Novel compounds and their use in treating emotional and behavioral disorders

Abstract

The present invention relates to a novel compound and its use in treating emotional and behavioral disorders. The pharmaceutical composition for preventing or treating emotional and behavioral disorders containing the novel compound of the present invention is expected to be useful in improving emotional and behavioral disorders such as autism spectrum disorder and schizophrenia, and symptoms associated with emotional and behavioral disorders such as lack of sociality and excessive behavior, by inhibiting agmatinase.

Description

[Technical field]

[0001] The present invention relates to novel compounds and their use in the treatment of emotional and behavioral disorders. [Background technology]

[0002] Emotional and behavioral disorders are the only psychiatric disorders for which there is no cure, and are characterized by social and communication difficulties, stereotyped behavior, and a variety of coexisting symptoms such as seizures, anxiety, depression, aggression, and cognitive impairment.

[0003] The exact pathogenesis of emotional and behavioral disorders has not been elucidated, and the most extensive research has been done on the excitatory / inhibitory imbalance. Modulation of the excitatory / inhibitory imbalance affects neural connectivity and integration, suggesting the possibility of improving important symptoms of emotional and behavioral disorders such as autism. Summary of the Invention [Problem to be solved by the invention]

[0004] An object of the present invention is to provide a novel compound, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

[0005] An object of the present invention is to provide a novel compound, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, which is useful for the prevention or treatment of an emotional and behavioral disorder.

[0006] An object of the present invention is to provide a novel compound, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, which is useful for the prevention or treatment of symptoms associated with emotional and behavioral disorders.

[0007] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating an emotional and behavioral disorder, comprising the novel compound, a stereoisomer thereof or a pharma- ceutical acceptable salt thereof. [Means for solving the problem]

[0008] 1. A compound of the following chemical formula 1, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof: [ka] (wherein R1 is hydrogen or a tert-butyloxycarbonyl group; A is C5-C 10 is a mono- or bicyclic group of the formula each ring of the cyclic group is unsubstituted or substituted with 1 to 3 heteroatoms; The cyclic group is unsubstituted or substituted with halogen, C1-C5 alkyl, C1-C5 alkoxy, CN or NO2.

[0009] 2. In the above item 1, A is a compound, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof selected from the group consisting of the following cyclic groups: JPEG2024531663000003.jpg88118 (wherein R2, R3 and R4 are each independently hydrogen, halogen, C1-C5 alkyl, C1-C5 alkoxy, CN or NO2; Q1, Q2 and Q3 are each independently N, O or S.

[0010] 3. In the above item 1, A is a compound, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof selected from the group consisting of the following cyclic groups: JPEG2024531663000004.jpg59110 (wherein R2, R3 and R4 are each independently hydrogen, halogen, C1-C5 alkyl, C1-C5 alkoxy, CN or NO2; Q1, Q2 and Q3 are each independently N, O or S.

[0011] 4. In the above item 1, A is a compound, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof selected from the group consisting of the following cyclic groups: JPEG2024531663000005.jpg66108 (wherein R2, R3, and R4 are each independently hydrogen, halogen, C1-C5 alkyl, C1-C5 alkoxy, CN, or NO2.)

[0012] 5. In the above item 1, a compound, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof selected from the group consisting of the following compounds: tert-Butyl-4-((4-methylbenzoyl)carbamoyl)piperazine-1-carboxylate; tert-Butyl-4-((4-methoxybenzoyl)carbamoyl)piperazine-1-carboxylate; tert-Butyl-4-((4-chlorobenzoyl)carbamoyl)piperazine-1-carboxylate; tert-Butyl-4-(benzoylcarbamoyl)piperazine-1-carboxylate; N-(4-methylbenzoyl)piperazine-1-carboxamide; N-(4-methylbenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(4-Methoxybenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(4-chlorobenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-Benzoylpiperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(2-naphthoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(4-cyanobenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(furan-2-carbonyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(4-nitrobenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(2-naphthoyl)piperazine-1-carboxamide hydrochloride; N-(4-cyanobenzoyl)piperazine-1-carboxamide hydrochloride; N-(4-nitrobenzoyl)piperazine-1-carboxamide hydrochloride; N-Benzoylpiperazine-1-carboxamide hydrochloride; N-(furan-2-carbonyl)piperazine-1-carboxamide hydrochloride; N-(4-methylbenzoyl)piperazine-1-carboxamide hydrochloride; N-(4-Methoxybenzoyl)piperazine-1-carboxamide hydrochloride; N-(4-chlorobenzoyl)piperazine-1-carboxamide hydrochloride; N-(2,4-dichlorobenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(4-bromobenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(thiophene-2-carbonyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(benzo[b]thiophene-2-carbonyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(4-fluorobenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-isonicotinoylpiperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(2,4-dichlorobenzoyl)piperazine-1-carboxamide hydrochloride; N-(4-bromobenzoyl)piperazine-1-carboxamide hydrochloride; N-(benzo[b]thiophene-2-carbonyl)piperazine-1-carboxamide hydrochloride; N-isonicotinoylpiperazine-1-carboxamide hydrochloride; N-(4-fluorobenzoyl)piperazine-1-carboxamide hydrochloride; N-(thiophene-2-carbonyl)piperazine-1-carboxamide hydrochloride; N-(3-chlorobenzoyl)piperazine-1-carboxamide hydrochloride; N-(3-methylbenzoyl)piperazine-1-carboxamide hydrochloride; N-(3-Methoxybenzoyl)piperazine-1-carboxamide hydrochloride; N-(3-chlorobenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(3-methylbenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(3-Methoxybenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate.

[0013] 6. A pharmaceutical composition for preventing or treating symptoms associated with emotional and behavioral disorders, comprising the compound according to any one of items 1 to 5, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

[0014] 7. A pharmaceutical composition for preventing or treating symptoms associated with emotional and behavioral disorders in accordance with item 6, wherein the symptoms associated with emotional and behavioral disorders are any one selected from the group consisting of lack of sociability, lack of social cognitive ability, stereotyped behavior, excessive behavior, impulsivity, and distractibility.

[0015] 8. A pharmaceutical composition for preventing or treating an emotional and behavioral disorder, comprising the compound according to any one of items 1 to 5, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

[0016] 9. A pharmaceutical composition for preventing or treating a neurodegenerative disease, comprising the compound according to any one of items 1 to 5, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

[0017] 10. A pharmaceutical composition for the prevention or treatment of an emotional and behavioral disorder according to item 8, wherein the emotional and behavioral disorder is any one selected from the group consisting of autism spectrum disorder, schizophrenia, obsessive-compulsive disorder, depression, anxiety disorder, panic disorder and attention-deficit hyperactivity disorder. Effect of the Invention

[0018] The novel compound of the present invention, its stereoisomer or a pharma- ceutically acceptable salt thereof acts as an agmatinase inhibitor and is effective in improving emotional and behavioral disorders and symptoms associated therewith. [Brief description of the drawings]

[0019] [Figure 1] FIG. 1 shows the agmatinase inhibitory activity for some of the compounds of the present invention shown in Tables 1-7. [Diagram 2] FIG. 2 shows the effect of improving the sociality of VPA mice by treatment with the compound of the present invention. [Diagram 3] FIG. 3 confirms the cognitive improving effect of the compound of the present invention on VPA mice. [Figure 4] FIG. 4 shows the results of a self-grooming test performed using an animal model of VPA (valproic acid)-induced autism. [Diagram 5] FIG. 5 shows the neuroprotective effect of treatment with the compound of the present invention. [Figure 6] FIG. 6 shows the neuroprotective effect of treatment with the compound of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] The present invention will be described in detail below.

[0021] All technical terms used herein, unless otherwise defined, are used in the manner commonly understood by those skilled in the art to which the invention pertains. In addition, although preferred methods and samples are described herein, similar or equivalent methods and samples are also within the scope of the invention.

[0022] The present invention relates to a compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

[0023] [ka]

[0024] In the above structural formula, when no substituent is described at a site where a substituent is required, it means that a hydrogen substituent is omitted. This applies equally to all structural formulas of the present invention.

[0025] In the above formula, R1 may be hydrogen or a tert-butyloxycarbonyl group.

[0026] In the above formula, A is C5-C 10 and may be, for example, but not limited to, benzene, naphthalene, indene, cyclopenta-1,3-diene, cyclohexane, tetrahydronaphthalene, and the like.

[0027] Each ring of the cyclic group may be substituted with 1 to 3 heteroatoms. The heteroatoms refer to atoms that can constitute a ring in atoms other than C, and for example, 1 to 3 atoms may each be independently substituted with any one or more selected from the group consisting of N, S, and O, but are not limited thereto.

[0028] In the cyclic group, the positions at which a heteroatom can be substituted may specifically be Q1 to Q3 in the structures shown below, but are not limited thereto. JPEG2024531663000007.jpg48112

[0029] The cyclic group may be substituted with halogen, C1-C5 alkyl, C1-C5 alkoxy, CN or NO2, such as, but not limited to, F, Cl, Br, methyl group (Me), ethyl group (Et), methoxy group (OMe), ethoxy group (OEt), CN, NO2, etc.

[0030] In the cyclic group, the positions at which substitution with halogen, C1-C5 alkyl, C1-C5 alkoxy, CN or NO2 may be specifically R2 to R4, but are not limited thereto.

[0031] According to one embodiment of the present invention, A may be selected from the following cyclic groups: JPEG2024531663000008.jpg86115 (wherein R2, R3 and R4 are each independently hydrogen, halogen, C1-C5 alkyl, C1-C5 alkoxy, CN or NO2; Q1, Q2 and Q3 are each independently N, O or S.

[0032] According to one embodiment of the present invention, more specifically, A can be selected from the following cyclic groups: JPEG2024531663000009.jpg58107 (wherein R2, R3 and R4 are each independently hydrogen, halogen, C1-C5 alkyl, C1-C5 alkoxy, CN or NO2; Q1, Q2 and Q3 are each independently N, O or S.

[0033] Moreover, according to one embodiment of the present invention, most specifically, A can be selected from the following cyclic groups: JPEG2024531663000010.jpg67111 (wherein R2, R3, and R4 are each independently hydrogen, halogen, C1-C5 alkyl, C1-C5 alkoxy, CN, or NO2.)

[0034] The following Tables 1 to 7 show examples of the compound structure represented by Chemical Formula 1 and some of its pharma- ceutically acceptable salts, specifically, examples of the compound structure represented by Chemical Formula 1 depending on the combination of R1 and A. The order in the following tables refers to the compound numbers in this specification.

[0035] [Table 1]

[0036] [Table 2]

[0037] [Table 3]

[0038] [Table 4]

[0039] [Table 5]

[0040] [Table 6]

[0041] [Table 7]

[0042] The present invention may relate to a compound selected from the group consisting of the following compounds, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof: tert-Butyl-4-((4-methylbenzoyl)carbamoyl)piperazine-1-carboxylate; tert-Butyl-4-((4-methoxybenzoyl)carbamoyl)piperazine-1-carboxylate; tert-Butyl-4-((4-chlorobenzoyl)carbamoyl)piperazine-1-carboxylate; tert-Butyl-4-(benzoylcarbamoyl)piperazine-1-carboxylate; N-(4-methylbenzoyl)piperazine-1-carboxamide; N-(4-methylbenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(4-Methoxybenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(4-chlorobenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-Benzoylpiperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(2-naphthoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(4-cyanobenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(furan-2-carbonyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(4-nitrobenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(2-naphthoyl)piperazine-1-carboxamide hydrochloride; N-(4-cyanobenzoyl)piperazine-1-carboxamide hydrochloride; N-(4-nitrobenzoyl)piperazine-1-carboxamide hydrochloride; N-Benzoylpiperazine-1-carboxamide hydrochloride; N-(furan-2-carbonyl)piperazine-1-carboxamide hydrochloride; N-(4-methylbenzoyl)piperazine-1-carboxamide hydrochloride; N-(4-Methoxybenzoyl)piperazine-1-carboxamide hydrochloride; N-(4-chlorobenzoyl)piperazine-1-carboxamide hydrochloride; N-(2,4-dichlorobenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(4-bromobenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(thiophene-2-carbonyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(benzo[b]thiophene-2-carbonyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(4-fluorobenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-isonicotinoylpiperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(2,4-dichlorobenzoyl)piperazine-1-carboxamide hydrochloride; N-(4-bromobenzoyl)piperazine-1-carboxamide hydrochloride; N-(benzo[b]thiophene-2-carbonyl)piperazine-1-carboxamide hydrochloride; N-isonicotinoylpiperazine-1-carboxamide hydrochloride; N-(4-fluorobenzoyl)piperazine-1-carboxamide hydrochloride; N-(thiophene-2-carbonyl)piperazine-1-carboxamide hydrochloride; N-(3-chlorobenzoyl)piperazine-1-carboxamide hydrochloride; N-(3-methylbenzoyl)piperazine-1-carboxamide hydrochloride; N-(3-Methoxybenzoyl)piperazine-1-carboxamide hydrochloride; N-(3-chlorobenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(3-methylbenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(3-Methoxybenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate.

[0043] The present invention also relates to a pharmaceutical composition comprising said compound, its stereoisomer or a pharma- ceutically acceptable salt thereof.

[0044] Agmatinase is an enzyme that breaks down agmatine, and it has been confirmed that the content of agmatine is actually reduced in some autistic patients. This is believed to be due to the excessive action of agmatinase. In addition, it is expected that inhibiting agmatinase will inhibit excessive excitatory nerve activity, and thus preventive or therapeutic effects against emotional behavior disorders and their associated symptoms are expected. The compound of the present invention has agmatinase inhibitory activity, and the above-mentioned effects can be expected.

[0045] The pharmaceutical composition may be a pharmaceutical composition for preventing or treating symptoms associated with emotional and behavioral disorders, which specifically include, but are not limited to, lack of sociality, lack of social cognition, stereotyped behavior, excessive behavior, impulsivity, and distractibility.

[0046] In the present invention, "social deficiency" refers to a state in which the subject patient is unable to form normal and harmonious relationships with the people he or she must be in contact with or with the people around him or her, or is unable to lead a normal social life, such as a state in which the subject is unable to interact with people and is absorbed in his or her own world.

[0047] In the present invention, "deficiency of social cognitive ability" means a state in which a person lacks social cognitive ability, which is an inherent ability that determines social behavior useful for adapting to interpersonal relationships and social life. For example, it means a state in which a person is unable to understand and reason about the facial expressions, behavior, and emotions of others in a situation in which he or she is placed, and is unable to normally behave in accordance with the social customs, morality, and appropriate behavior in relationships expected of the group.

[0048] In the present invention, "stereotypic behavior" refers to persistent and repetitive behavior, such as shaking the body back and forth, continuously moving the hands, or repeating meaningless sounds, and refers to a state in which the same behavior is continuously performed regardless of the surrounding circumstances.

[0049] In the present invention, "hyperactivity" is also called "excessive behavior" and refers to abnormally excessive activity or movement, etc., which interferes with learning and causes serious problems in behavioral control.

[0050] In the present invention, "impulsivity" refers to the tendency to act suddenly and spontaneously, driven by inner urges, without thinking and with little regard for the consequences of the action.

[0051] In the present invention, "distractibility" refers to a state in which one is unable to continue one activity, has no perseverance, quickly moves on to another activity, or is confused because one does not know what to do.

[0052] In addition, the pharmaceutical composition may be a pharmaceutical composition for preventing or treating an emotional and behavioral disorder, specifically, a pharmaceutical composition for preventing or treating autism spectrum disorder, schizophrenia, obsessive-compulsive disorder, depression, anxiety disorder, panic disorder, and attention-deficit hyperactivity disorder, but is not limited thereto.

[0053] In the present invention, "autism spectrum disorder" is also called "autism spectrum disorder" and refers to a representative developmental disorder that shows serious maladjustment. Basically, it shows defects in social interaction and communication skills, restricted, repetitive, and stereotyped behavioral characteristics, and highly diverse characteristics in behaviors, skills, preferences, functional execution, learning, etc. required according to growth.

[0054] In the present invention, "schizophrenia" refers to a disease formerly known as "schizophrenia," and refers to a mental disease that causes a wide range of clinical abnormal symptoms across various aspects of personality, such as thinking, emotion, perception, behavior, etc. Schizophrenia appears in various types and is considered not to be a single disease but a group of diseases consisting of several diseases with common characteristics.

[0055] In the present invention, "obsessive-compulsive disorder" refers to a subtype of anxiety disorder in which certain thoughts and actions are repeated against one's will, and its main symptoms are obsessions, which are painful thoughts, impulses or images that repeatedly permeate the consciousness, and compulsions, which are repeatedly performed to reduce anxiety. Compulsions appear in the form of cleaning, checking, repetitive behaviors, lining up, procrastination, etc., and are repeated in order to recover from the anxiety caused by obsessions, even if the person knows that they are inappropriate and excessive.

[0056] In the present invention, "depression" does not mean a temporary state of depressed mood, but means a state of general decline in mental functions, including thought content, thought process, motivation, will, interest, behavior, sleep, and physical activity, occurring almost all day, every day.

[0057] In the present invention, "anxiety disorder" refers to mental disorders that cause impairment in daily life due to various types of abnormal or pathological anxiety or fear, and includes panic disorder, agoraphobia, social anxiety disorder, specific phobia, separation anxiety disorder, etc.

[0058] In the present invention, the term "panic disorder" refers to a type of anxiety disorder that is characterized by repeated panic attacks, which are sudden, intense fears such as "I might die."

[0059] In the present invention, "attention deficit hyperactivity disorder" is a mental disorder commonly known as ADHD, the main symptoms of which are inattention, excessive behavior, and impulsivity, and is characterized by onset in early childhood and a chronic course.

[0060] The pharmaceutical composition may be a pharmaceutical composition for preventing or treating a neurodegenerative disease.

[0061] The compounds of the present invention can improve symptoms of sociality and social cognitive ability, and have the effect of protecting neurons from cell damage and cell death caused by oxidative stress, and therefore can exhibit medicinal effects against various neurodegenerative diseases.

[0062] The neurodegenerative disease can be, for example, but not limited to, Alzheimer's disease, Parkinson's disease, multiple sclerosis, neuroblastoma, stroke, Lou Gehrig's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, post-traumatic stress disorder, depression, schizophrenia, neurological autoimmune diseases, frontotemporal dementia, dementia with Lewy bodies, corticobasal degeneration, amyotrophic lateral sclerosis, and decline in memory and cognitive abilities.

[0063] In the present invention, the pharmaceutical composition may be prepared or administered to a mammal using pharma- ceutical suitable and physiologically acceptable auxiliary agents in addition to the active ingredient, which is the compound of the present invention, which may include excipients, disintegrants, sweeteners, binders, coating agents, swelling agents, lubricants, glidants, or flavoring agents.

[0064] In addition, the pharmaceutical composition of the present invention can be preferably formulated as a pharmaceutical composition by further containing one or more pharma- ceutically acceptable carriers in addition to the above-mentioned pharma- ceutical effective amount of the active ingredient for administration.

[0065] The "pharmacologically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to any medical treatment, and the level of an effective dose can be determined by factors including the type and severity of the patient's disease, the activity of the drug, sensitivity to the drug, administration time, administration route and excretion rate, duration of treatment, co-administered drugs, and other factors well known in the medical field. The pharmaceutical composition according to the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with conventional therapeutic agents, and can be administered singly or multiple times. It is important to administer an amount that provides maximum effect at a minimum amount without side effects, taking into consideration all of the above factors, and this can be easily determined by one skilled in the art.

[0066] Specifically, the effective amount of the pharmaceutical composition of the present invention varies depending on the age, sex, condition, and weight of the patient, the degree of absorption, inactivation rate, and excretion rate of the active ingredient in the body, the type of disease, and the concomitant drugs, and can generally be administered at 0.001 to 150 mg, preferably 0.01 to 100 mg per kg of body weight every day or every other day, or in 1 to 3 divided doses per day. However, since the amount can be increased or decreased depending on the administration route, the severity of obesity, sex, weight, age, etc., the above dosage does not limit the scope of the present invention in any way.

[0067] In addition, the term "pharmaceutical acceptable" means that the compound is physiologically acceptable and does not normally cause allergic reactions such as gastrointestinal disorders and dizziness or similar reactions when administered to humans.

[0068] Examples of the carrier, excipient and diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginic acid, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, etc. In addition, fillers, anti-agglomerating agents, lubricants, wetting agents, flavorings, emulsifiers and preservatives, etc. may be further included.

[0069] The compositions of the present invention can be formulated using methods known in the art so as to provide quick, sustained or delayed release of the active ingredient after administration to an individual in need of the pharmaceutical composition of the present invention, including humans. The formulations may be powders, granules, tablets, emulsions, syrups, aerosols, soft or hard gelatin capsules, sterile injection solutions, or sterile powders.

[0070] The compound represented by Chemical Formula 1 of the present invention can be prepared by the methods described in various documents. In the following preparation examples, the synthesis methods of some of the compounds shown in Table 1 are briefly described, but the present invention is not limited to these.

[0071] The present invention will be described in detail below with reference to Production Examples and Examples of the present invention. EXAMPLES

[0072] Manufacturing Example 1. Synthesis of Compound 1 [Reaction Scheme 1] JPEG2024531663000018.jpg27137

[0073] A flame-dried round-bottom flask equipped with a magnetic stirrer was charged with a solution of SMI (1 mmol) and anhydrous THF (10 ml). NaH (5 mmol) was added to the RM at 0°C and stirred under nitrogen for about 2 h. Then, aryl chloride (SMII, 2 mmol) dissolved in THF (5 ml) was slowly added to the reaction mixture and stirred overnight. Saturated ammonium chloride solution (7-10 ml) was added to the reaction and extracted with CHCl. ​​The organic layer was dried over MgSO, filtered, and concentrated in vacuum to give a white solid. The residue was purified by flask column chromatography with n-hexane:ethyl acetate (4:1 and 2:1) to give the desired product as a white solid. Retention factor: 0.41 (H:E=1:1) Yield: 229mg (66%) NMR data: 1H NMR (500MHz, CDCl3): δ8.44(s,1H),7.76(d,J=8.15Hz,2H),7.27-7.26(m,2H,overlapped with CDCl3),3.52(s,8H),2.41(s,3H),1.47(s,9H).

[0074] 2. Synthesis of Compound 3 [Reaction Scheme 2] JPEG2024531663000019.jpg24144A flame-dried round-bottom flask equipped with a magnetic stirrer was charged with SMI (1 mmol) and anhydrous THF (10 ml) solution. NaH (5 mmol) was added to the RM at 0°C and stirred under nitrogen for about 2 h. Then, aryl chloride (SMII, 2 mmol) dissolved in THF (5 ml) was slowly added to the reaction mixture and stirred overnight. Saturated ammonium chloride solution (7-10 ml) was added to the reaction and extracted with CHCl. ​​The organic layer was dried over MgSO, filtered, and concentrated in vacuum to give a white solid. The residue was purified by flask column chromatography with n-hexane:ethyl acetate (4:1 and 2:1) to give the desired product as a white solid. Retention factor: 0.30 (H:E=1:1) Yield: 225mg (62%) NMR data: 1H NMR (500MHz, CDCl3): δ8.45(s,1H),7.84(d,J=8.75Hz,2H),6.95(d,J=8.8Hz,2H),3.87(s,3H),3.52(s,8H),1.47(s,9H).

[0075] 3. Synthesis of Compound 5 [Reaction Scheme 3] JPEG2024531663000020.jpg26140A flame-dried round-bottom flask equipped with a magnetic stirrer was charged with SMI (1 mmol) and anhydrous THF (10 ml) solution. NaH (5 mmol) was added to the RM at 0°C and stirred under nitrogen for about 2 h. Then, aryl chloride (SMII, 2 mmol) dissolved in THF (5 ml) was slowly added to the reaction mixture and stirred overnight. Saturated ammonium chloride solution (7-10 ml) was added to the reaction and extracted with CHCl. ​​The organic layer was dried over MgSO, filtered, and concentrated in vacuum to give a white solid. The residue was purified by flask column chromatography with n-hexane:ethyl acetate (4:1 and 2:1) to give the desired product as a white solid. Retention factor: 0.43 (H:E=1:1) Yield: 220mg (60%) NMR data: 1H NMR (500MHz, CDCl3): δ9.13(s,1H),7.85(d,J=8.35Hz,2H),7.50(d,J=8.65Hz,2H),3.52(s,8H),1.48(s,9H).

[0076] 4. Synthesis of Compound 6 [Reaction Scheme 4] JPEG2024531663000021.jpg28140A flame-dried round-bottom flask equipped with a magnetic stirrer was charged with SMI (1 mmol) and anhydrous THF (10 ml) solution. NaH (5 mmol) was added to the RM at 0°C and stirred under nitrogen for about 2 h. Then, aryl chloride (SMII, 2 mmol) dissolved in THF (5 ml) was slowly added to the reaction mixture and stirred overnight. Saturated ammonium chloride solution (7-10 ml) was added to the reaction and extracted with CHCl. ​​The organic layer was dried over MgSO, filtered, and concentrated in vacuum to give a white solid. The residue was purified by flask column chromatography with n-hexane:ethyl acetate (4:1 and 2:1) to give the desired product as a white solid. Retention factor: 0.40 (H:E=1:1) Yield: 234 (70%) NMR data: 1H NMR (500MHz, CDCl3): δ8.32(s,1H),7.85(d,J=7.1Hz,2H),7.59-7.56(m,1H),7.49-7.46(m,2H),3.52(s,8H),1.47(s,9H).

[0077] 5. Synthesis of Compound 28 [Reaction Scheme 5] JPEG2024531663000022.jpg28129Anhydrous CH2Cl2 (3 ml) and SMI (0.28 mmol) solution were placed in a flame-dried round bottom flask equipped with a magnetic stirrer. TFA (5.6 mmol) was added to the RM and stirred overnight. The RM was then concentrated in vacuo and dissolved in water. The pH of the RM was neutralized with NaOH and extracted with CH2Cl2. The RM was dried with MgSO4 and evaporated. Column chromatography was performed using a CH2Cl2:MeOH gradient to give the desired product as a viscous liquid. Retention factor: 0.41 (H:E:EtOH=1:1) Yield: 14mg (>20%) NMR data: 1H NMR (500MHz, DMSO): δ7.75-7.74(m,2H),7.29-7.27(m,4H,overlapped with CDCl3),3.55(s,4H),2.96-2.94(m,4H),2.43(s,3H).

[0078] 6. Synthesis of Compound 29 [Reaction Scheme 6] JPEG2024531663000023.jpg21139Anhydrous CHCl (3 ml) and SMI (0.32 mmol) solution were placed in a flame-dried round bottom flask equipped with a magnetic stirrer. TFA (6.4 mmol) was added to the RM and stirred overnight. The RM was then concentrated in vacuo with methanol and dichloromethane (DCM) to give a solid product. The resulting product was washed with DCM and filtered to give the desired product as a white solid. Retention factor:NA Yield: 106mg (92%) NMR data: 1H NMR (500MHz, DMSO): δ10.31(s,1H),9.24(s,2H),7.79(d,J=7.7Hz,2H),7.30(d,J=7.75Hz,2H),3.64(s,4H),3.16(s,4H),2.36(s,3H).

[0079] 7. Synthesis of Compound 32 [Reaction Scheme 7] JPEG2024531663000024.jpg25153Anhydrous CHCl (3 ml) and SMI (0.27 mmol) solution were placed in a flame-dried round bottom flask equipped with a magnetic stirrer. TFA (5.4 mmol) was added to the RM and stirred overnight. The RM was then concentrated in vacuo with methanol and dichloromethane (DCM) to give a solid product. The resulting product was washed with DCM and filtered to give the desired product as a white solid. Retention factor:NA Yield: 88mg (87%) NMR data: 1H NMR (500MHz, DMSO): δ10.26(s,1H),9.27(s,2H),7.88(d,J=8.45Hz,2H),7.01(d,J=8.45Hz,2H),3.81(s,3H),3.64(s,4H),3.17(s,4H).

[0080] 8. Synthesis of Compound 35 [Reaction Scheme 8] JPEG2024531663000025.jpg21150Anhydrous CHCl (3 ml) and SMI (0.32 mmol) solution were placed in a flame-dried round bottom flask equipped with a magnetic stirrer. TFA (6.4 mmol) was added to the RM and stirred overnight. The RM was then concentrated in vacuo with methanol and dichloromethane (DCM) to give a solid product. The resulting product was washed with DCM and filtered to give the desired product as a white solid. Retention factor: NA Yield: 117% (96%) NMR data: 1H NMR (500MHz, DMSO): δ10.48(s,1H),9.16(s,2H),7.88(d,J=8.1Hz,2H),7.57(d,J=8.1Hz,m,2H),3.65-3.63(m,4H),3.16-3.15(m,4H).

[0081] 9. Synthesis of Compound 37 [Reaction Scheme 9] TIFF2024531663000026.tif21143Anhydrous CHCl (5 ml) and SMI (0.42 mmol) solution were placed in a flame-dried round bottom flask equipped with a magnetic stirrer. TFA (8.4 mmol) was added to the RM and stirred overnight. The RM was then concentrated in vacuo with methanol and dichloromethane (DCM) to give a solid product. The resulting product was washed with DCM and filtered to give the desired product as a white solid. Retention factor:NA Yield: 144mg (99%) NMR data: 1H NMR (500MHz, DMSO): δ10.38(s,1H),9.01(s,2H),7.87(d,J=7.4Hz,2H),7.62-7.59(m,1H),7.52-7.49(m,2H),3.65-3.63(m,4H),3.17-3.15(m,4H).

[0082] 10. Synthesis of Compound 76 [Reaction Scheme 10] JPEG2024531663000027.jpg19153Anhydrous CHCl (3 ml) and SMI (0.31 mmol) solution were placed in a flame-dried round bottom flask equipped with a magnetic stirrer. TFA (6.2 mmol) was added to the RM and stirred overnight. The RM was then concentrated in vacuo with methanol and dichloromethane (DCM) to give a solid product. The resulting product was washed with DCM and filtered to give the desired product as a white solid. Retention factor:NA Yield: 110mg (90%) NMR data: 1H NMR(500MHz,DMSO):δ10.53(s,1H),8.89(s,2H),8.50(s,1H),8.00-7.99(m,3 H),7.90(d,J=8.55Hz,1H),7.66-7.60(m,2H),3.67-3.65(m,4H),3.17(s,4H).

[0083] 11. Synthesis of Compound 39 [Reaction Scheme 11] JPEG2024531663000028.jpg22143Anhydrous CHCl (3 ml) and SMI (0.39 mmol) solution were placed in a flame-dried round bottom flask equipped with a magnetic stirrer. TFA (7.8 mmol) was added to the RM and stirred overnight. The RM was then concentrated in vacuo with methanol and dichloromethane (DCM) to give a solid product. The resulting product was washed with DCM and filtered to give the desired product as a white solid. Retention factor:NA Yield: 132mg (91%) NMR data: 1H NMR (500MHz, DMSO): δ10.66(s,1H),9.03(s,2H),7.97(s,4H),3.64-3.62(m,4H),3.14(s,4H).

[0084] 12. Synthesis of Compound 102 [Reaction scheme 12] JPEG2024531663000029.jpg20138Anhydrous CHCl (5 ml) and SMI (0.43 mmol) solution were placed in a flame-dried round bottom flask equipped with a magnetic stirrer. TFA (8.6 mmol) was added to the RM and stirred overnight. The RM was then concentrated in vacuo with methanol and dichloromethane (DCM) to give a solid product. The resulting product was washed with DCM and filtered to give the desired product as a white solid. Retention factor:NA Yield: 123mg (85%) NMR data: 1H NMR (500MHz, DMSO): δ10.29(s,1H),8.90(s,2H),7.94(d,J=1.65Hz,1H),7.37(d,J=3.5Hz,1H),6.69-6.68(m,1H),3.61-3.59(m,4H),3.13(s,4H).

[0085] 13. Synthesis of Compound 41 [Reaction Scheme 13] JPEG2024531663000030.jpg22152Anhydrous CHCl (3 ml) and SMI (0.37 mmol) solution were placed in a flame-dried round bottom flask equipped with a magnetic stirrer. TFA (7.4 mmol) was added to the RM and stirred overnight. The RM was then concentrated in vacuo with methanol and dichloromethane (DCM) to give a solid product. The resulting product was washed with DCM and filtered to give the desired product as a white solid. Retention factor:NA Yield: 135mg (93%) NMR data: 1H NMR (500MHz, DMSO): δ10.73(s,1H),8.92(s,2H),8.32(d,J=8.55Hz,2H),8.04(d,J=8.5Hz,2H),3.65-3.63(m,4H),3.15(s,4H).

[0086] 14. Synthesis of Compound 77 [Reaction Scheme 14] JPEG2024531663000031.jpg22138A flame-dried round-bottom flask equipped with a magnetic stirrer was charged with anhydrous CH2Cl2 (2 ml) and SMI (0.31 mmol) solution. HCl (2 mmol) in diethyl ether (3.1 mmol) was added to the RM at 0 °C and stirred overnight. The RM was then filtered to give the desired product as a white solid. Retention factor:NA Yield: 89mg (90%) NMR data: 1H NMR(500MHz,DMSO):δ10.56(s,1H),9.47(s,2H),8.54-8.53(m,1H),8.05-7.99( m,3H),7.93-7.91(m,1H),7.67-7.60(m,2H),3.72-3.70(m,4H),3.14(s,4H);13C NMR(125MHz,DMSO):δ152.6,134.60,131.9,130.41,129.07,129.03,128.2,128.0,127.6,126.9,124.4,42.6

[0087] 15. Synthesis of Compound 40 [Reaction Scheme 15] JPEG2024531663000032.jpg24142Anhydrous CH2Cl2 (2 ml) and SMI (0.33 mmol) solution were placed in a flame-dried round bottom flask equipped with a magnetic stirrer. HCl (2 mmol) in diethyl ether (3.3 mmol) was added to the RM at 0 °C and stirred overnight. The RM was then filtered to give the desired product as a white solid. Retention factor:NA Yield: 88.5mg (91%) NMR data: 1H NMR (500MHz, DMSO): δ10.70(s,1H),9.44(s,2H),8.00(s,4H),3.69-3.67(m,4H),3.12(s,4H);13C NMR(125MHz,DMSO):δ166.1,152.6,137.8,132.8,129.3,118.6,114.8,43.0

[0088] 16. Synthesis of Compound 42 [Reaction Scheme 16] JPEG2024531663000033.jpg23146Anhydrous CH2Cl2 (5 ml) and SMI (0.37 mmol) solution were placed in a flame-dried round bottom flask equipped with a magnetic stirrer. HCl (2 mmol) in diethyl ether (3.7 mmol) was added to the RM at 0 °C and stirred overnight. The RM was then filtered to give the desired product as a white solid. Retention factor:NA Yield: 107mg (92%) NMR data: 1H NMR (500MHz, DMSO): δ10.79(s,1H),9.48(s,2H),8.32(d,J=8.8Hz,2H),8.07(d,J=8.75Hz,2H),3.71-3.69(m,4H),3.13(s,4H);13C NMR(125MHz,DMSO):δ166.0,152.6,149.9,139.5,130.0,123.9,43.0

[0089] 17. Synthesis of compound 38 [Reaction Scheme 17] JPEG2024531663000034.jpg23141Anhydrous CH2Cl2 (2 ml) and SMI (0.33 mmol) solution were placed in a flame-dried round bottom flask equipped with a magnetic stirrer. HCl (2 mmol) in diethyl ether (3.3 mmol) was added to the RM at 0 °C and stirred overnight. The RM was then filtered to give the desired product as a white solid. Retention factor:NA Yield: 83mg (93.24%) NMR data: 1H NMR (500MHz, DMSO): δ10.42(s,1H),9.57(s,2H),7.88-7.87(m,2H),7.61-7.58(m,1H),7.51-7.48(m,2H),3.69-3.67(m,4H),3.13-3.11(m,4H).

[0090] 18. Synthesis of Compound 103 [Reaction Scheme 18] JPEG2024531663000035.jpg27142Anhydrous CH2Cl2 (2 ml) and SMI (0.40 mmol) solution were placed in a flame-dried round bottom flask equipped with a magnetic stirrer. HCl (2 mmol) in diethyl ether (4 mmol) was added to the RM at 0 °C and stirred overnight. The RM was then filtered to give the desired product as a white solid. Retention factor:NA Yield: 91.5mg (88%) NMR data: 1H NMR(500MHz,DMSO):δ10.32(s,1H),9.49(s,2H),7.93(d,J=1.5Hz,1H),7.42(d,J= 3.4Hz,1H),6.67(dd,J=3.55,1.7Hz,1H),3.66-3.64(m,4H),3.10-3.09(m,4H);13C NMR(125MHz,DMSO):δ156.6,151.9,146.7,146.1,116.5,112.2,42.5

[0091] 19. Synthesis of Compound 30 [Reaction Scheme 19] JPEG2024531663000036.jpg26144Anhydrous CH2Cl2 (2 ml) and SMI (0.28 mmol) solution were placed in a flame-dried round bottom flask equipped with a magnetic stirrer. HCl (2 mmol) in diethyl ether (2.8 mmol) was added to the RM at 0 °C and stirred overnight. The RM was then filtered to give the desired product as a white solid. Retention factor:NA Yield: 73mg (92%) NMR data: 1H NMR (500MHz, DMSO): δ10.30(s,1H),9.44(s,2H),7.78(d,J=8.2Hz,2H),7.30-7.29(m,2H),3.67-3.66(m,4H),3.11(s,4H),2.36(s,3H);13C NMR(125MHz,DMSO):δ166.3,152.7,142.6,130.2,128.9,128.2,42.5,21.0

[0092] 20. Synthesis of Compound 33 [Reaction Scheme 20] JPEG2024531663000037.jpg23144Anhydrous CH2Cl2 (2 ml) and SMI (0.31 mmol) solution were placed in a flame-dried round bottom flask equipped with a magnetic stirrer. HCl (2 mmol) in diethyl ether (3.1 mmol) was added to the RM at 0 °C and stirred overnight. The RM was then filtered to give the desired product as a white solid. Retention factor:NA Yield: 84.56mg (91%) NMR data: 1H 13C NMR(125MHz,DMSO):δ166.7,162.5,152.9,130.3,125.0,113.6,55.5,42.5

[0093] 21. Synthesis of Compound 36 [Reaction Scheme 21] JPEG2024531663000038.jpg25144Anhydrous CH2Cl2 (2 ml) and SMI (0.38 mmol) solution were placed in a flame-dried round bottom flask equipped with a magnetic stirrer. HCl (2 mmol) in diethyl ether (3.8 mmol) was added to the RM at 0 °C and stirred overnight. The RM was then filtered to give the desired product as a white solid. Retention factor:NA Yield: 106mg (92%) NMR data: 1H NMR (500MHz, DMSO): δ10.50(s,1H),9.50(s,2H),7.89(d,J=8.86Hz,2H),7.57(d,J=8.6Hz,2H),3.68-3.66(m,4H),3.11(s,4H);13C NMR(125MHz,DMSO):δ165.6,152.4,137.1,131.9,130.1,128.4,42.5

[0094] 22. Synthesis of Compound 43 [Reaction Scheme 22] JPEG2024531663000039.jpg23149Anhydrous CHCl (5 ml) and SMI (0.38 mmol) solution were placed in a flame-dried round bottom flask equipped with a magnetic stirrer. TFA (7.6 mmol) was added to the RM and stirred overnight. The RM was then concentrated in vacuo with methanol and dichloromethane (DCM) to give a solid product. The resulting product was washed with DCM and filtered to give the desired product as a white solid. Retention factor:NA Yield: 142mg (90%) NMR data: 1H NMR (500MHz, DMSO): δ10.73(s,1H),9.04(s,2H),7.63(s,1H),7.48-7.43(m,2H),3.58-3.56(m,4H),3.08(s,4H).

[0095] 23. Synthesis of compound 45 [Reaction Scheme 23] JPEG2024531663000040.jpg23148Anhydrous CHCl (5 ml) and SMI (0.26 mmol) solution were placed in a flame-dried round bottom flask equipped with a magnetic stirrer. TFA (5.2 mmol) was added to the RM and stirred overnight. The RM was then concentrated in vacuo with methanol and dichloromethane (DCM) to give a solid product. The resulting product was washed with DCM and filtered to give the desired product as a white solid. Retention factor:NA Yield: 97.5mg (88%) NMR data: 1H NMR (500MHz, DMSO): δ10.48(s,1H),9.14(s,2H),7.80-7.71(m,4H),3.64(s,4H),3.16(s,4H).

[0096] 24. Synthesis of Compound 104 [Reaction Scheme 24] JPEG2024531663000041.jpg21146Anhydrous CHCl (5 ml) and SMI (0.32 mmol) solution were placed in a flame-dried round bottom flask equipped with a magnetic stirrer. TFA (6.4 mmol) was added to the RM and stirred overnight. The RM was then concentrated in vacuo with methanol and dichloromethane (DCM) to give a solid product. The resulting product was washed with DCM and filtered to give the desired product as a white solid. Retention factor:NA Yield: 104mg (92%) NMR data: 1H NMR (500MHz, DMSO): δ10.42(s,1H),9.04(s,2H),7.94-7.86(m,2H),7.19-7.16(m,1H),3.64-3.62(m,4H),3.16-3.14(m,4H).

[0097] 25. Synthesis of Compound 129 [Reaction Scheme 25] JPEG2024531663000042.jpg22141Anhydrous CH2Cl2 (5 ml) and SMI (0.23 mmol) solution were placed in a flame-dried round bottom flask equipped with a magnetic stirrer. TFA (4.6 mmol) was added to the RM and stirred overnight. The RM was then concentrated in vacuo with methanol and dichloromethane (DCM) to give a solid product. The resulting product was washed with DCM and filtered to give the desired product as a white solid. Retention factor:NA Yield: 79mg (85%) NMR data: 1H NMR(500MHz,DMSO):δ10.68(s,1H),8.97(s,2H),8.31(s,1H),8.07-8.05(m ,1H),7.08-7.98(m,1H),7.53-7.42(m,2H),3.67-3.65(m,4H),3.17(s,4H).

[0098] 26. Synthesis of compound 47 [Reaction Scheme 26] JPEG2024531663000043.jpg21143Anhydrous CHCl (5 ml) and SMI (0.36 mmol) solution were placed in a flame-dried round bottom flask equipped with a magnetic stirrer. TFA (7.2 mmol) was added to the RM and stirred overnight. The RM was then concentrated in vacuo with methanol and dichloromethane (DCM) to give a solid product. The resulting product was washed with DCM and filtered to give the desired product as a white solid. Retention factor:NA Yield: 105mg (80%) NMR data: 1H NMR (500MHz, DMSO): δ10.42(s,1H),9.08(s,2H),7.96-7.94(m,2H),7.35-7.27(m,2H),3.65-3.63(m,4H),3.16(s,4H).

[0099] 27. Synthesis of Compound 154 [Reaction Scheme 27] JPEG2024531663000044.jpg22144Anhydrous CHCl (5 ml) and SMI (0.50 mmol) solution were placed in a flame-dried round bottom flask equipped with a magnetic stirrer. TFA (10 mmol) was added to the RM and stirred overnight. The RM was then concentrated in vacuo with methanol and dichloromethane (DCM) to give a solid product. The resulting product was washed with DCM and filtered to give the desired product as a white solid. Retention factor:NA Yield: 150mg (86.13) NMR data: 1H NMR (500MHz, DMSO): δ10.82(s,1H),9.31(s,2H),8.80(s,2H),7.82(s,2H),3.67(s,4H),3.17(s,4H).

[0100] 28. Synthesis of compound 44 [Reaction Scheme 28] JPEG2024531663000045.jpg28141Anhydrous CH2Cl2 (2 ml) and SMI (0.20 mmol) solution were placed in a flame-dried round bottom flask equipped with a magnetic stirrer. HCl (2 mmol) in diethyl ether (1 ml) was added to the RM at 0 °C and stirred overnight. The RM was then filtered to give the desired product as a white solid. Retention factor:NA Yield: 62mg (91.55%) NMR data: 1H NMR (500MHz, DMSO): δ10.79(s,1H),9.46(s,2H),7.69(d,J=1.85Hz,1H),7.54-7.48(m,2H),3.66-3.64(m,4H),3.10-3.08(m,4H).

[0101] 29. Synthesis of Compound 46 [Reaction Scheme 29] JPEG2024531663000046.jpg23144Anhydrous CH2Cl2 (2 ml) and SMI (0.19 mmol) solution were placed in a flame-dried round bottom flask equipped with a magnetic stirrer. HCl (2 mmol) in diethyl ether (0.95 ml) was added to the RM at 0 °C and stirred overnight. The RM was then filtered to give the desired product as a white solid. Retention factor:NA Yield: 61mg (92.10%) NMR data: 1H NMR (500MHz, DMSO): δ10.51(s,1H),9.53(s,2H),7.81(d,J=8.6Hz,2H),7.70(d,J=8.6Hz,2H),3.68-3.66(m,4H),3.10(s,4H);13C NMR(125MHz,DMSO):δ165.8,152.4,132.3,131.4,130.2,126.2,42.5

[0102] 30. Synthesis of Compound 130 [Reaction Scheme 30] JPEG2024531663000047.jpg25140Anhydrous CH2Cl2 (2 ml) and SMI (0.21 mmol) solution were placed in a flame-dried round bottom flask equipped with a magnetic stirrer. HCl (2 mmol) in diethyl ether (1.05 ml) was added to the RM at 0 °C and stirred overnight. The RM was then filtered to give the desired product as a white solid. Retention factor:NA Yield: 60mg (87.70%) NMR data: 1H NMR(500MHz,DMSO):δ10.76(s,1H),9.53(s,2H),8.38(s,1H),8.06-8.04(m,1H ),8.00-7.97(m,1H),7.52-7.45(m,2H),3.72-3.69(m,4H),3.15-3.13(m,4H).

[0103] 31. Synthesis of Compound 155 [Reaction Scheme 31] JPEG2024531663000048.jpg25137A flame-dried round-bottom flask equipped with a magnetic stirrer was charged with anhydrous CHCl (2 mL) and SMI (1 mmol) solution. HCl (2 mmol) in diethyl ether (2 ml) was added to the RM at 0° C. and stirred overnight. The RM was then filtered to give the desired product as a white solid. Retention factor:NA Yield: 97mg (89.50%) NMR data: 1H NMR (500MHz, DMSO): δ11.17(s,1H),9.40(s,2H),8.98-8.95(m,2H),8.16-8.14(m,2H),3.53-3.51(m,4H),3.02-2.98(m,4H).

[0104] 32. Synthesis of compound 48 [Reaction Scheme 32] JPEG2024531663000049.jpg25143Anhydrous CHCl (2 ml) and SMI (0.31 mmol) solution were placed in a flame-dried round bottom flask equipped with a magnetic stirrer. HCl (2 mmol) in diethyl ether (3.1 mmol) was added to the RM at 0° C. and stirred overnight at room temperature. The RM was then filtered to give the desired product as a white solid. Retention factor:NA Yield:>90% NMR data: 1H NMR (500MHz, DMSO): δ10.45(s,1H),9.51(m,2H),7.97-7.95(m,2H),7.35-7.32(m,2H),3.69-3.66(m,4H),3.12-3.10(m,4H).

[0105] 33. Synthesis of Compound 105 [Reaction Scheme 33] JPEG2024531663000050.jpg25139Anhydrous CHCl (2 ml) and SMI (0.35 mmol) solution were placed in a flame-dried round bottom flask equipped with a magnetic stirrer. HCl (2 mmol) in diethyl ether (3.5 mmol) was added to the RM at 0° C. and stirred overnight at room temperature. The RM was then filtered to give the desired product as a white solid. Retention factor:NA Yield:>90% NMR data: 1H NMR(500MHz,DMSO):δ10.46(s,1H),9.35(s,2H),8.02-8.01(m,1H),7.92-7 .91(m,1H),7.21(dd,J=5,3.8Hz,1H),3.69-3.66(m,4H),3.12-3.10(m,4H).

[0106] 34. Synthesis of Compound 51 [Reaction Scheme 34] JPEG2024531663000051.jpg29144Anhydrous CHCl (2 ml) and SMI (0.30 mmol) solution were placed in a flame-dried round bottom flask equipped with a magnetic stirrer. HCl (2 mmol) in diethyl ether (3.0 mmol) was added to the RM at 0° C. and stirred overnight at room temperature. The RM was then filtered to give the desired product as a white solid. Retention factor:NA Yield:>90% NMR data: 1H NMR(500MHz,DMSO):δ10.54(s,1H),9.52(s,2H),7.92-7.91(m,1H),7.84-7.82 (m,1H),7.68-7.65(m,1H),7.55-7.52(m,1H),3.69-3.67(m,4H),3.10(s,4H).

[0107] 35. Synthesis of compound 53 [Reaction Scheme 35] JPEG2024531663000052.jpg25135Anhydrous CHCl (2 ml) and SMI (0.30 mmol) solution were placed in a flame-dried round bottom flask equipped with a magnetic stirrer. HCl (2 mmol) in diethyl ether (3.0 mmol) was added to the RM at 0° C. and stirred overnight at room temperature. The RM was then filtered to give the desired product as a white solid. Retention factor:NA Yield:>85% NMR data: 1H NMR (500MHz, DMSO): δ10.39(s,1H),9.66(s,2H),7.74-7.69(m,2H),7.43-7.37(m,2H),3.71-3.69(m,4H),3.17-3.13(m,4H),2.37(s,3H).

[0108] 36. Synthesis of Compound 55 [Reaction Scheme 36] JPEG2024531663000053.jpg29137Anhydrous CHCl (2 ml) and SMI (0.37 mmol) solution were placed in a flame-dried round bottom flask equipped with a magnetic stirrer. HCl (2 mmol) in diethyl ether (3.7 mmol) was added to the RM at 0° C. and stirred overnight at room temperature. The RM was then filtered to give the desired product as a white solid. Retention factor:NA Yield:>85% NMR data: 1H NMR (500MHz, DMSO): δ10.43(s,1H),9.65(s,2H),7.48-7.39(m,3H),7.17-7.15(m,1H),3.80(s,3H),3.69-3.67(m,4H),3.12-3.09(m,4H).

[0109] 37. Synthesis of Compound 52 [Reaction Scheme 37] JPEG2024531663000054.jpg26136Anhydrous CHCl (2 ml) and SMI (0.43 mmol) solution were placed in a flame-dried round bottom flask equipped with a magnetic stirrer. TFA (8.6 mmol) was added to the RM at 0° C. and stirred at room temperature overnight. The RM was then concentrated in vacuo with methanol and dichloromethane (DCM) to give a solid product. The resulting product was washed with DCM and filtered to give the desired product as a white solid. Retention factor:NA Yield:>90% NMR data: 1H NMR(500MHz,DMSO):δ10.52(s,1H),9.19(s,2H),7.90-7.89(m,1H),7.83-7.81(m ,1H),7.68-7.66(m,1H),7.56-7.52(m,1H),3.66-3.64(m,4H),3.17-3.16(m,4H).

[0110] 38. Synthesis of Compound 54 [Reaction Scheme 38] JPEG2024531663000055.jpg25146Anhydrous CHCl (2 ml) and SMI (0.40 mmol) solution were placed in a flame-dried round bottom flask equipped with a magnetic stirrer. TFA (8 mmol) was added to the RM at 0° C. and stirred at room temperature overnight. The RM was then concentrated in vacuo with methanol and dichloromethane (DCM) to give a solid product. The resulting product was washed with DCM and filtered to give the desired product as a white solid. Retention factor:NA Yield:>85% NMR data: 1H NMR (500MHz, DMSO): δ10.37(s,1H),9.31(s,2H),7.70-7.65(m,2H),7.40-7.35(m,2H),3.66-3.64(m,4H),3.16-3.14(m,4H),2.35(s,3H).

[0111] 39. Synthesis of Compound 56 [Reaction Scheme 39] JPEG2024531663000056.jpg26130Anhydrous CHCl (2 ml) and SMI (0.39 mmol) solution were placed in a flame-dried round bottom flask equipped with a magnetic stirrer. TFA (7.8 mmol) was added to the RM at 0°C and stirred at room temperature overnight. The RM was then concentrated in vacuo with methanol and dichloromethane (DCM) to give a solid product. The resulting product was washed with DCM and filtered to give the desired product as a white solid. Retention factor:NA Yield:>85% NMR data: 1H NMR (500MHz, DMSO): δ10.39(s,1H),9.23(s,2H),7.47-7.39(m,3H),7.17-7.15(m,1H),3.80(s,3H),3.65-3.63(m,4H),3.16-3.14(m,4H).

[0112] Working Example 1. Confirmation of agmatinase inhibitory activity of compounds - Use of Urea Assay (1) Experimental reagents and manufacturing methods Agmatinase inhibitory activity (FIG. 1) was measured for some of the compounds of the present invention shown in Table 1. The assay buffer used was a Mg-containing buffer. Agmatinase (speB) and recombinant proteins were used at 0.1 ml (final concentration: 2 mg / ml).

[0113] (2) Experimental methods and results After the sample and agmatinase were added to the activity buffer and reacted, 1 ul (final conc. 500 uM) of agmatine was added. After that, the assay was performed to measure the absorbance, and the amount was converted according to the standard curve.

[0114] The urea concentration was calculated using the following chemical formula 1. [Mathematical formula 1] JPEG2024531663000057.jpg19123

[0115] After treating each compound with concentrations of 1uM, 10uM, 30uM, 50uM, and 300uM, the agmatinase inhibitory activity was measured as a percentage. As can be seen from FIG. 1, the agmatinase inhibitory activity increased with increasing concentration.

[0116] As can be seen from FIG. 1, most of the compounds of the present invention exhibit agmatinase inhibitory activity.

[0117] 2. Confirmation of the compound's social and cognitive improving effects in an animal model of autism To confirm the therapeutic effect of the compound of the present invention on the lack of sociality, which is one of the phenotypes of developmental disorders, a three-chamber test was performed using a VPA (valproic acid)-induced autism animal model. The chamber duration was shown as stranger (time spent on mouse), empty (time spent on empty space), and center (time spent on center space), and a longer time spent on mouse than on empty space was judged to be social.

[0118] The results of the experiment showed that VPA mice spent more time in the open space than they did in the mice, which means that they were less social.

[0119] In contrast, when VPA mice were treated with the compound of the present invention, it was confirmed that they spent more time in the mouse space than in the empty space, which means that the sociality of the VPA mice was improved by treatment with the compound (Figure 2).

[0120] The experimental animals were allowed to explore the stimulus mouse (familiar) for 10 minutes, and then a new stimulus mouse (novel) was introduced and allowed to explore for another 10 minutes. After that, we evaluated whether the animals spent more time with the novel mouse than with the familiar mouse, and confirmed the results (Figure 3). Here, the previous mouse was designated "familiar" and the newly introduced mouse was designated "novel" (if the animals spent more time with the novel mouse than with the familiar mouse, it was determined that they had social cognitive ability). In other words, it was determined that they had the cognitive ability to distinguish between the existing familiar mouse and the new novel mouse.

[0121] As the results of the experiment, the time that the test mouse explored each mouse or the sniffing time of the test mouse to each mouse were measured and shown. The more time the test mouse spent with the novel mouse than with the familiar mouse, or the more time the test mouse spent sniffing the novel mouse than with the familiar mouse, the higher the social preference.

[0122] The results of the experiment showed that VPA mice spent more time with familiar mice than novel mice and spent more time sniffing familiar mice than novel mice, indicating a decrease in social preference.

[0123] In contrast, when VPA mice were treated with the compound of the present invention, they spent more time with Novel mice than familiar mice, and the sniffing time for Novel mice was increased more than that for familiar mice. This shows that social preference can be improved by treating with the compound of the present invention (Figures 2-3).

[0124] As a result of confirming sociability and social preference, it was found that when sociability and social preference are improved, symptoms of sociability and social cognitive ability are improved, and when these symptoms are improved, it is expected that there will be an effect on the prevention or treatment of not only emotional behavioral disorders such as autism spectrum disorder and schizophrenia, but also cognitive ability-related intellectual disabilities, or neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Therefore, when the compound of the present invention is administered to the group of patients with the emotional behavioral disorder, it can be predicted that there will be a preventive or therapeutic effect.

[0125] Repetitive behavior experiments In order to confirm the therapeutic effect of the compound of the present invention on stereotypy, which is one of the phenotypes of developmental disorders, a self-grooming test was performed using a VPA (valproic acid)-induced autism animal model (FIG. 4).

[0126] An animal was placed in an empty cage, and the duration of the act of licking and grooming its body (called "self-grooming") per hour was measured and plotted on a graph. An increase in duration indicates the emergence of repetitive behaviors.

[0127] If the repetitive behavior is confirmed and there is an improvement such as a decrease in repetitive behavior, the symptoms of stereotypic behavior and impulsivity are improved, and if the symptoms of stereotypic behavior are improved, it is expected to be effective in preventing or treating emotional behavior disorders such as autism spectrum disorder and obsessive-compulsive disorder. In addition, if the symptoms of impulsivity are improved, it is expected to be effective in preventing or treating emotional behavior disorders such as autism spectrum disorder, obsessive-compulsive disorder, depression, anxiety disorder, panic disorder, and attention deficit hyperactivity disorder. Therefore, when the compound is administered to the group of patients with the emotional behavior disorder, it can be predicted that there will be a preventive or therapeutic effect.

[0128] GSH assay To confirm the neuroprotective effect of the compound of the present invention, oxidative stimulation of cells was induced with H2O2 24 hours after pretreatment, and GSH assay was performed (Figure 5), and cell images were confirmed (Figure 6). The cells used were primary neuronal cells, and the compound of the present invention was treated at 0.1, 1, 10, 50, 100, and 300 uM.

Claims

1. A compound of the following formula 1, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof: [Formula 1] (In the formula, R １ is hydrogen or a tert-butyloxycarbonyl group, A is C ５ -C １０ is a mono- or bicyclic group of the formula each ring of the cyclic group is unsubstituted or substituted with 1 to 3 heteroatoms; The cyclic group is selected from the group consisting of halogen, C １ -C ５ Alkyl, C １ -C ５ Alkoxy, CN or NO ２ substituted or unsubstituted.

2. The compound according to claim 1 , its stereoisomer or a pharma- ceutically acceptable salt thereof, wherein A is selected from the group consisting of the following cyclic groups: (In the formula, R ２ , R ３ and R ４ are each independently hydrogen, halogen, or C １ -C ５ Alkyl, C １ -C ５ Alkoxy, CN or NO ２ and Q １ , Q ２ and Q. ３ are each independently N, O or S.

3. The compound according to claim 1 , its stereoisomer or a pharma- ceutically acceptable salt thereof, wherein A is selected from the group consisting of the following cyclic groups: (In the formula, R ２ , R ３ and R ４ are each independently hydrogen, halogen, or C １ -C ５ Alkyl, C １-C ５ Alkoxy, CN or NO ２ and Q １ , Q ２ and Q. ３ are each independently N, O or S.

4. The compound according to claim 1 , its stereoisomer or a pharma- ceutically acceptable salt thereof, wherein A is selected from the group consisting of the following cyclic groups: (In the formula, R ２ , R ３ and R ４ are each independently hydrogen, halogen, or C １ -C ５ Alkyl, C １ -C ５ Alkoxy, CN or NO ２ It is.)

5. 2. The compound of claim 1, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of the following compounds: tert-Butyl-4-((4-methylbenzoyl)carbamoyl)piperazine-1-carboxylate; tert-Butyl-4-((4-methoxybenzoyl)carbamoyl)piperazine-1-carboxylate; tert-Butyl-4-((4-chlorobenzoyl)carbamoyl)piperazine-1-carboxylate; tert-Butyl-4-(benzoylcarbamoyl)piperazine-1-carboxylate; N-(4-methylbenzoyl)piperazine-1-carboxamide; N-(4-methylbenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(4-methoxybenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(4-chlorobenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-benzoylpiperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(2-naphthoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(4-cyanobenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(furan-2-carbonyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(4-nitrobenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(2-naphthoyl)piperazine-1-carboxamide hydrochloride; N-(4-cyanobenzoyl)piperazine-1-carboxamide hydrochloride; N-(4-nitrobenzoyl)piperazine-1-carboxamide hydrochloride; N-benzoylpiperazine-1-carboxamide hydrochloride; N-(furan-2-carbonyl)piperazine-1-carboxamide hydrochloride; N-(4-methylbenzoyl)piperazine-1-carboxamide hydrochloride; N-(4-methoxybenzoyl)piperazine-1-carboxamide hydrochloride; N-(4-chlorobenzoyl)piperazine-1-carboxamide hydrochloride; N-(2,4-dichlorobenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(4-bromobenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(thiophene-2-carbonyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(benzo[b]thiophene-2-carbonyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(4-fluorobenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-isonicotinoylpiperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(2,4-dichlorobenzoyl)piperazine-1-carboxamide hydrochloride; N-(4-bromobenzoyl)piperazine-1-carboxamide hydrochloride; N-(benzo[b]thiophene-2-carbonyl)piperazine-1-carboxamide hydrochloride; N-isonicotinoylpiperazine-1-carboxamide hydrochloride; N-(4-fluorobenzoyl)piperazine-1-carboxamide hydrochloride; N-(thiophene-2-carbonyl)piperazine-1-carboxamide hydrochloride; N-(3-chlorobenzoyl)piperazine-1-carboxamide hydrochloride; N-(3-methylbenzoyl)piperazine-1-carboxamide hydrochloride; N-(3-methoxybenzoyl)piperazine-1-carboxamide hydrochloride; N-(3-chlorobenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(3-methylbenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; N-(3-methoxybenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate.

6. A pharmaceutical composition for preventing or treating symptoms associated with emotional and behavioral disorders, comprising the compound according to any one of claims 1 to 5, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

7. The pharmaceutical composition for preventing or treating symptoms associated with emotional and behavioral disorders according to claim 6, wherein the symptoms associated with emotional and behavioral disorders are any one selected from the group consisting of lack of sociability, lack of social cognitive ability, stereotyped behavior, excessive behavior, impulsivity and distractibility.

8. A pharmaceutical composition for preventing or treating an emotional and behavioral disorder, comprising the compound according to any one of claims 1 to 5, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

9. A pharmaceutical composition for preventing or treating a neurodegenerative disease, comprising the compound according to any one of claims 1 to 5, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

10. The pharmaceutical composition for preventing or treating an emotional and behavioral disorder according to claim 8, wherein the emotional and behavioral disorder is any one selected from the group consisting of autism spectrum disorder, schizophrenia, obsessive-compulsive disorder, depression, anxiety disorder, panic disorder and attention deficit hyperactivity disorder.

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