Compounds and their use for the treatment of mood and behavior disorders

Abstract

The present invention relates to novel compounds and their use for the treatment of emotional behavioral disorders. Pharmaceutical compositions comprising the novel compounds according to the present invention for the prevention or treatment of emotional behavioral disorders inhibit guanfacine enzymes and are therefore expected to contribute to the improvement of emotional behavioral disorders such as autism spectrum disorders and schizophrenia, as well as symptoms associated with emotional behavioral disorders such as hyperactivity and lack of sociability.

Description

Technical Field

[0001] This invention relates to novel compounds and their use in treating mood and behavioral disorders. Background Technology

[0002] Mood and behavioral disorders are the only incurable mental illnesses and can be defined as a spectrum of disorders characterized by difficulties in social and communication as well as stereotyped behaviors and a variety of coexisting symptoms such as epilepsy, anxiety, depression, aggression, and cognitive impairment.

[0003] The exact pathogenesis of mood and behavioral disorders remains unclear, and most research focuses on excitation / inhibition imbalances. Modulating these imbalances in excitatory / inhibitory neurons, affecting neural connectivity and integration, suggests the potential to improve core symptoms of mood and behavioral disorders such as autism. Summary of the Invention

[0004] The problem the invention aims to solve

[0005] The purpose of this invention is to provide a novel compound, its stereoisomers, or pharmaceutically acceptable salts.

[0006] Another object of the present invention is to provide a novel compound, its stereoisomer, or a pharmaceutically acceptable salt that can be used to prevent or treat mood and behavioral disorders.

[0007] Furthermore, another object of the present invention is to provide a novel compound, its stereoisomer, or a pharmaceutically acceptable salt thereof that can be used to prevent or treat symptoms associated with mood and behavioral disorders.

[0008] Furthermore, another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of mood and behavioral disorders, comprising novel compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0009] Solution for solving the problem

[0010] 1. A compound represented by Formula 1, its stereoisomer, or a pharmaceutically acceptable salt thereof:

[0011] [Formula 1]

[0012]

[0013] (where R1 is hydrogen or tert-butoxycarbonyl,)

[0014] A is C5-C 10 Monocyclic or bicyclic groups,

[0015] The rings of the cyclic group are either unsubstituted or substituted by 1 to 3 heteroatoms, and

[0016] The cyclic group is either unsubstituted or substituted with halogen, C1-C5 alkyl, C1-C5 alkoxy, CN, or NO2.

[0017] 2. The compound, its stereoisomer, or pharmaceutically acceptable salt according to 1 above, wherein A is selected from the group consisting of the following cyclic groups:

[0018]

[0019] (where R2, R3, and R4 are each independently hydrogen, halogen, C1-C5 alkyl, C1-C5 alkoxy, CN, or NO2, and)

[0020] Q1, Q2, and Q3 are each independently N, O, or S.

[0021] 3. The compound, its stereoisomer, or pharmaceutically acceptable salt according to 1 above, wherein A is selected from the group consisting of the following cyclic groups:

[0022]

[0023] (where R2, R3, and R4 are each independently hydrogen, halogen, C1-C5 alkyl, C1-C5 alkoxy, CN, or NO2; and)

[0024] Q1, Q2, and Q3 are each independently N, O, or S.

[0025] 4. The compound, its stereoisomer, or pharmaceutically acceptable salt according to 1 above, wherein A is selected from the group consisting of the following cyclic groups:

[0026]

[0027] (where R2, R3 and R4 are each independently hydrogen, halogen, C1-C5 alkyl, C1-C5 alkoxy, CN or NO2).

[0028] 5. The compound according to 1 above, its stereoisomer, or a pharmaceutically acceptable salt, wherein said compound is selected from the group consisting of:

[0029] 4-((4-methylbenzoyl)carbamoyl)piperazine-1-carboxylic acid tert-butyl ester;

[0030] 4-((4-methoxybenzoyl)carbamoyl)piperazine-1-carboxylic acid tert-butyl ester;

[0031] 4-((4-chlorobenzoyl)carbamoyl)piperazine-1-carboxylic acid tert-butyl ester;

[0032] 4-(benzoylcarbamoyl)piperazine-1-carboxylic acid tert-butyl ester;

[0033] N-(4-methylbenzoyl)piperazine-1-carboxamide;

[0034] N-(4-methylbenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate;

[0035] N-(4-methoxybenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate;

[0036] N-(4-chlorobenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate;

[0037] N-benzoylpiperazine-1-carboxamide-2,2,2-trifluoroacetate;

[0038] N-(2-Naphthoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate;

[0039] N-(4-cyanobenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate;

[0040] N-(furan-2-carbonyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate;

[0041] N-(4-nitrobenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate;

[0042] N-(2-Naphthoyl)piperazine-1-carboxamide hydrochloride;

[0043] N-(4-cyanobenzoyl)piperazine-1-carboxamide hydrochloride;

[0044] N-(4-Nitrobenzoyl)piperazine-1-carboxamide hydrochloride;

[0045] N-benzoylpiperazine-1-carboxamide hydrochloride;

[0046] N-(furan-2-carbonyl)piperazine-1-carboxamide hydrochloride;

[0047] N-(4-methylbenzoyl)piperazine-1-carboxamide hydrochloride;

[0048] N-(4-methoxybenzoyl)piperazine-1-carboxamide hydrochloride;

[0049] N-(4-Chlorobenzoyl)piperazine-1-carboxamide hydrochloride;

[0050] N-(2,4-dichlorobenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate;

[0051] N-(4-bromobenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate;

[0052] N-(thiophene-2-carbonyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate;

[0053] N-(benzo[b]thiophene-2-carbonyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate;

[0054] N-(4-fluorobenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate;

[0055] N-Isoninoylpiperazine-1-carboxamide-2,2,2-trifluoroacetate;

[0056] N-(2,4-dichlorobenzoyl)piperazine-1-carboxamide hydrochloride;

[0057] N-(4-bromobenzoyl)piperazine-1-carboxamide hydrochloride;

[0058] N-(benzo[b]thiophene-2-carbonyl)piperazine-1-carboxamide hydrochloride;

[0059] N-Isoninoylpiperazine-1-carboxamide hydrochloride;

[0060] N-(4-fluorobenzoyl)piperazine-1-carboxamide hydrochloride;

[0061] N-(thiophene-2-carbonyl)piperazine-1-carboxamide hydrochloride;

[0062] N-(3-Chlorobenzoyl)piperazine-1-carboxamide hydrochloride;

[0063] N-(3-methylbenzoyl)piperazine-1-carboxamide hydrochloride;

[0064] N-(3-methoxybenzoyl)piperazine-1-carboxamide hydrochloride;

[0065] N-(3-Chlorobenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate;

[0066] N-(3-methylbenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; and

[0067] N-(3-methoxybenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate.

[0068] 6. A pharmaceutical composition for the prevention or treatment of symptoms associated with mood and behavioral disorders, said pharmaceutical composition comprising a compound, its stereoisomer, or a pharmaceutically acceptable salt as defined in any one of 1 to 5 above.

[0069] 7. The pharmaceutical composition according to 6 above, wherein the symptoms associated with mood and behavioral disorders are selected from any one of the group consisting of lack of social skills, lack of social cognitive skills, stereotyped behaviors, hyperactivity, impulsivity and inattention.

[0070] 8. A pharmaceutical composition for the prevention or treatment of mood and behavioral disorders, said pharmaceutical composition comprising a compound, its stereoisomer, or a pharmaceutically acceptable salt as defined in any one of 1 to 5 above.

[0071] 9. A pharmaceutical composition for the prevention or treatment of degenerative neurological diseases, said pharmaceutical composition comprising a compound, its stereoisomer, or a pharmaceutically acceptable salt as defined in any one of 1 to 5 above.

[0072] 10. The pharmaceutical composition according to 8 above, wherein the mood and behavioral disorder is selected from any one of the group consisting of autism spectrum disorder, schizophrenia, obsessive-compulsive disorder, depression, anxiety disorder, panic disorder and attention deficit hyperactivity disorder.

[0073] The effects of the invention

[0074] The novel compounds of the present invention, their stereoisomers, or pharmaceutically acceptable salts are used as agmatinase inhibitors and are effective in improving mood and behavioral disorders and related symptoms. Attached Figure Description

[0075] Figure 1 The guanidine amino acid inhibitory activities of some of the compounds of the present invention shown in Tables 1 to 7 are illustrated.

[0076] Figure 2 The results demonstrate the social improvement effect of treating VPA mice with the compounds of the present invention.

[0077] Figure 3 The results demonstrate the cognitive improvement effect of treating VPA mice with the compounds of the present invention.

[0078] Figure 4 The self-grooming test is shown in an animal model of autism induced by valproic acid (VPA).

[0079] Figure 5 and Figure 6 The protective effect on neuronal cells induced by treatment with the compounds of the present invention is shown. Detailed Implementation

[0080] The present invention will be described in detail below.

[0081] Unless otherwise defined, all technical terms used in this invention are used in the same sense as would be commonly understood by those skilled in the art in the relevant field of this invention. Furthermore, while preferred methods or examples will be described in this specification, similar or equivalent methods are also included within the scope of this invention.

[0082] This invention relates to compounds represented by Formula 1, their stereoisomers, or pharmaceutically acceptable salts:

[0083] [Formula 1]

[0084]

[0085] In the above formula, if a substituent is required at a site but no substituent is shown at that site, it means that the hydrogen substituent is omitted. This applies to all formulas in this invention.

[0086] In the above formula, R1 is hydrogen or tert-butoxycarbonyl.

[0087] In the above formula, A is C5-C 10 It can be a monocyclic or bicyclic group, and can be, for example, benzene, naphthalene, indene, cyclopent-1,3-diene, cyclohexane, tetrahydronaphthalene, etc., but is not limited thereto.

[0088] Each ring of a cyclic group can be replaced by one to three heteroatoms, and a heteroatom is an atom other than carbon that can form a ring. For example, one to three heteroatoms can be independently replaced by any one or more of the group consisting of N, S, and O, and they are not limited thereto.

[0089] In cyclic groups, the sites where heteroatoms can be substituted can be the same as Q1 to Q3 in the structures listed below, but they are not limited thereto.

[0090]

[0091] The cyclic group can be substituted with halogen, C1-C5 alkyl, C1-C5 alkoxy, CN or NO2, and can be, for example, F, Cl, Br, methyl (Me), ethyl (Et), methoxy (OMe), ethoxy (OEt), CN and NO2, but is not limited thereto.

[0092] In cyclic groups, heteroatoms can be substituted at sites that are the same as R2 to R4, such as halogens, C1-C5 alkyl groups, C1-C5 alkoxy groups, CN groups, or NO2 groups, but they are not limited to these sites.

[0093] According to one embodiment of the present invention, A may be selected from the following cyclic groups.

[0094]

[0095] R2, R3, and R4 are each independently hydrogen, halogen, C1-C5 alkyl, C1-C5 alkoxy, CN, or NO2, and

[0096] Q1, Q2, and R3 are each independently N, O, or S.

[0097] Furthermore, according to one embodiment of the present invention, more specifically, A may be selected from the following cyclic groups.

[0098]

[0099] (where R2, R3, and R4 are each independently hydrogen, halogen, C1-C5 alkyl, C1-C5 alkoxy, CN, or NO2, and)

[0100] Q1, Q2, and Q3 are each independently N, O, or S.

[0101] Furthermore, according to one embodiment of the present invention, most specifically, A may be selected from the following cyclic groups.

[0102]

[0103] (where R2, R3 and R4 are each independently hydrogen, halogen, C1-C5 alkyl, C1-C5 alkoxy, CN or NO2).

[0104] Tables 1 to 7 below illustrate examples of the structures of compounds represented by Formula 1, along with some of their pharmaceutically acceptable salts, through combinations of R1 and A in the compounds represented by Formula 1. The order in the tables indicates the compound numbers in this specification.

[0105] [Table 1]

[0106]

[0107] [Table 2]

[0108]

[0109] [Table 3]

[0110]

[0111] [Table 4]

[0112]

[0113] [Table 5]

[0114]

[0115] [Table 6]

[0116]

[0117] [Table 7]

[0118]

[0119] This invention relates to compounds selected from the group consisting of: compounds and their stereoisomers or pharmaceutically acceptable salts:

[0120] 4-((4-methylbenzoyl)carbamoyl)piperazine-1-carboxylic acid tert-butyl ester;

[0121] 4-((4-methoxybenzoyl)carbamoyl)piperazine-1-carboxylic acid tert-butyl ester;

[0122] 4-((4-chlorobenzoyl)carbamoyl)piperazine-1-carboxylic acid tert-butyl ester;

[0123] 4-(benzoylcarbamoyl)piperazine-1-carboxylic acid tert-butyl ester;

[0124] N-(4-methylbenzoyl)piperazine-1-carboxamide;

[0125] N-(4-methylbenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate;

[0126] N-(4-methoxybenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate;

[0127] N-(4-chlorobenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate;

[0128] N-benzoylpiperazine-1-carboxamide-2,2,2-trifluoroacetate;

[0129] N-(2-Naphthoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate;

[0130] N-(4-cyanobenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate;

[0131] N-(furan-2-carbonyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate;

[0132] N-(4-nitrobenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate;

[0133] N-(2-Naphthoyl)piperazine-1-carboxamide hydrochloride;

[0134] N-(4-cyanobenzoyl)piperazine-1-carboxamide hydrochloride;

[0135] N-(4-Nitrobenzoyl)piperazine-1-carboxamide hydrochloride;

[0136] N-benzoylpiperazine-1-carboxamide hydrochloride;

[0137] N-(furan-2-carbonyl)piperazine-1-carboxamide hydrochloride;

[0138] N-(4-methylbenzoyl)piperazine-1-carboxamide hydrochloride;

[0139] N-(4-methoxybenzoyl)piperazine-1-carboxamide hydrochloride;

[0140] N-(4-Chlorobenzoyl)piperazine-1-carboxamide hydrochloride;

[0141] N-(2,4-dichlorobenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate;

[0142] N-(4-bromobenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate;

[0143] N-(thiophene-2-carbonyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate;

[0144] N-(benzo[b]thiophene-2-carbonyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate;

[0145] N-(4-fluorobenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate;

[0146] N-Isoninoylpiperazine-1-carboxamide-2,2,2-trifluoroacetate;

[0147] N-(2,4-dichlorobenzoyl)piperazine-1-carboxamide hydrochloride;

[0148] N-(4-bromobenzoyl)piperazine-1-carboxamide hydrochloride;

[0149] N-(benzo[b]thiophene-2-carbonyl)piperazine-1-carboxamide hydrochloride;

[0150] N-Isoninoylpiperazine-1-carboxamide hydrochloride;

[0151] N-(4-fluorobenzoyl)piperazine-1-carboxamide hydrochloride;

[0152] N-(thiophene-2-carbonyl)piperazine-1-carboxamide hydrochloride;

[0153] N-(3-Chlorobenzoyl)piperazine-1-carboxamide hydrochloride;

[0154] N-(3-methylbenzoyl)piperazine-1-carboxamide hydrochloride;

[0155] N-(3-methoxybenzoyl)piperazine-1-carboxamide hydrochloride;

[0156] N-(3-Chlorobenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate;

[0157] N-(3-methylbenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate; and

[0158] N-(3-methoxybenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate.

[0159] Furthermore, the present invention relates to pharmaceutical compositions comprising the compound, its stereoisomers, or pharmaceutically acceptable salts.

[0160] Guanidinase is an enzyme that breaks down guanidine, and it has been confirmed that guanidine levels are reduced in some patients with autism, which has been identified as being due to excessive activity of guanidinase. Furthermore, inhibition of guanidinase is expected to suppress overactive neural activity and therefore holds promise for preventative or therapeutic effects on mood and behavioral disorders and their associated symptoms. Since the compounds of the present invention possess guanidinase inhibitory activity, it is understood that the aforementioned effects are contemplated.

[0161] The pharmaceutical composition may be a pharmaceutical composition for the prevention or treatment of symptoms associated with mood and behavioral disorders, and specifically, symptoms associated with mood and behavioral disorders may include, but are not limited to, lack of social skills, lack of social cognitive skills, stereotyped behaviors, hyperactivity, impulsivity and inattention.

[0162] In this invention, a lack of social competence refers to a condition in which the patient is unable to form normal, healthy relationships with others who require contact with them or with people around them, or lacks a normal social life. For example, this condition refers to a state in which a person is unable to integrate into relationships with others and instead remains immersed in their own world.

[0163] In this invention, a lack of social cognitive ability refers to a state of lacking social cognitive ability, which is the inherent ability to determine social behaviors that contribute to adapting to interpersonal relationships or social life. For example, it refers to a state of not exhibiting behavior that understands and infers facial expressions, actions, emotions, etc., and not normally performing the customary, moral, and appropriate behaviors required in group interactions.

[0164] In this invention, stereotyped behavior refers to continuous and repetitive behaviors, such as swaying the body back and forth, waving the hands continuously, repeating meaningless sounds, etc., and continuously repeating the same behavior regardless of the surrounding circumstances.

[0165] In this invention, hyperactivity is also called excessive behavior, which refers to abnormally excessive activity or movement, and signifies a state that interferes with learning and causes serious problems in behavioral control.

[0166] In this invention, impulse refers to the tendency to act suddenly in response to an inner impulse without thinking and with little regard for the consequences of the action.

[0167] In this invention, distraction refers to a state in which one is unable to perform an activity continuously, lacks persistence, and quickly switches to another activity or feels confused about what to do.

[0168] In addition, the pharmaceutical composition may be a pharmaceutical composition for the prevention or treatment of mood and behavioral disorders, specifically a pharmaceutical composition for the prevention or treatment of autism spectrum disorder, schizophrenia, obsessive-compulsive disorder, depression, anxiety disorder, panic disorder and attention deficit hyperactivity disorder, but is not limited thereto.

[0169] In this invention, autism spectrum disorder, also known as autism spectrum disorder, refers to a typical developmental disorder characterized by severe maladaptive impairment. Essentially, it is characterized by deficits in social interaction and communication skills, limited, repetitive, and stereotyped behavioral features, and a highly diverse range of behaviors, skills, preferences, functional performance, and learning required for development.

[0170] In this invention, schizophrenia refers to the illness formerly known as mental illness, and specifically to a mental disorder that causes a wide range of clinical abnormalities in various aspects of personality, such as thinking, emotion, perception, and behavior. Schizophrenia occurs in different types and is not a single disease, but rather identified as a group of diseases consisting of several diseases with common characteristics.

[0171] In this invention, obsessive-compulsive disorder (OCD) refers to a subtype of anxiety disorder in which unwanted thoughts and behaviors are repeated to alleviate OCD and anxiety. These are recurring, distressing thoughts, impulses, or images that permeate consciousness. Repetitive compulsive behaviors are the primary symptom. Compulsive behaviors take the form of cleaning behaviors, checking behaviors, repetitive behaviors, tidying behaviors, and procrastination behaviors. Even when individuals know that the behavior is undesirable and excessive, they repeat it to relieve the anxiety caused by obsessive thoughts.

[0172] In this invention, depression does not refer to a state of temporary low mood, but rather to a state of overall reduced mental function, such as thought content, thought processes, motivation, drive, interest, behavior, sleep and physical activity, which occurs almost all day and every day.

[0173] In this invention, anxiety disorder refers to a mental illness that impairs daily life due to various forms of abnormal or pathological anxiety and fear, including panic disorder, agoraphobia, social anxiety disorder, specific phobia, and separation anxiety disorder.

[0174] In this invention, panic disorder is a type of anxiety disorder, and specifically refers to an anxiety disorder characterized by recurrent panic attacks, including sudden spikes of intense anxiety and intense fear of impending death.

[0175] In this invention, attention deficit hyperactivity disorder (also commonly referred to as ADHD) is a mental illness in which inattention, hyperactivity, and impulsivity are considered as the main symptoms, and is characterized by onset in early childhood and a subsequent chronic course.

[0176] In addition, the pharmaceutical composition can be a pharmaceutical composition used for the prevention or treatment of degenerative neurological diseases.

[0177] Because the compounds of the present invention can improve symptoms of social and cognitive abilities and have the effect of protecting nerve cells from cell damage and death caused by oxidative stress, they can exhibit pharmacological efficacy against a variety of degenerative neurological diseases.

[0178] Neurodegenerative diseases can include, for example, 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, autoimmune diseases of the nervous system, frontotemporal dementia, Lewy body dementia, cortical dysplasia, amyotrophic lateral sclerosis, and memory and cognitive decline, but they are not limited to these.

[0179] In this invention, in addition to the active ingredient of the compound of this invention, pharmaceutical compositions may be prepared using pharmaceutically suitable and physiologically acceptable additives. The compositions can be administered to mammals. As such additives, excipients, disintegrants, sweeteners, binders, coating agents, swelling agents, lubricants, flow aids, or flavoring agents may be used.

[0180] Furthermore, the pharmaceutical compositions of the present invention may preferably be formulated as pharmaceutical compositions comprising, in addition to the pharmaceutically effective amount of active ingredient described above for administration, at least one pharmaceutically acceptable carrier.

[0181] "Pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio suitable for medical treatment, and the effective dose level can be determined based on the type and severity of the patient's disease, drug activity, drug sensitivity, timing of administration, route of administration and excretion rate, duration of treatment, factors including concurrently used drugs, and other factors known in the medical field. The pharmaceutical composition according to the invention can be administered as a single therapeutic agent or in combination with other therapeutic agents. Furthermore, the composition can be administered sequentially or simultaneously with conventional therapeutic agents, and can be administered in single or multiple doses. Taking all the above factors into account, it is important to administer the minimum amount that yields the maximum effect without side effects; such an amount can be readily determined by those skilled in the art.

[0182] Specifically, the effective amount of the pharmaceutical composition according to the invention can vary depending on the patient's age, sex, condition and / or weight, the absorption, inactivation and excretion rate of the active ingredient in the body, the type of disease, and the drugs to be used in combination. Generally, 0.001 to 150 mg, preferably 0.01 to 100 mg per kg of body weight, can be administered daily or every other day, or divided into 1 to 3 doses per day. However, the dosage can be increased or decreased depending on the route of administration, the severity of obesity, sex, weight, age, etc., and therefore does not limit the scope of the invention in any way.

[0183] In addition, "pharmaceutical acceptable" means a composition that is physiologically acceptable and, when administered to humans, will not typically cause allergic reactions such as gastrointestinal symptoms and dizziness or similar reactions.

[0184] Examples of carriers, excipients, and diluents may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, polyvinylpyrrolidone, water, methylparaben, propylparaben, talc, magnesium stearate, and mineral oil. Additionally, fillers, anti-aggregating agents, lubricants, wetting agents, flavoring agents, emulsifiers, and preservatives may be included.

[0185] Furthermore, the compositions of the present invention can be formulated using any method known in the art to provide rapid, sustained, or delayed release of the active ingredient after administration to subjects, including humans, who require treatment with the pharmaceutical compositions of the present invention. Formulations may be powders, granules, tablets, emulsions, syrups, aerosols, soft or hard gelatin capsules, sterile solutions for injection, or sterile powders for injection.

[0186] The compounds represented by Formula 1 according to the present invention can be prepared by any method known in various literatures. The following preparation examples briefly describe the synthetic methods of some compounds listed in Table 1; however, they are not limited thereto.

[0187] The present invention will be described in detail below with the aid of preparation examples and embodiments.

[0188] Preparation Example

[0189] 1. Synthesis of Compound 1

[0190] [Option 1]

[0191]

[0192] A solution of SMI (1 mmol) and anhydrous THF (10 mL) was placed in a flame-dried round-bottom flask equipped with a magnetic stirrer. NaH (5 mmol) was added to the reaction mixture at 0°C and the mixture was stirred under nitrogen for approximately 2 h. Then, aryl chloride (SMII, 2 mmol) in THF (5 mL) was slowly added to the reaction mixture and stirred overnight. A saturated ammonium chloride solution (7–10 mL) was added to the reaction mixture and extracted with CH₂Cl₂. The organic layer was dried over MgSO₄, filtered, and concentrated under vacuum to give a white solid. The residue was purified by rapid column chromatography using n-hexane:ethyl acetate (4:1 and 2:1) to obtain the desired product as a white solid.

[0193] Retention factor: 0.41 (H:E = 1:1)

[0194] Yield: 229 mg (66%)

[0195] NMR data: 1H NMR (500 MHz, CDCl3): δ 8.44 (s, 1H), 7.76 (d, J = 8.15 Hz, 2H), 7.27–7.26 (m, 2H, overlapping with CDCl3), 3.52 (s, 8H), 2.41 (s, 3H), 1.47 (s, 9H).

[0196] 2. Synthesis of Compound 3

[0197] [Option 2]

[0198]

[0199] A solution of SMI (1 mmol) and anhydrous THF (10 mL) was placed in a flame-dried round-bottom flask equipped with a magnetic stirrer. NaH (5 mmol) was added to the reaction mixture at 0°C and the mixture was stirred under nitrogen for approximately 2 h. Then, aryl chloride (SMII, 2 mmol) in THF (5 mL) was slowly added to the reaction mixture and stirred overnight. A saturated ammonium chloride solution (7–10 mL) was added to the reaction mixture and extracted with CH₂Cl₂. The organic layer was dried over MgSO₄, filtered, and concentrated under vacuum to give a white solid. The residue was purified by rapid column chromatography using n-hexane:ethyl acetate (4:1 and 2:1) to obtain the desired product as a white solid.

[0200] Retention factor: 0.30 (H:E = 1:1)

[0201] Yield: 225 mg (62%)

[0202] NMR data: 1H NMR (500 MHz, CDCl3): δ 8.45 (s, 1H), 7.84 (d, J = 8.75 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 3.87 (s, 3H), 3.52 (s, 8H), 1.47 (s, 9H).

[0203] 3. Synthesis of Compound 5

[0204] [Option 3]

[0205]

[0206] A solution of SMI (1 mmol) and anhydrous THF (10 mL) was placed in a flame-dried round-bottom flask equipped with a magnetic stirrer. NaH (5 mmol) was added to the reaction mixture at 0°C and the mixture was stirred under nitrogen for approximately 2 h. Then, aryl chloride (SMII, 2 mmol) in THF (5 mL) was slowly added to the reaction mixture and stirred overnight. A saturated ammonium chloride solution (7–10 mL) was added to the reaction mixture and extracted with CH₂Cl₂. The organic layer was dried over MgSO₄, filtered, and concentrated under vacuum to give a white solid. The residue was purified by rapid column chromatography using n-hexane:ethyl acetate (4:1 and 2:1) to obtain the desired product as a white solid.

[0207] Retention factor: 0.43 (H:E = 1:1)

[0208] Yield: 220 mg (60%)

[0209] NMR data: 1H NMR (500 MHz CDCl3): δ 9.13 (s, 1H), 7.85 (d, J = 8.35 Hz, 2H), 7.50 (d, J = 8.65 Hz, 2H), 3.52 (s, 8H), 1.48 (s, 9H).

[0210] 4. Synthesis of Compound 6

[0211] [Option 4]

[0212]

[0213] A solution of SMI (1 mmol) and anhydrous THF (10 mL) was placed in a flame-dried round-bottom flask equipped with a magnetic stirrer. NaH (5 mmol) was added to the reaction mixture at 0°C and the mixture was stirred under nitrogen for approximately 2 h. Then, aryl chloride (SMII, 2 mmol) in THF (5 mL) was slowly added to the reaction mixture and stirred overnight. A saturated ammonium chloride solution (7–10 mL) was added to the reaction mixture and extracted with CH₂Cl₂. The organic layer was dried over MgSO₄, filtered, and concentrated under vacuum to give a white solid. The residue was purified by rapid column chromatography using n-hexane:ethyl acetate (4:1 and 2:1) to obtain the desired product as a white solid.

[0214] Retention factor: 0.40 (H:E = 1:1)

[0215] Yield: 234 (70%)

[0216] NMR data: 1H NMR (500 MHz, CDCl3): δ 8.32 (s, 1H), 7.85 (d, J = 7.1 Hz, 2H), 7.59–7.56 (m, 1H), 7.49–7.46 (m, 2H), 3.52 (s, 8H), 1.47 (s, 9H).

[0217] 5. Synthesis of Compound 28

[0218] [Option 5]

[0219]

[0220] A solution of anhydrous CH2Cl2 (3 ml) and SMI (0.28 mmol) was 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 under vacuum and dissolved in water. The pH of the RM was adjusted to neutral using NaOH and extracted with CH2Cl2. The RM was dried over MgSO4 and evaporated. Column chromatography was performed using a CH2Cl2:MeOH concentration gradient to obtain the desired product in a viscous liquid state.

[0221] Retention factor: 0.41 (H:E:EtOH = 1:1)

[0222] Yield: 14mg (> 20%)

[0223] NMR data: 1H NMR (500 MHz, DMSO): δ 7.75–7.74 (m, 2H), 7.29–7.27 (m, 4H, overlapping with CDCl3), 3.55 (s, 4H), 2.96–2.94 (m, 4H), 2.43 (s, 3H).

[0224] 6. Synthesis of Compound 29

[0225] [Option 6]

[0226]

[0227] A solution of anhydrous CH2Cl2 (3 ml) and SMI (0.32 mmol) was placed in a flame-dried round-bottom flask equipped with a magnetic stirrer. TFA (6.4 mmol) was added to the RM and the mixture was stirred overnight. The RM was then concentrated under vacuum using methanol and dichloromethane (DCM) to obtain a solid product. The obtained product was washed with DCM and filtered to obtain the desired product as a white solid.

[0228] Retention factor: NA

[0229] Yield: 106 mg (92%)

[0230] NMR data: 1H NMR (500 MHz, DMSO): δ 10.31 (s, 1H), 9.24 (s, 2H), 7.79 (d, J = 7.7 Hz, 2H), 7.30 (d, J = 7.75 Hz, 2H), 3.64 (s, 4H), 3.16 (s, 4H), 2.36 (s, 3H).

[0231] 7. Synthesis of Compound 32

[0232] [Option 7]

[0233]

[0234] A solution of anhydrous CH2Cl2 (3 ml) and SMI (0.27 mmol) was placed in a flame-dried round-bottom flask equipped with a magnetic stirrer. TFA (5.4 mmol) was added to the RM and the mixture was stirred overnight. The RM was then concentrated under vacuum using methanol and dichloromethane (DCM) to obtain a solid product. The obtained product was washed with DCM and filtered to obtain the desired product as a white solid.

[0235] Retention factor: NA

[0236] Yield: 88 mg (87%)

[0237] NMR data: 1H NMR (500 MHz, DMSO): δ 10.26 (s, 1H), 9.27 (s, 2H), 7.88 (d, J = 8.45 Hz, 2H), 7.01 (d, J = 8.45 Hz, 2H), 3.81 (s, 3H), 3.64 (s, 4H), 3.17 (s, 4H).

[0238] 8. Synthesis of Compound 35

[0239] [Option 8]

[0240]

[0241] A solution of anhydrous CH2Cl2 (3 ml) and SMI (0.32 mmol) was placed in a flame-dried round-bottom flask equipped with a magnetic stirrer. TFA (6.4 mmol) was added to the RM and the mixture was stirred overnight. The RM was then concentrated under vacuum using methanol and dichloromethane (DCM) to obtain a solid product. The obtained product was washed with DCM and filtered to obtain the desired product as a white solid.

[0242] Retention factor: NA

[0243] Yield: 117% (96%)

[0244] NMR data: 1H NMR (500 MHz, DMSO): δ 10.48 (s, 1H), 9.16 (s, 2H), 7.88 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 8.1 Hz, m, 2H), 3.65–3.63 (m, 4H), 3.16–3.15 (m, 4H).

[0245] 9. Synthesis of Compound 37

[0246] [Option 9]

[0247]

[0248] A solution of anhydrous CH2Cl2 (5 ml) and SMI (0.42 mmol) was placed in a flame-dried round-bottom flask equipped with a magnetic stirrer. TFA (8.4 mmol) was added to the RM and the mixture was stirred overnight. The RM was then concentrated under vacuum using methanol and dichloromethane (DCM) to obtain a solid product. The obtained product was washed with DCM and filtered to obtain the desired product as a white solid.

[0249] Retention factor: NA

[0250] Yield: 144 mg (99%)

[0251] NMR data: 1H NMR (500 MHz, DMSO): δ 10.38 (s, 1H), 9.01 (s, 2H), 7.87 (d, J = 7.4 Hz, 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).

[0252] 10. Synthesis of Compound 76

[0253] [Option 10]

[0254]

[0255] A solution of anhydrous CH2Cl2 (3 ml) and SMI (0.31 mmol) was placed in a flame-dried round-bottom flask equipped with a magnetic stirrer. TFA (6.2 mmol) was added to the RM and the mixture was stirred overnight. The RM was then concentrated under vacuum using methanol and dichloromethane (DCM) to obtain a solid product. The obtained product was washed with DCM and filtered to obtain the desired product as a white solid.

[0256] Retention factor: NA

[0257] Yield: 110 mg (90%)

[0258] NMR data: 1H NMR (500 MHz, DMSO): δ 10.53 (s, 1H), 8.89 (s, 2H), 8.50 (s, 1H), 8.00–7.99 (m, 3H), 7.90 (d, J = 8.55 Hz, 1H), 7.66–7.60 (m, 2H), 3.67–3.65 (m, 4H), 3.17 (s, 4H).

[0259] 11. Synthesis of Compound 39

[0260] [Option 11]

[0261]

[0262] A solution of anhydrous CH2Cl2 (3 ml) and SMI (0.39 mmol) was placed in a flame-dried round-bottom flask equipped with a magnetic stirrer. TFA (7.8 mmol) was added to the RM and the mixture was stirred overnight. The RM was then concentrated under vacuum using methanol and dichloromethane (DCM) to obtain a solid product. The obtained product was washed with DCM and filtered to obtain the desired product as a white solid.

[0263] Retention factor: NA

[0264] Yield: 132 mg (91%)

[0265] NMR data: 1H NMR (500 MHz, DMSO): δ 10.66 (s, 1H), 9.03 (s, 2H), 7.97 (s, 4H), 3.64-3.62 (m, 4H), 3.14 (s, 4H).

[0266] 12. Synthesis of Compound 102

[0267] [Option 12]

[0268]

[0269] A solution of anhydrous CH2Cl2 (5 ml) and SMI (0.43 mmol) was placed in a flame-dried round-bottom flask equipped with a magnetic stirrer. TFA (8.6 mmol) was added to the RM and the mixture was stirred overnight. The RM was then concentrated under vacuum using methanol and dichloromethane (DCM) to obtain a solid product. The obtained product was washed with DCM and filtered to obtain the desired product as a white solid.

[0270] Retention factor: NA

[0271] Yield: 123 mg (85%)

[0272] NMR data: 1H NMR (500 MHz, DMSO): δ 10.29 (s, 1H), 8.90 (s, 2H), 7.94 (d, J = 1.65 Hz, 1H), 7.37 (d, J = 3.5 Hz, 1H), 6.69–6.68 (m, 1H), 3.61–3.59 (m, 4H), 3.13 (s, 4H).

[0273] 13. Synthesis of Compound 41

[0274] [Option 13]

[0275]

[0276] A solution of anhydrous CH2Cl2 (3 ml) and SMI (0.37 mmol) was placed in a flame-dried round-bottom flask equipped with a magnetic stirrer. TFA (7.4 mmol) was added to the RM and the mixture was stirred overnight. The RM was then concentrated under vacuum using methanol and dichloromethane (DCM) to obtain a solid product. The obtained product was washed with DCM and filtered to obtain the desired product as a white solid.

[0277] Retention factor: NA

[0278] Yield: 135mg (93%)

[0279] NMR data: 1H NMR (500 MHz, DMSO): δ 10.73 (s, 1H), 8.92 (s, 2H), 8.32 (d, J = 8.55 Hz, 2H), 8.04 (d, J = 8.5 Hz, 2H), 3.65-3.63 (m, 4H), 3.15 (s, 4H).

[0280] 14. Synthesis of Compound 77

[0281] [Option 14]

[0282]

[0283] A solution of anhydrous CH2Cl2 (2 ml) and SMI (0.31 mmol) was 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 the mixture was stirred overnight. The RM was then filtered to obtain the desired product as a white solid.

[0284] Retention factor: NA

[0285] Yield: 89mg (90%)

[0286] NMR data: 1H NMR (500 MHz, DMSO): δ 10.56 (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 (125 MHz, DMSO): δ 152.6, 134.60, 131.9, 130.41, 129.07, 129.03, 128.2, 128.0, 127.6, 126.9, 124.4, 42.6.

[0287] 15. Synthesis of Compound 40

[0288] [Option 15]

[0289]

[0290] A solution of anhydrous CH2Cl2 (2 ml) and SMI (0.33 mmol) was 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 the mixture was stirred overnight. The RM was then filtered to obtain the desired product as a white solid.

[0291] Retention factor: NA

[0292] Yield: 88.5 mg (91%)

[0293] NMR data: 1H NMR (500 MHz, DMSO): δ 10.70 (s, 1H), 9.44 (s, 2H), 8.00 (s, 4H), 3.69-3.67 (m, 4H), 3.12 (s, 4H); 13C NMR (125 MHz, DMSO): δ 166.1, 152.6,137.8, 132.8, 129.3, 118.6, 114.8, 43.0.

[0294] 16. Synthesis of Compound 42

[0295] [Option 16]

[0296]

[0297] A solution of anhydrous CH2Cl2 (5 ml) and SMI (0.37 mmol) was 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 the mixture was stirred overnight. The RM was then filtered to obtain the desired product as a white solid.

[0298] Retention factor: NA

[0299] Yield: 107 mg (92%)

[0300] NMR data: ¹H NMR (500 MHz, DMSO): δ 10.79 (s, 1H), 9.48 (s, 2H), 8.32 (d, J = 8.8 Hz, 2H), 8.07 (d, J = 8.75 Hz, 2H), 3.71–3.69 (m, 4H), 3.13 (s, 4H); ¹³C NMR (125 MHz, DMSO): δ 166.0, 152.6, 149.9, 139.5, 130.0, 123.9, 43.0.

[0301] 17. Synthesis of Compound 38

[0302] [Option 17]

[0303]

[0304] A solution of anhydrous CH2Cl2 (2 ml) and SMI (0.33 mmol) was 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 the mixture was stirred overnight. The RM was then filtered to obtain the desired product as a white solid.

[0305] Retention factor: NA

[0306] Yield: 83 mg (93.24%)

[0307] NMR data: 1H NMR (500 MHz, DMSO): δ 10.42 (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).

[0308] 18. Synthesis of Compound 103

[0309] [Option 18]

[0310]

[0311] A solution of anhydrous CH2Cl2 (2 ml) and SMI (0.40 mmol) was 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 the mixture was stirred overnight. The RM was then filtered to obtain the desired product as a white solid.

[0312] Retention factor: NA

[0313] Yield: 91.5 mg (88%)

[0314] NMR data: 1H NMR (500 MHz, DMSO): δ10.32(s, 1H), 9.49(s, 2H), 7.93(d, J= 1.5 Hz, 1H), 7.42(d, J = 3.4 Hz, 1H), 6.67(dd, J = 3.55, 1.7 Hz, 1H), 3.66-3.64(m, 4H), 3.10-3.09(m, 4H); 13C NMR (125 MHz, DMSO): δ 156.6, 151.9, 146.7, 146.1, 116.5, 112.2, 42.5.

[0315] 19. Synthesis of Compound 30

[0316] [Option 19]

[0317]

[0318] A solution of anhydrous CH2Cl2 (2 ml) and SMI (0.28 mmol) was 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 the mixture was stirred overnight. The RM was then filtered to obtain the desired product as a white solid.

[0319] Retention factor: NA

[0320] Yield: 73 mg (92%)

[0321] NMR data: 1H NMR (500 MHz, DMSO): δ 10.30 (s, 1H), 9.44 (s, 2H), 7.78 (d, J = 8.2 Hz, 2H), 7.30–7.29 (m, 2H), 3.67–3.66 (m, 4H), 3.11 (s, 4H), 2.36 (s, 3H); 13C NMR (125 MHz, DMSO): δ 166.3, 152.7, 142.6, 130.2, 128.9, 128.2, 42.5, 21.0.

[0322] 20. Synthesis of Compound 33

[0323] [Option 20]

[0324]

[0325] A solution of anhydrous CH2Cl2 (2 ml) and SMI (0.31 mmol) was 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 the mixture was stirred overnight. The RM was then filtered to obtain the desired product as a white solid.

[0326] Retention factor: NA

[0327] Yield: 84.56 mg (91%)

[0328] NMR data: ¹H NMR (500 MHz, DMSO): δ 10.22 (s, 1H), 9.45 (s, 2H), 7.88 (d, J = 8.85 Hz, 2H), 7.02 (d, J = 8.9 Hz, 2H), 3.82 (s, 3H), 3.66–3.64 (m, 4H), 3.11 (s, 4H); ¹³C NMR (125 MHz, DMSO): δ 166.7, 162.5, 152.9, 130.3, 125.0, 113.6, 55.5, 42.5.

[0329] 21. Synthesis of Compound 36

[0330] [Option 21]

[0331]

[0332] A solution of anhydrous CH2Cl2 (2 ml) and SMI (0.38 mmol) was 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 the mixture was stirred overnight. The RM was then filtered to obtain the desired product as a white solid.

[0333] Retention factor: NA

[0334] Yield: 106 mg (92%)

[0335] NMR data: ¹H NMR (500 MHz, DMSO): δ 10.50 (s, ¹H), 9.50 (s, 2H), 7.89 (d, J = 8.86 Hz, 2H), 7.57 (d, J = 8.6 Hz, 2H), 3.68–3.66 (m, 4H), 3.11 (s, 4H); ¹³C NMR (125 MHz, DMSO): δ 165.6, 152.4, 137.1, 131.9, 130.1, 128.4, 42.5.

[0336] 22. Synthesis of Compound 43

[0337] [Option 22]

[0338]

[0339] A solution of anhydrous CH2Cl2 (5 ml) and SMI (0.38 mmol) was placed in a flame-dried round-bottom flask equipped with a magnetic stirrer. TFA (7.6 mmol) was added to the RM and the mixture was stirred overnight. The RM was then concentrated under vacuum using methanol and dichloromethane (DCM) to obtain a solid product. The obtained product was washed with DCM and filtered to obtain the desired product as a white solid.

[0340] Retention factor: NA

[0341] Yield: 142 mg (90%)

[0342] NMR data: 1H NMR (500 MHz, DMSO): δ 10.73 (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).

[0343] 23. Synthesis of Compound 45

[0344] [Option 23]

[0345]

[0346] A solution of anhydrous CH2Cl2 (5 ml) and SMI (0.26 mmol) was placed in a flame-dried round-bottom flask equipped with a magnetic stirrer. TFA (5.2 mmol) was added to the RM and the mixture was stirred overnight. The RM was then concentrated under vacuum using methanol and dichloromethane (DCM) to obtain a solid product. The obtained product was washed with DCM and filtered to obtain the desired product as a white solid.

[0347] Retention factor: NA

[0348] Yield: 97.5 mg (88%)

[0349] NMR data: 1H NMR (500 MHz, DMSO): δ 10.48 (s, 1H), 9.14 (s, 2H), 7.80-7.71 (m, 4H), 3.64 (s, 4H), 3.16 (s, 4H).

[0350] 24. Synthesis of Compound 104

[0351] [Option 24]

[0352]

[0353] A solution of anhydrous CH2Cl2 (5 ml) and SMI (0.32 mmol) was placed in a flame-dried round-bottom flask equipped with a magnetic stirrer. TFA (6.4 mmol) was added to the RM and the mixture was stirred overnight. The RM was then concentrated under vacuum using methanol and dichloromethane (DCM) to obtain a solid product. The obtained product was washed with DCM and filtered to obtain the desired product as a white solid.

[0354] Retention factor: NA

[0355] Yield: 104 mg (92%)

[0356] NMR data: 1H NMR (500 MHz, DMSO): δ 10.42 (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).

[0357] 25. Synthesis of Compound 129

[0358] [Option 25]

[0359]

[0360] A solution of anhydrous CH2Cl2 (5 ml) and SMI (0.23 mmol) was placed in a flame-dried round-bottom flask equipped with a magnetic stirrer. TFA (4.6 mmol) was added to the RM and the mixture was stirred overnight. The RM was then concentrated under vacuum using methanol and dichloromethane (DCM) to obtain a solid product. The obtained product was washed with DCM and filtered to obtain the desired product as a white solid.

[0361] Retention factor: NA

[0362] Yield: 79 mg (85%)

[0363] NMR data: 1H NMR (500 MHz, DMSO): δ 10.68 (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).

[0364] 26. Synthesis of Compound 47

[0365] [Option 26]

[0366]

[0367] A solution of anhydrous CH2Cl2 (5 ml) and SMI (0.36 mmol) was placed in a flame-dried round-bottom flask equipped with a magnetic stirrer. TFA (7.2 mmol) was added to the RM and the mixture was stirred overnight. The RM was then concentrated under vacuum using methanol and dichloromethane (DCM) to obtain a solid product. The obtained product was washed with DCM and filtered to obtain the desired product as a white solid.

[0368] Retention factor: NA

[0369] Yield: 105 mg (80%)

[0370] NMR data: 1H NMR (500 MHz, DMSO): δ 10.42 (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).

[0371] 27. Synthesis of Compound 154

[0372] [Option 27]

[0373]

[0374] A solution of anhydrous CH2Cl2 (5 ml) and SMI (0.50 mmol) was placed in a flame-dried round-bottom flask equipped with a magnetic stirrer. TFA (10 mmol) was added to the RM and the mixture was stirred overnight. The RM was then concentrated under vacuum using methanol and dichloromethane (DCM) to obtain a solid product. The obtained product was washed with DCM and filtered to obtain the desired product as a white solid.

[0375] Retention factor: NA

[0376] Yield: 150 mg (86.13)

[0377] NMR data: 1H NMR (500 MHz, DMSO): δ 10.82 (s, 1H), 9.31 (s, 2H), 8.80 (s, 2H), 7.82 (s, 2H), 3.67 (s, 4H), 3.17 (s, 4H).

[0378] 28. Synthesis of Compound 44

[0379] [Option 28]

[0380]

[0381] A solution of anhydrous CH2Cl2 (2 ml) and SMI (0.20 mmol) was placed in a flame-dried round-bottom flask equipped with a magnetic stirrer. HCl (2 mmol) in 1 ml of diethyl ether was added to the RM at 0 °C and the mixture was stirred overnight. The RM was then filtered to obtain the desired product as a white solid.

[0382] Retention factor: NA

[0383] Yield: 62 mg (91.55%)

[0384] NMR data: 1H NMR (500 MHz, DMSO): δ 10.79 (s, 1H), 9.46 (s, 2H), 7.69 (d, J = 1.85 Hz, 1H), 7.54–7.48 (m, 2H), 3.66–3.64 (m, 4H), 3.10–3.08 (m, 4H).

[0385] 29. Synthesis of Compound 46

[0386] [Option 29]

[0387]

[0388] A solution of anhydrous CH2Cl2 (2 ml) and SMI (0.19 mmol) was placed in a flame-dried round-bottom flask equipped with a magnetic stirrer. HCl (2 mmol) in 0.95 ml of diethyl ether was added to the RM and stirred overnight. The RM was then filtered to obtain the desired product as a white solid.

[0389] Retention factor: NA

[0390] Yield: 61 mg (92.10%)

[0391] NMR data: ¹H NMR (500 MHz, DMSO): δ 10.51 (s, ¹H), 9.53 (s, 2H), 7.81 (d, J = 8.6 Hz, 2H), 7.70 (d, J = 8.6 Hz, 2H), 3.68–3.66 (m, 4H), 3.10 (s, 4H); ¹³C NMR (125 MHz, DMSO): δ 165.8, 152.4, 132.3, 131.4, 130.2, 126.2, 42.5.

[0392] 30. Synthesis of Compound 130

[0393] [Option 30]

[0394]

[0395] A solution of anhydrous CH2Cl2 (2 ml) and SMI (0.21 mmol) was placed in a flame-dried round-bottom flask equipped with a magnetic stirrer. HCl (2 mmol) in 1.05 ml of diethyl ether was added to the RM at 0 °C and the mixture was stirred overnight. The RM was then filtered to obtain the desired product as a white solid.

[0396] Retention factor: NA

[0397] Yield: 60 mg (87.70%)

[0398] NMR data: 1H NMR (500 MHz, DMSO): δ 10.76 (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).

[0399] 31. Synthesis of Compound 155

[0400] [Option 31]

[0401]

[0402] A solution of anhydrous CH2Cl2 (2 ml) and SMI (1 mmol) was placed in a flame-dried round-bottom flask equipped with a magnetic stirrer. HCl (2 mmol) in ether (2 ml) was added to the RM at 0 °C and stirred overnight. The RM was then filtered to obtain the desired product as a white solid.

[0403] Retention factor: NA

[0404] Yield: 97 mg (89.50%)

[0405] NMR data: 1H NMR (500 MHz, DMSO): δ 11.17 (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).

[0406] 32. Synthesis of Compound 48

[0407] [Option 32]

[0408]

[0409] A solution of anhydrous CH2Cl2 (2 ml) and SMI (0.31 mmol) was added to 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 the mixture was stirred overnight at room temperature. The RM was then filtered to obtain the desired product as a white solid.

[0410] Retention factor: NA

[0411] Yield: > 90%

[0412] NMR data: 1H NMR (500 MHz, DMSO): δ 10.45 (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).

[0413] 33. Synthesis of Compound 105

[0414] [Option 33]

[0415]

[0416] A solution of anhydrous CH2Cl2 (2 ml) and SMI (0.35 mmol) was added to 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 the mixture was stirred overnight at room temperature. The RM was then filtered to obtain the desired product as a white solid.

[0417] Retention factor: NA

[0418] Yield: > 90%

[0419] NMR data: 1H NMR (500 MHz, DMSO): δ 10.46(s, 1H), 9.35(s, 2H), 8.02-8.01(m, 1H), 7.92-7.91(m, 1H), 7.21(dd, J = 5, 3.8 Hz, 1H), 3.69-3.66(m, 4H),3.12-3.10(m, 4H).

[0420] 34. Synthesis of Compound 51

[0421] [Option 34]

[0422]

[0423] A solution of anhydrous CH2Cl2 (2 ml) and SMI (0.30 mmol) was added to 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 the mixture was stirred overnight at room temperature. The RM was then filtered to obtain the desired product as a white solid.

[0424] Retention factor: NA

[0425] Yield: > 90%

[0426] NMR data: 1H NMR (500 MHz, DMSO): δ 10.54 (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).

[0427] 35. Synthesis of Compound 53

[0428] [Option 35]

[0429]

[0430] A solution of anhydrous CH2Cl2 (2 ml) and SMI (0.30 mmol) was added to 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 the mixture was stirred overnight at room temperature. The RM was then filtered to obtain the desired product as a white solid.

[0431] Retention factor: NA

[0432] Yield: > 85%

[0433] NMR data: 1H NMR (500 MHz, DMSO): δ 10.39 (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).

[0434] 36. Synthesis of Compound 55

[0435] [Option 36]

[0436]

[0437] A solution of anhydrous CH2Cl2 (2 ml) and SMI (0.37 mmol) was added to 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 the mixture was stirred overnight at room temperature. The RM was then filtered to obtain the desired product as a white solid.

[0438] Retention factor: NA

[0439] Yield: > 85%

[0440] NMR data: 1H NMR (500 MHz, DMSO): δ 10.43 (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).

[0441] 37. Synthesis of Compound 52

[0442] [Option 37]

[0443]

[0444] A solution of anhydrous CH2Cl2 (2 ml) and SMI (0.43 mmol) was 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 the mixture was stirred overnight at room temperature. The RM was then concentrated under vacuum using methanol and dichloromethane (DCM) to obtain a solid product. The obtained product was washed with DCM and filtered to obtain the desired product as a white solid.

[0445] Retention factor: NA

[0446] Yield: > 90%

[0447] NMR data: 1H NMR (500 MHz, DMSO): δ 10.52 (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).

[0448] 38. Synthesis of Compound 54

[0449] [Option 38]

[0450]

[0451] A solution of anhydrous CH2Cl2 (2 ml) and SMI (0.40 mmol) was 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 the mixture was stirred overnight at room temperature. The RM was then concentrated under vacuum using methanol and dichloromethane (DCM) to obtain a solid product. The obtained product was washed with DCM and filtered to obtain the desired product as a white solid.

[0452] Retention factor: NA

[0453] Yield: > 85%

[0454] NMR data: 1H NMR (500 MHz, DMSO): δ 10.37 (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).

[0455] 39. Synthesis of Compound 56

[0456] [Option 39]

[0457]

[0458] A solution of anhydrous CH2Cl2 (2 ml) and SMI (0.39 mmol) was 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 the mixture was stirred overnight at room temperature. The RM was then concentrated under vacuum using methanol and dichloromethane (DCM) to obtain a solid product. The obtained product was washed with DCM and filtered to obtain the desired product as a white solid.

[0459] Retention factor: NA

[0460] Yield: > 85%

[0461] NMR data: 1H NMR (500 MHz, DMSO): δ 10.39 (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).

[0462] Example

[0463] 1. Confirm the guanidine aminotransferase inhibitory activity of the compound - using urea assay.

[0464] (1) Experimental reagents and manufacturing methods

[0465] The guanidine amino acid enzyme inhibitory activity of some of the compounds of the present invention shown in Table 1 was measured. Figure 1 ).

[0466] The assay buffer contained Mg was used, and 0.1 ml (final concentration: 2 mg / ml) of guanidine amino acid enzyme (SPEB) and recombinant protein were used.

[0467] (2) Experimental methods and results

[0468] After adding the sample and guanidine aminotransferase to the activity buffer and reacting, 1 μl (final concentration 500 μM) of guanidine aminotransferase was added. Subsequently, an assay was performed to measure the absorbance, and the amount was calculated based on a standard curve.

[0469] The urea concentration is calculated using the following Equation 1.

[0470] [Equation 1]

[0471]

[0472] After treatment with each compound at concentrations of 1 μM, 10 μM, 30 μM, 50 μM, and 300 μM, the guanidine aminotransferase inhibitory activity was determined as a percentage. Figure 1 As shown in the figure, the higher the concentration, the greater the inhibitory activity of guanidine aminotransferase.

[0473] like Figure 1 As shown in the figure, it can be seen that most of the compounds of the present invention exhibit guanidine aminotransferase inhibitory activity.

[0474] 2. Confirm the effects of the compound on improving social skills and cognition in animal models of autism.

[0475] To confirm the therapeutic effect of the compounds according to the invention on a lack of social skills (one of the phenotypes of developmental disorders), a three-compartment test was performed using a valproic acid (VPA)-induced autism animal model. Chamber duration was shown as the time spent in the stranger (time spent in the mouse), the time spent in the empty space (time spent in the empty space), and the time spent in the center (time spent in the center space), and if the mouse spent more time in the stranger than in the empty space, it was considered social.

[0476] As a result of the experiment, in the case of VPA mice, the time spent in open spaces was longer than that spent in mice, which means that socialization was reduced.

[0477] On the other hand, when VPA mice were treated with the compounds of the present invention, it was confirmed that the mice spent more time in open spaces than in open spaces, which means that the social abilities of VPA mice were improved by compound treatment. Figure 2 ).

[0478] Allow a familiar mouse to explore the experimental animal for 10 minutes, then add a new mouse to the animal. After another 10-minute exploration, confirm whether the new mouse spends more time than the familiar mouse. Figure 3 At this point, the previously introduced mice are referred to as familiar, and the newly introduced mice are referred to as new (if the time spent with the new mice is longer than with the familiar mice, then social cognitive ability is considered to exist). In other words, it is determined that they have the cognitive ability to distinguish between existing familiar mice and new mice.

[0479] The experimental results were expressed by measuring the time a test mouse spent exploring each mouse or the time a test mouse spent sniffing each mouse. This means that the more time spent with a new mouse than with a familiar mouse, or the more time spent sniffing a new mouse than with a familiar mouse, the higher the social preference.

[0480] As a result of the experiment, in the case of VPA mice, they spent more time with familiar mice than with new mice, and spent more time sniffing familiar mice than with new mice, which means that their social preference is reduced.

[0481] On the other hand, when VPA mice were treated with the compounds of the present invention, they spent more time with new mice than with familiar mice, and the sniffing time with new mice increased compared to familiar mice. Therefore, it can be seen that treatment with the compounds of the present invention can improve social preference (…). Figures 2 to 3 ).

[0482] By confirming the results of social competence and social preference, when social competence and social preference are improved, the symptoms of social competence and social cognitive ability are improved, and when these symptoms are improved, there is an effect not only on preventing or treating mood and behavioral disorders such as autism spectrum disorder and schizophrenia, but also on preventing or treating cognitive-related intellectual disabilities or degenerative neurological diseases such as Alzheimer's disease and Parkinson's disease. Therefore, it can be predicted that applying the compounds of the present invention to patient populations with mood and behavioral disorders can achieve preventive or therapeutic effects.

[0483] Repetitive behavior experiment

[0484] To confirm the therapeutic effect of the compounds according to the present invention on homology (one of the phenotypes of developmental disorders), a self-grooming test was performed using a valproic acid (VPA)-induced autism animal model. Figure 4 ).

[0485] Place the animal in an empty cage and measure and plot the duration of licking or grooming (defined as self-grooming) per hour. An increase in duration indicates the presence of repetitive behavior.

[0486] By demonstrating the effects of repetitive behaviors, if these behaviors are improved, symptoms of stereotyped behaviors and impulsivity can be improved. When symptoms of stereotyped behaviors are improved, preventative or therapeutic effects on mood and behavioral disorders such as autism spectrum disorder and obsessive-compulsive disorder can be expected. Furthermore, if impulsivity symptoms are improved, preventative or therapeutic effects on mood and behavioral disorders such as autism spectrum disorder, obsessive-compulsive disorder, depression, anxiety disorders, panic disorder, and attention deficit hyperactivity disorder can be anticipated. Therefore, preventative or therapeutic effects can be expected when this compound is applied to patient populations with mood and behavioral disorders.

[0487] GSH measurement

[0488] To confirm the neuroprotective effect of the compound according to the invention, after a 24-hour pretreatment, cellular oxidative stimulation was induced with H2O2, and GSH assays were performed. Figure 5 After that, confirm the cell image ( Figure 6 The cells used in this article are primary nerve cells, and were treated with 0.1, 1, 10, 50, 100 and 300 μM of the compounds of the present invention.

Claims

1. A compound represented by Formula 1 or a pharmaceutically acceptable salt thereof: [Formula 1] in, R1 is hydrogen or tert-butoxycarbonyl. A is selected from the group consisting of the following cyclic groups: R2, R3, and R4 are each independently hydrogen, halogen, C1-C5 alkyl, C1-C5 alkoxy, or CN.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: 4-((4-methylbenzoyl)carbamoyl)piperazine-1-carboxylic acid tert-butyl ester; 4-((4-methoxybenzoyl)carbamoyl)piperazine-1-carboxylic acid tert-butyl ester; 4-((4-chlorobenzoyl)carbamoyl)piperazine-1-carboxylic acid tert-butyl ester; 4-(benzoylcarbamoyl)piperazine-1-carboxylic acid tert-butyl ester; 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-(2-Naphthoyl)piperazine-1-carboxamide hydrochloride; N-(4-cyanobenzoyl)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-Isoninoylpiperazine-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-Isoninoylpiperazine-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; and N-(3-methoxybenzoyl)piperazine-1-carboxamide-2,2,2-trifluoroacetate.

3. A pharmaceutical composition for the prevention or treatment of symptoms associated with mood and behavioral disorders, said pharmaceutical composition comprising a compound as defined in claim 1 or 2 or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical composition of claim 3, wherein the symptoms associated with mood and behavioral disorders are selected from any one of the group consisting of lack of social skills, lack of social cognitive skills, stereotyped behaviors, hyperactivity, impulsivity, and inattention.

5. A pharmaceutical composition for the prevention or treatment of mood and behavioral disorders, said pharmaceutical composition comprising a compound as defined in claim 1 or 2 or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition for the prevention or treatment of degenerative neurological diseases, said pharmaceutical composition comprising a compound as defined in claim 1 or 2 or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition according to claim 5, wherein the mood and behavioral disorder is selected from any one of 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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