overexpressed human MDR1P-gp. Compounds are assigned permeability / absorption classes by comparison with the AB permeability of a reference compound with known in vitro permeability and oral absorption in humans. Identical or similar permeability in both transport directions suggests passive permeability and a point of permeability in the vector to further active transport mechanisms. Higher PEBA than PEAB suggests the involvement of active efflux mediated by MDR1 P-gp. Active transport is concentration-dependently saturable.

[0021] MDCK-MDR1 cells (1~2×10e5 cells / 1cm 2Cells were seeded on a filter insert (Costar transwell polycarbonate or PET filter, pore size 0.4 μm) and cultured for 7 days (DMEM). Subsequently, MDR1 expression was increased by culturing the cells in complete medium with 5 mM sodium butyrate for 2 days. The compound was dissolved in a suitable solvent (such as DMSO, a 1-20 mM stock solution). The stock solution was diluted with HTP-4 buffer (128.13 mM NaCl, 5.36 mM KCl, 1 mM MgSO4, 1.8 mM CaCl2, 4.17 mM NaHCO3, 1.19 mM Na2HPO4 × 7H2O, 0.41 mM NaH2PO4 × H2O, 15 mM HEPES, 20 mM glucose, 0.25% BSA, pH 7.4) to prepare a transport solution (0.1-300 μM compound, final DMSO ≤ 0.5%). The transport solution (TL) is applied to the apical or basolateral donor side to measure AB permeability or BA permeability (3 filter repeats), respectively. The receiver side contains the same buffer as the donor side. Samples are collected from the donor at the start and end of the experiment, and also from the receiver side at various time intervals up to 2 hours for concentration measurement by HPLC-MS / MS or scintillation counting. The sampled receiver volume is replaced with unused receiver solution.

[0022] Evaluation of efficacy against impulsive behavior in rats using the 5-choice reaction time task and the 5-CSRTT. The efficacy of the treatment for motor impulse behavior can be studied as follows: 5-CSRTT task training was performed according to the standard protocol (Isherwood et al. Neuropharmacology 2017, 123: 249-260). In short, rats were trained to stick their noses into one of five positions on the curved wall of an operant chamber where a light cue was presented (Med Associates Inc, St. Albans, Vermont). If a rat stuck its nose into the lit position for 1 second or up to 1 second after stimulus presentation, a sugar pellet was delivered into a reward container located across the chamber. Infrared beams at each selection opening and reward container allowed for precise detection of the rat's response to this task related to the operant. Any response at any nose-poking opening that occurred before the start of the light cue (premature response) was defined as motor impulse behavior.

[0023] After achieving stable performance, a new analytical approach was applied, which revealed characteristic (long-term) stability in the number of premature responses made by individual animals over several months. In general, this analysis allowed for reliable stratification of animals into high-impulse and low-impulse groups based on a long-term assessment of the number of premature responses they made during training.

[0024] All subjects received both the vehicle and the compound on separate days, with each dose separated by approximately two weeks, in a crossover experiment. The order of vehicle and compound administration was randomized within the subjects, while a third group received atomoxetine on both experimental days as a technical control.

[0025] As a standardized numerical threshold for impulse levels, animals with >40 premature responses in the vehicle (out of 200 initiated trials) were labeled as high impulse, and animals with <40 premature responses were labeled as low impulse. Importantly, this numerical threshold-based labeling overlapped >80% with long-term analysis of the training data (as described above). The high convergence of these two approaches to stratification allowed us to reliably compare the compound effects in consistently high-impulse rats with those in consistently low-impulse rats in the 5-CSRTT. Biological data

[0026] [Table 1]

[0027] The compound of the present invention is structurally different from the structurally closest compound in the prior art (i.e., Examples 8, 12, 125 and Intermediate-250 in WO2019 / 138017) in that the heterocyclic linkage as a carboxamide is a pyrazine (6-membered heteroaryl) group rather than a pyrazole or isoxazole moiety (5-membered heteroaryl). While the structurally closest compound disclosed in WO2019 / 138017 is the immunomodulator (IL-17 modulator) disclosed therein, the compound of the present invention is unexpectedly a highly potent mGluR4 negative modulator (see Table 2). The structurally closest compound disclosed in WO2019 / 138017 was tested in Assay A and found to lack therapeutic activity as an mGluR4 modulator (Table 1). Unexpectedly, the compound of the present invention is >100-fold potent in Assay A (compare the data in Table 1 with the data in Table 2).

[0028] [Table 2-1] [Table 2-2] [Table 2-3]

[0029] Use / Method of Use in Treatment The present invention relates to compounds useful in the treatment and / or prevention of diseases, disorders and conditions in which inhibition of mGluR4 activity has therapeutic benefits, including but not limited to the treatment of psychiatric and neurological conditions associated with lack of impulse control or maladaptive impulses. Such lack of impulse control is seen in addiction, including substance use disorders; personality disorders, e.g., borderline personality disorder, antisocial personality disorder, conduct disorder; eating disorders, e.g., binge eating disorder; attention deficit hyperactivity disorder; bipolar disorder; stress-related disorders, e.g., post-traumatic stress disorder; tic disorders such as Tourette syndrome; and other behavioral disorders, e.g., restless legs syndrome. According to further aspects of the present invention, the compounds of the present invention are useful in the treatment of mGluR4-related pathophysiological disturbances, cognition, motivational behavior / reward, mood and stress, and aggression. In addition, there are therapeutic benefits in cancer and related disorders associated with maladaptive tumor formation such as osteosarcoma. According to a further aspect of the present invention, the compounds of the present invention are useful in treating metabolic disorders by mGluR4-related modulation of satiety pathways and / or signaling, for the treatment of disorders including but not limited to obesity.

[0030] In terms of their pharmacological effects, the compounds of the present invention are suitable for use in the treatment and / or prevention of diseases or conditions selected from the following enumeration: (1) Disorders related to dysfunction in impulse control, e.g., gambling addiction, trichotillomania, intermittent explosive disorder, conduct disorder, antisocial personality disorder, kleptomania, pyromania, shopping addiction, internet addiction, obsessive-compulsive disorder, sexual disorders, sexual dysfunction, psychosexual disorders, eating disorders, e.g., binge eating, bulimia nervosa, anorexia nervosa, other specific feeding or eating disorders, obesity, overweight, cachexia, appetite / taste disorders, vomiting, nausea, Prader-Willi syndrome, bulimia nervosa, appetite / taste disorders, bipolar disorder, post-traumatic stress disorder; (2) Drug abuse / dependence / craving, or addiction (including, but not limited to, drugs such as cocaine, opiates, morphine, barbiturates, benzozeadipines, amphetamines, nicotine / tobacco, and other psychostimulants) and prevention of relapse, alcohol dependence and alcohol-related disorders, drug abuse or addiction or relapse, tolerance to or withdrawal from drugs; (3) Psychiatric and neurological conditions, e.g., attention deficit hyperactivity disorder, conduct disorder, inattention and related disorders, sleep disorders, anxiety disorders, e.g., generalized anxiety disorder, panic disorder, phobias, post-traumatic stress disorder, schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's disease and Tourette's syndrome (Gilles de la), restless limb syndrome, dementia, motor disorders, severe intellectual disability, neurodegenerative disorders, including those relating to disease classifications, e.g., disinhibition-dementia-Parkinson's disease-muscle atrophy complex, palpidopont-nigral degeneration, mood disorders, bipolar disorder, attachment, depression, attachment depression, borderline personality disorder, antisocial personality disorder, aggression, e.g., impulsive aggression, suicidal tendencies, frontotemporal dementia, obsessive-compulsive disorder, delirium, affective neurosis / disorder, depressive neurosis / disorder, anxiety neurosis, Dysthymia; neurological disorders such as cerebral edema and angioedema, Parkinson's disease and Alzheimer's disease, senile dementia and other brain dementias; multiple sclerosis, epilepsy, temporal lobe epilepsy, drug-resistant epilepsy, convulsive disorders, stroke, myasthenia gravis, encephalomyelitis, meningitis and other infections of the brain and meninges, HIV and schizophrenia, delusional disorder, autism, mood disorders, and Tourette syndrome, as well as other tic disorders and other behavioral disorders, epilepsy (dpilepsia), chronic pain; (4) Cognitive impairment in psychiatric or neurological disorders, cognitive impairment associated with schizophrenia, Alzheimer's disease, and other neurological and psychiatric disorders; (5) Personality disorders, such as borderline personality disorder, antisocial personality disorder, paranoid personality disorder, schizophrenia and schizotypal personality disorder, histrionic personality disorder, narcissistic personality disorder, avoidant personality disorder, dependent personality disorder, and other specific and nonspecific personality disorders; (6) Sleep disorders, such as narcolepsy, jet lag, sleep apnea, insomnia, parasomnias, disturbances of biological and circadian rhythms, and sleep disturbances associated with psychiatric and neurological disorders; (7) Non-neurological conditions, including metabolic conditions such as diabetes mellitus, insulin resistance, metabolic syndrome, overweight, obesity, and use for weight loss, cosmetic weight loss, prevention of relapse during or after obesity treatment, weight maintenance, vomiting, cardiovascular disorders, and disorders related to maladaptive blood pressure control such as hypertension or hypotension; (8) Cancer and related disorders, including maladaptive tumor formation such as osteosarcoma, breast cancer, ependymoma, bladder cancer, and colorectal cancer.

[0031] The applicable daily dose of the compound of the present invention may vary between 0.1 and 2000 mg. The actual effective or therapeutic dose will depend on factors known to those skilled in the art, such as the patient's age and weight, route of administration, and severity of the disease. In all cases, the drug substance will be administered in a dose and manner that enables the effective dose to be delivered, which is appropriate for the patient's condition.

[0032] Combination therapy The compounds according to the present invention may be used in conjunction with other treatment options known to be used in the art in connection with any of the treatment instructions that are the focus of the present invention. Such active pharmaceutical ingredients or treatment options that are considered suitable for use in combination with compounds and for treatments according to the present invention include antidepressants, mood stabilizers, typical and atypical antipsychotics, anxiolytics, antiepileptics, antiparkinsonian drugs, hypnotics, nootropics, stimulants, drugs for attention-deficit hyperactivity disorder, further psychotropic drugs, anti-inflammatory drugs, analgesics, chemotherapeutic agents, and treatment options used for metabolic disorders, liver diseases and kidney diseases.

[0033] Experiment Section JPEG2026512961000005.jpg250170 JPEG2026512961000006.jpg65170

[0034] method: HPLC-MS method: Method A

[0035] [Table 3] Method B

[0036] [Table 4] Method C

[0037] [Table 5] Chiral SFC analysis method: Method 1:

[0038] [Table 6] Method 2:

[0039] [Table 7] Method 3:

[0040] [Table 8] Method 4:

[0041] [Table 9] Method 5:

[0042] [Table 10] Method 6:

[0043] Table 11 Method 7:

[0044] Table 12 Method 8:

[0045] Table 13 Method 9:

[0046] Table 14 Method 10:

[0047] Table 15 Method 11:

[0048] Table 16 Method 12:

[0049] Table 17 Method 13:

[0050] Table 18 Method 14:

[0051] Table 19 Method 15:

[0052] Table 20 Method 16:

[0053] Table 21 Method 17:

[0054] Table 22 Method 18:

[0055] Table 23 Method 19:

[0056] Table 24 Method 20:

[0057] Table 25 Method 21:

[0058] Table 26 Method 22:

[0059] Table 27 Method 23:

[0060] Table 28 Method 24:

[0061] Table 29 Method 25:

[0062] Table 30 Method 26:

[0063] Table 31 Method 27:

[0064] Table 32 Method 28:

[0065] Table 33 Method 29:

[0066] Table 34 Method 30:

[0067] Table 35 Method 31:

[0068] Table 36 Method 32:

[0069] Table 37 Method 33:

[0070] Table 38 Method 34:

[0071] Table 39 Method 35:

[0072] Table 40 Method 36:

[0073] Table 41 Method 37:

[0074] Table 42 Method 38:

[0075] Table 43 Method 39:

[0076] Table 44 Method 40:

[0077] Table 45 Method 41:

[0078] Table 46 Method 42:

[0079] Table 47 Method 43:

[0080] Table 48 Method 44:

[0081] Table 49 Method 45:

[0082] Table 50 Method 46:

[0083] Table 51 Method 47:

[0084] Table 52 Method 48:

[0085] Table 53 Method 49:

[0086] Table 54 Method 50:

[0087] Table 55 Method 51:

[0088] Table 56 Method 52:

[0089] Table 57 Method 53:

[0090] Table 58 Method 54:

[0091] Table 59 Method 55:

[0092] Table 60 Method 56:

[0093] Table 61 Method 57:

[0094] Table 62 Method 58:

[0095] Table 63 Method 59:

[0096] Table 64 Method 60:

[0097] Table 65 Method 61:

[0098] Table 66 Method 62:

[0099] Table 67 Method 63:

[0100] Table 68 Method 64:

[0101] Table 69 Method 65:

[0102] Table 70 Method 63:

[0103] Table 71 Method 64:

[0104] Table 72 Method 65:

[0105] Table 73 Method 66:

[0106] Table 74 Method 67:

[0107] Table 75 Method 68:

[0108] Table 76 Method 69:

[0109] Table 77 Method 70:

[0110] Table 78 Method 71

[0111] Table 79 Method 72

[0112] Table 80 Method 73

[0113] Table 81 Method 74

[0114] Table 82 Method 75

[0115] Table 83 Method 76

[0116] Table 84 Method 77

[0117] Table 85 Method 78

[0118] Table 86 Method 79

[0119] Table 87 Method 80

[0120] Table 88 Method 81

[0121] Table 89 Method 82

[0122] Table 90 Method 83

[0123] Table 91 Method 84

[0124] Table 92 Method 85

[0125] Table 93 Method 86

[0126] Table 94 Method 87

[0127] Table 95 Method 88

[0128] Table 96 Method 89

[0129] Table 97 method 90

[0130] [Table 98]

[0131] NMR method: NMR spectra were recorded on a Bruker AVANCE IIIHD 400MHz instrument using TopSpin3.2pl6 software. Chemical shifts were assigned in δ units, downfield from an internal reference such as trimethylsilane and / or water and / or solvent (e.g., d6-DMSO) to parts per million (ppm). Selected data were reported in the following manner: chemical shift (multiplicity, coupling coefficient (J), number of hydrogens). Abbreviations are as follows: s (singularity), d (doubleity), t (triplicity), q (quadripleity), spt (septuplicity), m (multiplicity), br (broadly multiplicity). [Examples]

[0132] (Example 1) [ka]

[0133] Step 1: Sodium (0.95 g, 41.2 mmol) was charged into 80 mL of EtOH, and the mixture was cooled so as not to exceed 35 °C and stirred for 45 minutes. N1-Methyl-4-(trifluoromethyl)-benzene-1,2-diamine (2.50 g, 12.9 mmol) and ethyl diethoxyacetate (4.15 mL, 23.2 mmol) in 20 mL of EtOH were added, and the mixture was heated to reflux for 20 hours. Then, 200 mL of saturated aqueous NH4Cl was added, the mixture was concentrated in vacuo, the residue was diluted with 250 mL of water, and extracted with ethyl acetate. The combined organic layers were dehydrated with MgSO4 and concentrated in vacuo. The residue was taken up in THF / MeOH and purified by column chromatography (XBridge C18, 10 μm, eluent gradient (H2O + 0.15% NH3): ACN 56:44~>36:64). The fractions containing the product were combined and lyophilized. The solid was taken up in DCM and concentrated in vacuo. Yield: 1.78 g (5.89 mmol; 46%) Intermediate-1a MS(ESI + ): (M+H) + 303; HPLC: RT = 1.05 minutes, method: Z011_S03

[0134] Step 2: A mixture of Intermediate-1a (12.8 g, 42.3 mmol) and hydrochloric acid in dioxane (4N; 128 mL, 512 mmol) was stirred and heated to reflux for 1.5 hours. Heating was removed, and the mixture was poured into a mixture of 800 mL of water and 500 mL of saturated aqueous NaHCO3. The mixture was stirred for 5 minutes and filtered. The solid was washed with water and dried in vacuo, and the residue was taken up in n-butyl acetate and concentrated in vacuo. Yield: 9.33 g (40.1 mmol; 95%) Intermediate-1b MS(ESI + ): (M+H) + 229; HPLC: RT = 0.88 minutes, method: Z011_S03

[0135] Step 3: Intermediate-1b (23.2 g, 99.6 mmol), (S)-(-)-2-methyl-2-propane-sulfinamide (13.3 g, 105 mmol), and Cs2CO3 (42.2 g, 130 mmol) in 370 mL of DCM are stirred under heating and refluxed for 1.25 hours. Then, the heating is removed, MgSO4 is added, the mixture is filtered, and the filtrate is concentrated under vacuum. The residue is taken out in DCM and di-isopropyl ether and concentrated under vacuum. The formed solid is filtered and recovered. The filtrate is further concentrated under vacuum, and the residue is purified by column chromatography (silica gel; eluent gradient petroleum ether: siRNA 80:20~>45:55). The products containing the fractions are combined and concentrated under vacuum. The residue is combined with the recovered solid. Yield: 31.6g (95.4 mmol; 96%) Intermediate-1c MS(ESI + ):(M+H) + 332;HPLC:RT=1.07min, Method:Z018_S04 Chiral SFC Rt 4.27 minutes (Method: I_SA_10_IPA_NH3_003)

[0136] Step 4: Under an argon atmosphere and in an additionally dried glass container, 1-4 dioxene (17.18 mL, 211.25 mmol) is added to 150 mL of THF at -35°C, while keeping the temperature below -30°C, and n-hexyl lithium (2.45 N in hexane; 76.98 mL, 188.52 mmol) is added. Then, the cooling is removed and the mixture is warmed to 20°C. The mixture is immediately cooled to 0°C and stirred at this temperature for 30 minutes. The mixture is then cooled to -65°C and added to the mixture of intermediate-1c (50 g, 150.89 mmol) in 500 mL of THF at -75°C under argon, in an additionally dried glass container, while keeping the temperature of the mixture below -70°C. The mixture is then stirred at -70°C for 20 minutes. The mixture is then poured into 650 mL of saturated NH4Cl aqueous solution. 650 ml of tert-butyl methyl ether was added, and the mixture was warmed to room temperature with stirring. The aqueous layer was extracted with tert-butyl methyl ether, the combined organic layers were washed with brine, dehydrated with MgSO4, and concentrated under vacuum. 70 ml of ethyl phosphate was added to the residue. The mixture was filtered, washed with ethyl phosphate, and the solid was recovered. The resulting product contained only one stereoisomer. Yield: 38.5 g (92 mmol; 61%) Intermediate-1d Chiral SFC Rt 5.38 min (Method: I_IH_15_IPA_NH3_003)

[0137] Step 5: To intermediate-1d (15.4 g, approximately 90%, 33.2 mmol) in 47 mL of MeOH3 at 10°C, hydrogen chloride in dioxane (4N, 18.3 mL, 73.0 mmol) is added. After 5 minutes, the cooling is removed and the mixture is stirred at ambient temperature for 22 hours. Next, concentrated NH3 aqueous solution is added to adjust the pH to 7.5, and the mixture is concentrated under vacuum. The residue is adjusted to pH 8 by adding concentrated NH3 aqueous solution, 300 mL of water is added, and the mixture is extracted with DCM. The aqueous layer is adjusted to pH 10 by adding Na2CO2 solution (aqueous, 2N) and extracted with siRNA. The organic layers are washed with water, combined, dehydrated with MgSO4, and concentrated under vacuum. Yield: 12.4g (content approximately 75%; 29.8 mmol; 90%) Intermediate-1e MS(ESI + ):(M+H) + 314;HPLC:RT=0.87min, Method:Z011_S03 Chiral SFC Rt 3.51 minutes (Method: I_IG_20_IPA_NH3_003)

[0138] Step 6: Boc2O (8.3g, 38.0 mmol) is added to intermediate-1e (12.4g, approximately 75%, 29.8 mmol) and TEA (8.8 mL, 63.3 mmol) in 250 mL of DCM, and the mixture is stirred at ambient temperature for 15.5 hours. The organic layer is washed with water, dehydrated with MgSO4, and concentrated under vacuum. It is then purified by chromatography (silica gel, eluent gradient petroleum ether: siRNA 75:25~>45:55). The products containing the fractions are combined and concentrated under vacuum. Yield: 9.82 g (23.7 mmol; 75%) Intermediate-1f MS (ESI + ):(M+H) + 414 Chiral SFC Rt 4.64 minutes (Method: I_IG_10_IPA_NH3_003)

[0139] Step 7: Intermediate-1f (8.8g, 21.3 mmol) in 300 mL of THF is mixed with activated carbon-supported palladium (10%, 1.3 g). The mixture is hydrogenated under a hydrogen atmosphere at 60 psi for 22 hours. Then, additional activated carbon-supported palladium (10%, 1 g) is added, and hydrogenation is continued for 5 hours. Then, additional activated carbon-supported palladium (10%, 0.5 g) is added, and hydrogenation is continued for 3 hours. The mixture is allowed to stand overnight, then filtered and concentrated under vacuum. The product is obtained as a mixture of stereoisomers and is used without further separation. In the synthesis scheme, only the major isomers are shown. Yield: 8.76 g (21.1 mmol; 99%) Intermediate-1 g MS(ESI + ):(M+H) + 416;HPLC:RT=1.04 min, method:Z011_S03 Stereoisomer 1: Chiral SFC Rt 2.69 min (Method: I_IG_10_IPA_NH3_003) Stereoisomer 2: Chiral SFC Rt 3.33 min (Method: I_IG_10_IPA_NH3_003)

[0140] Step 8: Add TFA (14.3 mL, 186 mmol) to 1 g (7.7 g, 18.7 mmol) of intermediate in 65 mL of DCM at 5°C. Remove the cooler and stir the mixture at ambient temperature for 3.8 hours. Add 150 g of ice and adjust the pH of the mixture to approximately 10 by adding concentrated NH3 aqueous solution. Extract the aqueous layer with DCM, dehydrate the combined organic layer with MgSO4, and concentrate under vacuum. Yield: 5.92 g (18.7 mmol; quantitative) intermediate - 1h Chiral SFC Rt 2.57 minutes (Method: I_SA_10_MEOH_NH3_003)

[0141] Step 9: To a 59 mL mixture of intermediate-1h (5.9 g, 18.7 mmol) and NMM (5.1 mL, 46.8 mmol) in toluene, methylpyrazine-2-carboxylic acid (3.2 g, 22.6 mmol) is added, and the mixture is cooled to 0°C while stirring. Then, while maintaining the temperature below 10°C, PPA (50% in toluene; 14.5 mL, 24.3 mmol) is added dropwise. After 5 minutes, the cooling is removed, and the mixture is stirred at ambient temperature for 75 minutes. Water is added, and the mixture is adjusted to pH 9 by adding NMM. The aqueous layer is extracted with toluene, and the combined organic layers are washed with semi-concentrated brine, activated carbon is added, and the mixture is stirred and dehydrated with MgSO4. After filtration, the mixture is concentrated under vacuum, and the residue is taken out in toluene and purified by chromatography (silica gel, eluent toluene:EtOH 97:3). The products containing the fractions are combined and concentrated under vacuum. The product is obtained as a mixture of two stereoisomers, which is then purified by chiral SFC. Yield: 4.05 g (9.30 mmol) Example 1, and 0.71 g (1.63 mmol) Example 1-1

[0142] [Table 99]

[0143] [Table 100]

[0144] (Example 2) [ka]

[0145] Step 1: To intermediate-3b (1.30 g, 4.4 mmol) in 30 mL of ACN and 10 mL of water, add cer(IV)-ammonium nitrate (3.62 g, 6.6 mmol) and stir the mixture at ambient temperature for 3 hours. Then, concentrate the mixture under vacuum, remove the residue with water, and extract with SiO. Dehydrate the combined organic layer with Na2SO4 and concentrate under vacuum. Remove the residue in 3 mL of THF and 10 mL of TEA, add Boc2O (3.48 g, 6.4 mmol), and stir the mixture at ambient temperature for 3 hours. After that, concentrate the mixture under vacuum. Yield: 0.80 g (2.8 mmol; 63%) Intermediate-2a MS(ESI + ):(M+H) + 290

[0146] Step 2: LiOH (0.10 g, 4.2 mmol) is added to intermediate-2a (0.80 g, 2.8 mmol) in 10 mL of MeOH and 3 mL of water, and the mixture is stirred at ambient temperature for 3 hours. The mixture is then concentrated under vacuum and purified by preparative HPLC. Yield: 0.60 g (2.3 mmol, 82%) Intermediate-2b as a mixture of stereoisomers MS(ESI + ):(M+H) + 262 Step 3: Mix 1,4-difluoro-2-nitrobenzene (100 g; 0.63 mol) and 2,2-difluoroethylamine (266 mL; 3.8 mol) with K2CO3 (400 g; 1.3 mol) in 800 mL of ACN, and stir at 80°C for 2 days. Filter the mixture and concentrate the filtrate under vacuum. Use the residue without further purification. R f :0.4(PE / Â 85:15) Yield: 105g (0.48mol; 76%) Intermediate-2c MS(ESI + ):(M+H) + 221;HPLC:RT=1.00min, method:Z018_S04

[0147] Step 4: A mixture of intermediate-2c (50 g, 0.23 mol) and 10 g of Raney nickel in 500 mL of MeOH is hydrogenated at ambient temperature for 4 hours at 50 psi (hydrogen gas). The mixture is then filtered, washed with siRNA, and concentrated under vacuum. The residue is used without further purification. R f :0.4(PE / Â 85:15) Yield: 45g (0.22mol; 98%) Intermediate-2d MS(ESI + ):(M+H) + 191;HPLC:RT=0.71 min, method:Z018_S04

[0148] Step 5: To a mixture of intermediate-2d (280 mg, 1.4 mmol), intermediate-2b (377 mg, 1.4 mmol), and NMM (0.95 mL, 8.7 mmol) in 3 mL of DCM, PPA (50% in siRNA; 1.3 mL, 2.2 mmol) is added at 0°C. After stirring at 0°C for 2 hours, the mixture is concentrated under vacuum. Then, 2.1 g of acetic acid is added, and the mixture is stirred at 50°C for 8 days. The mixture is concentrated under vacuum. The mixture contains four stereoisomers, which can be separated into two pairs of enantiomers via preparative HPLC (C-18 Sunfire 10 μm, eluent gradient (water + 0.15% TFA): ACN 64:36~>44:56). The products containing the fractions are combined and lyophilized. Only one pair of the enantiomers (intermediate-2e) is used in step 6, which is depicted in the reaction scheme. Stereoisomers: Intermediate as a mixture of enantiomers - 2e: Yield: 119 mg (0.29 mmol; 20%) MS(ESI + ):(M+H) + 416;HPLC:RT=0.98 min, method:Z018_S04 Stereoisomers to 2: As a mixture of enantiomers; Yield: 104 mg (0.25 mmol; 17%) MS(ESI + ):(M+H) + 416;HPLC:RT=0.97min, Method:Z018_S04

[0149] Step 6: Intermediate-2e (119 mg, 0.29 mmol) is stirred in HCl in dioxane (4N; 3.0 mL, 12 mmol) at ambient temperature for 2 hours. The mixture is concentrated under vacuum. Yield: 111 mg (0.29 mmol; quantitative) Intermediate-2f as a mixture of enantiomers MS(ESI + ):(M+H) + 316

[0150] Step 7: A mixture of intermediate-2f (111 mg, 0.29 mmol), 5-methylpyrazine-2-carboxylic acid (39 mg, 0.29 mmol), and NMM (189 μL, 1.7 mmol) in 3.5 mL of DCM was stirred at 0°C, and PPA (50% in Â; 0.3 mL, 0.5 mmol) was added. The mixture was stirred at 0°C for 1 hour. The mixture was concentrated under vacuum, removed in ACN, filtered, and the filtrate was purified by preparative HPLC (C-18 X-Bridge 10 μm, eluent gradient (water + 0.15% NH3): ACN 71:29~>51:49). The products containing the fractions were combined and lyophilized. Subsequently, chiral SFC was performed to obtain the desired enantiomer (Examples 2 and 2-1). Yield: 28 mg Example 2, and 25 mg Example 2-1

[0151] [Table 101]

[0152] [Table 102]

[0153] (Example 3) [ka]

[0154] Step 1: A mixture of 4-methoxyaniline (10 g, 81 mmol), ethyl glyoxylate polymer form (47% in toluene, 17 mL, 81 mmol), and MgSO4 (24 g, 203 mmol) in 125 mL of DCM is stirred at 40°C for 3 hours. The mixture is filtered, and the filtrate is evaporated at 25°C. The residue is used without further purification. Yield: 20.8 g (approximately 80% content; 81 mol; quantitative) Intermediate-3a MS(ESI + ):(M+H) +208;HPLC:RT=0.90min, method:Z011_S03

[0155] Step 2: Intermediate-3a (21 g, 80% content, 81 mmol) is degassed from 150 mL of dioxane (unstabilized) and kept under nitrogen. Copper(II) chloride (0.54 g, 4 mmol) and tert.-butyl hydroperoxide (5.5 M in decane; 17.5 mL, 96 mmol) are added, and the mixture is stirred at 50°C for 16 hours. The mixture is concentrated under vacuum and purified by continuous column chromatography (silica gel, PE / siRNA gradient 9:1 to >4:1, then 7:3, then 4:1, combining the products containing the fractions in each step, concentrating under vacuum, and then performing the next purification). Yield: 6.4 g (22 mmol; 27%) Intermediate-3b as a mixture of stereoisomers MS(ESI + ):(M+H) + 296;HPLC:RT=0.90min, method:Z011_S03

[0156] Step 3 Intermediate-3b (300 mg, 1.02 mmol) is mixed with cerium(IV) ammonium nitrate (835 mg, 1.6 mmol) in 10 mL of ACN containing 3 mL of water, and stirred at ambient temperature for 3 hours. The mixture is then filtered and concentrated under vacuum. Yield: 300 mg (Purity: approx. 33%; 0.53 mmol; 52%) Intermediate-3c as a mixture of stereoisomers MS(ESI + ):(M+H) + 190;TLC:Rf=0.5(Eluent:DCM:MeOH 95:5) Step 4: Boc-anhydrous (5.2 g; 24 mmol) was added to a mixture of intermediate-3c (3.0 g; 16 mmol) and TEA (8.0 g; 79 mmol) in 15 mL of THF. The mixture was stirred at ambient temperature for 18 hours, then concentrated under vacuum, and purified by silica gel column chromatography (eluent gradient hexane:siRNA 100:0 to >60:40). Yield: 1.0 g (Purity: approx. 65%; 2.2 mmol; 9%) Intermediate-3d as a mixture of stereoisomers MS(ESI + ):(M+H) + 234; TLC: Rf = 0.5 (Eluent: Hexane: siRNA 7:3)

[0157] Step 5: LiOH (100 mg; 4.2 mmol) was added to intermediate-3d (0.8 g, 2.8 mmol) in 10 mL of MeOH containing 3 mL of water. The mixture was stirred at ambient temperature for 3 hours, concentrated under vacuum, and purified by preparative HPLC. Yield: 0.5g (1.9 mmol; 68%) Intermediate-3e as a mixture of stereoisomers MS(ESI + ):(M+H) + 262;TLC:Rf=0.5(Eluent:DCM:MeOH 95:5) Step 6: To 100 mL of DCM, 1-fluoro-2-nitro-4-trifluoromethylbenzene (2.2 mL; 15.7 mmol) is added, to which ethylamine (2 M in THF; 15.7 mL, 31.4 mmol) is added, and the mixture is stirred at ambient temperature for 20 hours. 100 mL of DCM is added, and the mixture is extracted with 100 mL of water. The organic layer is collected, dehydrated with Na2SO4, filtered, and concentrated under vacuum. Yield: 3.30 g (14.1 mmol; 90%) Intermediate-3f MS(ESI + ):(M+H) + 235;HPLC:RT=1.10 min, method:Z017_S04

[0158] Step 7: Intermediate-3f (200 mg, 0.85 mmol) is mixed with activated carbon-supported palladium (10%, 50 mg) in 20 mL of MeOH and hydrogenated at a hydrogen pressure of 50 psi for 3.5 hours. The mixture is then filtered and concentrated under vacuum. Yield: 170 mg (0.83 mol; 97%) Intermediate - 3 g MS(ESI + ):(M+H)+ 205;HPLC:RT=0.86 min, method:Z018_S04

[0159] Step 8: Intermediate-3e (210 mg, 0.80 mmol), intermediate-3 g (170 mg, 0.83 mmol), and NMM 350 μL in 5 mL of DCM are stirred at ambient temperature, and PPA (50% in siRNA; 600 μL, 1.0 mmol) is added. After stirring at ambient temperature for 16 hours, water is added, and the mixture is stirred at ambient temperature for 20 minutes. Then, 5 mL of AcOH is added, and the mixture is stirred at 50°C for 3 hours, at ambient temperature for 16 hours, and at 80°C for 2 hours. The mixture contains four stereoisomers, which can be separated into two pairs of enantiomers by HPLC (C-18 Sunfire, 50°C, eluent gradient (water + 0.15% TFA): ACN 58:42~>38:62). The products containing the fractions are combined and freeze-dried. Only one pair of enantiomers (intermediate-60h) is used in step 9 of the reaction scheme. Stereoisomer vs. 1: Yield: 70 mg (0.13 mmol; 16%) Intermediate as a mixture of enantiomers - 3h MS(ESI + ):(M+H) + 430;HPLC:RT=1.03 min, method:Z018_S04 Stereoisomer vs. 2: Yield: 120 mg as a mixture of enantiomers MS(ESI + ):(M+H) + 430;HPLC:RT=1.04 min, method:Z018_S04

[0160] Step 9: Intermediate-3h (70 mg, 0.13 mmol) is stirred in 4 mL of hydrochloric acid (4 M in dioxane) at ambient temperature for 1 hour. The mixture is concentrated under vacuum. Yield: 52 mg (0.13 mmol; quantitative) Intermediate-3i as a mixture of enantiomers MS(ESI + ):(M+H) +330;HPLC:RT=0.77min, Method:Z018_S04

[0161] Step 10: A mixture of intermediate-3i (52 mg, 0.13 mmol), 5-methylpyrazine-2-carboxylic acid (22 mg, 0.16 mmol), TBTU (44 mg, 0.14 mmol), and TEA (100 μL, 0.72 mmol) in 4.0 mL of DMF is stirred at ambient temperature for 15 minutes. Water is added, and the mixture is purified by preparative HPLC (C-18 X-Bridge, 50°C, eluent gradient (water + 0.15% NH3): ACN 61:39~>41:59). The products containing the fractions are combined and freeze-dried. Then, chiral SFC is performed to obtain the desired stereoisomer. Yield: 15 mg (0.033 mol; 36%) Example 3

[0162] [Table 103]

[0163] (Examples 4 and 5) Similar to Example 1 (see below), starting with 4-chloro-1-fluoro-2-nitrobenzene and excluding step 7, the following compounds are obtained:

[0164] (Example 1) [ka]

[0165] (Examples 4 and 5) [ka]

[0166] Step 7: A mixture of intermediate-4f (2.9 g, 6.75 mmol) and Wilkinson catalyst (950 mg, 1.03 mmol) in ethanol (145 ml) is hydrogenated at 40°C for 22 hours under a hydrogen atmosphere at 40 psi. The mixture is filtered and concentrated under vacuum. The residue is dissolved in THF / MeOH and purified by column chromatography (XBridge C18, 10 μm, eluent gradient (H2O + 0.1% NH4OH) 58:42 to >38:62). The fractions containing the product are combined and concentrated under vacuum. The product is isolated as a mixture of stereoisomers and used as is in the following steps. Yield: 2.05 g (4.74 mmol; 70.4%) Intermediate - 4 g MS(ESI + ):(M+H) + 432, HPLC: RT=1.03 min, method: Z011_S03 Chiral SFC Rt stereoisomer 1:0.66 min (Method: I_AC_10_IPA_NH3_002) Chiral SFC Rt stereoisomer 2: 0.86 min (Method: I_AC_10_IPA_NH3_002)

[0167] Step 8: The title compound was synthesized from 4g of the intermediate in a manner similar to Step 8 of Example 1, as a mixture of stereoisomers, and this compound was used as is in the next step. Yield: 1.18 g (3.56 mmol; 76.8%) intermediate - 4h MS(ESI + ):(M+H) + 332;HPLC:RT=0.84 min, method:Z011_S03 Chiral SFC Rt diastereomer 1:1.23 min (Method: I_IG_20_MEOH_NH3_002) Chiral SFC Rt diastereomer 2: 1.56 min (Method: I_IG_20_MEOH_NH3_002)

[0168] Step 9: Examples 4 and 5 were synthesized from intermediate -4h in a manner similar to Step 9 of Example 1, and these were separated by chiral SFC. Yield: 1.18 g (3.56 mmol; 76.8%) Examples 4 and 5 MS(ESI + ):(M+H) + 332;HPLC:RT=0.84 min, method:Z011_S03

[0169] [Table 104]

[0170] [Table 105]

[0171] Similar to Example 1, the following compound is obtained starting from 2-fluoro-1-nitro-4-(trifluoromethyl)benzene. The product is a mixture of two stereoisomers. Isolating one stereoisomer: Example 6

[0172] [Table 106]

[0173] Similar to Example 1, the following compounds are obtained starting from 2-fluoro-1-nitro-4-(trifluoromethyl)benzene. The product is a mixture of two stereoisomers, which are separated by chiral SFC: Example 7, 7-1

[0174] [Table 107]

[0175] [Table 108]

[0176] Similar to Example 1, the following compound is obtained starting from 2,4-difluoro-1-nitrobenzene. The product is a mixture of two stereoisomers, which are separated by chiral SFC: Example 8, 8-1

[0177] [Table 109]

[0178] [Table 110]

[0179] Similar to Example 1, the following compounds are obtained starting from 1,2,4-trifluoro-5-nitrobenzene. The product is a mixture of two stereoisomers, which are separated by chiral SFC: Example 9, 9-1

[0180] [Table 111]

[0181] [Table 112]

[0182] (Examples 10 and 11) The following compounds are obtained in a manner similar to Example 1 (see below), except for step 8. In step 8, the product, which consists of two stereoisomers, is purified by crystallization to obtain a single stereoisomer.

[0183] (Synthesis of Example 1) [ka]

[0184] (Examples 10 and 11) [ka] 10 g of the intermediate was synthesized using 1,4-difluoro-2-nitrobenzene as the starting material, with similarity to 1 g of the intermediate.

[0185] [Table 113]

[0186] Step 8: Add TFA (5.083 ml, 65.88 mmol) to 10 g (2.5 g, 6.589 mmol) of intermediate in 30 ml of DCM at 5°C. Remove the cooler and stir the mixture at ambient temperature for 6.5 hours. Add DCM (50 ml) to the mixture, then add water (150 ml). Extract the organic phase twice with water (100 ml). Adjust the pH of the combined aqueous phase to approximately 10 by adding concentrated NH3 aqueous solution. Extract the aqueous layer with ethyl acetate (250 ml). Dehydrate the combined organic layer with MgSO4 and concentrate under vacuum. Add ethanol (11.75 ml) and water (0.62 ml) to the residue (1.67 g). Heat the mixture to 70°C. Then add 5-methylpyrazine-2-carboxylic acid (0.775 g, 5.612 mmol). To this mixture, add ethanol (5.87 ml) and water (0.31 ml), and heat the mixture at 70°C for 1 hour. Then, slowly cool the mixture to room temperature. Next, cool the mixture to 20°C in less than 1 minute. Filter the mixture, wash with ethanol (3 ml), and dry in a dry spray machine at 50°C. Yield: 1.81 g (4.33 mmol; 73%) Intermediate as a salt containing 5-methylpyrazine-2-carboxylic acid - 10h

[0187] Step 9: Intermediate as a salt containing 5-methylpyrazine-2-carboxylic acid (0.55 g, 1.32 mmol): 10h, a mixture of NMM (0.581 mL, 5.27 mmol) and 5-methylpyrazine-2-carboxylic acid (90.9 mg, 0.66 mmol) in 5.5 ml of ethyl acetate is cooled to 0°C with stirring. Then, PPA (50% in ethyl acetate; 1.165 mL, 1.97 mmol) is added. After 10 minutes, the cooling is removed and the mixture is stirred at ambient temperature for 45 minutes. Ethyl acetate (20 ml) is added to the mixture, and then it is extracted twice with sodium bicarbonate solution. The combined organic phase is dehydrated with MgSO4. After filtration, the mixture is concentrated under vacuum, and the residue is separated in THF / MeOH and purified by chromatography (XBridge C18, 10, (H2O + 0.1% NH4OH + 28~48% ACN)). The products containing the fractions are combined and concentrated under vacuum. The product is obtained as a single stereoisomer. Yield: 0.461 mg (1.15 mmol; 87%) Example 10.

[0188] [Table 114]

[0189] Similar to Example 10, the following compound, Example 11, was obtained. 11 g of the intermediate was synthesized using 1,2,4-trifluoro-5-nitrobenzene as the starting material, similar to 1 g of the intermediate.

[0190] [Table 115]

[0191] [Table 116]

Claims

【Request Item 1】 【Chemistry 1-1】 【Chemistry 1-2】 A compound selected from the group consisting of the following.

2. A pharmaceutically acceptable salt of the compound described in claim 1.

3. A compound according to claim 1, or a pharmaceutically acceptable salt according to claim 2, for use as a drug.

4. A pharmaceutical composition comprising the compound described in claim 1, or a pharmaceutically acceptable salt described in claim 2.

5. A compound according to claim 1, or a pharmaceutically acceptable salt according to claim 2, for use in the treatment and / or prevention of a disease or disorder in which inhibition of the activity of metabomodulatory glutamate receptor subtype 4 (mGluR4) is of therapeutic benefit.

6. The compound according to claim 1, or the pharmaceutically acceptable salt according to claim 2, for use according to claim 5, wherein the disease or disorder is a psychiatric, neurological, neurodegenerative, non-neurological, or metabolic disease, cancer, or related disorder.

7. The compound according to claim 1, or the pharmaceutically acceptable salt according to claim 2, for use according to any one of claims 5 and 6, wherein the disease or disorder is selected from the group consisting of psychiatric and neurological conditions associated with lack of impulse control or maladaptive impulses; substance use disorders; personality disorders, e.g., borderline personality disorder, antisocial personality disorder, conduct disorder; eating disorders, e.g., binge eating disorder; attention deficit hyperactivity disorder; bipolar disorder; stress-related disorders, e.g., post-traumatic stress disorder; tic disorders such as Tourette syndrome; behavioral disorders, e.g., restless legs syndrome; cognitive impairment in psychiatric or neurological disorders, schizophrenia, Alzheimer's disease and other neurological and psychiatric disorders; overweight, obesity; cancer and associated disorders associated with maladaptive tumor formation such as osteosarcoma.

Images