Pharmaceutical composition for preventing or treating mental disorders

Abstract

A pharmaceutical composition for the prevention or treatment of a psychiatric disorder is disclosed. More specifically, the pharmaceutical composition is directed to the prevention or treatment of a psychiatric disorder. 2A Pharmaceutical compositions are disclosed for the treatment or prevention of psychiatric disorders, including substance-related and addictive disorders, depressive disorders, anxiety disorders, or post-traumatic stress disorders, by using compounds that simultaneously modulate R.

Description

[Technical field]

[0001] A pharmaceutical composition for the prevention or treatment of a psychiatric disorder is disclosed. More specifically, the pharmaceutical composition is directed to the prevention or treatment of a psychiatric disorder. 2A Pharmaceutical compositions are disclosed for the treatment or prevention of psychiatric disorders, including substance-related and addictive disorders, depressive disorders, anxiety disorders, or post-traumatic stress disorders, by using compounds that simultaneously modulate R. [Background technology]

[0002] Mental disorders (mental illnesses) are disorders that, due to abnormal symptoms of brain function, cause difficulties in social and occupational adaptation, including interactions with others, and show various types of behavioral and mental abnormalities. Mental disorders are caused by a complex interplay of various causes, including genetic, psychological, biological, and environmental factors, but many diseases have unknown causes. When the cause is known, mental disorders usually occur under extremely stressful situations. However, experts on mental disorders believe that the main cause is an imbalance in neurotransmitter secretion in the brain, that is, abnormalities in neurotransmitter regulation, such as excessive secretion or deficiency. In fact, functional changes have been shown in brain images such as magnetic resonance imaging (MRI) and positron emission tomography (PET), similar to neurological disorders such as Alzheimer's disease (Non-Patent Documents 1, 2).

[0003] Mental disorders are primarily classified according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM) published by the American Psychiatric Association. Currently, the fifth edition of the DSM (2013), DSM-5, is used by most mental health professionals. Representative mental disorders classified according to DSM-5 include substance-related and addictive disorders, depressive disorders, anxiety disorders, trauma- and stressor-related disorders, etc. (DSM-5 TM , 2013).

[0004] Substance-related and addictive disorders are broadly divided into substance use disorders and substance-induced disorders. The substances that cause disorders are classified into 10 types: alcohol, anxiolytics and sedatives, caffeine, cannabis, hallucinogens, inhalants, opioids, stimulants, tobacco, and others (including non-substances), all of which directly or indirectly affect the brain's reward system. Activating the system induces a craving for the substance through pleasure and satisfaction. Substance use disorders are disorders involving cognitive, behavioral, and physiological patterns that lead to continued use of drugs despite problems resulting from substance use, and are distinct from addiction. Substance-induced disorders include addiction, withdrawal, and other substance / drug-induced mental disorders. Addiction is a disorder in which the use of a substance causes sensory and emotional problems, leading to intense aggression and hallucinations, making it difficult to make rational decisions. Withdrawal symptoms are physical and psychological abnormalities that occur when drug use is discontinued, and in this case, it becomes difficult to properly lead daily life. Furthermore, substance-induced psychosis means that the psychotic symptoms are much more severe than those of addiction.

[0005] Depressive disorders are mental illnesses in which depressive symptoms due to decreased motivation and activity appear persistently and repeatedly, causing various cognitive and delusional disorders, and leading to a decline in daily life functions. Symptoms include a marked decline in motivation due to depressed mood and hopelessness, overeating or fasting, poor quality sleep or lack of sleep, decreased physical activity, decreased libido, increased fatigue, and decreased concentration. Excessive feelings of guilt and despair about the future often lead to thoughts of death or suicide, which causes major disruptions to various aspects of social life. In most cases, long-term treatment is required due to the high possibility of recurrence.

[0006] Anxiety disorder is a general term for mental disorders characterized by abnormal and pathological fear, worry, anxiety, and panic in various forms. It is generalized as an overreaction to ordinary situations without realistic risk factors, and the target is unclear. Anxiety disorders are excessive fear, anxiety, and avoidance behavior in general situations, often with unclear targets and situations, and are accompanied by hyperactivity of the autonomic nervous system, such as palpitations, elevated blood pressure, tachycardia, tremors, dilated pupils, tremors, gastrointestinal disorders, and frequent urination as physical symptoms. In the DSM-6, anxiety disorders are classified into panic disorder, generalized anxiety disorder, obsessive-compulsive disorder, phobias, post-traumatic stress disorder (PTSD), and acute stress disorder. Post-traumatic stress disorder is a state of persistent anxiety after experiencing a traumatic event such as war, accidents, natural disasters, or severe external mental or physical violence. However, in the DSM-5, obsessive-compulsive disorder and its related disorders and trauma- and stress-related disorders (including PTSD) are classified into separate categories. [Prior art documents] [Patent documents]

[0007] [Non-Patent Document 1] Videbech, Acta Psychiatr Scand., 2000 [Non-Patent Document 2] Fu et al., Exp Ther Med., 2018 Summary of the Invention [Problem to be solved by the invention]

[0008] An object of the present invention is to provide a pharmaceutical composition for preventing or treating a mental disorder.

[0009] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating substance-related and addictive disorders.

[0010] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating depressive disorder, anxiety disorder or post-traumatic stress disorder.

[0011] Another object of the present invention is to provide a method for preventing or treating a psychiatric disorder.

[0012] It is another object of the present invention to provide a method for preventing or treating substance-related and addictive disorders.

[0013] Another object of the present invention is to provide a method for preventing or treating a depressive disorder, an anxiety disorder or a post-traumatic stress disorder. [Means for solving the problem]

[0014] In order to achieve the above object, a compound represented by the following formula (1) [ka] (wherein X1, X2, R1, R2, R3, R4, R5, l and m are as defined herein) or a pharma- ceutically acceptable salt thereof, together with a pharma- ceutically acceptable carrier or excipient, for the prevention or treatment of psychiatric disorders, including substance-related and addictive disorders, depressive disorders, anxiety disorders or post-traumatic stress disorders, is provided. Effect of the Invention

[0015] The disclosed pharmaceutical compositions can effectively prevent or treat psychiatric disorders, including substance-related and addictive disorders, depressive disorders, anxiety disorders, or post-traumatic stress disorders. [Brief description of the drawings]

[0016] [Figure 1] 1 to 3 are graphs showing the results of measuring the therapeutic effects of test compounds A, B and C on drug dependence in animal models. [Diagram 2] 1 to 3 are graphs showing the results of measuring the therapeutic effects of test compounds A, B and C on drug dependence in animal models. [Diagram 3]1 to 3 are graphs showing the results of measuring the therapeutic effects of test compounds A, B and C on drug dependence in animal models. [Figure 4] 4 and 5 are graphs showing the results of measuring the preventive effects of test compounds A and C on drug dependence in animal models, respectively. [Diagram 5] 4 and 5 are graphs showing the results of measuring the preventive effects of test compounds A and C on drug dependence in animal models, respectively. [Figure 6] 6 and 7 are graphs showing the results of measuring the effect of test compound A in preventing relapse into addiction in an animal model. [Figure 7] 6 and 7 are graphs showing the results of measuring the effect of test compound A in preventing relapse into addiction in an animal model. [Figure 8] FIG. 8 is a graph showing the results of measuring the effect of test compound B in preventing relapse into addiction in an animal model. [Figure 9] FIG. 9 is a graph showing the results of measuring the therapeutic effect of test compound A on withdrawal symptoms in an animal model. [Figure 10] FIG. 10 is a graph showing the results of measuring the therapeutic effect of test compound A on depressive disorder in an animal model. [Figure 11] FIG. 11 is a graph showing the results of measuring the therapeutic effect of test compound A on anxiety disorders in an animal model. [Figure 12] FIG. 12 is a graph showing the results of measuring the therapeutic effect of test compound A on post-traumatic stress disorder in an animal model. BEST MODE FOR CARRYING OUT THEINVENTION

[0017] The present invention will now be described in more detail.

[0018] According to one aspect of the present invention, a compound represented by the following formula (1) [ka] (wherein X1 and X2, together with the carbon atom to which they are attached, form a cyclobutane, cyclopentane, cyclohexane, oxetane, tetrahydrofuran, or tetrahydropyran ring; R1 is fluoro, hydroxy or C1-C5 alkyl; R2 is hydrogen, fluoro, hydroxy, C1-C5 alkyl or C1-C5 alkoxy; R3 is hydrogen, deuterium or C1-C5 alkyl; R4 and R5 are each independently hydrogen or fluoro, provided that at least one is fluoro; l and m each independently represent an integer of 0 to 2; and n is 1 or 2.) or a pharma- ceutical composition for preventing or treating mental disorders, including substance-related and addictive disorders, depressive disorders, anxiety disorders, or post-traumatic stress disorders, is provided, the pharmaceutical composition comprising a compound represented by the formula:

[0019] In one embodiment of the present invention, the compound of formula (1) is represented by the following formula (2): [ka] (wherein X1 and X2, together with the carbon atom to which they are attached, form a cyclobutane, cyclopentane, cyclohexane, oxetane, tetrahydrofuran, or tetrahydropyran ring; R1 is fluoro, hydroxy or methyl; R2 is hydrogen, fluoro, hydroxy, methyl, ethyl or methoxy; R4 and R5 are each independently hydrogen or fluoro, provided that at least one is fluoro; and m is an integer of 0 to 2.

[0020] In another embodiment of the present invention, representative examples of the compound of formula (1) include, but are not limited to, the following compounds:

[0021] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0022] The compound of formula (1) binds to mGluR5 (metabotropic glutamate receptor 5) and 5-HT 2A It was employed as a dual receptor modulator with an affinity of 1 μM or less for both receptors.

[0023] The compound of formula (1) according to one embodiment can be prepared by anyone having ordinary knowledge of compound synthesis in this technical field using known compounds or compounds that can be easily prepared from them. For example, the compound of formula (1) can be synthesized according to the following preparation examples, but this is merely an exemplary method, and the order of unit operations can be selectively changed as necessary. It is not intended to limit the scope of the present invention.

[0024] Pharmaceutical Compositions The present invention provides a pharmaceutical composition for preventing or treating a mental disorder, comprising a therapeutically effective amount of the compound of formula (1) or a pharma- ceutically acceptable salt thereof together with a pharma- ceutically acceptable carrier or excipient.

[0025] The pharmaceutical effect of the compound according to one embodiment of the present invention can be maintained even in the form of a pharma- ceutically acceptable salt. The pharma-ceutically acceptable salt includes both acid or base addition salts and their stereochemical isomers. The salt is not particularly limited as long as it maintains the activity of the parent compound in the subject of administration and does not have undesirable effects.

[0026] The pharmaceutical compositions can be formulated in various oral or parenteral dosage forms, such as tablets, pills, hard / soft capsules, liquids, suspensions, emulsions, syrups, granules, or elixirs, or any other dosage form for oral administration.

[0027] When the pharmaceutical composition is formulated into a parenteral dosage form, it is administered by parenteral administration methods such as subcutaneous injection, intravenous injection, intramuscular injection, intrathoracic injection, etc. In this case, in order to formulate the pharmaceutical composition into a parenteral administration preparation, the pharmaceutical composition can be prepared as a solution or suspension by mixing the active ingredient, i.e., the compound of formula (1) or a pharma- ceutical acceptable salt thereof, with a stabilizer or buffer in water, and such a solution or suspension can be prepared as a unit dosage form in an ampoule or vial.

[0028] The compound of formula (1) or a pharma- ceutical acceptable salt thereof may be contained in the pharmaceutical composition in an effective amount of 0.1 to 1,000 mg / kg (body weight), preferably 0.5 to 500 mg / kg (body weight) per day for mammals, including humans. Such a pharmaceutical composition may be administered once a day or in two or more divided doses via oral or parenteral routes.

[0029] medical utility According to yet another aspect of the present invention, there is provided a method for preventing or treating a psychiatric disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of said compound of formula (1) or a pharma- ceutically acceptable salt thereof, said psychiatric disorders including substance-related and addictive disorders, depressive disorders, anxiety disorders and post-traumatic stress disorders.

[0030] Substance-Related and Addictive Disorders One embodiment of the present invention is to provide a method for preventing or treating substance-related and addictive disorders in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of said compound of formula (1) or a pharma- ceutically acceptable salt thereof.

[0031] In another embodiment of the present invention, the substance or drug causing the disorder may be, for example, alcohol; anxiolytics and sedatives (including benzodiazepines, zolpidem, propofol, ketamine, esketamine, phenobarbital, etc.); caffeine; cannabis (including marijuana, synthetic cannabis, etc.); hallucinogens (such as LSD, phencyclidine, psilocybin, etc.); inhalants (such as paint thinner, some glues, etc.); opioids (such as fentanyl, morphine, oxycodone, pethidine, methadone, hydromorphone, hydrocodone, oxymorphone, codeine, heroin, etc.); stimulants (such as methamphetamine, ecstasy, amphetamine, cocaine, etc.); tobacco; and others (including appetite suppressants such as phentermine, phendimetrazine, diethylpropion, mazindol, synthetic anabolic steroids, other commonly abused substances, and non-substances such as gambling, sex, the internet, stocks, etc.).

[0032] The above 10 drugs are not only highly likely to cause substance use disorders, but also contribute significantly to substance-induced disorders, i.e., the induction of dependence and associated tolerance due to increased mental / physical dependence caused by abuse of the drug, the occurrence of withdrawal symptoms due to a decrease in the amount of the drug used, and the further development of comorbid psychiatric disorders related to the drug itself or the drug treatment process. Also, the drugs in question may cause a vicious cycle that leads to relapse by failing to suppress cravings for drugs during or after the completion of treatment.

[0033] mGluR5 is expressed in the ventral tegmental area (VTA) and nucleus accumbens in the midbrain, which form the mesolimbic dopamine pathway, a central neural circuit involved in addiction, and is therefore known to play an important role in the addiction process (Lu et al., Molecular Brain Research, 1999; Cleva and Olive, Wiley Interdiscip Rev Membr Transp Signal., 2012).

[0034] It has been reported that mice lacking the mGluR5 gene have a lower drug dependency (Blednov and Harris, Int J Neuropsychopharmacol., 2008). When mGluR5 antagonists were injected into rats addicted to drugs such as cocaine, morphine, amphetamine, ketamine, methamphetamine, and nicotine, conditioned reward behavior and self-administration were reduced, and reinstatement of drug seeking symptoms were reduced (Cleva and Olive, Wiley Interdiscip Rev Membr Transp Signal., 2012). The clinical efficacy of mavoglurant, one of the mGluR5 inhibitory modulators, was confirmed in a clinical trial involving 68 patients with cocaine use disorder. Treatment with mGluR5 antagonists may promote serotonin secretion and subsequent dopamine secretion depending on the route of administration and the drug administered. However, 5-HT, as with oral administration, is not effective. 2A If dopamine secretion can be suppressed by adding the antagonistic effect of R, it is expected that this will have a preventive or therapeutic effect on drug addiction.

[0035] 5-HT 2A R is expressed in excitatory neurons that send axons to the ventral tegmental area and directly or indirectly affects the regulation of dopamine, which plays a central role in addiction. 2A R has been reported to increase (Herin, et. al., Front Psychiatry, 2013). 2AThe 5-HT agonist 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) promoted dopamine secretion by increasing the activity of neurons in the ventral tegmental area. 2A Treatment with 5-HT R antagonists suppressed dopamine secretion. 2A Pretreatment with the R antagonist ketanserin inhibited cocaine-induced increases in dopamine (Bubar and Cunningham, Curr Top Med Chem., 2006), attenuated morphine-induced behavioral sensitization (Gang et. al., 2016), and reduced cue-reinstated self-administration in cocaine-addicted rats (Dhonnchadha et. al., Behav Neurosci., 2009).

[0036] One embodiment of the present invention is based on the discovery that the compounds of formula (1) have novel and unique pharmacological properties. The compounds of formula (1) inhibit mGluR5 and 5-HT 2A It has a dual regulatory effect on R, and in animal models, it has been confirmed to be effective in preventing and treating addiction to substances of abuse, treating withdrawal symptoms, preventing relapse, and treating associated substance-induced psychiatric disorders such as depression and anxiety.

[0037] For example, a patient may be addicted or at risk of becoming addicted to a therapeutic substance administered to treat a disorder or disease. For example, a risk of addiction may arise when exposed to an addictive therapeutic substance, such as a narcotic opioid analgesic. In light of this situation, the compound of formula (1) may be provided to a patient alone or in combination with other additional therapeutic agents or addictive therapeutic substances. The compound of formula (1) may be provided for the prevention or treatment of secondary addiction caused by opioid analgesics administered to a patient suffering from or at risk of pain.

[0038] The compounds of formula (1) may be used in combination with anti-addiction drugs, including replacement or replacement drugs, which may be naloxone, naltrexone, nalmefene, disulfiram, acamprosate, topiramate, risperidone, paliperidone, ondansetron, fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine, venlafaxine, duloxetine, mirtazapine, or bupropion. For example, naloxone can be administered as an antidote to opioids, in which case the compound of formula (1) can treat the withdrawal symptoms caused by naloxone. In this way, the compound of formula (1) can be provided for the control of withdrawal symptoms and associated psychiatric disorders.

[0039] The compounds of formula (1) may also be provided to prevent or reduce the likelihood of relapse to abuse of a substance in a patient attempting to discontinue use of the substance which causes a substance-related and addictive disorder.

[0040] Depressive disorders Another embodiment of the present invention is to provide a method for preventing or treating a depressive disorder in a subject in need of treatment, comprising administering to said subject a therapeutically effective amount of a compound of formula (1) or a pharma- ceutically acceptable salt thereof.

[0041] Selective serotonin reuptake inhibitors (SSRIs), which are widely used to treat depressive disorders, have various side effects such as vomiting, diarrhea, headache, dizziness, insomnia, anxiety, loss of appetite and libido, and impulsive suicidal behavior, and they usually take several weeks to show therapeutic effects. In addition, one-third of patients prescribed SSRIs do not show antidepressant efficacy. Ketamine, an antagonist of the N-methyl-D-aspartate (NMDA) receptor, is known to be clinically effective in patients with treatment-resistant depression.

[0042] mGluR5 antagonists partially suppress NMDAR function, and as such are attracting attention as a potential treatment for depressive disorders (Barnes et al., Biol Psychiatry, 2018). In the mouse tail suspension test, an animal model related to depressive disorders, the mGluR5 antagonist MPEP dose-dependently reduced immobility time. Furthermore, in the rat forced swimming test, another mGluR5 antagonist, MTEP (3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine), reduced immobility time (Tatarczynska et al., Br J Pharmacol., 2001). The indirect inhibition of NMDAR by mGluR5 antagonists effectively treats depressive disorders by reducing symptoms such as increased arterial pressure / heart rate / cardiac output, hallucinations, delirium, and cognitive impairment, which are side effects of direct NMDAR antagonists such as ketamine.

[0043] 5-HT 2A R antagonists are known to be effective in improving treatment-resistant depression when used in combination with SSRIs. In fact, mirtazapine and mianserin are clinically used as adjunctive treatments for treatment-resistant depression (Marek et al., Neuropsychopharmacology, 2003; Celada et al., Rev Psychiatr Neurosci., 2004).

[0044] Therefore, mGluR5 and 5-HT 2AThe compound of formula (1) having a modulating effect on both R can be used for the prevention and treatment of depressive disorders, particularly treatment-resistant depression.

[0045] Anxiety and post-traumatic stress disorder Another embodiment of the present invention is to provide a method for preventing or treating anxiety disorders and post-traumatic stress disorder (PTSD) in a subject in need of treatment, comprising administering to said subject a therapeutically effective amount of a compound of formula (1) or a pharma- ceutically acceptable salt thereof.

[0046] In the amygdala, a central region related to typical anxiety, mGluR5 is known to play an important role in the acquisition of fear and anxiety behavior. Treatment with MPEP, an mGluR5 antagonist, has been shown to inhibit the fear / anxiety acquisition process by suppressing the formation of long-term potentiation (LTP) in the amygdala (Rodrigues et. al., J Neurosci., 2002). Injection of MPEP into the amygdala increased the time that the subject spent in the light area in the light-dark box test, and increased the time that the subject spent in the open arms and the number of entries into the open arms in the elevated plus maze test. These results indicate a significant anxiolytic effect (de ra Mora et al., Eur J Neurosci, 2006).

[0047] In addition, 5-HT in the amygdala 2A R is also closely related to anxiety behavior, 2A It is known that direct administration of R agonists into the amygdala promotes anxiety behavior. In fact, 5-HT2AR antagonists such as mirtazapine, trazodone, and mianserin are used clinically as treatments for anxiety disorders (Murphy, Br J Clin Pharmac., 1978; Chea and Giorgi, Am J Ani Vet Sci., 2017).

[0048] Therefore, mGluR5 and 5-HT 2A The compounds of formula (1) having a modulating effect on both R can be used for the prevention and treatment of anxiety disorders and post-traumatic stress disorder.

[0049] The specific administration method and therapeutically effective amount of the compound of formula (1) or a pharma- ceutically acceptable salt thereof can be easily determined by a person skilled in the art in consideration of the type of target mammal, the type of disorder, the type of compound of formula (1), etc., and are not particularly limited. EXAMPLES

[0050] The present invention will now be described in more detail with reference to the following examples, but it should be understood that the scope of protection of the present disclosure is not limited to the examples.

[0051] Preparation Example 1: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide (Compound 1) [ka]

[0052] Step 1: Synthesis of 4-((2-fluorophenyl)ethynyl)benzoic acid [ka] 1-Ethynyl-2-fluorobenzene (0.500 g, 4.162 mmol), methyl 4-bromobenzoate (0.940 g, 4.370 mmol), copper iodide (0.016 g, 0.083 mmol), tetrakis(triphenylphosphine)palladium (0.096 g, 0.083 mmol) and triethylamine (5.801 mL, 41.622 mmol) were dissolved in toluene (10 mL) at room temperature. The resulting solution was stirred at 95° C. for 8 hours, and then the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was filtered through a Celite pad to remove solids, water was added to the filtrate, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography and concentrated to give methyl 4-((2-fluorophenyl)ethynyl)benzoate (0.775 g, 73.2%) as a white solid.

[0053] Next, the obtained product and lithium hydroxide monohydrate (0.256 g, 6.096 mmol) were dissolved in tetrahydrofuran (5 mL) / methanol (5 mL) / water (5 mL) at room temperature and stirred at 50° C. for 6 hours, and then the temperature was lowered to room temperature to terminate the reaction. After removing the solvent from the reaction mixture under reduced pressure, 1N aqueous hydrochloric acid was added to the concentrate and stirred. The precipitated solid was filtered, washed with water, and dried to obtain 4-((2-fluorophenyl)ethynyl)benzoic acid (0.703 g, 96.0%) as a pale yellow solid: LRMS (ES) m / z 239.12 [MH] + , calculated MW 240.23.

[0054] Step 2: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide [ka] A solution of 4-((2-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.291 mmol), (tetrahydro-2H-pyran-4-yl)methanamine (0.050 g, 0.437 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC-HCl, 0.084 g, 0.437 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (HOBt, 0.059 g, 0.437 mmol) and N,N-diisopropylethylamine (0.254 mL, 1.457 mmol) dissolved in N,N-dimethylformamide (3 mL) at room temperature was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography and concentrated to give 4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide (0.075 g, 76.3%) as a white solid: LRMS (ES) m / z 338.21 [M+H]. + , calculated MW 337.39; 1 H-NMR (400 MHz, CD3OD) d 7.82 (d, J = 8.8 Hz, 2 H), 7.60 (d, J = 8.8 Hz, 2 H), 7.55 (t, J = 7.6 Hz, 1 H), 7.45 - 7.37 (m, 1 H), 7.21 - 7.14 (m, 2 H), 3.93 (dd, J = 11.2, 4.0 Hz, 2 H), 3.39 (t, J = 11.8 Hz, 2 H), 3.28 - 3.26 (m, 2 H), 1.90 - 1.86 (m, 1 H), 1.69 (s, 2 H), 1.37 - 1.27 (m, 2 H).

[0055] Production Example 2: Synthesis of N-((4,4-difluorocyclohexyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide (Compound 2) [ka] Using 4-((2-fluorophenyl)ethynyl)benzoic acid (0.200 g, 0.833 mmol) and (4,4-difluorocyclohexyl)methanamine hydrochloride (0.232 g, 1.249 mmol) as starting materials, N-((4,4-difluorocyclohexyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide (0.175 g, 56.6%) was obtained as a white solid in the same manner as in Step 2 of Production Example 1: LRMS (ES) m / z 372.23 [M+H] + , calculated MW 371.4; 1 H-NMR (400 MHz, DMSO-d6) d 8.63 (t, J = 6.0 Hz, 1 H), 7.87 (d, J = 8.8 Hz, 2 H), 7.65 - 7.61 (m, 3 H), 7.49 - 7.45 (m, 1 H), 7.33 (t, J = 9.2 Hz, 1 H), 7.25 (td, J = 7.6, 1.2 Hz, 1 H), 3.14 (t, J = 6.4 Hz, 2 H), 2.01 - 1.96 (m, 2 H), 1.81 - 1.66 (m, 5 H), 1.22 - 1.13 (m, 2 H).

[0056] Preparation Example 3: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-(1-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide (Compound 3) [ka]

[0057] Step 1: Synthesis of (Z)-2-methyl-N-((tetrahydro-2H-pyran-4-yl)methylene)propane-2-sulfinamide [ka] 2-Methylpropane-2-sulfinamide (1.000g, 8.251mmol), tetrahydro-2H-pyran-4-carbaldehyde (2.072g, 18.152mmol), magnesium sulfate (MgSO4, 5.462g, 45.380mmol) and pyridinium p-toluenesulfonate (0.107g, 0.495mmol) were dissolved in 1,2-dichloroethane (14mL) at room temperature, and the resulting solution was stirred at the same temperature for 24 hours under visible light (blue LED, 40W). Water was poured into the reaction mixture, which was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography and concentrated to give (Z)-2-methyl-N-((tetrahydro-2H-pyran-4-yl)methylene)propane-2-sulfinamide (0.800 g, 44.6%) as a white solid.

[0058] Step 2: Synthesis of 1-(tetrahydro-2H-pyran-4-yl)ethan-1-amine hydrochloride [ka] (Z)-2-Methyl-N-((tetrahydro-2H-pyran-4-yl)methylene)propane-2-sulfinamide (0.800 g, 3.681 mmol) and methylmagnesium bromide (1.40 M solution in THF / toluene, 5.259 mL, 7.362 mmol) were dissolved in dichloromethane (15 mL), and the resulting solution was stirred at room temperature for 1 h and further stirred at the same temperature for 18 h. Water was poured into the reaction mixture, and it was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography to obtain 2-methyl-N-(1-(tetrahydro-2H-pyran-4-yl)ethyl)propane-2-sulfinamide (0.475 g, 55.3%) as a colorless liquid. The obtained product (0.400 g, 1.714 mmol) and hydrogen chloride (4.00 M solution in 1,4-oxane, 1.286 mL, 5.142 mmol) were dissolved in methanol (2 mL) at room temperature, and the obtained solution was stirred at the same temperature for 30 minutes. After removing the solvent from the reaction mixture under reduced pressure, ethyl acetate (1 mL) and hexane (10 mL) were added to the concentrate and stirred. The precipitated solid was filtered, washed with hexane, and dried to obtain 1-(tetrahydro-2H-pyran-4-yl)ethan-1-amine hydrochloride (0.143 g, 50.4%) as a pink solid.

[0059] Step 3: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-(1-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide [ka] 1-(tetrahydro-2H-pyran-4-yl)ethan-1-amine hydrochloride (0.035 g, 0.211 mmol), 4-((2-fluorophenyl)ethynyl)benzoic acid (0.051 g, 0.211 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazole-de[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.104 g, 0.275 mmol) and N,N-diisopropylethylamine (0.184 mL, 1.056 mmol) were dissolved in N,N-dimethylformamide (2 mL) at room temperature, and the resulting solution was stirred at the same temperature for 5 hours. The solvent was removed from the reaction mixture under reduced pressure, and a saturated aqueous solution of sodium bicarbonate was poured into the resulting concentrate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography and concentrated to give 4-((2-fluorophenyl)ethynyl)-N-(1-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide (0.045 g, 60.6%) as a white solid: LRMS (ES) m / z 352.13 [M+H]. + , calculated MW 351.42; 1 H-NMR (400 MHz, DMSO-d6) d 8.27 (d, J = 8.4 Hz, 1 H), 7.87 (d, J = 8.4 Hz, 2 H), 7.63 - 7.61 (m, 3 H), 7.46 (m, 1 H), 7.32 (t, J = 15.4 Hz, 1 H), 7.26 (t, J = 4.0 Hz, 1 H), 3.88 - 3.77 (m, 3 H), 3.24 (q, J = 14.0 Hz, 2 H), 1.62 - 1.56 (m, 3 H), 1.22 - 1.15 (m, 2 H), 1.09 (d, J = 6.8Hz, 3H).

[0060] Production Example 4: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide (Compound 4) [ka] Using 4-((2-fluorophenyl)ethynyl)benzoic acid (0.150 g, 0.624 mmol) and (tetrahydrofuran-3-yl)methanamine (0.098 mL, 0.937 mmol) as starting materials, 4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide (0.143 g, 70.8%) was obtained as a white solid in the same manner as in Step 2 of Preparation 1: LRMS (ES) m / z 324.21 [M+H]. + , calculated MW 323.37; 1 H-NMR (400 MHz, DMSO-d6) d 8.68 (t, J = 5.6 Hz, 1 H), 7.86 (dd, J = 6.8, 2.0 Hz, 2 H), 7.64 - 7.59 (m, 3 H), 7.50 - 7.44 (m, 1 H), 7.33 (t, J = 8.6 Hz, 1 H), 7.25 (td, J = 7.6, 0.9 Hz, 1 H), 3.71 - 3.54 (m, 3 H), 3.45 - 3.36 (m, 2 H), 3.30 - 3.13 (m, 2 H), 1.93 - 1.87 (m, 1 H), 1.62 - 1.50 (m, 1 H).

[0061] Preparation Example 5: Synthesis of 4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide (Compound 5) [ka]

[0062] Step 1: Synthesis of 4-((2,4-difluorophenyl)ethynyl)benzoic acid [ka] Methyl 4-ethynylbenzoate (2.000 g, 12.487 mmol) and 1-bromo-2,4-difluorobenzene (2.410 g, 12.487 mmol) were used in a similar manner to Preparation 1, Step 1 to give methyl 4-((2,4-difluorophenyl)ethynyl)benzoate (0.780 g, 22.9%) as a white solid, followed by 4-((2,4-difluorophenyl)ethynyl)benzoic acid (0.730 g, 98.7%) as a white solid: LRMS (ES) m / z 256.98 (M-1) [M+H] + , calculated MW 258.22.

[0063] Step 2: Synthesis of 4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide [ka] 4-((2,4-difluorophenyl)ethynyl)benzoic acid (0.150 g, 0.581 mmol) and (tetrahydro-2H-pyran-4-yl)methanamine (0.074 g, 0.639 mmol) were used in a similar manner to step 3 of preparation 3 to give 4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide (0.156 g, 75.6%) as a white solid: LRMS (ES) m / z 356.42 [M+H] + , calculated MW 355.38; 1H-NMR (400 MHz, DMSO-d6) d 8.58 (t, J = 5.6 Hz, 1 H), 7.86 (d, J = 8.4 Hz, 2 H), 7.70 (q, J = 7.9 Hz, 1 H), 7.61 (d, J = 8.0 Hz, 2 H), 7.42 (td, J = 9.6, 2.8 Hz, 1 H), 7.17 (td, J = 7.8, 2.5 Hz, 1 H), 3.80 (dd, J = 11.2, 2.4 Hz, 2 H), 3.22 (t, J = 11.8 Hz, 2 H), 3.12 (t, J = 6.2 Hz, 2 H), 1.78 - 1.73 (m, 1 H), 1.55 (d, J = 12.8 Hz, 2 H), 1.20 - 1.10 (m, 2 H).

[0064] Preparation Example 6: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((3-methyloxetan-3-yl)methyl)benzamide (Compound 6) [ka] Using 4-((2-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.291 mmol) and (3-methyloxetan-3-yl)methanamine (0.044 g, 0.437 mmol) as starting materials, 4-((2-fluorophenyl)ethynyl)-N-((3-methyloxetan-3-yl)methyl)benzamide (0.052 g, 55.2%) was obtained as a white solid in the same manner as in Step 2 of Production Example 1: LRMS (ES) m / z 324.33 [M+H] + , calculated MW 323.37; 1H-NMR (400 MHz, DMSO-d6) d 8.71 (t, J = 6.0 Hz, 1 H), 7.88 (dd, J = 6.4, 2.0 Hz, 2 H), 7.66 - 7.61 (m, 3 H), 7.50 - 7.45 (m, 1 H), 7.33 (td, J = 9.1, 1.1 Hz, 1 H), 7.25 (td, J = 7.6, 1.1 Hz, 1 H), 4.44 (d, J = 5.2 Hz, 2 H), 4.17 (d, J = 5.2 Hz, 2 H), 3.44 (d, J = 6.0 Hz, 2 H), 1.22 (s, 3 H).

[0065] Production Example 7: Synthesis of N-((3,3-difluorocyclobutyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide (Compound 7) [ka] Using 4-((2-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.291 mmol) and (3,3-difluorocyclobutyl)methanamine hydrochloride (0.069 g, 0.437 mmol) as starting materials, N-((3,3-difluorocyclobutyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide (0.075 g, 75.0%) was obtained as a white solid in the same manner as in Step 3 of Preparation 3: LRMS (ES) m / z 344.22 [M+H] + , calculated MW 343.35; 1 H-NMR (400 MHz, DMSO-d6) d 8.72 (t, J = 5.6 Hz, 1 H), 7.86 (d, J = 7.6 Hz, 2 H), 7.64 - 7.61 (m, 3 H), 7.47 (q, J = 6.4 Hz, 1 H), 7.33 (t, J = 9.2 Hz, 1 H), 7.25 (t, J = 7.6 Hz, 1 H), 2.63 - 2.55 (m, 3 H), 2.38 - 2.29 (m, 4 H).

[0066] Preparation Example 8: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((4-methoxytetrahydro-2H-pyran-4-yl)methyl)benzamide (Compound 8) [ka] Using 4-((2-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.291 mmol) and (4-methoxytetrahydro-2H-pyran-4-yl)methanamine (0.042 g, 0.291 mmol) as starting materials, 4-((2-fluorophenyl)ethynyl)-N-((4-methoxytetrahydro-2H-pyran-4-yl)methyl)benzamide (0.080 g, 74.7%) was obtained as a pale yellow oil in the same manner as in Step 3 of Preparation 3: LRMS (ES) m / z 368.20 [M+H] + , calculated MW 367.42; 1 H-NMR (400 MHz, CDCl3) d 7.76 (d, J = 8.0 Hz, 2 H), 7.61 (d, J = 7.6 Hz, 2 H), 7.52 (m, 1 H), 7.35 - 7.33 (m, 1 H), 7.16 - 7.11 (m, 2 H), 6.32 (bs, 1 H), 3.73 (m, 4 H), 3.57 (d, J = 4.8 Hz, 2 H), 3.26 (s, 3 H), 1.82 - 1.67 (m, 4 H).

[0067] Production Example 9: Synthesis of (R)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide (Compound 9) [ka] Using 4-((2-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.291 mmol) and (R)-(tetrahydrofuran-3-yl)methanamine hydrochloride (0.043 g, 0.321 mmol) as starting materials, (R)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide (0.080 g, 84.9%) was obtained as a white solid in the same manner as in Step 3 of Preparation 3: LRMS (ES) m / z 324.23 [M+H]. + , calculated MW 323.37; 1 H-NMR (400 MHz, DMSO-d6) d 8.67 (t, J = 5.4 Hz, 1 H), 7.86 (d, J = 8.4 Hz, 2 H), 7.64 - 7.62 (m, 3 H), 7.50 - 7.45 (m, 1 H), 7.33 (t, J = 9.2 Hz, 1 H), 7.25 (t, J = 7.6 Hz, 1 H), 3.71 - 3.55 (m, 3 H), 3.45 - 3.42 (m, 1 H), 3.27 - 3.19 (m, 2 H), 3.13 - 3.12 (m, 1 H), 1.95 - 1.86 (m, 1 H), 1.60 - 1.52 (m, 1 H).

[0068] Preparation Example 10: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((3-hydroxyoxetan-3-yl)methyl)benzamide (Compound 10) [ka] Using 4-((2-fluorophenyl)ethynyl)benzoic acid (0.100 g, 0.416 mmol) and 3-(aminomethyl)oxetan-3-ol (0.052 g, 0.500 mmol) as starting materials, 4-((2-fluorophenyl)ethynyl)-N-((3-hydroxyoxetan-3-yl)methyl)benzamide (0.082 g, 60.5%) was obtained as an ivory solid in the same manner as in Step 3 of Preparation 3: LRMS (ES) m / z 326.22 [M+H] +, calculated MW 325.34; 1 H-NMR (400 MHz, DMSO-d6) d 8.71 (t, J = 6.2 Hz, 1 H), 7.90 (dd, J = 6.8, 1.6 Hz, 2 H), 7.65 - 7.61 (m, 3 H), 7.49 - 7.47 (m, 1 H), 7.33 (t, J = 8.4 Hz, 1 H), 7.25 (td, J = 7.5, 0.9 Hz, 1 H), 5.86 (s, 1 H), 4.46 (d, J = 6.8 Hz, 2 H), 4.36 (d, J = 6.4 Hz, 2 H), 3.53 (d, J = 6.0 Hz, 2 H).

[0069] Preparation Example 11: Synthesis of 4-((4-fluorophenyl)ethynyl)-N-((3-methyloxetan-3-yl)methyl)benzamide (Compound 11) [ka]

[0070] Step 1: Synthesis of 4-((4-fluorophenyl)ethynyl)benzoic acid [ka] Using methyl 4-bromobenzoate (0.985 g, 4.578 mmol) and 1-ethynyl-4-fluorobenzene (0.500 g, 4.162 mmol) as starting materials, methyl 4-((4-fluorophenyl)ethynyl)benzoate (0.779 g, 73.6%) was obtained as a white solid in the same manner as in Step 3 of Preparation 3, followed by 4-((4-fluorophenyl)ethynyl)benzoic acid (0.672 g, 91.3%) as a pale yellow solid: LRMS (ES) m / z 239.05 [MH] + , calculated MW 240.23.

[0071] Step 2: Synthesis of 4-((4-fluorophenyl)ethynyl)-N-((3-methyloxetan-3-yl)methyl)benzamide [ka] Using 4-((4-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.291 mmol) and (3-methyloxetan-3-yl)methanamine (0.035 g, 0.350 mmol) as starting materials, 4-((4-fluorophenyl)ethynyl)-N-((3-methyloxetan-3-yl)methyl)benzamide (0.089 g, 94.5%) was obtained as a white solid in the same manner as in Step 3 of Preparation 3: LRMS (ES) m / z 324.11 [M+H]. + , calculated MW 323.37; 1 H-NMR (400 MHz, DMSO-d6) d 8.69 (t, J = 6.2 Hz, 1 H), 7.87 (d, J = 8.0 Hz, 2 H), 7.64 - 7.58 (m, 4 H), 7.29 - 7.23 (m, 2 H), 4.44 (d, J = 5.6 Hz, 2 H), 4.17 (d, J = 6.0 Hz, 2 H), 3.43 (d, J = 6.0 Hz, 2 H), 1.22 (s, 3 H).

[0072] Preparation Example 12: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)methyl)benzamide (Compound 12) [ka] Using 4-((2-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.291 mmol) and (1s,3s)-3-(aminomethyl)-1-methylcyclobutan-1-ol (0.044 g, 0.379 mmol) as starting materials, 4-((2-fluorophenyl)ethynyl)-N-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)methyl)benzamide (0.097 g, 98.7%) was obtained as a white solid in the same manner as in Step 3 of Production Example 3: LRMS (ES) m / z 338.08 [M+H] +, calculated MW 337.39; 1 H-NMR (400 MHz, DMSO-d6) d 8.53 (t, J = 5.8 Hz, 1 H), 7.86 (dd, J = 6.4, 2.0 Hz, 2 H), 7.65 - 7.61 (m, 3 H), 7.53 - 7.44 (m, 1 H), 7.33 (t, J = 9.6 Hz, 1 H), 7.25 (td, J = 7.6, 0.9 Hz, 1 H), 4.84 (s, 1 H), 3.24 (t, J = 6.0 Hz, 2 H), 1.97 - 1.92 (m, 3 H), 1.73 - 1.67 (m, 2 H), 1.16 (s, 3 H).

[0073] Production Example 13: Synthesis of (R)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide (Compound 13) [ka] Using 4-((2-fluorophenyl)ethynyl)benzoic acid (0.050 g, 0.208 mmol) and (R)-(tetrahydro-2H-pyran-3-yl)methanamine hydrochloride (0.035 g, 0.229 mmol) as starting materials, (R)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide (0.055 g, 78.3%) was obtained as a white solid in the same manner as in Step 3 of Preparation 3: LRMS (ES) m / z 338.20 [M+H] + , calculated MW 337.39; 1H-NMR (400 MHz, DMSO-d6) d 8.58 (t, J = 5.8 Hz, 1 H), 7.86 (dd, J = 6.6, 1.8 Hz, 2 H), 7.65 - 7.61 (m, 3 H), 7.44 - 7.35 (m, 1 H), 7.33 (td, J = 9.2, 0.8 Hz, 1 H), 7.25 (td, J = 7.6, 1.1 Hz, 1 H), 3.75 - 3.72 (m, 1 H), 3.69 (s, 1 H), 3.30 - 3.25 (m, 1 H), 3.15 - 3.05 (m, 3 H), 1.79 - 1.72 (m, 2 H), 1.57 - 1.52 (m, 1 H), 1.49 - 1.35 (m, 1 H), 1.26 - 1.21 (m, 1 H).

[0074] Production Example 14: Synthesis of (S)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide (Compound 14) [ka] 4-((2-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.291 mmol) and (S)-(tetrahydrofuran-3-yl)methanamine (0.032 g, 0.321 mmol) were used in a similar manner to step 3 of preparation 3 to give (S)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide (0.089 g, 94.5%) as a clear liquid: LRMS (ES) m / z 324.05 [M+H] + , calculated MW 323.37; 1H-NMR (400 MHz, DMSO-d6) d 8.68 (t, J = 5.8 Hz, 1 H), 7.86 (dd, J = 6.8, 2.0 Hz, 2 H), 7.65 - 7.61 (m, 3 H), 7.50 - 7.43 (m, 1 H), 7.33 (td, J = 9.1, 1.1 Hz, 1 H), 7.25 (td, J = 7.7, 1.1 Hz, 1 H), 3.75 - 3.69 (m, 1 H), 3.68 - 3.62 (m, 1 H), 3.60 - 3.55 (m, 1 H), 3.45 - 3.40 (m, 1 H), 3.33 - 3.19 (m, 3 H), 1.95 - 1.87 (m, 1 H), 1.61 - 1.51 (m, 1 H).

[0075] Preparation Example 15: Synthesis of 4-((4-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide (Compound 15) [ka] Using 4-((4-fluorophenyl)ethynyl)benzoic acid (0.070 g, 0.291 mmol) and (tetrahydrofuran-3-yl)methanamine (0.035 g, 0.350 mmol) as starting materials, 4-((4-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide (0.079 g, 83.8%) was obtained as an ivory solid in the same manner as in Step 3 of Preparation 3: LRMS (ES) m / z 324.14 [M+H]. + , calculated MW 323.37; 1H-NMR (400 MHz, DMSO-d6) d 8.64 (t, J = 5.8 Hz, 1 H), 7.85 (dd, J = 6.8, 2.0 Hz, 2 H), 7.64 - 7.58 (m, 4 H), 7.29 - 7.23 (m, 2 H), 3.73 - 3.68 (m, 1 H), 3.65 - 3.63 (m, 1 H), 3.61 - 3.55 (m, 1 H), 3.45 - 3.42 (m, 1 H), 3.22 - 3.15 (m, 3 H), 1.95 - 1.86 (m, 1 H), 1.60 - 1.52 (m, 1 H).

[0076] Preparation Example 16: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((3-methyloxetan-3-yl)methyl-d)benzamide (Compound 16) [ka]

[0077] Step 1: Synthesis of (3-methyloxetan-3-yl)methane-d-amine [ka] 3-Methyloxetane-3-carbaldehyde (2.000 g, 19.976 mmol), phenylmethanamine (2.141 g, 19.976 mmol) and acetic acid (0.114 mL, 1.998 mmol) were dissolved in tetrahydrofuran (18 mL) and the resulting solution was stirred at room temperature for 1 h. Sodium borodeuteride (1.254 g, 29.964 mmol) was added and further stirred at the same temperature for 24 h. Saturated aqueous sodium bicarbonate was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous ammonium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give N-benzyl-1-(3-methyloxetan-3-yl)methan-d-amine (3.800 g, 98.9%, pale yellow oil): LRMS (ES) m / z 193.15 [M+H] + , calculated MW 192.28.

[0078] The resulting product, 10% Pd / C (600 mg) and ammonium formate (4.985 g, 79.051 mmol) were dissolved in methanol (20 mL) at room temperature. The resulting solution was stirred at 65° C. for 14 h, and then the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was filtered through a Celite pad to remove solids, and the filtrate was stripped of solvent under reduced pressure to give (3-methyloxetan-3-yl)methan-d-amine (1.280 g, 63.4%, yellow oil): LRMS (ES) m / z 102.97 [M+H]. + , calculated MW 102.16.

[0079] Step 2: Synthesis of 4-((2-fluorophenyl)ethynyl)-N-((3-methyloxetan-3-yl)methyl-d)benzamide [ka] Using 4-((2-fluorophenyl)ethynyl)benzoic acid (3.010 g, 12.529 mmol) and (3-methyloxetan-3-yl)methan-d-amine (1.280 g, 12.529 mmol) as starting materials, 4-((2-fluorophenyl)ethynyl)-N-((3-methyloxetan-3-yl)methyl-d)benzamide (1.750 g, 43.1%) was obtained as a white solid in the same manner as in Step 3 of Preparation 3: LRMS (ES) m / z 325.14 [M+H] + , calculated MW 324.37; 1 H-NMR (400 MHz, DMSO-d6) d 8.69 (d, J = 6.0 Hz, 1 H), 7.88 (dd, J = 7.0, 1.8 Hz, 2 H), 7.65 - 7.63 (m, 3 H), 7.51 - 7.45 (m, 1 H), 7.33 (m, 1 H), 7.25 (m, 1 H), 4.44 (d, J = 6.0 Hz, 2 H), 4.17 (d, J = 5.6 Hz, 2 H), 3.41 (d, J = 6.0 Hz, 1 H), 1.22 (s, 3 H).

[0080] Production Example 17: Synthesis of (S)-4-((4-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide (Compound 17) [ka] Using 4-((4-fluorophenyl)ethynyl)benzoic acid (0.150 g, 0.624 mmol) and (S)-(tetrahydrofuran-3-yl)methanamine (0.076 g, 0.749 mmol) as starting materials, (S)-4-((4-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide (0.152 g, 75.3%) was obtained as a yellow solid in the same manner as in Step 3 of Preparation 3: LRMS (ES) m / z 324.08 [M+H]. + , calculated MW 323.37; 1 H-NMR (400 MHz, DMSO-d6) d 8.66 (t, J = 5.6 Hz, 1 H), 7.85 (d, J = 8.4 Hz, 2 H), 7.63 - 7.60 (m, 4 H), 7.29 - 7.24 (m, 2 H), 3.73 - 3.68 (m, 1 H), 3.66 - 3.62 (m, 1 H), 3.60 - 3.55 (m, 1 H), 3.45 - 3.42 (m, 1 H), 3.29 - 3.12 (m, 3 H), 1.94 - 1.86 (m, 1 H), 1.60 - 1.52 (m, 1 H).

[0081] Production Example 18: Synthesis of (R)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide (Compound 18) [ka] Using 4-((2,4-difluorophenyl)ethynyl)benzoic acid (0.200 g, 0.775 mmol) and (R)-(tetrahydrofuran-3-yl)methanamine (0.086 g, 0.852 mmol) as starting materials, (R)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide (0.230 g, 87.0%) was obtained as a white solid in the same manner as in Step 3 of Preparation 3: LRMS (ES) m / z 342.18 [M+H]. + , calculated MW 341.36; 1 H-NMR (400 MHz, DMSO-d6) d 8.66 (t, J = 5.8 Hz, 1 H), 7.86 (d, J = 8.8 Hz, 2 H), 7.74 - 7.68 (m, 1 H), 7.63 (d, J = 14.8 Hz, 2 H), 7.47 - 7.38 (m, 1 H), 7.19 - 7.15 (m, 1 H), 3.73 - 3.69 (m, 1 H), 3.67 - 3.63 (m, 1 H), 3.61 - 3.55 (m, 1 H), 3.45 - 3.42 (m, 1 H), 3.26 - 3.17 (m, 2 H), 3.13 (d, J = 5.6 Hz, 1 H), 1.96 - 1.84 (m, 1 H), 1.60 - 1.52 (m, 1 H).

[0082] Production Example 19: Synthesis of (S)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide (Compound 19) [ka] Using 4-((2,4-difluorophenyl)ethynyl)benzoic acid (0.060 g, 0.232 mmol) and (S)-(tetrahydrofuran-3-yl)methanamine (0.026 g, 0.256 mmol) as starting materials, (S)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide (0.073 g, 92.0%) was obtained as a white solid in the same manner as in Step 3 of Preparation 3: LRMS (ES) m / z 342.18 [M+H]. + , calculated MW 341.36; 1 H-NMR (400 MHz, DMSO-d6) d 8.66 (t, J = 5.6 Hz, 1 H), 7.86 (dd, J = 6.6, 2.2 Hz, 2 H), 7.71 (q, J = 7.9 Hz, 1 H), 7.62 (d, J = 8.8 Hz, 2 H), 7.43 (dt, J = 16.4, 4.8 Hz, 1 H), 7.18 (d, J = 26.0 Hz, 1 H), 3.73 - 3.63 (m, 2 H), 3.61 - 3.42 (m, 2 H), 3.26 - 3.16 (m, 3 H), 1.95 - 1.86 (m, 1 H), 1.61 - 1.52 (m, 1 H).

[0083] Production Example 20: Synthesis of (S)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide (Compound 20) [ka] Using (S)-(tetrahydro-2H-pyran-3-yl)methanamine hydrochloride (0.050 g, 0.330 mmol) and 4-((2,4-difluorophenyl)ethynyl)benzoic acid (0.102 g, 0.396 mmol) as starting materials, (S)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide (0.050 g, 42.7%) was obtained as a white solid in the same manner as in Step 3 of Production Example 3: LRMS (ES) m / z 356.18 [M+H] + , calculated MW 355.38; 1 H-NMR (400 MHz, CD3OD) d 8.54 (bs, 1 H), 7.81 (d, J = 6.4 Hz, 2 H), 7.58 (d, J = 7.2 Hz, 3 H), 6.98 - 7.05 (m, 2 H), 3.79 - 3.88 (m, 2 H), 3.42 (m, 1 H), 3.25 (m, 2 H), 1.89 (m, 2 H), 1.56 - 1.64 (m, 2 H), 1.30 - 1.32 (m, 2 H).

[0084] Production Example 21: Synthesis of N-((3,3-difluorocyclobutyl)methyl)-4-((2,4-difluorophenyl)ethynyl)benzamide (Compound 21) [ka] Using (3,3-difluorocyclobutyl)methanamine hydrochloride (0.050 g, 0.317 mmol) and 4-((2,4-difluorophenyl)ethynyl)benzoic acid (0.098 g, 0.381 mmol) as starting materials, in a similar manner to step 3 of Production Example 3, N-((3,3-difluorocyclobutyl)methyl)-4-((2,4-difluorophenyl)ethynyl)benzamide (0.049 g, 42.7%) was obtained as a white solid: LRMS (ES) m / z 362.19 [M+H] + , calculated MW 361.34; 1H-NMR (400 MHz, CD3OD) d 7.75 - 7.81 (m, 2 H), 7.54 - 7.59 (m, 3 H), 7.02 (m, 2 H), 3.48 (d, J = 6.0 Hz, 2 H), 3.28 - 3.29 (m, 1 H), 2.62 (m, 2 H), 2.32 (m, 2 H).

[0085] Preparation Example 22: Synthesis of 4-((2,4-difluorophenyl)ethynyl)-N-((3-ethyloxetan-3-yl)methyl)benzamide (Compound 22) [ka] Using (3-ethyloxetan-3-yl)methanamine (0.050 g, 0.434 mmol) and 4-((2,4-difluorophenyl)ethynyl)benzoic acid (0.135 g, 0.521 mmol) as starting materials, 4-((2,4-difluorophenyl)ethynyl)-N-((3-ethyloxetan-3-yl)methyl)benzamide (0.070 g, 45.4%) was obtained as a white solid in the same manner as in Step 3 of Preparation 3: LRMS (ES) m / z 356.18 [M+H] + , calculated MW 355.38; 1 H-NMR (400 MHz, CD3OD) d 7.82 (d, J = 8.4 Hz, 2 H), 7.58 (d, J = 8.4 Hz, 2 H), 7.54 - 7.60 (m, 1 H), 6.96 - 7.07 (m, 2 H), 4.56 (d, J = 6.4 Hz, 2 H), 4.39 (d, J = 6.0 Hz, 2 H), 3.59 (s, 2 H), 1.74 (q, J = 7.5 Hz, 2 H), 0.97 (t, J = 7.4 Hz, 3 H).

[0086] Preparation Example 23: Synthesis of 4-((2,4-difluorophenyl)ethynyl)-N-((3-fluorooxetan-3-yl)methyl)benzamide (Compound 23) [ka] Using (3-fluorooxetan-3-yl)methanamine (0.050 g, 0.476 mmol) and 4-((2,4-difluorophenyl)ethynyl)benzoic acid (0.147 g, 0.571 mmol) as starting materials, 4-((2,4-difluorophenyl)ethynyl)-N-((3-fluorooxetan-3-yl)methyl)benzamide (0.090 g, 54.8%) was obtained as a white solid in the same manner as in Step 3 of Preparation 3: LRMS (ES) m / z 346.21 [M+H] + , calculated MW 345.32; 1 H-NMR (400 MHz, CD3OD) d 7.83 (d, J = 8.0 Hz, 2 H), 7.58 (d, J = 8.4 Hz, 2 H), 7.54 - 7.60 (m, 1 H), 7.04 (td, J = 9.4, 2.4 Hz, 1 H), 6.99 (td, J = 8.6, 2.0 Hz, 1 H), 4.74 (s, 2 H), 4.69 (s, 2 H), 3.90 (d, J = 20.0 Hz, 2 H).

[0087] Preparation Example 24: Synthesis of 4-((2,4-difluorophenyl)ethynyl)-N-((4-methyltetrahydro-2H-pyran-4-yl)methyl)benzamide (Compound 24) [ka] Using (4-methyltetrahydro-2H-pyran-4-yl)methanamine (0.050 g, 0.387 mmol) and 4-((2,4-difluorophenyl)ethynyl)benzoic acid (0.120 g, 0.464 mmol) as starting materials, 4-((2,4-difluorophenyl)ethynyl)-N-((4-methyltetrahydro-2H-pyran-4-yl)methyl)benzamide (0.042 g, 29.4%) was obtained as a white solid in the same manner as in Step 3 of Production Example 3: LRMS (ES) m / z 370.25 [M+H] + , calculated MW 369.41; 1H-NMR (400 MHz, CD3OD) d 7.82 (d, J = 8.0 Hz, 2 H), 7.59 (d, J = 8.8 Hz, 2 H), 7.55 - 7.61 (m, 1 H), 6.97 - 7.09 (m, 2 H), 3.58 - 3.76 (m, 4 H), 3.26 - 3.35 (m, 2 H), 1.52 - 1.57 (m, 2 H), 1.34 (m, 2 H), 1.02 (s, 3 H).

[0088] Preparation Example 25: Synthesis of 4-((2,4-difluorophenyl)ethynyl)-N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide (Compound 25) [ka] Using 2-(tetrahydro-2H-pyran-4-yl)ethan-1-amine (0.042 g, 0.325 mmol) and 4-((2,4-difluorophenyl)ethynyl)benzoic acid (0.070 g, 0.271 mmol) as starting materials, 4-((2,4-difluorophenyl)ethynyl)-N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide (0.050 g, 49.9%) was obtained as a white solid in the same manner as in Step 3 of Preparation 3: LRMS (ES) m / z 370.25 [M+H] + , calculated MW 369.41; 1H-NMR (400 MHz, DMSO-d6) d 8.53 (t, J = 5.6 Hz, 1 H), 7.85 (d, J = 8.8 Hz, 2 H), 7.68 - 7.73 (m, 1 H), 7.62 (d, J = 8.8 Hz, 2 H), 7.43 (td, J = 9.7, 2.5 Hz, 1 H), 7.15 - 7.19 (m, 1 H), 3.78 (dd, J = 10.8, 3.2 Hz, 2 H), 3.19 - 3.29 (m, 4 H), 1.58 (d, J = 16.0 Hz, 2 H), 1.47 - 1.54 (m, 1 H), 1.43 (q, J = 7.1 Hz, 2 H), 1.12 (ddd, J = 23.5, 12.1, 4.1 Hz, 2 H).

[0089] Preparation Example 26: Synthesis of 4-((4-fluorophenyl)ethynyl)-N-((1-hydroxycyclohexyl)methyl)benzamide (Compound 26) [ka] Using 1-(aminomethyl)cyclohexan-1-ol hydrochloride (0.050 g, 0.300 mmol) and 4-((4-fluorophenyl)ethynyl)benzoic acid (0.060 g, 0.250 mmol) as starting materials, 4-((4-fluorophenyl)ethynyl)-N-((1-hydroxycyclohexyl)methyl)benzamide (0.054 g, 61.5%) was obtained in the form of a yellow solid in a similar manner to step 3 of preparation example 3: LRMS (ES) m / z 352.28 [M+H]. + , calculated MW 351.42; 1H-NMR (400 MHz, DMSO-d6) d 8.25 (t, J = 6.0 Hz, 1 H), 7.87 (d, J = 8.8 Hz, 2 H), 7.59 - 7.64 (m, 4 H), 7.26 (t, J = 9.0 Hz, 2 H), 4.32 (s, 1 H), 3.23 (d, J = 5.6 Hz, 2 H), 1.47 - 1.55 (m, 2 H), 1.36 - 1.42 (m, 4 H), 1.12 - 1.36 (m, 4 H).

[0090] Preparation Example 27: Synthesis of 4-((4-fluorophenyl)ethynyl)-N-((1-hydroxycyclobutyl)methyl)benzamide (Compound 27) [ka] Using 1-(aminomethyl)cyclobutan-1-ol (0.030 g, 0.300 mmol) and 4-((4-fluorophenyl)ethynyl)benzoic acid (0.060 g, 0.250 mmol) as starting materials, 4-((4-fluorophenyl)ethynyl)-N-((1-hydroxycyclobutyl)methyl)benzamide (0.049 g, 60.7%) was obtained as an ivory solid in the same manner as in Step 3 of Preparation 3: LRMS (ES) m / z 324.28 [M+H]. + , calculated MW 323.37; 1 H-NMR (400 MHz, DMSO-d6) d 8.39 (t, J = 5.8 Hz, 1 H), 7.88 (dd, J = 6.4, 1.6 Hz, 2 H), 7.59 - 7.64 (m, 4 H), 7.23 - 7.29 (m, 2 H), 5.15 (s, 1 H), 3.39 (d, J = 6.0 Hz, 2 H), 1.98 - 2.04 (m, 2 H), 1.83 - 1.91 (m, 2 H), 1.55 - 1.64 (m, 1 H), 1.38 - 1.49 (m, 1 H).

[0091] Preparation Example 28: Synthesis of 4-((2,4-difluorophenyl)ethynyl)-N-((1-hydroxycyclohexyl)methyl)benzamide (Compound 28) [ka] Using 1-(aminomethyl)cyclohexan-1-ol hydrochloride (0.046 g, 0.279 mmol) and 4-((2,4-difluorophenyl)ethynyl)benzoic acid (0.060 g, 0.232 mmol) as starting materials, 4-((2,4-difluorophenyl)ethynyl)-N-((1-isopropylcyclohexyl)methyl)benzamide (0.057 g, 66.4%) was obtained as an ivory solid in the same manner as in Step 3 of Preparation 3: LRMS (ES) m / z 370.23 [M+H]. + , calculated MW 369.41; 1 H-NMR (400 MHz, DMSO-d6) d 8.25 (t, J = 6.0 Hz, 1 H), 7.89 (dd, J = 6.4, 2.0 Hz, 2 H), 7.68 - 7.74 (m, 1 H), 7.62 (dd, J = 6.4, 2.0 Hz, 2 H), 7.42 (td, J = 9.6, 2.0 Hz, 1H), 7.15 - 7.19 (m, 1H), 4.31 (s, 1H), 3.24 (d, J = 6.0Hz, 2H), 1.46 - 1.55 (m, 2H), 1.39 - 1.43 (m, 4 H), 1.13 - 1.36 (m, 4 H).

[0092] Preparation Example 29: Synthesis of 4-((2,4-difluorophenyl)ethynyl)-N-((1-hydroxycyclobutyl)methyl)benzamide (Compound 29) [ka] Using 1-(aminomethyl)cyclobutan-1-ol (0.028 g, 0.279 mmol) and 4-((2,4-difluorophenyl)ethynyl)benzoic acid (0.060 g, 0.232 mmol) as starting materials, 4-((2,4-difluorophenyl)ethynyl)-N-((1-hydroxycyclobutyl)methyl)benzamide (0.045 g, 56.7%) was obtained as an ivory solid in the same manner as in Step 3 of Preparation 3: LRMS (ES) m / z 342.24 [M+H] + , calculated MW 341.36; 1 H-NMR (400 MHz, DMSO-d6) d 8.40 (t, J = 5.8 Hz, 1 H), 7.89 (dd, J = 6.8, 2.0 Hz, 2 H), 7.71 (q, J = 8.0 Hz, 1 H), 7.62 (dd, J = 6.8, 1.6 Hz, 2 H), 7.42 (td, J = 9.0, 3.6 Hz, 1 H), 7.15 - 7.19 (m, 1 H), 5.10 (s, 1 H), 3.39 (d, J = 6.0 Hz, 2 H), 1.98 - 2.04 (m, 2 H), 1.83 - 1.91 (m, 2 H), 1.55 - 1.64 (m, 1 H), 1.38 - 1.50 (m, 1 H).

[0093] Production Example 30: Synthesis of N-(cyclobutylmethyl)-4-((2,4-difluorophenyl)ethynyl)benzamide (Compound 30) [ka] Using cyclobutylmethanamine (0.030 g, 0.352 mmol) and 4-((2,4-difluorophenyl)ethynyl)benzoic acid (0.109 g, 0.423 mmol) as starting materials, N-(cyclobutylmethyl)-4-((2,4-difluorophenyl)ethynyl)benzamide (0.075 g, 65.4%) was obtained as a white solid in the same manner as in Step 3 of Production Example 3: LRMS (ES) m / z 326.26 [M+H] + , calculated MW 325.36;1 H-NMR (400 MHz, DMSO-d6) d 8.52 (t, J = 5.8 Hz, 1 H), 7.85 (d, J = 8.4 Hz, 2 H), 7.70 (q, J = 7.7 Hz, 1 H), 7.61 (d, J = 8.8 Hz, 2 H), 7.42 (td, J = 9.7, 2.7 Hz, 1 H), 7.19 - 7.14 (m, 1 H), 3.25 (d, J = 6.0 Hz, 2 H), 2.53 - 2.49 (m, 1 H), 1.98 - 1.92 (m, 2 H), 1.83 - 1.75 (m, 2 H), 1.72 - 1.65 (m, 2 H).

[0094] Experimental example 1: Fluorescence-based Ca 2+ Recruitment assay To measure the activity of β-glucose on mGluR5, we used HEK293 cells constitutively overexpressing mGluR5 to measure the intracellular Ca 2+ An experiment was carried out to confirm the change in Ca levels. Cells in cell culture medium were distributed onto a 384-well plate coated with poly-D-lysine and cultured in a 37°C incubator supplied with 5% CO2. The next day, the medium was removed and the Ca 2+ A dye loading buffer containing a reagent capable of measuring EC was added and incubated at 37°C for 60 minutes. Compounds were dissolved in 100% DMSO to prepare stock solutions with a final concentration of 10 mM. A starting concentration of 10 μM was prepared from the stock solution, which was then serially diluted to prepare a working solution (test compound working solution). The test compound working solution was added to the cells incubated in the dye loading buffer and incubated at room temperature in the dark for 30 minutes before measurement. EC 80 The Ca concentration induced by L-glutamate at 2+ The change in Ca level was measured for 2 min using FLIPR Tetra (MDS). 2+ The signal value was calculated as EC 80The fluorescence signal induced by the L-glutamate concentration was normalized as 100% and the fluorescence signal induced by the vehicle was normalized as 0%, and the inhibition rate of the test compound was calculated. The efficacy of the test compound was evaluated using the IC 50 The values ​​were calculated and shown in Table 2 (+: 500-1,000 nM, ++: 100-500 nM, +++: less than 100 nM).

[0095] Experimental example 2: HTRF-based IP1 accumulation assay Human 5-HT 2A The 5-HT receptor was constitutively overexpressed in HEK293 cells, and the amount of IP1 produced was measured to determine the efficacy of the test compound. 2A The receptor antagonistic effect was confirmed. The test compound was dissolved in 100% DMSO and a stock solution was prepared at a final concentration of 10 mM. A starting concentration of 10 μM was prepared from the stock solution, and then serially diluted to prepare a standard dilution solution in a buffer containing lithium chloride (LiCl). The cells prepared in the test buffer and each compound were placed in a 96-well plate and incubated at room temperature for 10 minutes. EC 80 Serotonin was added at a concentration of 0.01 mg / mL, and the cells were incubated at 37°C for 30 minutes in the dark. To measure intracellular IP1 accumulation, IP1-d2 acceptor and IP1-cryptate donor, which are HTRF-based fluorescent signal substances, were added and incubated at room temperature for 1 hour in the dark. The fluorescent emission signals of the acceptor and donor were detected, and the HTRF ratio was calculated as the ratio of the serotonin-treated group (EC 80 ) was subtracted from the mean value. The activation rate was calculated by normalizing the serotonin treatment group (0%) and the IP1 treatment group (100%). The IC50 values ​​of the test compounds are shown in Table 2 (+: 500 to 1,000 nM, ++: 100 to 500 nM, +++: less than 100 nM).

[0096] [Table 2]

[0097] Example 1: Efficacy test of drug addiction treatment using animal models Morphine is a narcotic opioid with strong analgesic properties. Morphine is prescribed and used to relieve severe pain, but its use is limited due to various side effects (Dowell et al., 2016). Specifically, clinical trials of morphine are difficult due to serious side effects that induce drug dependence and withdrawal symptoms (Kim et al., 2016).

[0098] Drug self-administration is a valid preclinical research method for identifying drug dependence (Panlilio & Goldberg, 2007), and many previous studies have demonstrated that morphine is an addictive substance that induces self-administration (Ma et al., 2018; Ucha et al., 2019).

[0099] As experimental animals, male Sprague-Dawley rats (230–250 g) were purchased from Orient Bio Co., Ltd. (Korea) and provided by the Laboratory Animal Research Center of Sungkyunkwan University. The rats were kept in a breeding room maintained at 22 ± 2 °C with a 12-h light / dark cycle. Each rat was housed singly in a separate cage from the time of acquisition until the end of the experiment, and had free access to food and water during the experiment, except during the food training period. All experiments were performed during the light cycle from 10:00 to 18:00.

[0100] Intravenous self-administration (IVSA) experiments were performed according to previously reported experimental methods ( Ma et al., 2017 ; Ucha et al., 2019 ) with minor modifications.

[0101] During the experimental sessions, each rat was placed in an operant testing chamber (Med Associates Inc., St. Albans, VT) equipped with two response levers and a fixed ratio of 1 (FR1) was used, requiring one press of the active lever to obtain one injection of morphine. To promote operant responding on the levers, rats were trained to earn a 45 mg food pellet by pressing the active lever. Training was conducted in 1-h sessions every day, with food deprivation for 12 h before the start of training, until acquisition criteria (80 pellets on 3 consecutive days) were met. Rats that met the training criteria underwent jugular catheterization and, after a 7-day recovery period, drug self-administration experiments began.

[0102] To investigate the therapeutic effects of test compounds on morphine addiction, rats recovering from surgery were trained in intravenous self-administration (IVSA) of morphine using a fixed ratio 1 (FR1) (0.1 mg / kg / infusion, 0.1 mL administered within 4 s) for 2 h per session for 7 consecutive days. After rats demonstrated stable responding (less than 20% variability in daily drug infusions over three consecutive sessions), the effects of test compounds on the maintenance of morphine IVSA were tested for three consecutive days. As test compounds, compound 6, 4-((2-fluorophenyl)ethynyl)-N-((3-methyloxetan-3-yl)methyl)benzamide (hereinafter referred to as "test compound A"), compound 9, (R)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide (hereinafter referred to as "test compound B"), and compound 1, 4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide (hereinafter referred to as "test compound C") were used. Test compounds A, B, and C were dissolved in water containing 0.5% HPMC (hydroxypropyl methylcellulose) and 1% Tween 80, and orally administered at doses of 10 mg, 10 mg, and 100 mg / kg, respectively, 2 hours before morphine IVSA. The therapeutic effect on the maintenance of morphine IVSA was measured, and the results are shown in Figures 1 to 3, respectively.

[0103] As shown in Figures 1 to 3, the control group pretreated with only the solvent continued to self-administer morphine, whereas the group pretreated with the test compound significantly reduced the number of injections and the number of active lever presses, suppressing the maintenance of morphine self-administration. These results confirmed the effectiveness of the test compound against morphine addiction.

[0104] Example 2: Efficacy experiment on prevention of drug addiction using animal models The experimental animals and intravenous self-administration experiment method were the same as in Example 1, and test compounds A and C were used as test compounds.

[0105] To investigate the preventive effect of test compounds on morphine addiction, rats recovered from surgery were subjected to morphine intravenous self-administration (IVSA) for 2 h per session for 8 consecutive days using fixed ratio 1 (FR1) (0.1 mg / kg / infusion, 0.1 mL administered within 4 s). Test compound A and test compound C were dissolved in water containing 0.5% HPMC (hydroxypropyl methylcellulose) and 1% Tween 80 and orally administered at doses of 5 mg / kg and 100 mg / kg, respectively, 2 h before morphine IVSA. The preventive effect on the acquisition of morphine IVSA was measured, and the results are shown in Figures 4 and 5.

[0106] As shown in Figures 4 and 5, the control group pretreated with the solvent alone maintained a high injection frequency, indicating that morphine self-administration had been acquired. However, the groups pretreated with test compound A and test compound C significantly decreased the injection frequency, suppressing the acquisition of morphine self-administration. These results confirmed that when morphine is used as a pain suppressant, the use of the test compound together with morphine can prevent morphine addiction.

[0107] Example 3: Efficacy experiment on preventing relapse of drug addiction using animal models 3-1: Efficacy experiment on preventing relapse in a morphine addiction model Relapse in drug addiction is one of the major problems that emerge during the withdrawal process after prolonged drug exposure and is characterized by strong drug-seeking behavior (Dowell, Haegerich & Chou, 2016). Therefore, relapse prevention is necessary to treat drug abuse. In human addicts and animal recovery models, cues related to reexposure to drugs or the drug-taking environment can induce drug craving and relapse (Lee et al., 2012; Ma et al., 2017).

[0108] The experimental animals and intravenous self-administration experimental method were the same as in Example 1, and the following test was performed to examine the inhibitory effect of the test compound on morphine addiction reinstatement induced by priming injection of morphine after a washout period in morphine-addicted animals. Rats recovered from surgery were trained in morphine intravenous self-administration (IVSA) for at least 8 consecutive days, 2 hours per session, using fixed ratio 1 (FR1) (1 mg / kg / infusion, 0.1 mL administered within 4 seconds). After the rats showed stable responses (daily drug infusion fluctuations of less than 20% for three consecutive sessions), they were given a washout period without any treatment for 1 week (Lee et al., 2012). To test addiction reinstatement by morphine priming, rats were subcutaneously injected with morphine (1.0 mg / kg, s.c.) 10 minutes before the reinstatement session. The dose and treatment method of morphine priming showed stable reinstatement, which is consistent with previously published studies (Swain, et. al., 2020). During the reinstatement test, when the rat pressed the active lever, saline was administered instead of morphine. Test compound A was used as the test compound, dissolved in water containing 0.5% HPMC (hydroxypropyl methylcellulose) and 1% Tween 80, and orally administered at a dose of 5 mg / kg 2 hours before the reinstatement session. The effect of preventing relapse of morphine addiction was measured, and the results are shown in Figure 6.

[0109] As shown in FIG. 6, when the test compound was pretreated, the number of drug injections caused by pressing the active lever was significantly reduced, indicating an inhibitory effect on the relapse of morphine addiction.

[0110] 3-2: Efficacy experiment of relapse prevention in cocaine addiction model The experimental animals and intravenous self-administration experimental method were the same as in Example 1, and the following test was performed to examine the inhibitory effect of the test compound on cocaine addiction reinstatement induced by a priming injection of cocaine after a drug withdrawal period in cocaine-addicted animals.

[0111] In the case of testing the inhibitory effect of Test Compound A on cocaine addiction reinstatement, rats recovered from surgery were trained in intravenous cocaine self-administration (IVSA) using fixed ratio 1 (FR1) (0.5 mg / kg / infusion, 0.1 mL administered within 4 seconds) for 2 hours per session for 10 consecutive days. In the case of testing the inhibitory effect of Test Compound B on cocaine addiction reinstatement, rats recovered from surgery were trained in intravenous cocaine self-administration (IVSA) using fixed ratio 1 (FR1) for 2 hours per session for 5 consecutive days, and then trained in intravenous cocaine self-administration (IVSA) using fixed ratio 2 (FR2) for 2 hours per session for 7 consecutive days. When the cocaine self-administration response was stably established, cocaine administration was discontinued the next day, and a washout period was given without any action for 1 week. After the cocaine self-administration response had stably disappeared, cocaine was administered intraperitoneally (10 mg / kg, intraperitoneally) to test addiction reinstatement by cocaine priming. Test compounds A and B were dissolved in water containing 0.5% HPMC (hydroxypropyl methylcellulose) and 1% Tween 80, and orally administered at doses of 2.5 mg / kg for test compound A and 2.5 mg / kg, 5 mg / kg, and 10 mg / kg for test compound B 1 hour before the reinstatement session. The effect of preventing relapse of cocaine addiction was measured, and the results are shown in Figures 7 and 8.

[0112] As shown in Figures 7 and 8, treatment with the test compound significantly reduced the number of drug infusions elicited by pressing the active lever, indicating an inhibitory effect on cocaine addiction reinstatement.

[0113] Example 4: Experiments on the treatment of withdrawal symptoms after drug addiction using animal models Male Sprague-Dawley rats (260-300 g) were obtained from Orient Bio Co., Ltd. (Korea) and provided by the Animal Center of Sungkyunkwan University. The rats were kept in a breeding room maintained at 22 ± 2°C with a 12-h light-dark cycle. Each rat was housed singly in a separate cage from the time of acquisition until the end of the experiment, and had free access to food and water during the experiment, except during the food training period. All experiments were performed during the light cycle from 10:00 to 18:00.

[0114] Experiments on the treatment of withdrawal symptoms in morphine addiction were performed using a previously reported method (Maldonado et al., 1992) with minor modifications.

[0115] Rats were anesthetized with pentobarbital (50 mg / kg, intraperitoneally) and fixed in a stereotaxic frame (Stoelting). A guide cannula (21 G; Small Parts, USA) was implanted in the right lateral ventricle (AP, -0.5 mm; ML, 1.3 mm; DV, 4.5 mm) of the rat and fixed to the skull with dental cement. The rats were allowed to recover for 7 days before implantation of the osmotic pump. The osmotic pump (Model 2001, Alzet®, Durect Corporation, USA) was filled with saline or morphine dissolved in saline (26 nmol / μL) and connected to a 3 cm long PE-60 tube (Becton Dickinson, USA) with a syringe needle (26 G; Small Parts, USA). The osmotic pump was primed overnight in sterile saline at 37°C and then implanted subcutaneously on the back of the rat. Immediately after implantation, morphine was infused into the cerebral ventricle at 1 μL / h for 72 hours through the osmotic pump. 72 hours after morphine administration, the tube between the osmotic pump and the injection needle was cut off, and drug administration was discontinued. Two hours before behavioral testing, test compound A (5 mg / kg) was dissolved in water containing 0.5% HPMC (hydroxypropyl methylcellulose) and 1% Tween 80 and orally administered to the rats. One hour before the test, the rats were acclimated to the test box (30 × 30 × 30 cm), and naloxone (2 mg / kg, intraperitoneally) was administered to induce morphine withdrawal syndrome immediately before behavioral testing. Morphine withdrawal syndrome was evaluated for 30 minutes using the Maldonado method, and the results are shown in Figure 9.

[0116] [Table 3]

[0117] As shown in FIG. 9, it was confirmed that when the test compound was pretreated, the morphine withdrawal symptoms were significantly reduced, and these results indicate that the test compound is effective in suppressing the withdrawal symptoms of morphine addicts.

[0118] Example 5: Experiments on the treatment of depressive disorders using animal models The experimental animals were 7-8 week-old male BALB / c mice obtained from Orient Bio Co., Ltd. (Korea) and provided by the Experimental Animal Center of Naason Science Co., Ltd. The mice were kept in a breeding room maintained at a temperature of 22 ± 1°C and humidity of 30-50%, with a 12-h light / dark cycle. During the test period, the mice had free access to food and water.

[0119] Test compound A was dissolved in water containing 5% HPMC (hydroxypropyl methylcellulose) and 1% Tween 80, and administered orally at doses of 0.2 mg / kg, 5 mg / kg, and 10 mg / kg 1 hour before the test. The reference compounds fluoxetine and MPEP were dissolved in water for injection and administered intraperitoneally at a dose of 20 mg / kg. The mouse tail suspension test (TST) was performed in a polyvinyl chloride (PVC) chamber (33 × 33 × 31.75 cm). Transparent tape was applied to the tail of each mouse, which was then taped to a transducer that measured the suspension force of the tail. During the 10-minute test period, the mice were videotaped and the immobility time, defined as the state without excitement, was measured, and the results are shown in Figure 10.

[0120] As shown in Figure 10, the immobility time was significantly reduced when the test compound was administered compared to the vehicle-administered test group. These results suggest that the test compound is effective as an antidepressant.

[0121] Example 6: Experiments on the treatment of anxiety disorder using an animal model Male Sprague-Dawley rats aged 8-9 weeks were purchased from Coretec and provided by the Laboratory Animal Center of Naason Science. Mice were housed in a breeding room maintained at a temperature of 22±1°C and humidity of 30-50%, with a 12-h light-dark cycle. During the test period, mice were allowed free access to food and water.

[0122] Test compound A was dissolved in water containing 0.5% HPMC (hydroxypropyl methylcellulose) and 1% Tween 80, and orally administered at a dose of 10 mg / kg 2 hours before the test. The reference compound, diazepam, was dissolved in water for injection and intraperitoneally administered at a dose of 1 mg / kg.

[0123] The elevated plus maze (EPM) consisted of a black acrylic platform (105 cm in diameter, 10 cm in width, and 65 cm above ground level). The maze was divided into four equal parts, two of which were surrounded by black acrylic walls 27 cm high. Walls were placed both inside and outside the platform to provide the "closed" arms of the maze, and the "open" arms had no walls. A camera was installed 2 m above ground level, and the maze was surrounded by a curtain to prevent interference from the surroundings. Two hours after drug administration, each rat was placed in the plus maze, and the animal's behavior was recorded for 5 min. The results are shown in Figure 11.

[0124] As shown in Figure 11, animals treated with the test compound spent significantly more time in the open arms of the maze compared to the vehicle-treated group. These results suggest that the test compound is effective as an anxiolytic agent.

[0125] Example 7: Experiments on the treatment of post-traumatic stress disorder (PTSD) using animal models Four-week-old male Sprague-Dawley rats were purchased from Coretec Co., Ltd. (Korea) and provided by the Experimental Animal Center of Naason Science Co., Ltd. Mice were housed in a breeding room maintained at a temperature of 22±1°C and humidity of 30-50%, with a 12-hour light-dark cycle. During the test period, mice were allowed free access to food and water.

[0126] Rats were induced with post-traumatic stress disorder (PTSD) under the following conditions.

[0127] 1) Underwater trauma (UWT): Rats were allowed to acclimate to the laboratory for 10 min before testing, and then exposed to 40 s of swimming in an underwater zero maze (WAZM) for three consecutive days. On the fourth day of testing, rats were again exposed to 40 s and then subjected to UWT stress in the WAZM. To apply UWT stress, rats were placed in the center of the WAZM and immediately pushed and held in water for 20 s using a special metal net (20 × 10 × 15 cm), which was repeated twice. The control group (without PTSD) was exposed to testing in a WAZM without water for three consecutive days. On the tenth day of testing, all rats were again exposed to the WAZM, and only the PTSD test group was exposed to 40 s of swimming.

[0128] 2) Restraint stress: On the fourth day of the test, after exposure to UWT stress, the animals were restrained in a rat restrainer (IWOO Scientific, Korea) for 2 hours, and the same stress was administered again on the tenth day of the test.

[0129] 3) Cued fear conditioning with electric shock: On the fourth day of testing, rats were acclimated to the test chamber (Med Associates, USA) for 2 min, and then exposed to a set of 20 s white noise conditioned stimuli (CS) and 1 s electric shock (0.6 mA) for a total of five trials, with a 1 min interval between each trial. After the last electric shock, rats were left in the chamber for 30 s and then returned to their home cage. Cued fear conditioning was performed again on the 10th day of testing.

[0130] Test compound A was dissolved in water containing 0.5% HPMC (hydroxypropyl methylcellulose) and 1% Tween 80, and orally administered at doses of 5 mg / kg and 10 mg / kg. Drug administration was performed for five consecutive days at each stage: 11-15 days (first stage), 26-30 days (second stage), and 56-60 days (third stage) after the start of the test. The cued fear conditioning test was performed one hour after the final administration of each stage.

[0131] To assess cued fear memory, we performed contextual and cued fear conditioning tests developed to assess memory in rats. Rats were returned to the testing room on days 14, 30, and 60 after the start of testing. During the cued test, rats were placed in a novel environment (different walls, new orange scent) for 4 min, and the 4 min exposure consisted of 1 min Pre-CS (cued stimulus), 2 min CS-test, and 1 min Post-CS. Fear memory was assessed by measuring freezing, defined as complete immobility except for breathing. Freezing behavior was quantified using the Actimtrucs Freezeframe software. The quantified test results are shown in Figure 12.

[0132] As shown in FIG. 12, animals treated with the test compound exhibited significantly reduced freezing behavior compared to the control group, and these results suggest that the test compound is an effective treatment for post-traumatic stress disorder.

Claims

1. The following formula (1) 【Chemistry 1】 (In the formula, X 1 and X 2 form together with the carbon atoms to which they are attached a cyclobutane, cyclopentane, cyclohexane, oxetane, tetrahydrofuran or tetrahydropyran ring; R 1 is fluoro, hydroxy or C 1 -C 5 is alkyl; R 2 is hydrogen, fluoro, hydroxy, C 1 -C 5 Alkyl or C 1 -C 5 is alkoxy; R 3 is hydrogen, deuterium or C 1 -C 5 is alkyl; R 4 and R 5 are each independently hydrogen or fluoro, provided that at least one is fluoro; l and m are each independently an integer from 0 to 2; and n is 1 or 2. A pharmaceutical composition for preventing or treating a mental disorder, comprising a compound represented by the formula:

2. The following formula (2) 【Chemistry 2】 (In the formula, X 1 and X 2 form together with the carbon atoms to which they are attached a cyclobutane, cyclopentane, cyclohexane, oxetane, tetrahydrofuran or tetrahydropyran ring; R 1 is fluoro, hydroxy or methyl; R 2 is hydrogen, fluoro, hydroxy, methyl, ethyl or methoxy; R 4 and R 5 are each independently hydrogen or fluoro, provided that at least one is fluoro; and m is an integer of 0 to 2.) or a pharma- ceutical composition for preventing or treating a mental disorder according to claim 1, comprising a compound represented by the formula:

3. The pharmaceutical composition for preventing or treating a mental disorder according to claim 1, wherein the compound of formula (1) is selected from the group consisting of the following compounds: 4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide; N-((4,4-difluorocyclohexyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide; 4-((2-fluorophenyl)ethynyl)-N-(1-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide; 4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide; 4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide; 4-((2-fluorophenyl)ethynyl)-N-((3-methyloxetan-3-yl)methyl)benzamide; N-((3,3-difluorocyclobutyl)methyl)-4-((2-fluorophenyl)ethynyl)benzamide; 4-((2-fluorophenyl)ethynyl)-N-((4-methoxytetrahydro-2H-pyran-4-yl)methyl)benzamide; (R)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide; 4-((2-fluorophenyl)ethynyl)-N-((3-hydroxyoxetan-3-yl)methyl)benzamide; 4-((4-fluorophenyl)ethynyl)-N-((3-methyloxetan-3-yl)methyl)benzamide; 4-((2-fluorophenyl)ethynyl)-N-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)methyl)benzamide; (R)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide; (S)-4-((2-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide; 4-((4-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide; 4-((2-fluorophenyl)ethynyl)-N-((3-methyloxetan-3-yl)methyl-d)benzamide; (S)-4-((4-fluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide; (R)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide; (S)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydrofuran-3-yl)methyl)benzamide; (S)-4-((2,4-difluorophenyl)ethynyl)-N-((tetrahydro-2H-pyran-3-yl)methyl)benzamide; N-((3,3-difluorocyclobutyl)methyl)-4-((2,4-difluorophenyl)ethynyl)benzamide; 4-((2,4-difluorophenyl)ethynyl)-N-((3-ethyloxetan-3-yl)methyl)benzamide; 4-((2,4-difluorophenyl)ethynyl)-N-((3-fluorooxetan-3-yl)methyl)benzamide; 4-((2,4-difluorophenyl)ethynyl)-N-((4-methyltetrahydro-2H-pyran-4-yl)methyl)benzamide; 4-((2,4-difluorophenyl)ethynyl)-N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide; 4-((4-fluorophenyl)ethynyl)-N-((1-hydroxycyclohexyl)methyl)benzamide; 4-((4-fluorophenyl)ethynyl)-N-((1-hydroxycyclobutyl)methyl)benzamide; 4-((2,4-difluorophenyl)ethynyl)-N-((1-hydroxycyclohexyl)methyl)benzamide; 4-((2,4-difluorophenyl)ethynyl)-N-((1-hydroxycyclobutyl)methyl)benzamide; and N-(cyclobutylmethyl)-4-((2,4-difluorophenyl)ethynyl)benzamide.

4. The pharmaceutical composition for preventing or treating a mental disorder according to claim 1, wherein the mental disorder is a substance-related disorder or an addictive disorder.

5. The substance that induces the disorder is 5. A pharmaceutical composition for the prevention or treatment of a mental disorder according to claim 4, which is alcohol; anxiolytics and sedatives (including benzodiazepines, zolpidem, propofol, ketamine, esketamine, phenobarbital); caffeine; cannabis (including marijuana, synthetic cannabis); hallucinogens (including LSD, phencyclidine, psilocybin); inhalants (including paint thinners, some glues); opioids (including fentanyl, morphine, oxycodone, pethidine, methadone, hydromorphone, hydrocodone, oxymorphone, codeine, heroin); stimulants (including methamphetamine, ecstasy, amphetamine, cocaine); tobacco; or other (including appetite suppressants such as phentermine, phendimetrazine, diethylpropion, mazindol, synthetic anabolic steroids, and other commonly abused substances).

6. 5. A pharmaceutical composition for preventing or treating a mental disorder according to claim 4, which is for treating or attenuating withdrawal symptoms of a substance that induces said disorder.

7. A pharmaceutical composition for the prevention or treatment of mental disorders according to claim 4, used in combination with anti-addictive agents including other alternative or supplemental drugs.

8. The pharmaceutical composition for preventing or treating a mental disorder according to claim 7, wherein the anti-addictive agent is one or more selected from naloxone, naltrexone, nalmefene, disulfiram, acamprosate, topiramate, risperidone, paliperidone, ondansetron, fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine, venlafaxine, duloxetine, mirtazapine and bupropion.

9. A pharmaceutical composition for the prevention or treatment of a mental disorder as described in claim 4, for preventing or reducing the possibility of relapse to abuse of the substance in a patient who is attempting to discontinue use of the substance that induces the disorder.

10. The pharmaceutical composition for preventing or treating a mental disorder according to claim 1, wherein the mental disorder is a depressive disorder or an anxiety disorder.

11. The pharmaceutical composition for preventing or treating a mental disorder according to claim 1, wherein the mental disorder is post-traumatic stress disorder.

12. A compound selected from the group consisting of: 4-((2,4-difluorophenyl)ethynyl)-N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)benzamide; 4-((4-fluorophenyl)ethynyl)-N-((1-hydroxycyclohexyl)methyl)benzamide; 4-((4-fluorophenyl)ethynyl)-N-((1-hydroxycyclobutyl)methyl)benzamide; 4-((2,4-difluorophenyl)ethynyl)-N-((1-hydroxycyclohexyl)methyl)benzamide; 4-((2,4-difluorophenyl)ethynyl)-N-((1-hydroxycyclobutyl)methyl)benzamide; and N-(cyclobutylmethyl)-4-((2,4-difluorophenyl)ethynyl)benzamide.

Images