Five-membered heteroaryl derivatives containing at least one N and pharmaceutical compositions containing the same as active ingredients for preventing or treating mental disorders

Abstract

The present invention relates to a N-containing five-membered heteroaryl derivative and a pharmaceutical composition containing the same as an active ingredient for preventing or treating mental disorders, wherein the derivative has an excellent triple reuptake inhibitory effect of serotonin, norepinephrine and dopamine, and can therefore be used to treat mental disorders.

Description

Technical Field

[0001] The present invention relates to N-containing five-membered heteroaryl derivatives and pharmaceutical compositions containing the same as active ingredients for preventing or treating mental disorders. Background Art

[0002] Mental disorders refer to pathological abnormalities in the brain characterized by identifiable symptoms that cause abnormal cognition, affect, mood, or emotion. Representative mental disorders include attention deficit hyperactivity disorder (ADHD), panic disorder, bipolar disorder, depression, schizophrenia, eating disorders, dissociative disorders, post-traumatic stress disorder, etc., and these disorders are characterized by varying functional impairments, severity, and duration of symptoms. Factors that lead to mental disorders include: 1) brain secretion disorders caused by excessive or insufficient neurotransmitters affecting brain nerve function, 2) brain damage and brain function degeneration, 3) abnormal hormone secretion, 4) stress, etc.

[0003] The numerous neurons that make up the brain regulate neural function by communicating with different neurons, and these neurons have two main modes of transmission. One mode is electrical transmission, which is the mode of transmission within neurons, and the other mode is chemical transmission, which is the mode of transmission outside neurons between neurons. Chemical transmission occurs at synapses (the junction of the axon terminal of a neuron and the dendrite of the next neuron), and it is the mode of secreting neurotransmitters (i.e., chemicals) in the presynaptic process and transferring them to another synapse. As a postsynaptic process, according to the number of neurotransmitters, when the threshold is exceeded, the neurons that receive neurotransmitters through synapses are activated and excited. The neurons so activated generate electrical signals in dendrites and transmit the signals to axons, which secrete neurotransmitters through synapses, and the whole process is repeated. It is known that the neurotransmitters secreted by neurons regulate the synaptic reactions with neurons and ultimately control the neural circuits, which are the most important factors regulating human behavior.

[0004] When a neuron secretes a neurotransmitter, a specific receptor in a postsynaptic neuron that forms a synapse with the neuron binds to the neurotransmitter and is activated, and the postsynaptic neuron and synaptic activation can be regulated according to the signal transduction of the receptor. It is assumed that human behavior is regulated by the regulation of neurotransmitters on neuron and synaptic activation, and mutations in neurotransmitter genes (when the neurotransmitter is a peptide), enzymes that produce neurotransmitters, or neurotransmitter receptor genes have been reported to be associated with behavioral control disorders. In addition, it is known that drugs that regulate the amount of neurotransmitters or transmit signals through receptors can regulate human behavior.

[0005] Neurotransmitters that regulate behavior as described above include monovalent amines (eg, catecholamines and serotonin), acetylcholine, excitatory or inhibitory amino acids, and various neuropeptides and their receptors are mainly classified into ionotropic receptors, G protein-coupled receptors, and tyrosine kinase receptors.

[0006] Among the various neurotransmitters in the brain, dopamine is a catecholamine-based neurotransmitter that can be an excitatory signal or an inhibitory signal depending on the type of postsynaptic dopamine receptor. Dopamine is related to behavior, attention, learning, motivation, reward system, reinforcement effect, etc. in our body. When dopamine activity decreases, depressive symptoms appear (e.g., drowsiness, decreased motivation, decreased energy, etc.). In addition, dopamine excites frontal lobe neurons and affects mental activities such as short-term memory, planning, and strategy. In particular, the reward provided by dopamine plays a very important role in the construction of early brain neural pathways, because rewards make people repeat behaviors and learn to feel the pleasure brought by such rewards.

[0007] Norepinephrine is a catecholamine-based neurotransmitter found in the autonomic nervous system, known as a secondary neurotransmitter of dopamine, which is secreted through the release of dopamine. Norepinephrine is associated with arousal, which makes the body tense, pay attention to and be alert to the surrounding environment, and is involved in fear or stress reactions. In particular, norepinephrine is closely related to emotions and is considered to be the cause of mood disorders (e.g., depression and bipolar disorder). That is, there is a hypothesis that depression is a state of reduced function of norepinephrine or dopamine, and mania is a state of over-accelerated function of norepinephrine.

[0008] Serotonin is a neurotransmitter that usually acts in an inhibitory manner and is related to many basic human physiological phenomena (e.g., sleep, appetite, pain, temperature regulation, cardiovascular response, sexual desire, anxiety, depression, etc.). Clinically, serotonin is believed to be related to the etiology of a variety of neuropsychiatric disorders (e.g., depression, schizophrenia, obsessive-compulsive disorder, anxiety, eating disorders, sleep disorders, sexual disorders, impulse control disorders, developmental disorders, degenerative brain diseases, stress disorders, movement disorders, etc.), especially the relationship with depression is very important.

[0009] Neurotransmitters are contained in synaptic vesicles of neurons, and when stimulation is transmitted to neurons, calcium ion channels open before the synapse between neurons, causing calcium to flow into neurons to move synaptic vesicles to the cell membrane of neurons. Vesicles migrate to the cell membrane and are released into synapses by exocytosis at the axon terminal. The released neurotransmitters interact with receptors, excite or inhibit neurons that have received the neurotransmitters, and the remaining neurotransmitters after acting on the receptors are reabsorbed in the axon terminal of the presynaptic neuron, degraded by enzymes present in the postsynaptic membrane, or diffused outward and cleared by glial cells.

[0010] The reuptake process occurs through neurotransmitter transporters. Depending on the type of neurotransmitter, there are specific neurotransmitter transporters, which are present in the synaptic membrane and are responsible for the reuptake of neurotransmitters present in the synaptic cleft into the presynaptic neuron. The concentration of neurotransmitters regulated by this process ultimately affects the intensity and duration of activation of various receptors present in the postsynaptic neuron.

[0011] As mentioned above, neurotransmitter reuptake refers to the process in which neurotransmitters are reuptaken into the presynaptic neuron by specific neurotransmitter transporters in the membrane of the presynaptic neuron that released the neurotransmitter and inactivated. Increased neurotransmitter reuptake leads to neurotransmitter deficiency and imbalance, resulting in diseases related to neurotransmitter reuptake. The treatment of these reuptake-related diseases improves symptoms by blocking the reuptake of these substances to increase the concentration of neurotransmitters in the synapse.

[0012] Neurotransmitter reuptake inhibitors include selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, selective norepinephrine reuptake inhibitors, dopamine-norepinephrine reuptake inhibitors, serotonin receptor antagonist-serotonin reuptake inhibitors, etc. These inhibitors are used to treat depression, mood disorders, ADHD, chronic neuropathic pain, obsessive-compulsive disorder, panic disorder, anxiety disorder, menopausal symptoms, etc.

[0013] Drugs for treating mental disorders are being continuously developed, among which, as related technologies related to neurotransmitter reuptake inhibitors, Korean Patent Publication No. 10-2009-0089439 discloses chromogen-2-one derivatives, their use as monoamine neurotransmitter reuptake inhibitors and use for treating mental disorders, and Korean Patent Publication No. 10-2009-0117736 relates to a composition for selective serotonin reuptake inhibition and a preparation method thereof, disclosing a composition containing asiaticoside and madecassoside.

[0014] However, current treatments for mental disorders in the brain and nervous system only act on one of the multiple neurotransmitters believed to be the relevant causal mechanisms, or are insufficiently selective for neurotransmitters, resulting in many problems with therapeutic efficacy and patient compliance, and leading to serious adverse effects (e.g., growth retardation, sleep disorders, and dependence); therefore, there is a need to develop drugs that can flexibly regulate multiple targets with different selectivities for neurotransmitters.

[0015] In this regard, the development of drugs that modulate multiple targets is underway, among which Korean Patent Publication No. 10-2013-0026292, which relates to a novel azetidine derivative and an antidepressant composition containing the same, discloses an antidepressant composition containing an azetidine derivative capable of simultaneously inhibiting the reuptake of dopamine, serotonin, and norepinephrine; Korean Patent Publication No. 2002-0079730 discloses the use of aryl and heteroaryl substituted tetrahydroisoquinolines for blocking the reuptake of norepinephrine, dopamine, and serotonin; and Korean Patent Publication No. 10-2010019982, which relates to phenyl substituted cycloalkylamines as monoamine reuptake inhibitors, discloses phenyl substituted cycloalkylamines that inhibit the reuptake of endogenous monoamines (e.g., dopamine, serotonin, and norepinephrine) from the synaptic cleft and modulate one or more monoamine transporters.

[0016] The present inventors have attempted to develop drugs that can flexibly regulate multiple targets by ensuring differential selectivity in their neuronal function control based on substances that simultaneously regulate the dopamine, norepinephrine and serotonin nervous systems, and confirmed that 5-membered heteroaryl derivatives containing at least one N have a triple reuptake inhibitory effect on serotonin, norepinephrine and dopamine, and can therefore be used to treat mental disorders, thereby completing the present invention. Summary of the invention

[0017] Technical issues

[0018] One object of the present invention is to provide a N-containing 5-membered heteroaryl derivative.

[0019] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating mental disorders, which contains a N-containing five-membered heteroaryl derivative as an active ingredient.

[0020] Another object of the present invention is to provide a triple reuptake inhibitor of serotonin, norepinephrine and dopamine for preventing or treating mental disorders, which contains a N-containing five-membered heteroaryl derivative as an active ingredient.

[0021] Technical Solution

[0022] To achieve these goals,

[0023] One aspect of the present invention provides a compound represented by the following Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0024] [Formula 1]

[0025]

[0026] In formula 1,

[0027] n is an integer from 0 to 5;

[0028] A 1 is O, NH or S;

[0029] A 2 is N or CH;

[0030] L 1 Is it a straight chain or branched chain C 1-5 Alkylene or C(═O);

[0031] R 1 yes

[0032] Among them A 3 is NH, O or S, A 4 is NH, O or S,

[0033] R a1 , R a2 , R a3 , R a4 and R a5 are independently hydrogen, halogen, hydroxy, amino, CN, a linear or branched C 1-10 Alkyl, unsubstituted or substituted by one or more halogen straight chain or branched C 1-10 Alkoxy, -C(=O)OR c 、-C(=O)N(R c )2 or -NR c C(=O)R c , or R a2 and R a3 Together with the carbon to which they are attached, they form a 5- or 6-membered heterocycloalkenyl containing one or more O,

[0034] R b1 and R b2 are independently hydrogen, halogen, CN, unsubstituted or substituted with one or more halogen straight or branched chain C 1-10 Alkyl, unsubstituted or substituted by one or more halogen straight chain or branched C 1-10 Alkoxy, -C(=O)OR c 、-C(=O)N(R c )2.-NR c C(=O)R c or phenoxy, or R b1 and R b2 Together with the carbon to which they are attached, they form a 5- or 6-membered heterocycloalkenyl group containing one or more O, and R b3 is hydrogen, hydroxyl, C 1-3 Alkyl or C 1-3 Alkoxy,

[0035] R c are independently hydrogen, substituted or unsubstituted straight or branched chain C 1-10 Alkyl, wherein the substituted alkyl is substituted with one or more substituents selected from the group consisting of halogen, amino, methylamino and dimethylamino; and

[0036] R 2 yes Where R d1 , R d2 , R d3 , R d4 , R e1 , R e2 , R e3 and R e4 are independently hydrogen, halogen, unsubstituted or substituted with one or more halogens, linear or branched C 1-10 Alkyl, or unsubstituted or substituted by one or more halogen straight chain or branched C 1-10 Alkoxy.

[0037] Another aspect of the present invention provides a pharmaceutical composition for preventing or treating mental disorders, which contains the compound represented by the above formula 1, its stereoisomer or a pharmaceutically acceptable salt thereof as an active ingredient.

[0038] Another aspect of the present invention provides a triple reuptake inhibitor of serotonin, norepinephrine and dopamine for preventing or treating mental disorders, which contains the compound represented by the above formula 1, its stereoisomer or a pharmaceutically acceptable salt thereof as an active ingredient.

[0039] Another aspect of the present invention provides a method for preventing or treating mental disorders, which comprises administering a pharmaceutical composition containing the compound represented by Formula 1 above, its stereoisomers or pharmaceutically acceptable salts thereof to a subject in need thereof.

[0040] Another aspect of the present invention provides use of a pharmaceutical composition containing the compound represented by the above formula 1, its stereoisomers or pharmaceutically acceptable salts thereof as an active ingredient in preventing or treating mental disorders.

[0041] Beneficial Effects

[0042] The compound represented by Formula 1 according to the present invention is superior in triple reuptake inhibition of serotonin, norepinephrine and dopamine, and thus can be used to treat mental disorders. DETAILED DESCRIPTION

[0043] Hereinafter, the present invention will be described in detail.

[0044] Meanwhile, the embodiments of the present invention can be modified in various forms, and the scope of the present invention is not limited to the embodiments described below. In addition, embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art. In addition, throughout the specification, "comprising" a certain component means that other components can be further included rather than excluding other components, unless otherwise stated.

[0045] One aspect of the present invention provides a compound represented by the following Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0046] [Formula 1]

[0047]

[0048] In the above formula 1,

[0049] n is an integer from 0 to 5;

[0050] A 1 is O, NH or S;

[0051] A 2 is N or CH;

[0052] L 1 Is it a straight chain or branched chain C 1-5 Alkylene or C(═O);

[0053] R 1 yes

[0054] Among them A 3 is NH, O or S, A 4 is NH, O or S,

[0055] R a1 , R a2 , R a3 , R a4 and R a5 are independently hydrogen, halogen, hydroxy, amino, CN, a linear or branched C 1-10 Alkyl, unsubstituted or substituted by one or more halogen straight chain or branched C 1-10 Alkoxy, -C(=O)OR c 、-C(=O)N(R c )2 or -NR c C(=O)R c , or R a2 and R a3 Together with the carbon to which they are attached, they form a 5- or 6-membered heterocycloalkenyl containing one or more O,

[0056] R b1 and Rb2 are independently hydrogen, halogen, CN, unsubstituted or substituted with one or more halogen straight or branched chain C 1-10 Alkyl, unsubstituted or substituted by one or more halogen straight chain or branched C 1-10 Alkoxy, -C(=O)OR c 、-C(=O)N(R c )2.-NR c C(=O)R c or phenoxy, or R b1 and R b2 Together with the carbon to which they are attached, they form a 5- or 6-membered heterocycloalkenyl group containing one or more O, and R b3 is hydrogen, hydroxyl, C 1-3 Alkyl or C 1-3 Alkoxy,

[0057] R c are independently hydrogen, substituted or unsubstituted straight or branched chain C 1-10 Alkyl, wherein the substituted alkyl is substituted with one or more substituents selected from the group consisting of halogen, amino, methylamino and dimethylamino; and

[0058] R 2 yes Where R d1 , R d2 , R d3 , R d4 , R e1 , R e2 , R e3 and R e4 are independently hydrogen, halogen, unsubstituted or substituted with one or more halogens, linear or branched C 1-10 Alkyl, or unsubstituted or substituted by one or more halogen straight chain or branched C 1-10 Alkoxy.

[0059] In the above formula 1,

[0060] R 1 yes

[0061] Among them A 3 is NH, O or S, A 4 is NH, O or S,

[0062] R a1 , R a2 , R a3 , R a4 and R a5 are independently hydrogen, halogen, hydroxy, amino, CN, a linear or branched C1-5 Alkyl, unsubstituted or substituted by one or more halogen straight chain or branched C 1-5 Alkoxy, -C(=O)OR c 、-C(=O)N(R c )2 or -NR c C(=O)R c , or R a2 and R a3 Together with the carbon to which they are attached, they form a 5- or 6-membered heterocycloalkenyl containing one or two O;

[0063] R b1 and R b2 are independently hydrogen, halogen, CN, unsubstituted or substituted with one or more halogen straight or branched chain C 1-5 Alkyl, unsubstituted or substituted by one or more halogen straight chain or branched C 1-5 Alkoxy, -C(=O)OR c 、-C(=O)N(R c )2.-NR c C(=O)R c or phenoxy, or R b1 and R b2 Together with the carbon to which they are attached, they form a 5- or 6-membered heterocycloalkenyl containing one or two O;

[0064] R c are independently hydrogen, substituted or unsubstituted straight or branched chain C 1-5 Alkyl, wherein the substituted alkyl is substituted with amino, methylamino or dimethylamino; and

[0065] R 2 yes Where R d1 , R d2 , R d3 , R d4 , R e1 , R e2 , R e3 and R e4 are independently hydrogen, halogen, unsubstituted or substituted with one or more halogens, linear or branched C 1-5 Alkyl, or unsubstituted or substituted by one or more halogen straight chain or branched C 1-5 Alkoxy.

[0066] In the above formula 1,

[0067] n is an integer from 0 to 2;

[0068] A 1 is O, NH or S;

[0069] A2 is N or CH;

[0070] L 1 is CH2 or C(=O);

[0071] R 1 yes

[0072] Among them A 3 is NH, O or S, A 4 is NH, O or S, R a1 , R a2 , R a3 , R a4 and R a5 are independently hydrogen, F, Cl, OH, -NH2, CN, methyl, -CF3, methoxy, -C(=O)OCH3 or -C(=O)OH, R b1 and R b2 are independently hydrogen or methoxy, or R b1 and R b2 Together with the carbon to which they are attached, they form 1,3-dioxole; and

[0073] R 2 yes Where R d1 , R d2 , R d3 and R d4 may be hydrogen, and R e1 , R e2 , R e3 and R e4 can independently be hydrogen, Cl or methoxy.

[0074] In the above formula 1,

[0075] n is an integer of 0 or 1;

[0076] A 1 is O, NH or S;

[0077] A 2 is N or CH;

[0078] L 1 is CH2 or C(=O);

[0079] R 1 yes

[0080]

[0081] as well as

[0082]

[0083] and R 2 Can be

[0084]

[0085] Examples of the compound represented by Formula 1 according to the present invention may include compounds of the following groups:

[0086] <1> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indole;

[0087] <2> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5-fluoro-1H-indole;

[0088] <3> 2-(5-((4-phenylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indole;

[0089] <4> 2-(5-((4-Benzylpiperazin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indole;

[0090] <5> 2-(5-((4-(3,4-dichlorobenzyl)piperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indole;

[0091] <6> 2-(5-((4-(4-methoxybenzyl)piperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indole;

[0092] <7> 2-(5-((4-(4-chlorobenzyl)piperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indole;

[0093] <8> 2-(5-((4-(3-chlorobenzyl)piperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indole;

[0094] <9> 4-Benzyl-1-((5-phenyl-4H-1,2,4-triazol-3-yl)methyl)piperidine;

[0095] <10> 4-Benzyl-1-((5-(4-methoxyphenyl)-4H-1,2,4-triazol-3-yl)methyl)piperidine;

[0096] <11> (4-Benzylpiperidin-1-yl)(5-(4-methoxyphenyl)-4H-1,2,4-triazol-3-yl)methanone;

[0097] <12> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5,6-dimethoxy-1H-indole;

[0098] <13> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5-methoxy-1H-indole;

[0099] <14> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5-chloro-1H-indole;

[0100] <15> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5-methyl-1H-indole;

[0101] <16> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-6-fluoro-1H-indole;

[0102] <17> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indole-5-carbonitrile;

[0103] <18> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-6-methoxy-1H-indole;

[0104] <19> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-7-methoxy-1H-indole;

[0105] <20> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indole-5-carboxylic acid methyl ester;

[0106] <21> 4-Benzyl-1-((5-(naphthalen-2-yl)-4H-1,2,4-triazol-3-yl)methyl)piperidine;

[0107] <22> 3-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indole;

[0108] <23> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-indole;

[0109] <24> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-4-chloro-1H-indole;

[0110] <25> 1-((5-(Benzofuran-2-yl)-4H-1,2,4-triazol-3-yl)methyl)-4-benzylpiperidine;

[0111] <26> 1-((5-(Benzo[b]thiophen-2-yl)-4H-1,2,4-triazol-3-yl)methyl)-4-benzylpiperidine;

[0112] <27> 1-((5-(Benzo[d][1,3]dioxolan-5-yl)-4H-1,2,4-triazol-3-yl)methyl)-4-benzylpiperidine;

[0113] <28> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indole-5-carboxylic acid;

[0114] <29> 2-(5-((4-(3,4-dichlorobenzyl)piperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5-fluoro-1H-indole

[0115] <30> 2-(5-((4-(3,4-dichlorobenzyl)piperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5-methyl-1H-indole

[0116] <31> 2-(5-((4-(3,4-dichlorobenzyl)piperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5,6-dimethoxy-1H-indole;

[0117] <32> 2-(5-((4-(1H-indol-3-yl)piperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5-fluoro-1H-indole;

[0118] <33> 2-((4-Benzylpiperidin-1-yl)methyl)-5-(1H-indol-2-yl)-1,3,4-oxadiazole;

[0119] <34> 2-((4-(3,4-dichlorobenzyl)piperidin-1-yl)methyl)-5-(1H-indol-2-yl)-1,3,4-oxadiazole;

[0120] <35> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indole-5,6-diol;

[0121] <36> 3-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5-methoxy-1H-indole;

[0122] <37> 3-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-7-methoxy-1H-indole;

[0123] <38> 3-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-6-methyl-1H-indole;

[0124] <39> 3-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5-methyl-1H-indole;

[0125] <40> 3-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-7-chloro-1H-indole;

[0126] <41> 3-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5-chloro-1H-indole;

[0127] <42> 3-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indole-7-carboxylic acid methyl ester;

[0128] <43> 3-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indol-5-amine;

[0129] <44> 3-(5-((4-(3,4-dichlorobenzyl)piperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5-methoxy-1H-indole

[0130] <45> 3-(5-((4-(3,4-dichlorobenzyl)piperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-7-methoxy-1H-indole

[0131] <46> 4-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)benzonitrile;

[0132] <47> 4-Benzyl-1-((5-(4-fluorophenyl)-4H-1,2,4-triazol-3-yl)methyl)piperidine;

[0133] <48> 4-Benzyl-1-((5-(3,4-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl)methyl)piperidine;

[0134] <49> 4-Benzyl-1-((5-(4-(trifluoromethoxy)phenyl)-4H-1,2,4-triazol-3-yl)methyl)piperidine;

[0135] <50> 4-Benzyl-1-((5-(4-(trifluoromethyl)phenyl)-4H-1,2,4-triazol-3-yl)methyl)piperidine;

[0136] <51> N-(4-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)phenyl)acetamide;

[0137] <52> 6-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)naphthalen-2-ol;

[0138] <53> 4-Benzyl-1-((5-(4-phenoxyphenyl)-4H-1,2,4-triazol-3-yl)methyl)piperidine;

[0139] <54> 4-Benzyl-1-((5-(3-(trifluoromethoxy)phenyl)-4H-1,2,4-triazol-3-yl)methyl)piperidine;

[0140] <55> 4-Benzyl-1-((5-(3-(trifluoromethyl)phenyl)-4H-1,2,4-triazol-3-yl)methyl)piperidine;

[0141] <56> 3-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-6-methoxy-1H-indole;

[0142] <57> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indole-5-carboxamide;

[0143] <58> 4-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-N-(2-(dimethylamino)ethyl)benzamide;

[0144] <59> 3-(5-((4-(3,4-dichlorobenzyl)piperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-6-methoxy-1H-indole

[0145] <60> 3-(5-((4-(3,4-dichlorobenzyl)piperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indole-7-carboxylic acid methyl ester;

[0146] <61> 4-(3,4-dichlorobenzyl)-1-((5-(4-(trifluoromethoxy)phenyl)-4H-1,2,4-triazol-3-yl)methyl)piperidine;

[0147] <62> 4-(3,4-dichlorobenzyl)-1-((5-(4-(trifluoromethyl)phenyl)-4H-1,2,4-triazol-3-yl)methyl)piperidine;

[0148] <63> 2-amino-4-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoic acid methyl ester;

[0149] <64> 2-(5-((4-Benzylpiperazin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5-fluoro-1H-indole;

[0150] <65> 2-(5-((4-benzylpiperazin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5-chloro-1H-indole;

[0151] <66> N-(2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indol-5-yl)acetamide;

[0152] <67> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indol-5-ol;

[0153] <68> (4-Benzylpiperidin-1-yl)(5-(5-fluoro-1H-indol-2-yl)-4H-1,2,4-triazol-3-yl)methanone;

[0154] <69> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-6-butoxy-1H-indole;

[0155] <70> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-3-methyl-1H-indole;

[0156] <71> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-4,6-dichloro-1H-indole;

[0157] <72> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5,6-dichloro-1H-indole;

[0158] <73> 6-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5H-[1,3]dioxo[4,5-f]indole;

[0159] <74> 7-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-2,3-dihydro-6H-[1,4]dioxin[2,3-f]indole;

[0160] <75> 3-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-6-fluoro-1H-indole; and

[0161] <76> 6-(5-((4-Benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indole.

[0162] The compound shown in Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid can be used as the salt. Acid addition salts are obtained from inorganic acids (e.g., hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc.); non-toxic organic acids (e.g., aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanoates, hydroxyalkanoates and alkandioates, aromatic acids, aliphatic and aromatic sulfonic acids, etc.); organic acids (e.g., trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc.). These types of pharmaceutically non-toxic salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphate chlorides, bromides, iodides, fluorides, acetates, propylene The invention also includes but is not limited to benzoic acid, benzoic acid, chlorobenzoic acid, methyl benzoate, dinitrobenzoic acid, hydroxybenzoic acid, methoxybenzoic acid, phthalic acid, terephthalic acid, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenyl acetate, phenyl propionate, phenyl butyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, mandelate, and the like.

[0163] The acid addition salt according to the present invention can be prepared by conventional methods, for example, by dissolving the derivative of Formula 1 in an organic solvent (e.g., methanol, ethanol, acetone, dichloromethane, acetonitrile, etc.), adding an organic acid or an inorganic acid to filter and dry the resulting precipitate; or by distilling the solvent and excess acid under reduced pressure, drying and crystallizing in an organic solvent.

[0164] In addition, pharmaceutically acceptable metal salts can be prepared using alkali. For example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate to obtain an alkali metal salt or an alkaline earth metal salt. In this case, it is pharmaceutically suitable to prepare sodium salts, potassium salts or calcium salts as metal salts. In addition, by reacting an alkali metal salt or an alkaline earth metal salt with a suitable negative salt (for example, silver nitrate) to obtain a corresponding salt.

[0165] In addition, the present invention includes not only the compound represented by Formula 1 and pharmaceutically acceptable salts thereof, but also solvates, optical isomers, hydrates, etc. that can be prepared therefrom.

[0166] The term "hydrate" refers to a compound of the present invention or a salt thereof, which contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. The hydrate of the compound shown in Formula 1 of the present invention may contain a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. The hydrate may contain 1 equivalent or more, preferably 1-5 equivalents of water. Such hydrates can be prepared by crystallizing the compound shown in Formula 1 of the present invention, its stereoisomers, or pharmaceutically acceptable salts thereof from water or an aqueous solvent.

[0167] The term "solvate" refers to a compound of the present invention or a salt thereof that contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents include those that are inherently volatile, non-toxic and / or suitable for administration to humans.

[0168] The term "isomer" refers to a compound of the present invention or a salt thereof having the same chemical formula or molecular formula but different structures or spaces. These isomers include structural isomers (e.g., tautomers, etc.), R or S isomers with asymmetric carbon centers, stereoisomers (e.g., geometric isomers (trans, cis) and optical isomers (enantiomers)). All these isomers and mixtures thereof are also included within the scope of the present invention.

[0169] The compound represented by Formula 1 according to the present invention can be prepared as shown in the following Reaction 1, or can be prepared according to a preparation method, which comprises preparing the compound represented by Formula 1 by reacting the compound represented by Formula 2 with the compound represented by Formula 3.

[0170] [Reaction 1]

[0171]

[0172] In the above reaction 1,

[0173] R 1 , R 2 , A 1 , A 2 , L 1 and n are as defined in Formula 1 above.

[0174] Specifically, the preparation method of reaction 1 is a method for preparing the compound shown in formula 1 by dehydrating the hydroxyl group of the compound shown in formula 2 with the amine of the compound shown in formula 3 under Mitsunobu conditions. The preparation method can adopt reaction conditions known to those skilled in the art, and can be prepared according to the embodiments of the present invention, but this is only an example and is not limited thereto.

[0175] Another aspect of the present invention provides a pharmaceutical composition for preventing or treating mental disorders, which contains the compound represented by Formula 1, its optical isomer or a pharmaceutically acceptable salt thereof as an active ingredient.

[0176] The compound inhibits the reuptake of serotonin, norepinephrine, and dopamine.

[0177] The mental disorder may be at least one selected from the group consisting of bulimia nervosa, mood disorder, depression, atypical depression, depression secondary to pain, major depressive disorder, dysthymic disorder, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, mood disorder caused by general medical illness, substance-induced mood disorder, pseudodementia, Ganger syndrome, obsessive-compulsive disorder, panic disorder, panic disorder without agoraphobia, panic disorder with agoraphobia, agoraphobia without history of panic disorder, panic attack, memory impairment, memory loss, concentration ADHD, obesity, anxiety, generalized anxiety disorder, eating disorders, Parkinson's disease, Parkinson's symptoms, dementia, senile dementia, Alzheimer's disease, Down syndrome, acquired immune deficiency syndrome dementia syndrome, memory disorders of senility, specific phobia, social phobia, social anxiety disorder, post-traumatic stress disorder, acute stress disorder, chronic stress disorder, drug addiction, drug abuse, drug abuse tendency, cocaine abuse, nicotine abuse, tobacco abuse, alcohol addiction, alcoholism, pathological kleptomania, withdrawal syndrome caused by withdrawal from intoxicating substances, pain, chronic pain, Inflammatory pain, neuropathic pain, diabetic neuropathic pain, migraine, tension-type headache, chronic tension-type headache, depression-related pain, back pain, cancer pain, irritable bowel pain, irritable bowel syndrome, postoperative pain, post-mastectomy pain syndrome (PMPS), post-stroke pain, drug-induced neuropathy, diabetic neuropathy, persistent pain of the sympathetic nervous system, trigeminal neuralgia, toothache, facial muscle pain, phantom limb pain, anorexia, premenstrual syndrome, premenstrual dysphoric disorder, late luteal phase syndrome, post-traumatic syndrome, chronic fatigue syndrome, persistent vegetative state, urinary incontinence, stress force incontinence, urge incontinence, nocturnal incontinence, sexual dysfunction, premature ejaculation, erectile dysfunction, erectile dysfunction, restless legs syndrome, periodic limb movement disorder, eating disorders, anorexia nervosa, sleep disorders, pervasive developmental disorder, autism, Asperger's syndrome, Rett disorder, childhood disintegrative disorder, learning disabilities, motor skills disorders, mutism, trichotillomania, narcolepsy, post-stroke depression, brain damage caused by stroke, stroke-induced neurological damage, Tourette syndrome, tinnitus, tic disorder, body dysmorphic disorder, oppositional defiant disorder, and post-stroke disorder.

[0178] The compound represented by Formula 1 according to the present invention has excellent reuptake inhibitory effects on serotonin, norepinephrine and dopamine, and thus can be used to treat mental disorders (see Experimental Example 1 and Table 13).

[0179] In the pharmaceutical composition according to the present invention, the compound shown in the above formula 1 or its pharmaceutically acceptable salt can be applied in a variety of oral and parenteral dosage forms during clinical administration, more preferably, parenteral dosage forms. When formulated, a pharmaceutical composition is prepared using a diluent or excipient (such as a commonly used filler, extender, adhesive, wetting agent, disintegrant and surfactant). Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations are prepared by mixing at least one excipient (for example, starch, calcium carbonate, sucrose or lactose, gelatin, etc.) with one or more compounds. In addition to simple excipients, lubricants (such as magnesium stearate and talc) are also used. Liquid dosage forms for oral administration include suspensions, oral solutions, emulsions, syrups, etc., and in addition to water and liquid paraffin (they are commonly used simple diluents), various excipients such as wetting agents, sweeteners, spices and preservatives may also be included. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions and emulsions. As the non-aqueous solvent and the suspending solvent, propylene glycol, polyethylene glycol, vegetable oil (eg, olive oil), injectable ester (eg, ethyl oleate) and the like can be used.

[0180] The compound shown in Formula 1 or its pharmaceutically acceptable salt can be applied in a variety of oral and parenteral dosage forms during clinical administration. When formulated, a pharmaceutical composition is prepared using a diluent or excipient (such as a commonly used filler, extender, adhesive, wetting agent, disintegrant and surfactant). Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations are prepared by mixing at least one excipient (for example, starch, calcium carbonate, sucrose or lactose, gelatin, etc.) with one or more compounds. In addition to simple excipients, lubricants (such as magnesium stearate and talc) are also used. Liquid dosage forms for oral administration include suspensions, oral solutions, emulsions, syrups, etc., and in addition to water and liquid paraffin (which are commonly used simple diluents), various excipients such as wetting agents, sweeteners, spices and preservatives may also be included. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions and emulsions. As the non-aqueous solvent and the suspending solvent, propylene glycol, polyethylene glycol, vegetable oil (eg, olive oil), injectable ester (eg, ethyl oleate) and the like can be used.

[0181] The pharmaceutical composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient can be administered parenterally, and the parenteral administration is performed by subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection.

[0182] In this case, in order to be formulated into a dosage form for parenteral administration, the compound shown in the above formula 1 or a pharmaceutically acceptable salt thereof can be mixed with a stabilizer or a buffer in water to prepare a solution or suspension, which can be prepared in a unit dosage form in an ampoule or a vial. The composition can be sterilized and / or contain a preservative, a stabilizer, a wetting agent or an emulsifying promoter, a salt and / or a buffer for controlling osmotic pressure, and other therapeutically useful substances, and can be formulated according to conventional methods (e.g., mixing, granulation or coating).

[0183] Dosage forms for oral administration include, for example, tablets, pills, hard / soft capsules, liquids, suspensions, emulsifiers, syrups, granules, elixirs, lozenges, etc., and in addition to the active ingredient, these dosage forms also contain diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants (e.g., silicon dioxide, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycol). Tablets may contain binders (e.g., magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinyl pyrrolidine); optionally contain disintegrants (e.g., starch, agar, alginic acid or its sodium salt) or effervescent mixtures, and / or absorbents, colorants, flavorings and sweeteners.

[0184] A pharmaceutical composition for preventing or treating mental disorders, which contains as an active ingredient the compound represented by the above formula 1, its optical isomer or a pharmaceutically acceptable salt thereof, and can be administered as a single therapeutic agent or used in combination with other therapeutic agents.

[0185] Another aspect of the present invention provides a triple reuptake inhibitor of serotonin, norepinephrine and dopamine for preventing or treating mental disorders, which contains the compound represented by the above formula 1, its stereoisomers or pharmaceutically acceptable salts as an active ingredient.

[0186] Another aspect of the present invention provides a method for preventing or treating a mental disorder, which comprises administering to a subject in need thereof a pharmaceutical composition comprising as an active ingredient a compound represented by the above formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0187] Another aspect of the present invention provides use of a pharmaceutical composition comprising the compound represented by the above formula 1 or its stereoisomer or a pharmaceutically acceptable salt thereof as an active ingredient in preventing or treating mental disorders.

[0188] Mode for Carrying Out the Invention

[0189] The present invention is described in detail below through examples and experimental examples.

[0190] However, the following Examples and Experimental Examples are only for illustrating the present invention, and the contents of the present invention are not limited to the following Examples and Experimental Examples.

[0191] <Preparation Example 1> Preparation of Boric Acid

[0192] [Reaction 2]

[0193]

[0194] In the above reaction 2,

[0195] R a1 , R a2 , R a3 , R a4 and R a5 As defined in Formula 1 above.

[0196] Step 1: Indole (1 eq) and N,N-dimethylpyridin-4-amine (DMAP) (2-4 mol%) were dissolved in DMF, and then di-tert-butyl dicarbonate (Boc anhydride) (1.5 eq) was added dropwise at 0 °C. The reactants were stirred at room temperature for 12 hours. After the reaction was completed, water was added dropwise thereto and the reactants were extracted with ethyl acetate. The organic layer was washed with H2O and brine in sequence and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure to obtain boc-indole.

[0197] Step 2: After the boc-indole (1 eq) synthesized in step 1 is dissolved in anhydrous tetrahydrofuran (THF), triisopropyl borate (1.5 eq) is added dropwise thereto under a nitrogen atmosphere. After the reactant is cooled to 0, 2M lithium diisopropylamide solution (LDA 2.0M n-heptane / ethylbenzene / THF solution) (1.25 eq) is slowly added dropwise thereto within 15 minutes. The reactant is stirred at 0 until the reaction is complete, and after the reaction is complete, 1N HCl is added dropwise thereto and the resulting product is extracted with ethyl acetate. The organic layer is washed with H2O and salt water successively and dried over anhydrous Na2SO4, and then the solvent is removed under reduced pressure. Then, boric acid is obtained by solidifying with ethyl acetate and hexane.

[0198] <Example 1> Preparation of 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indole

[0199]

[0200] Step 1: 3-Bromo-1H-1,2,4-triazol-5-ylmethanol (1 eq) and indole-2-boronic acid pinacol ester (or indole-2 boronic acid) (1.1 eq) were added to a microwave vial and dissolved in 1,4-dioxane: water (4:1), and then the catalyst Pd(dppf)Cl2-CH2Cl2 (10 mol%) and K2CO3 (3 eq) were added dropwise thereto at room temperature and stirred for 5 minutes. The reaction mixture was reacted in a Biotage microwave at 100 for 1.5 hours. After the reaction was completed, the resultant was extracted with dichloromethane, the organic layer was washed with H2O and brine in sequence and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain (5-(1H-indol-2-yl)-4H-1,2,4-triazol-3-yl)methanol.

[0201] Step 2: At 0, (5-(1H-indol-2-yl)-4H-1,2,4-triazole-3-yl) (1eq), 4-benzylpiperidine (1.5eq) and triphenylphosphine (1.5eq) synthesized in step 1 are dissolved in tetrahydrofuran (THF), and then diethyl azodicarboxylate solution (DEAD) (1.5eq) is added dropwise thereto. The reactants are stirred at room temperature under a nitrogen atmosphere for 12 hours. After the reaction is completed, the solvent is removed under reduced pressure. After the resultant is extracted with dichloromethane, the organic layer is washed with H2O and brine in sequence and dried over anhydrous Na2SO4, and the solvent is removed under reduced pressure. Then, the reaction mixture is separated and purified by MPLC to obtain the compound of Example 1.

[0202] In step 1, using R listed in Table 1 below instead of indole-2-boronic acid pinacol ester (or indole-2-boronic acid), and using the same method as Example 1, the compound of Example 2 was obtained.

[0203] [Table 1]

[0204]

[0205] Using R listed in the following Table 2 instead of 4-benzylpiperidine in Step 2 and the same procedure as in Example 1, the compounds of Examples 3 to 8 were obtained.

[0206] [Table 2]

[0207]

[0208]

[0209] <Example 9> Preparation of 4-benzyl-1-((5-phenyl-4H-1,2,4-triazol-3-yl)methyl)piperidine

[0210]

[0211] The synthesized 4-benzyl-1-((5-bromo-4H-1,2,4-triazol-3-yl)methyl)piperidine (1eq), phenylboronic acid (1.3eq), Na2CO3 (4eq) and catalyst Pd(Ph3P)4 (0.5eq) were dissolved in DME in a microwave vial, and the reaction mixture was reacted in a Biotage microwave at 130 for 3 hours. After the reaction was completed, the resultant was extracted with dichloromethane, the organic layer was washed with H2O and brine in sequence and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the compound of Example 9.

[0212] <Example 10> Preparation of 4-benzyl-1-((5-(4-methoxyphenyl)-4H-1,2,4-triazol-3-yl)methyl)piperidine

[0213]

[0214] The synthesized 4-benzyl-1-((5-bromo-4H-1,2,4-triazol-3-yl)methyl)piperidine (1 eq), 2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.3 eq), Na2CO3 (5 eq) and catalyst PdCl2(dtbpf) (0.1 eq) were dissolved in 4-dioxane:water (3:1) in a microwave vial, and the reaction mixture was reacted in a Biotage microwave at 130 for 2 hours. After the reaction was completed, the resultant was extracted with dichloromethane, the organic layer was washed with H2O and brine in sequence and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the compound of Example 10.

[0215] <Example 11> Preparation of (4-benzylpiperidin-1-yl)(5-(4-methoxyphenyl)-4H-1,2,4-triazol-3-yl)methanone

[0216]

[0217] Step 1: After 5-bromo-4H-1,2,4-triazole-3-carboxylic acid (96 mg, 0.5 mmol, 1 eq) was dissolved in DMF, DIPEA (175 μL, 1.000 mmol, 2 eq), HATU (285 mg, 0.750 mmol, 1.5 eq) and 4-benzylpiperidine (105 μL, 0.600 mmol, 1.2 eq) were added dropwise thereto. The reactant was stirred at room temperature for 12 hours. After the reaction was completed, the resultant was extracted with ethyl acetate, and the organic layer was washed with H2O and brine in turn, and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain (4-benzylpiperidin-1-yl) (5-bromo-4H-1,2,4-triazole-3-yl) ketone compound.

[0218] Step 2: (4-benzylpiperidin-1-yl)(5-bromo-4H-1,2,4-triazol-3-yl)methanone (1 eq), 2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaboroline (1.3 eq), Na2CO3 (5 eq) and catalyst PdCl2(dtbpf) (0.1 eq) synthesized in step 1 were dissolved in 4-dioxane in a microwave vial, and the reaction mixture was reacted in a Biotage microwave at 130 for 2 hours. After the reaction was completed, the resultant was extracted with dichloromethane, the organic layer was washed with H2O and brine in sequence and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the compound of Example 11.

[0219] <Example 12> Preparation of 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5,6-dimethoxy-1H-indole

[0220]

[0221] Step 1: At 0, (5-bromo-4H-1,2,4-triazole-3-yl)methanol (500mg, 2.81mmol, 1eq), 4-benzylpiperidine (0.741mL, 4.21mmol, 1.5eq) and triphenylphosphine (1.105g, 4.21mmol, 1.5eq) were dissolved in tetrahydrofuran (THF), and diethyl azodicarboxylate (DEAD) solution (1.911mL, 4.21mmol, 1.5eq) was added dropwise thereto. The reactants were stirred at room temperature under nitrogen atmosphere for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure. After the resultant was extracted with dichloromethane, the organic layer was washed with H2O and brine in sequence and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain a 4-benzyl-1-((5-bromo-4H-1,2,4-triazol-3-yl)methyl)piperidine compound.

[0222] Step 2: 4-benzyl-1-((5-bromo-4H-1,2,4-triazol-3-yl)methyl)piperidine (1 eq), (1-(tert-butyloxycarbonyl)-5,6-dimethoxy-1H-indol-2-yl)boric acid (1.3 eq), Li2CO3 (2 eq) and catalyst Pd(Ph3P)4 (0.1 eq) synthesized in step 1 were dissolved in 4-dioxane: water (3:1) in a microwave vial, and the reaction mixture was reacted in a Biotage microwave at 130 for 30 minutes. After the reaction was completed, the resultant was extracted with dichloromethane, the organic layer was washed with H2O and brine in sequence and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the compound of Example 12.

[0223] Using R listed in the following Table 3 instead of (1-(tert-butoxycarbonyl)-5,6-dimethoxy-1H-indol-2-yl)boronic acid in Step 2 and the same procedure as Example 12, the compounds of Examples 13 to 27 were obtained.

[0224] [Table 3]

[0225]

[0226]

[0227] <Example 28> Preparation of 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indole-5-carboxylic acid

[0228]

[0229] After dissolving 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazole-3-yl)-1H-indole-5-carboxylic acid methyl ester (1eq) of Example 20 in methanol, 4M potassium hydroxide aqueous solution (150eq, excess) was added dropwise thereto and reacted at room temperature for 12 hours. After the reaction was completed, the resultant was neutralized with 1M hydrochloric acid aqueous solution, extracted with dichloromethane, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the compound of Example 28 in the form of a white solid.

[0230] <Example 29> Preparation of 2-(5-((4-(3,4-dichlorobenzyl)piperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5-fluoro-1H-indole

[0231]

[0232] Step 1: After dissolving 4-(3,4-dichlorobenzyl)piperidine HCl salt in dichloromethane, the resultant was washed with a 6M NaOH aqueous solution to adjust its pH to 12 or higher. After the organic layer solvent was dried over anhydrous Na2SO4, the solvent was removed under reduced pressure to obtain 4-(3,4-dichlorobenzyl)piperidine.

[0233] Step 2: At 0, (5-bromo-4H-1,2,4-triazol-3-yl)methanol (500mg, 2.81mmol, 1eq), 4-(3,4-dichlorobenzyl)piperidine (892mg, 3.65mmol, 1.3eq) obtained in step 1 and triphenylphosphine (1.105g, 4.21mmol, 1.5eq) were dissolved in tetrahydrofuran (THF), and diethyl azodicarboxylate (DEAD) solution (1.911mL, 4.21mmol, 1.5eq) was added dropwise thereto. The reactants were stirred at room temperature under nitrogen atmosphere for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure. The resultant was extracted with dichloromethane, the organic layer was washed with H2O and brine in turn and dried over anhydrous Na2SO4, and then the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain 1-((5-bromo-4H-1,2,4-triazol-3-yl)methyl)-4-(3,4-dichlorobenzyl)piperidine compound.

[0234] Step 3: After dissolving 1-((5-bromo-4H-1,2,4-triazol-3-yl)methyl)-4-(3,4-dichlorobenzyl)piperidine (1 eq), (1-(tert-butyloxycarbonyl)-5-fluoro-1H-indol-2-yl)boric acid (1.3 eq), Li2CO3 (2 eq) and catalyst Pd(Ph3P)4 (0.1 eq) synthesized in step 1 in 1,4-dioxane: water (3:1) in a microwave vial, the reaction mixture was reacted in a Biotage microwave at 130 for 30 minutes. After the reaction was completed, the resultant was extracted with dichloromethane, the organic layer was washed with H2O and brine in sequence and dried over anhydrous Na2SO4, and then the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the compound of Example 29.

[0235] In step 2, using R listed in Table 4 below instead of (1-(tert-butoxycarbonyl)-5-fluoro-1H-indol-2-yl)boronic acid and using the same method as Example 29, the compounds of Examples 30 and 31 were obtained.

[0236] [Table 4]

[0237]

[0238] <Example 32> Preparation of 2-(5-((4-(1H-indol-3-yl)piperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5-fluoro-1H-indole

[0239]

[0240] Step 1: At 0, (5-bromo-4H-1,2,4-triazol-3-yl)methanol (100 mg, 0.562 mmol, 1 eq), 3-(piperidin-4-yl)-1H-indole (146 mg, 0.730 mmol, 1.3 eq) and triphenylphosphine (221 mg, 0.843 mmol, 1.5 eq) were dissolved in tetrahydrofuran (THF) solution, and diethyl azodicarboxylate (DEAD) solution (0.367 ml, 0.843 mmol, 1.5 eq) was added dropwise thereto. The reactants were stirred at room temperature under nitrogen atmosphere for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure. The resultant was extracted with dichloromethane, the organic layer was washed with H2O and brine in turn and dried over anhydrous Na2SO4, and then the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain a 3-(1-((5-bromo-4H-1,2,4-triazol-3-yl)methyl)piperidin-4-yl)-1H-indole compound.

[0241] Step 2: After dissolving 3-(1-((5-bromo-4H-1,2,4-triazol-3-yl)methyl)piperidin-4-yl)-1H-indole (1 eq), (1-(tert-butoxycarbonyl)-5-fluoro-1H-indol-2-yl)boric acid (1.3 eq), Li2CO3 (2 eq) and catalyst Pd(Ph3P)4 (0.1 eq) synthesized in step 1 in 1,4-dioxane: water (3:1) in a microwave vial, the reaction mixture was reacted in a Biotage microwave at 130 for 30 minutes. After the reaction was completed, the resultant was extracted with dichloromethane, the organic layer was washed with H2O and brine in sequence and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the compound of Example 32.

[0242] <Example 33> Preparation of 2-((4-benzylpiperidin-1-yl)methyl)-5-(1H-indol-2-yl)-1,3,4-oxadiazole

[0243]

[0244] Step 1: After dissolving 4-benzylpiperidine (0.502mL, 2.85mmol), ethyl 2-bromoacetate (0.475mL, 4.28mmol) and triethylamine (0.390mL, 2.85mmol) in toluene, the reactant was stirred at 80°C for 12 hours. After the reaction was completed, water was added dropwise thereto. The resulting product was extracted with ethyl acetate, and the organic layer was washed with H2O and brine in turn and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain ethyl 2-(4-benzylpiperidin-1-yl)acetate.

[0245] Step 2: After dissolving the ethyl 2-(4-benzylpiperidin-1-yl)acetate (0.4 g, 1.530 mmol) synthesized in step 1 in tetrahydrofuran (THF): water (1:1), the reactant was cooled to 0. At 0, lithium hydroxide hydrate (0.071 g, 1.684 mmol) was added dropwise thereto, and the mixture was stirred for 30 minutes. Then, the reactant was heated to room temperature and stirred at room temperature for 12 hours. After the reaction was completed, ethyl acetate was added dropwise thereto for extraction, and the solvent and water layer were removed under reduced pressure. The obtained 2-(4-benzylpiperidin-1-yl) lithium acetate was used for the next step reaction without purification.

[0246] Step 3: 1H-indole-2-carbohydrazide (0.285mmol) and 2-(4-benzylpiperidin-1-yl) lithium acetate (0.314mmol) were dissolved in POCl3 (2M), and the resultant was stirred at 110°C for 3 hours. After the reaction was completed, ice water was added dropwise thereto and the mixture was stirred for 10 minutes. Ethyl acetate was added dropwise thereto for extraction, and the organic layer was washed with H2O and brine in turn and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the compound of Example 33.

[0247] <Example 34> Preparation of 2-((4-(3,4-dichlorobenzyl)piperidin-1-yl)methyl)-5-(1H-indol-2-yl)-1,3,4-oxadiazole

[0248]

[0249] Step 1: After dissolving 4-(3,4-dichlorobenzyl)piperidine HCl salt (0.3 g, 1.069 mmol), ethyl 2-bromoacetate (0.178 mL, 1.604 mmol) and triethylamine (0.146 mL, 1.069 mmol) in toluene, the reactant was stirred at 80° for 12 hours. After the reaction was completed, water was added dropwise thereto, and the resultant was extracted with ethyl acetate. The organic layer was washed with H2O and brine in turn and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain ethyl 2-(4-(3,4-dichlorobenzyl)piperidin-1-yl)acetate.

[0250] Step 2: After dissolving the 2-(4-(3,4-dichlorobenzyl)piperidin-1-yl)acetate (0.17 g, 0.515 mmol) synthesized in step 1 in tetrahydrofuran (THF): water (1:1), the reactant was cooled to 0. At 0, lithium hydroxide hydrate (0.024 g, 0.566 mmol) was added dropwise thereto, and the mixture was stirred for 30 minutes. Then, the reactant was heated to room temperature and stirred at room temperature for 12 hours. After the reaction was completed, ethyl acetate was added dropwise thereto for extraction, and the solvent and water layer were removed under reduced pressure. The obtained 2-(4-(-(3,4-dichlorobenzyl)piperidin-1-yl)acetic acid was used in the next step reaction without purification.

[0251] Step 3: After 1H-indole-2-carbohydrazide (0.285 mmol) and 2-(4-(-(3,4-dichlorobenzyl)piperidin-1-yl)acetic acid (0.314 mmol) were dissolved in POCl3 (2 M), the resultant was stirred at 110°C for 3 hours. After the reaction was completed, ice water was added dropwise thereto and the mixture was stirred for 10 minutes. Ethyl acetate was added dropwise thereto for extraction, the organic layer was washed with H2O and brine in sequence and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the compound of Example 34.

[0252] <Example 35> Preparation of 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indole-5,6-diol

[0253]

[0254] Step 1: At 0, (5-bromo-4H-1,2,4-triazole-3-yl)methanol (500mg, 2.81mmol, 1eq), 4-benzylpiperidine (0.741mL, 4.21mmol, 1.5eq) and triphenylphosphine (1.105g, 4.21mmol, 1.5eq) were dissolved in tetrahydrofuran (THF), and diethyl azodicarboxylate (DEAD) solution (DEAD) (1.911ml, 4.21mmol, 1.5eq) was added dropwise thereto. The reactants were stirred at room temperature under nitrogen atmosphere for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure. The resultant was extracted with dichloromethane, the organic layer was washed with H2O and brine in turn and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain a 4-benzyl-1-((5-bromo-4H-1,2,4-triazol-3-yl)methyl)piperidine compound.

[0255] Step 2: 4-benzyl-1-((5-bromo-4H-1,2,4-triazol-3-yl)methyl)piperidine (1 eq), (1-(tert-butoxycarbonyl)-5,6-dimethoxy-1H-indol-2-yl)boronic acid (1.3 eq), Li2CO3 (2 eq) and catalyst Pd(Ph3P)4 (0.2 eq) synthesized in step 1 were dissolved in 4-dioxane: water (3:1) in a microwave vial, and the reaction mixture was reacted in a Biotage microwave at 160 for 30 minutes. (1-(tert-butoxycarbonyl)-5,6-dimethoxy-1H-indol-2-yl)boronic acid (1.3 eq), Li2CO3 (2 eq) and catalyst Pd(Ph3P)4 (0.2 eq) were added dropwise to the reactant, and the reactant was reacted in a Biotage microwave at 160 for 30 minutes. After the reaction was completed, the resultant was extracted with dichloromethane, the organic layer was washed with H2O and brine in sequence and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5,6-dimethoxy-1H-indole.

[0256] Step 3: The 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5,6-dimethoxy-1H-indole (1 eq) synthesized in step 2 was dissolved in acetic acid, and hydrogen bromide (acetic acid solution) (30 eq) was added dropwise thereto at room temperature. The reaction mixture was refluxed and stirred for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the resultant was dissolved in a mixed solvent of ethyl acetate and tetrahydrofuran (THF). Saturated NaHCO3 aqueous solution was added dropwise, and the resultant was extracted with DCM, the organic layer was washed with H2O and brine in sequence and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the resultant was separated and purified by MPLC and Prep HPLC to obtain the compound of Example 35.

[0257] <Example 36> Preparation of 3-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5-methoxy-1H-indole

[0258]

[0259] Step 1: At 0, (5-bromo-4H-1,2,4-triazole-3-yl)methanol (500mg, 2.81mmol, 1eq), 4-benzylpiperidine (0.741ml, 4.21mmol, 1.5eq) and triphenylphosphine (1.105g, 4.21mmol, 1.5eq) were dissolved in tetrahydrofuran (THF), and diethyl azodicarboxylate (DEAD) solution (1.911mL, 4.21mmol, 1.5eq) was added dropwise thereto. The reactants were stirred at room temperature under a nitrogen atmosphere for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure. The resultant was extracted with dichloromethane, and the organic layer was washed with H2O and brine in turn and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain a 4-benzyl-1-((5-bromo-4H-1,2,4-triazole-3-yl)methyl)piperidine compound.

[0260] Step 2: After dissolving 4-benzyl-1-((5-bromo-4H-1,2,4-triazol-3-yl)methyl)piperidine (1 eq), 5-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-indole-1-carboxylic acid tert-butyl ester (1.3 eq), Li2CO3 (2 eq) and catalyst Pd(Ph3P)4 (0.2 eq) synthesized in step 1 in 4-dioxane: water (3:1) in a microwave vial, the reaction mixture was reacted in a Biotage microwave at 160 for 30 minutes. After the reaction was completed, the resultant was extracted with dichloromethane, the organic layer was washed with H2O and brine in sequence and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC and Prep HPLC to obtain the compound of Example 36.

[0261] Using R listed in Table 5 below instead of tert-butyl 5-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate in Step 2, and using the same procedure as Example 36, the compounds of Examples 37 to 42 were obtained.

[0262] [Table 5]

[0263]

[0264]

[0265] <Example 43> Preparation of 3-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indol-5-amine

[0266]

[0267] Step 1: After the synthesized 4-benzyl-1-((5-bromo-4H-1,2,4-triazol-3-yl)methyl)piperidine (1eq), (1-(tert-butoxycarbonyl)-5-((tert-butoxycarbonyl)amino)-1H-indol-3-yl)boronic acid (1.3eq), Li2CO3 (2eq) and catalyst Pd(Ph3P)4 (0.2eq) were dissolved in 4-dioxane: water (3:1) in a microwave vial, the reaction mixture was reacted in a Biotage microwave at 160 for 30 minutes. After the reaction was completed, the resultant was extracted with dichloromethane, the organic layer was washed with H2O and brine in sequence and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC and Prep HPLC to obtain tert-butyl (3-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indol-5-yl)carbamate.

[0268] Step 2: After dissolving tert-butyl (3-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indol-5-yl)carbamate (1eq) synthesized in step 1 in DCM, an excess of TFA (50eq) was added dropwise thereto and reacted at room temperature for 3 hours. After completion of the reaction, it was neutralized using a supersaturated aqueous sodium carbonate solution and then extracted with dichloromethane. The resultant was dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The reaction mixture was then separated and purified by preparative HPLC to obtain the compound of Example 43 as a white solid.

[0269] <Example 44> Preparation of 3-(5-((4-(3,4-dichlorobenzyl)piperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5-methoxy-1H-indole

[0270]

[0271] Step 1: After dissolving 4-(3,4-dichlorobenzyl)piperidine HCl salt in dichloromethane, the pH of the resultant was adjusted to 12 or higher by washing with a 6M NaOH aqueous solution. After the organic layer solvent was dried over anhydrous Na2SO4, the solvent was removed under reduced pressure to obtain 4-(3,4-dichlorobenzyl)piperidine.

[0272] Step 2: At 0, (5-bromo-4H-1,2,4-triazol-3-yl)methanol (500mg, 2.81mmol, 1eq), 4-(3,4-dichlorobenzyl)piperidine (892mg, 3.65mmol, 1.3eq) and triphenylphosphine (1.105g, 4.21mmol, 1.5eq) were dissolved in tetrahydrofuran (THF) solution, and diethyl azodicarboxylate (DEAD) solution (1.911ml, 4.21mmol, 1.5eq) was added dropwise thereto. The reactants were stirred at room temperature under nitrogen atmosphere for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure. The resultant was extracted with dichloromethane, the organic layer was washed with H2O and brine in turn and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain a 1-((5-bromo-4H-1,2,4-triazol-3-yl)methyl)-4-(3,4-dichlorobenzyl)piperidine compound.

[0273] Step 3: After dissolving 1-((5-bromo-4H-1,2,4-triazol-3-yl)methyl)-4-(3,4-dichlorobenzyl)piperidine (1 eq), 5-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-indole-1-carboxylic acid tert-butyl ester (1.3 eq), Li2CO3 (2 eq) and catalyst Pd(Ph3P)4 (0.2 eq) synthesized in step 1 in 4-dioxane: water (3:1) in a microwave vial, the reaction mixture was reacted in a Biotage microwave at 160 for 30 minutes. After the reaction was completed, the resultant was extracted with dichloromethane, the organic layer was washed with H2O and brine in sequence and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC and preparative HPLC to obtain the compound of Example 44.

[0274] Using R listed in Table 6 below instead of tert-butyl 5-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate and the same procedure as Example 44, the compound of Example 45 was obtained.

[0275] [Table 6]

[0276]

[0277] <Example 46> Preparation of 4-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)benzonitrile

[0278]

[0279] Step 1: At 0, (5-bromo-4H-1,2,4-triazole-3-yl)methanol (500mg, 2.81mmol, 1eq), 4-benzylpiperidine (0.741mL, 4.21mmol, 1.5eq) and triphenylphosphine (1.105g, 4.21mmol, 1.5eq) were dissolved in tetrahydrofuran (THF), and diethyl azodicarboxylate (DEAD) solution (1.911mL, 4.21mmol, 1.5eq) was added dropwise thereto. The reactants were stirred at room temperature under a nitrogen atmosphere for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure. The resultant was extracted with dichloromethane, and the organic layer was washed with H2O and brine in turn and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain a 4-benzyl-1-((5-bromo-4H-1,2,4-triazole-3-yl)methyl)piperidine compound.

[0280] Step 2: 4-benzyl-1-((5-bromo-4H-1,2,4-triazol-3-yl)methyl)piperidine (1 eq), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (1.3 eq), Li2CO3 (2 eq) and catalyst Pd(Ph3P)4 (0.2 eq) synthesized in step 1 were dissolved in 4-dioxane: water (3:1) in a microwave vial, and the reaction mixture was reacted in a Biotage microwave at 160 for 30 minutes. 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (1.3 eq), Li2CO3 (2 eq) and catalyst Pd(Ph3P)4 (0.2 eq) were added dropwise to the reactant, and the reactant was reacted in a Biotage microwave at 160 for 30 minutes. After the reaction was completed, the resultant was extracted with dichloromethane, the organic layer was washed with H2O and brine in sequence and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain 4-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)benzonitrile.

[0281] Using R listed in Table 7 below instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile in step 2 and the same procedure as in Example 46, the compound of Example 55 was obtained.

[0282] [Table 7]

[0283]

[0284]

[0285] <Example 56> Preparation of 3-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-6-methoxy-1H-indole

[0286]

[0287] Step 1: At 0, (5-bromo-4H-1,2,4-triazol-3-yl)methanol (500mg, 2.81mmol, 1eq), 4-benzylpiperidine (0.741mL, 4.21mmol, 1.5eq) and triphenylphosphine (1.105g, 4.21mmol, 1.5eq) were dissolved in tetrahydrofuran (THF), and diethyl azodicarboxylate (DEAD) solution (1.911mL, 4.21mmol, 1.5eq) was added dropwise thereto. The reactants were stirred at room temperature under nitrogen atmosphere for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure. The resultant was extracted with dichloromethane, the organic layer was washed with H2O and brine in turn and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain a 4-benzyl-1-((5-bromo-4H-1,2,4-triazol-3-yl)methyl)piperidine compound.

[0288] Step 2: After dissolving 4-benzyl-1-((5-bromo-4H-1,2,4-triazol-3-yl)methyl)piperidine (1 eq), 6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylic acid tert-butyl ester (1.3 eq), Li2CO3 (2 eq) and catalyst Pd(Ph3P)4 (0.2 eq) synthesized in step 1 in 4-dioxane: water (3:1) in a microwave vial, the reaction mixture was reacted in a Biotage microwave at 160 for 30 minutes. After the reaction was completed, the resultant was extracted with dichloromethane, the organic layer was washed with H2O and brine in sequence and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC and preparative HPLC to give the title compound 3-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-6-methoxy-1H-indole.

[0289] <Example 57> Preparation of 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indole-5-carboxamide

[0290]

[0291] After 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indole-5-carboxylic acid (1 eq) of Example 28 was dissolved in DMF, HBTU (3.5 eq), ammonium chloride (5 eq) and triethylamine (5 eq) were added dropwise at 0° C. The reactant was stirred at room temperature for 12 hours.

[0292] After the reaction was completed, the obtained product was extracted with ethyl acetate, and the organic layer was washed with saturated NaHCO3 aqueous solution and brine in turn and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indole-5-carboxamide.

[0293] <Example 58> Preparation of 4-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-N-(2-(dimethylamino)ethyl)benzamide

[0294]

[0295] Step 1: After 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenol (500mg, 2.272mmol), 2-(dimethylamino)ethane-1-ol (0.296ml, 2.95mmol) and triphenylphosphine (775mg, 2.95mmol, 1.3eq) were dissolved in tetrahydrofuran (THF) at 0, diethyl azodicarboxylate (DEAD) solution (1.34mL, 2.95mmol, 1.3eq) was added dropwise thereto. The reactants were stirred at room temperature under nitrogen atmosphere for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure. The resultant was extracted with dichloromethane, the organic layer was washed with H2O and brine in turn and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain an N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethan-1-amine compound.

[0296] Step 2: At 0, (5-bromo-4H-1,2,4-triazole-3-yl)methanol (500mg, 2.81mmol, 1eq), 4-benzylpiperidine (0.741mL, 4.21mmol, 1.5eq) and triphenylphosphine (1.105g, 4.21mmol, 1.5eq) were dissolved in tetrahydrofuran (THF), and diethyl azodicarboxylate (DEAD) solution (1.911mL, 4.21mmol, 1.5eq) was added dropwise thereto. The reactant was stirred at room temperature under a nitrogen atmosphere for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure. The resultant was extracted with dichloromethane, and the organic layer was washed with H2O and brine in turn and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain a 4-benzyl-1-((5-bromo-4H-1,2,4-triazole-3-yl)methyl)piperidine compound.

[0297] Step 3: After dissolving 4-benzyl-1-((5-bromo-4H-1,2,4-triazol-3-yl)methyl)piperidine (1 eq) synthesized in step 2, N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethan-1-amine (1.3 eq) synthesized in step 1, Li2CO3 (2 eq) and catalyst Pd(Ph3P)4 (0.2 eq) in 4-dioxane:water (3:1) in a microwave vial, the reaction mixture was reacted in a Biotage microwave at 160 for 30 min. After N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)phenoxy)ethyl-1-amine (1.3 eq), Li2CO3 (2 eq) and catalyst Pd(Ph3P)4 (0.2 eq) were added dropwise to the reactant again, the reactant was reacted at 160°C for 30 minutes. After the reaction was completed, the resultant was extracted with dichloromethane, the organic layer was washed with H2O and brine in sequence and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC and preparative HPLC to obtain the title compound 4-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-N-(2-(dimethylamino)ethyl)benzamide.

[0298] <Example 59> Preparation of 3-(5-((4-(3,4-dichlorobenzyl)piperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-6-methoxy-1H-indole

[0299]

[0300] Step 1: After dissolving 4-(3,4-dichlorobenzyl)piperidine hydrochloride in dichloromethane, the pH of the resultant was adjusted to 12 or higher by washing with a 6M NaOH aqueous solution. The organic layer solvent was dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure to obtain 4-(3,4-dichlorobenzyl)piperidine.

[0301] Step 2: (5-bromo-4H-1,2,4-triazole-3-yl)methanol (500mg, 2.81mmol, 1eq), 4-(3,4-dichlorobenzyl)piperidine (892mg, 3.65mmol, 1.3eq) and triphenylphosphine (1.105g, 4.21mmol, 1.5eq) were dissolved in tetrahydrofuran (THF) solution, and diethyl azodicarboxylate (DEAD) solution (1.911mL, 4.21mmol, 1.5eq) was added dropwise thereto. The reactants were stirred at room temperature under nitrogen atmosphere for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure. The resultant was extracted with dichloromethane, the organic layer was washed with H2O and brine in turn and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain a 1-((5-bromo-4H-1,2,4-triazol-3-yl)methyl)-4-(3,4-dichlorobenzyl)piperidine compound.

[0302] Step 3: After dissolving 1-((5-bromo-4H-1,2,4-triazol-3-yl)methyl)-4-(3,4-dichlorobenzyl)piperidine (1 eq), 6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylic acid tert-butyl ester (1.3 eq), Li2CO3 (2 eq) and catalyst Pd(Ph3P)4 (0.2 eq) synthesized in step 2 in 4-dioxane: water (3:1) in a microwave vial, the reaction mixture was reacted in a Biotage microwave at 160 for 30 minutes. After the reaction was completed, the resultant was extracted with dichloromethane, the organic layer was washed with H2O and brine in sequence and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain the title compound, 3-(5-((4-(3,4-dichlorobenzyl)piperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-6-methoxy-1H-indole.

[0303] Using R listed in Table 8 below instead of tert-butyl 6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate in Step 3, and using the same procedure as Example 59, the compounds of Examples 60 to 62 were obtained.

[0304] [Table 8]

[0305]

[0306] <Example 63> Preparation of methyl 2-amino-4-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoate

[0307]

[0308] Step 1: After 2-amino-4-bromobenzoic acid methyl ester (500mg, 2.173mmol), potassium acetate (427mg, 4.35mmol), bis(pinacol) diboron (717mg, 2.83mmol) and Pd(dppf)Cl2.CH2Cl2 (266mg, 0.326mmol) were dissolved in 1,4-dioxane (15mL), the reaction mixture was degassed with nitrogen. The reactant was stirred at 100 for 12 hours. After the reaction was completed, the reaction mixture was filtered through diatomaceous earth, and the organic layer was extracted with ethyl acetate. The organic layer was washed with 0.5M HCl aqueous solution and brine in turn and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the obtained product was separated and purified by MPLC to obtain 2-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid methyl ester compound.

[0309] Step 2: At 0, (5-bromo-4H-1,2,4-triazole-3-yl)methanol (500mg, 2.81mmol, 1eq), 4-benzylpiperidine (0.741mL, 4.21mmol, 1.5eq) and triphenylphosphine (1.105g, 4.21mmol, 1.5eq) were dissolved in tetrahydrofuran (THF), and diethyl azodicarboxylate (DEAD) solution (1.911mL, 4.21mmol, 1.5eq) was added dropwise thereto. The reactant was stirred at room temperature under a nitrogen atmosphere for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure. The resultant was extracted with dichloromethane, and the organic layer was washed with H2O and brine in turn and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain a 4-benzyl-1-((5-bromo-4H-1,2,4-triazole-3-yl)methyl)piperidine compound.

[0310] Step 3: After dissolving 4-benzyl-1-((5-bromo-4H-1,2,4-triazol-3-yl)methyl)piperidine (1 eq) synthesized in step 2, methyl 2-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.3 eq) synthesized in step 1, Li2CO3 (2 eq) and catalyst Pd(Ph3P)4 (0.2 eq) in 4-dioxane: water (3:1) in a microwave vial, the reaction mixture was heated in a Biotage microwave at 160 for 30 minutes. After the reaction was completed, the resultant was extracted with dichloromethane, the organic layer was washed with H2O and brine in sequence and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC and preparative HPLC to give the title compound, methyl 2-amino-4-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoate.

[0311] <Example 64> Preparation of 2-(5-((4-benzylpiperazin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5-fluoro-1H-indole

[0312]

[0313] Step 1: At 0, (5-bromo-4H-1,2,4-triazole-3-yl)methanol (500mg, 2.81mmol, 1eq), 1-benzylpiperazine (0.594mg, 3.37mmol, 1.2eq) and triphenylphosphine (1.105g, 4.21mmol, 1.5eq) were dissolved in tetrahydrofuran (THF), and diethyl azodicarboxylate (DEAD) solution (1.911mL, 4.21mmol, 1.5eq) was added dropwise thereto. The reactants were stirred at room temperature under a nitrogen atmosphere for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure. The resultant was extracted with dichloromethane, and the organic layer was washed with H2O and brine in turn and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain a 1-benzyl-4-((5-bromo-4H-1,2,4-triazole-3-yl)methyl)piperazine compound.

[0314] Step 2: After dissolving 1-benzyl-4-((5-bromo-4H-1,2,4-triazol-3-yl)methyl)piperazine (1 eq), (1-(tert-butyloxycarbonyl)-5-fluoro-1H-indol-2-yl)boric acid (1.3 eq), Li2CO3 (2 eq) and catalyst Pd(Ph3P)4 (0.2 eq) synthesized in step 1 in 4-dioxane: water (3:1) in a microwave vial, the reaction mixture was reacted in a Biotage microwave at 160 for 30 minutes. After the reaction was completed, the resultant was extracted with dichloromethane, the organic layer was washed with H2O and brine in sequence and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC and preparative HPLC to give the title compound 2-(5-((4-benzylpiperazin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5-fluoro-1H-indole.

[0315] Using R listed in the following Table 9 instead of (1-(tert-butoxycarbonyl)-5-fluoro-1H-indol-2-yl)boronic acid in step 2 and the same procedure as in Example 64, the compound of Example 65 was obtained.

[0316] [Table 9]

[0317]

[0318] <Example 66> Preparation of N-(2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indol-5-yl)acetamide

[0319]

[0320] Step 1: At 0, (5-bromo-4H-1,2,4-triazole-3-yl)methanol (500mg, 2.81mmol, 1eq), 4-benzylpiperidine (0.741mL, 4.21mmol, 1.5eq) and triphenylphosphine (1.105g, 4.21mmol, 1.5eq) were dissolved in tetrahydrofuran (THF), and diethyl azodicarboxylate (DEAD) solution (1.911mL, 4.21mmol, 1.5eq) was added dropwise thereto. The reactants were stirred at room temperature under a nitrogen atmosphere for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure. The resultant was extracted with dichloromethane, and the organic layer was washed with H2O and brine in turn and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain a 4-benzyl-1-((5-bromo-4H-1,2,4-triazole-3-yl)methyl)piperidine compound.

[0321] Step 2: After dissolving 1-((5-bromo-4H-1,2,4-triazol-3-yl)methyl)-4-(3,4-dichlorobenzyl)piperidine (1 eq), (1-(tert-butyloxycarbonyl)-5-((tert-butyloxycarbonyl)amino)-1H-indol-2-yl)boronic acid (1.3 eq), Li2CO3 (2 eq) and catalyst Pd(Ph3P)4 (0.2 eq) synthesized in step 1 in 4-dioxane: water (3:1) in a microwave vial, the reaction mixture was reacted in a Biotage microwave at 160 for 30 minutes. After the reaction was completed, the resultant was extracted with dichloromethane, the organic layer was washed with H2O and brine in sequence and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC and PrepHPLC to obtain tert-butyl (2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indol-5-yl)carbamate.

[0322] Step 3: After dissolving the tert-butyl (2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indol-5-yl)carbamate (1eq) synthesized in step 2 in DCM, an excess of TFA (50eq) was added dropwise thereto and reacted at room temperature for 3 hours. After the reaction was completed, saturated NaHCO3 aqueous solution was used for neutralization, and the resultant was extracted with dichloromethane. The resultant was dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indol-5-amine was obtained without further purification.

[0323] Step 4: After 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indol-5-amine (1 eq) was dissolved in DCM, triethylamine (1.1 eq) and acetic anhydride (1.1 eq) were added dropwise thereto, and the mixture was stirred at room temperature for 1.5 hours. After the reaction was completed, the resultant was extracted with dichloromethane and methanol, the organic layer was washed with H2O and brine in turn and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC and Prep TLC to obtain the title compound N-(2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indol-5-yl)acetamide.

[0324] <Example 67> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indol-5-ol

[0325]

[0326] After 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazole-3-yl)-5-methoxy-1H-indole (1 eq) of Example 13 was dissolved in dichloromethane, boron tribromide (2.5 eq) was added dropwise at 0. The reactant was stirred at room temperature under a nitrogen atmosphere for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure. The resulting product was extracted with dichloromethane, and the organic layer was washed with H2O and brine in turn and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazole-3-yl)-1H-indole-5-ol.

[0327] <Example 68> (4-Benzylpiperidin-1-yl)(5-(5-fluoro-1H-indol-2-yl)-4H-1,2,4-triazol-3-yl)methanone

[0328] Using R listed in the following Table 10 instead of (1-(tert-butoxycarbonyl)-5-yl-fluoro-1H-indol-2-yl)boronic acid in step 1 and the same procedure as in Example 11, the compound of Example 68 was obtained.

[0329] [Table 10]

[0330]

[0331] <Example 69> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-6-butoxy-1H-indole

[0332]

[0333] Step 1: After 6-butoxy-1H-indole-2-carboxylic acid (200 mg, 0.857 mmol, 1 eq) and dimethylformaldehyde (33 μL, 0.429 mmol, 0.5 eq) were dissolved in tetrahydrofuran (THF), oxalyl chloride (150 μL, 1.1715 mmol, 2 eq) was added dropwise at 0 °C. The reactants were stirred at room temperature under nitrogen atmosphere for 5 hours. After the reaction was completed, the solvent was removed under reduced pressure to obtain a 6-butoxy-1H-indole-2-carbonyl chloride compound.

[0334] Step 2: After the 6-butoxy-1H-indole-2-carbonyl chloride (1 eq) synthesized in step 1 is dissolved in tetrahydrofuran, ammonium hydroxide is added dropwise at 0 to adjust the pH value of the resultant to 9-10 and react at room temperature for 1 hour, and 5 mL of water is added dropwise thereto, and then stirred for 30 minutes. The resultant is extracted with dichloromethane, and the organic layer is washed with H2O and brine in turn and dried over anhydrous Na2SO4, and the solvent is removed under reduced pressure. Then, the reaction mixture is separated and purified by MPLC to obtain tert-butyl 6-butoxy-1H-indole-2-carboxamide.

[0335] Step 3: After dissolving the 6-butoxy-1H-indole-2-carboxamide (1 eq) synthesized in step 2 and Lawesson's reagent (1.2 eq) in tetrahydrofuran, the resultant was stirred at 80°C for 4 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the resultant was solidified with methanol to obtain 6-butoxy-1H-indole-2-carbothioamide.

[0336] Step 4: After dissolving the 6-butoxy-1H-indole-2-thiocarboxamide (1eq) and iodomethane (2eq) synthesized in step 3 in acetone, the reactant was stirred at 80°C for 4 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the resultant was reacted at room temperature for 1 hour, 5 mL of water was added dropwise thereto, and the resultant was stirred for 30 minutes. The resultant was extracted with dichloromethane, the organic layer was washed with H2O and brine in turn and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure to obtain 6-butoxy-1H-indole-2-iminothiomethyl ester.

[0337] Step 5: The methyl-6-butoxy-1H-indole-2-iminothiomethyl ester (1 eq), 2-(4-benzylpiperidin-1-yl)acetohydrazide (1 eq), and ammonium acetate (1.5 eq) synthesized in step 4 were dissolved in ethanol and stirred at 80°C for 6 hours. After the reaction was completed, the resultant was extracted with dichloromethane, the organic layer was washed with H2O and brine in sequence and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. Then, the reaction mixture was separated and purified by MPLC to obtain 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-6-butoxy-1H-indole.

[0338] Using R listed in the following Table 11 instead of 6-butoxy-1H-indole-2-carboxylic acid in Step 1 and using the same procedure as in Example 69, the compounds of Examples 70 to 76 were obtained.

[0339] [Table 11]

[0340]

[0341] The compound names, NMR analysis results, and mass analysis results of Examples 1 to 76 are summarized in Table 12 below.

[0342] [Table 12]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355] <Experimental Example 1> Evaluation of triple reuptake inhibition

[0356] In order to evaluate the reuptake inhibitory effect of the compounds according to the examples of the present invention on serotonin, norepinephrine and dopamine, the following experiment was performed, and the results are shown in Table 13.

[0357] In order to evaluate the reuptake inhibitory effect on dopamine, dopamine transporter cDNA was transfected using HEK-293 cell line, and then seeded into 24-well plates the next day. After removing the culture medium, each compound of the example or comparative example diluted to 1 μM in the uptake buffer was added to a concentration of 200 μl / well and incubated at 37 for 15 minutes. 100 μl of uptake buffer containing 20-30 nM [3H]-DA was added and incubated at 37 for 5 minutes. The reaction solution was quickly removed and washed 3 times with 1 mL of ice-cold uptake buffer. After dissolving the resultant in 1% SDS (0.5 mL), the degree of binding of radioactive isotope-labeled dopamine to the transporter was measured.

[0358] For norepinephrine (NE) and serotonin (5-HT), the extent of binding of radioisotope-labeled norepinephrine or serotonin to the transporter was measured in the same manner as above, except that [3H]-NE or [3H]-5-HT from cells transfected with NE or 5-HT transporter cDNA was used as a substrate.

[0359] Furthermore, when evaluating the reuptake inhibitory effect on dopamine, norepinephrine and serotonin, the same method was performed, but each compound of the Examples or Comparative Examples was not treated as a control, the degree of binding of radioisotope-labeled dopamine, norepinephrine and serotonin to the transporter was measured, and the triple reuptake inhibitory effect was evaluated as a relative ratio (ratio %) by taking it as a reference (100%). That is, in the control group, the binding of dopamine, norepinephrine and serotonin to the transporter was not inhibited, but when each compound of the Examples was treated and thus the binding was inhibited, the ratio % value decreased.

[0360] Meanwhile, the ratio % values ​​were compared, and in the case of the compounds of Examples 1, 2, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 and 31 having excellent reuptake inhibitory effects on dopamine, norepinephrine and serotonin, a concentration at which the ratio % was 50% was calculated using a total of 6 concentrations (1 nM, 5 nM, 10 nM, 50 nM, 100 nM and 1 μM), and the IC 50 express.

[0361] [Table 13]

[0362]

[0363]

[0364]

[0365] In the above Table 13, SERT represents serotonin transporter, NET represents norepinephrine transporter, and DAT represents dopamine transporter.

[0366] As shown in Table 13 above,

[0367] It can be seen that the compounds of the examples of the present invention can inhibit the reuptake of serotonin, norepinephrine and dopamine.

[0368] Industrial Applicability

[0369] The compound represented by Formula 1 according to the present invention has excellent triple reuptake inhibition of serotonin, norepinephrine and dopamine, and thus can be used to treat mental disorders.

Claims

1. A compound represented by the following formula 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof: [Formula 1] In the above formula 1, n is an integer from 0 to 1; A 1 It is NH; A 2 It is CH; L 1 is CH2 or C(=O); R 1 yes Among them A 3 is NH, O or S, R a1 , R a2 , R a3 , R a4 and R a5 are independently hydrogen, halogen, hydroxy, amino, CN, a linear or branched C 1-10 Alkyl, unsubstituted or substituted by one or more halogen straight chain or branched C 1-10 Alkoxy, -C(=O)OR c 、-C(=O)N(R c )2 or -NR c C(=O)R c , or R a2 and R a3 Together with the carbon to which they are attached, they form a 5- or 6-membered heterocycloalkenyl containing one or more O, R c are independently hydrogen, unsubstituted straight or branched chain C 1-10 Alkyl; and R 2 yes Where R e1 , R e2 , R e3 and R e4 are independently hydrogen, halogen, or a linear or branched C 1-10 Alkoxy.

2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R a1 , R a2 , R a3 , R a4 and R a5 are independently hydrogen, halogen, hydroxy, amino, CN, a linear or branched C 1-5 Alkyl, unsubstituted or substituted by one or more halogen straight chain or branched C 1-5 Alkoxy, -C(=O)OR c 、-C(=O)N(R c )2 or -NR c C(=O)R c , or R a2 and R a3 Together with the carbon to which they are attached, they form a 5- or 6-membered heterocycloalkenyl containing one or two O; R c are independently hydrogen, unsubstituted straight or branched chain C 1-5 Alkyl; and Where R e1 , R e2 , R e3 and R e4 are independently hydrogen, halogen, or a linear or branched C 1-5 Alkoxy.

3. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R a1 , R a2 , R a3 , R a4 and R a5 are independently hydrogen, halogen, OH, -NH2, CN, methyl, -CF3, methoxy, butoxy, -OCF3, -C(=O)OCH3, -C(=O)OH, -C(=O)NH2 or -NHC(=O)CH3, or R a2 and R a3 The carbon to which they are attached forms as well as Where R e1 , R e2 , R e3 and R e4 are independently hydrogen, Cl or methoxy.

4. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 1 yes:

5. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R 2 yes 6. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound represented by Formula 1 is any one selected from the group consisting of the following compounds: <1> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indole; <2> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5-fluoro-1H-indole; <3> 2-(5-((4-phenylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indole; <5> 2-(5-((4-(3,4-dichlorobenzyl)piperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indole; <6> 2-(5-((4-(4-methoxybenzyl)piperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indole; <7> 2-(5-((4-(4-chlorobenzyl)piperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indole; <8> 2-(5-((4-(3-chlorobenzyl)piperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indole; <12> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5,6-dimethoxy-1H-indole; <13> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5-methoxy-1H-indole; <14> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5-chloro-1H-indole; <15> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5-methyl-1H-indole; <16> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-6-fluoro-1H-indole; <17> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indole-5-carbonitrile; <18> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-6-methoxy-1H-indole; <19> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-7-methoxy-1H-indole; <20> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indole-5-carboxylic acid methyl ester; <22> 3-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indole; <23> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-indole; <24> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-4-chloro-1H-indole; <25> 1-((5-(Benzofuran-2-yl)-4H-1,2,4-triazol-3-yl)methyl)-4-benzylpiperidine; <26> 1-((5-(Benzo[b]thiophen-2-yl)-4H-1,2,4-triazol-3-yl)methyl)-4-benzylpiperidine; <28> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indole-5-carboxylic acid; <29> 2-(5-((4-(3,4-dichlorobenzyl)piperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5-fluoro-1H-indole <30> 2-(5-((4-(3,4-dichlorobenzyl)piperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5-methyl-1H-indole <31> 2-(5-((4-(3,4-dichlorobenzyl)piperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5,6-dimethoxy-1H-indole; <32> 2-(5-((4-(1H-indol-3-yl)piperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5-fluoro-1H-indole; <35> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indole-5,6-diol; <36> 3-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5-methoxy-1H-indole; <37> 3-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-7-methoxy-1H-indole; <38> 3-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-6-methyl-1H-indole; <39> 3-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5-methyl-1H-indole; <40> 3-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-7-chloro-1H-indole; <41> 3-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5-chloro-1H-indole; <42> 3-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indole-7-carboxylic acid methyl ester; <43> 3-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indol-5-amine; <44> 3-(5-((4-(3,4-dichlorobenzyl)piperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5-methoxy-1H-indole <45> 3-(5-((4-(3,4-dichlorobenzyl)piperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-7-methoxy-1H-indole <56> 3-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-6-methoxy-1H-indole; <57> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indole-5-carboxamide; <59> 3-(5-((4-(3,4-dichlorobenzyl)piperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-6-methoxy-1H-indole <60> 3-(5-((4-(3,4-dichlorobenzyl)piperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indole-7-carboxylic acid methyl ester; <66> N-(2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indol-5-yl)acetamide; <67> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-1H-indol-5-ol; <68> (4-Benzylpiperidin-1-yl)(5-(5-fluoro-1H-indol-2-yl)-4H-1,2,4-triazol-3-yl)methanone; <69> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-6-butoxy-1H-indole; <70> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-3-methyl-1H-indole; <71> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-4,6-dichloro-1H-indole; <72> 2-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5,6-dichloro-1H-indole; <73> 6-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-5H-[1,3]dioxo[4,5-f]indole; <74> 7-(5-((4-benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-2,3-dihydro-6H-[1,4]dioxin[2,3-f]indole; and <75> 3-(5-((4-Benzylpiperidin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)-6-fluoro-1H-indole.

7. Use of a pharmaceutical composition in the preparation of a medicament for preventing or treating a mental disorder, the pharmaceutical composition comprising the compound represented by formula 1 of claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

8. The use according to claim 7, wherein the compound inhibits the reuptake of serotonin, norepinephrine and dopamine.

9. The use according to claim 7, wherein the mental disorder is one or more selected from the group consisting of bulimia nervosa, mood disorders, depression, cyclothymic disorder, Ganger syndrome, obsessive-compulsive disorder, panic disorder, memory impairment, attention deficit hyperactivity disorder, anxiety disorder, Parkinson's disease, dementia, Down syndrome, social phobia, acute stress disorder, chronic stress disorder, drug addiction, drug abuse tendency, pathological kleptomania, withdrawal syndrome caused by withdrawal from intoxicating substances, premenstrual syndrome, late luteal phase syndrome, post-traumatic syndrome, chronic fatigue syndrome, persistent vegetative state, sexual dysfunction, restless legs syndrome, periodic limb movement disorder, eating disorders, sleep disorders, pervasive developmental disorders, autism, Asperger's syndrome, Rett disorder, childhood disintegrative disorder, learning disabilities, movement disorders, mutism, trichotillomania, Tourette syndrome, body dysmorphic disorder, oppositional defiant disorder and erectile dysfunction.

10. The method of claim 7, wherein the psychiatric disorder is selected from the group consisting of memory loss, memory impairment due to senility, pseudodementia, senile dementia, atypical depression, depression secondary to pain, major depressive disorder, dysthymic disorder, bipolar disorder, panic disorder without agoraphobia, panic disorder with agoraphobia, agoraphobia without history of panic disorder, panic attacks, acquired immunodeficiency syndrome dementia, premature ejaculation, erectile dysfunction, post-stroke depression, generalized anxiety disorder, social anxiety disorder, tension-type headache, depression-related pain, phantom limb pain, premenstrual dysphoric disorder, stress urinary incontinence, urge urinary incontinence, substance-induced mood disorders, and anorexia.

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