Composition for preventing or treating degenerative brain diseases containing a novel pyridoindole derivative compound as an active ingredient

Abstract

The present invention provides a composition for preventing or treating degenerative brain diseases, comprising a novel pyridoindole derivative compound as an active ingredient. The present invention goes beyond conventional symptomatic treatments that focus on controlling peripheral symptoms for degenerative brain diseases, specifically, various tauopathies caused by Tau protein aggregation, and can achieve fundamental elimination of the cause of neurodegeneration by significantly inhibiting the interaction between Tau protein and synaptogyrin-3.

Description

[Technical Field]

[0001] The present invention relates to novel pyridoindole compounds that can be used as pharmacological ingredients for various tauopathies, such as degenerative brain diseases, by inhibiting the interaction between tau protein and synaptogyrin 3. [Background technology]

[0002] Microtubules are important components of the cytoskeleton involved in various intracellular processes, including mitosis, cytokinesis, and vesicular transport. Tau protein is a microtubule-associated protein (MAP) that interacts with microtubules to stabilize them and induce their formation. It is present in various cells and tissues, but is particularly abundant in neurons. Because Tau plays a role in stabilizing microtubules, changes in Tau expression, activity, and function can affect various intracellular processes, which can lead to numerous neurodegenerative diseases, including tauopathies.

[0003] Tauopathy is a subtype of proteinopathy, encompassing a variety of neurodegenerative disorders in which hyperphosphorylation of tau protein leads to the formation of aggregates in the brain. It has been reported that mislocalization of tau in dendritic spines or interference with glutamate receptors contributes to the pathogenesis of tauopathy. However, in addition to postsynaptic localization, pathological tau also exists in the presynaptic compartment, suggesting that presynaptic tau function may also contribute to the pathogenesis of the disease.

[0004] On the other hand, the transmembrane synaptic vesicle protein synaptogrin-3 (SGN-3) mediates the binding between tau and synaptic vesicles (Zhou et al., Nature Communications 8:15295 (2017)). Reducing SGN-3 levels in neurons inhibits the binding of TGN-3 to synaptic vesicles, thereby reversing TGN-induced vesicle mobility defects and neurotransmitter secretion (J. McInnes et al., Neuron 97(4):823-835 (2018); Largo-Barrientos et al., Neuron 109:767-777 (2021)). Therefore, inhibiting the expression or activity of SGN-3 itself or the interaction between TGN-3 and SGN-3 could be an effective therapeutic strategy for tauopathies, and there is a growing demand for the discovery of such inhibitors.

[0005] Numerous papers and patent documents are referenced throughout this specification and citations are provided, the disclosures of which are incorporated herein by reference in their entirety to more clearly describe the state of the art and the content of the present invention. Summary of the Invention [Problem to be solved by the invention]

[0006] The present inventors have conducted extensive research to find an effective therapeutic composition that can fundamentally eliminate the causes of various degenerative brain diseases caused by hyperphosphorylation and aggregation of Tau protein. As a result, they have discovered that a pyridoindole derivative compound represented by Chemical Formula 1, described below, significantly inhibits the interaction between Tau protein and synaptogyrin-3, blocks the synaptic vesicle binding of Tau protein mediated by this interaction, and efficiently restores neurotransmitter secretion, thereby completing the present invention.

[0007] Therefore, an object of the present invention is to provide a novel pyridoindole derivative compound and a composition for preventing or treating degenerative brain diseases, which contains the compound as an active ingredient.

[0008] Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, the claims and the drawings. [Means for solving the problem]

[0009] According to one aspect of the present invention, there is provided a compound represented by the following formula 1: [ka] [In the above chemical formula, R1 is C1-C3 alkyl; or C6-C1 alkyl unsubstituted or substituted with C1-C3 alkyl, C3-C7 cycloalkyl, C1-C3 alkoxy, halogen, -CN, -NO2, or -NR3R4 (wherein R3 and R4 are each independently hydrogen or C1-C3 alkyl). 10 aryl, or 5- to 12-membered heteroaryl; R2 is a C6-C alkyl group unsubstituted or substituted with C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halogen, -CN, -NO2, or NR5R6 (wherein R5 and R6 are each independently hydrogen or C1-C3 alkyl). 10 aryl, 5-12 membered heteroaryl, C3-C7 cycloalkyl, or 6 membered heterocycloalkyl; R3 is hydrogen or C1-C3 alkyl; L1 is a direct bond or -NH-; L2 is a direct bond, -C(O)-, -C(S)-, -C(O)NH-, -C(S)NH-, or -S(O2)-].

[0010] The present inventors have conducted extensive research to find an effective therapeutic composition that can fundamentally eliminate the causes of various degenerative brain diseases caused by hyperphosphorylation and aggregation of Tau protein. As a result, they have found that the pyridoindole derivative compound of Chemical Formula 1 significantly inhibits the interaction between Tau protein and synaptogyrin-3, blocks the synaptic vesicle binding of Tau protein mediated by this interaction, and efficiently restores neurotransmitter secretion.

[0011] As used herein, the term "alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon group, including, for example, methyl, ethyl, propyl, isopropyl, etc. C1-C3 alkyl refers to an alkyl group having an alkyl unit with 1 to 3 carbon atoms, and when the C1-C3 alkyl is substituted, the number of carbon atoms of the substituent is not included.

[0012] As used herein, the term "halogen" refers to an element of the halogen family and includes, for example, fluoro, chloro, bromo, and iodo.

[0013] As used herein, the term "aryl" refers to a monocyclic or polycyclic carbon ring that is wholly or partially unsaturated and has aromaticity.

[0014] As used herein, the term "heteroaryl" refers to a heterocyclic aromatic group containing oxygen, sulfur, or nitrogen as heteroatoms in the ring. The number of heteroatoms contained in the ring is 1 to 3, specifically 1 to 2. The term "5- to 12-membered heteroaryl" refers to a heteroaryl having 5 to 12 atoms in the ring, including all carbon and heteroatoms, and the ring may be a monocycle or two fused rings (bicycle).

[0015] As used herein, the term "haloalkyl" refers to an alkyl group substituted with a halogen, for example, C1-C3 haloalkyl refers to a functional group in which one hydrogen atom in an alkyl group having 1 to 3 carbon atoms is substituted with a halogen atom. According to a specific embodiment, the haloalkyl of the present invention is trihalomethyl, more specifically, trifluoromethyl.

[0016] As used herein, the term "alkoxy" refers to a radical formed by removing a hydrogen from an alcohol, for example, C1-C3 alkoxy refers to a radical formed by removing a hydrogen from an alcohol having 1 to 3 carbon atoms.

[0017] According to a specific embodiment of the present invention, R1 is C1-C2 alkyl; or phenyl unsubstituted or substituted with C1-C3 alkyl, C5-C6 cycloalkyl, C1-C3 alkoxy, halogen, -CN, -NO2, -NH2 or -N(CH3)2, or a 5- to 9-membered heteroaryl. More specifically, the heteroaryl is a 6-membered heteroaryl, most specifically pyridine.

[0018] According to a specific embodiment of the present invention, R2 is unsubstituted or phenyl substituted with C1-C3 alkyl, trihalomethyl, C1-C3 alkoxy, -N(CH3)2, -CN or halogen, 5- to 9-membered heteroaryl, C5-C6 cycloalkyl or morpholine.

[0019] More specifically, said heteroaryl is selected from the group consisting of pyridine, pyrimidine, pyrazine, thiazole and indole.

[0020] More specifically, said C5-C6 cycloalkyl is cyclohexyl.

[0021] According to a specific embodiment of the present invention, when L2 is -C(O)NH- or -C(S)NH-, R2 is unsubstituted or phenyl substituted with C1-C2 alkyl or -CN.

[0022] According to a specific embodiment of the present invention, when L1 is -NH-, R1 is phenyl substituted with halogen, more specifically chlorophenyl.

[0023] According to a specific embodiment of the present invention, when L2 is -S(O2)-, R2 is a 6-membered heteroaryl, more specifically pyridine.

[0024] According to a more specific embodiment of the present invention, the compound represented by Chemical Formula 1 is selected from the group consisting of compounds represented by the following Chemical Formulas 2 to 77: [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0025] In another aspect, the present invention provides a composition for preventing or treating a degenerative brain disease, which comprises the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient.

[0026] According to yet another aspect of the present invention, there is provided a method for preventing or treating a degenerative brain disease, comprising administering to a subject the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0027] As used herein, the term "neurodegenerative diseases" encompasses diseases in which structural and functional degeneration occurs due to the irreversible loss of brain tissue and the cells that constitute it. Specifically, degenerative brain diseases that can be prevented or treated by the compositions of the present invention may be tauopathies, which can be treated by blocking the binding of tau protein to synaptic vesicles. As used herein, the term "tauopathy" encompasses diseases or pathological conditions caused by the overexpression, hyperphosphorylation, aggregation, and / or accumulation of tau protein in central nervous system cells, tissues, or organs.

[0028] According to a specific embodiment of the present invention, degenerative brain diseases that can be prevented or treated with the composition of the present invention include, for example, Alzheimer's disease, argyrophilic grain disease (AGD), dementia with Lewy bodies, frontotemporal dementia, progressive supranuclear palsy (PSP), progressive supranuclear palsy-parkinsonism syndrome (PSP-P), Richardson's syndrome, Pick's disease, Niemann-Pick disease, Rasmussen's syndrome, Parkinson's disease, atypical parkinsonism in Guadeloupe, frontotemporal dementia with parkinsonism associated with chromosome 17 (FTDP-17), progressive subcortical gliosis, and primary progressive aphasia. Aphasia, globular gill tauopathy, Lytico-Bodig disease, neurodegeneration with brain iron accumulation, pantothenate kinase-associated neurodegeneration (PKAN), postencephalitic parkinsonism, chronic traumatic encephalopathy;CTE, Familial British dementia, Familial Danish dementia, Huntington's disease, Down's syndrome, Gerstmann-Straussler-Scheinker disease, Myotonic dystrophy, Leukotonic tauopathy, Amyotrophic Lateral Sclerosis (ALS), Cerebral amyloid angiopathy, Senile dementia of the neurofibrillary tangle type, Motor neuron disease with neurofibrillary tangles, Diffuse neurofibrillary tangles with calcification, Corticobasal degeneration including, but not limited to, neurodegenerative disorders, primary age-related tauopathy, and traumatic brain injury;

[0029] According to a specific embodiment of the invention, the composition inhibits the interaction between Tau and synaptogyrin3.

[0030] Syngr3 mediates the binding between Tau and synaptic vesicles, and the composition of the present invention significantly inhibits this interaction between Tau and Syngr3, thereby blocking the binding between Tau and synaptic vesicles.In this specification, the term "inhibit interaction" means that the binding between Tau and Syngr3 (or the binding mediation between Tau and synaptic vesicles by synaptogrin-3) is inhibited to a measurable extent compared to a control group, specifically, it means that the vesicle mobility defect and / or neurotransmitter secretion defect caused by Tau is inhibited to a significant extent, more specifically, it means that the inhibition is 30% or more, even more specifically, 50% or more, and most specifically, 70% or more compared to a control group.

[0031] As used herein, the term "prevention" means inhibiting the occurrence of a disease or condition in a subject who has not been diagnosed as having the disease or condition but is susceptible to such disease or condition.

[0032] As used herein, the term "treatment" refers to (a) inhibiting the development of a disease, disorder, or symptom; (b) alleviating a disease, disorder, or symptom; or (c) eliminating a disease, disorder, or symptom. Administration of the compositions of the present invention to a subject blocks the interaction between Tau and Syngr3 in the central nervous system and inhibits the binding of Tau protein to synaptic vesicles, thereby inhibiting, eliminating, or alleviating the development of symptoms caused by the hyperphosphorylation, aggregation, and excessive accumulation of Tau protein. Therefore, the compositions of the present invention may be used alone to treat these diseases, or may be administered together with other pharmacological ingredients to serve as a therapeutic adjunct for the disease. Therefore, as used herein, the terms "treatment" or "therapeutic agent" encompass the meaning of "therapeutic adjunct" or "therapeutic adjunct."

[0033] As used herein, the term "administration" or "administering" refers to administering a therapeutically effective amount of a composition of the present invention directly to a subject, thereby allowing the same amount to be formed in the subject's body.

[0034] In the present invention, the term "therapeutically effective amount" means the content of the composition of the pharmacological component of the composition sufficient to provide a therapeutic or prophylactic effect to an individual to whom the pharmaceutical composition of the present invention is to be administered, and therefore includes a "prophylactically effective amount."

[0035] As used herein, the term "subject" includes, without limitation, a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, monkey, chimpanzee, baboon, or rhesus monkey. Specifically, the subject of the present invention is a human.

[0036] As used herein, the term "pharmaceutically acceptable salt" includes salts derived from pharmaceutically acceptable inorganic acids, organic acids, or bases. Examples of suitable acids include hydrochloric acid, bromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, trifluoroacetic acid, citric acid, methanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. Salts derived from suitable bases can include alkali metals such as sodium, alkaline earth metals such as magnesium, and ammonium.

[0037] When the composition of the present invention is prepared as a pharmaceutical composition, the pharmaceutical composition of the present invention contains a pharmaceutically acceptable carrier.

[0038] Pharmaceutically acceptable carriers contained in the pharmaceutical compositions of the present invention are those commonly used in formulations, including, but not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition to the above ingredients, the pharmaceutical compositions of the present invention may additionally contain lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, etc. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington's Pharmaceutical Sciences (19th ed., 1995).

[0039] The pharmaceutical composition of the present invention can be administered orally or parenterally, specifically, orally, intravenously or intracerebroventricularly.

[0040] The suitable dosage of the pharmaceutical composition of the present invention can be variously formulated depending on factors such as formulation method, administration method, age, weight, sex, pathological condition, diet, administration time, administration route, excretion rate, and reaction sensitivity of the patient, etc. The preferred dosage of the pharmaceutical composition of the present invention is within the range of 0.001-100 mg / kg for adults.

[0041] The pharmaceutical compositions of the present invention may be prepared in unit dose form or in multi-dose containers by formulating them with pharmaceutically acceptable carriers and / or excipients in a manner easily understood by those skilled in the art to which this invention pertains. In this case, the dosage form may be in the form of a solution, suspension, syrup, or emulsion in an oily or aqueous medium, or in the form of an extract, powder, granule, tablet, or capsule, and may additionally contain a dispersing agent or stabilizer.

[0042] According to yet another aspect of the present invention, there is provided a functional food composition for improving or preventing degenerative brain diseases, comprising the compound of the present invention or a nutrient-acceptable salt thereof as an active ingredient.

[0043] According to yet another aspect of the present invention, there is provided a method for improving or preventing a degenerative brain disease, comprising administering to a subject the compound of the present invention or a nutrient-acceptable salt thereof.

[0044] The pyridoindole derivative compound of Chemical Formula 1 used in the present invention and the degenerative brain diseases that can be improved or prevented thereby have already been described above, so a description thereof will be omitted to avoid excessive duplication.

[0045] As used herein, the term "food-based acceptable salt" refers to a salt in a form that can be used in food compositions, among salts in which a cation and anion are bound by electrostatic attraction, and specific examples thereof include the examples of "pharmaceutically acceptable salts" described above.

[0046] When the composition of the present invention is prepared as a food composition, it may contain, as active ingredients, not only the compound of the present invention but also carbohydrates, seasonings, and flavorings that are commonly added during food production. Examples of carbohydrates include, but are not limited to, monosaccharides such as glucose and fructose; disaccharides such as maltose and sucrose; polysaccharides such as dextrin and cyclodextrin; and sugar alcohols such as xylitol, sorbitol, and erythritol. Natural flavorings (thaumatin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.)) and synthetic flavorings (saccharin, aspartame, etc.) can be used as flavorings. For example, when the food composition of the present invention is prepared as a drink, in addition to the active ingredient pine bark extract of the present invention, it may additionally contain citric acid, liquid fructose, sugar, glucose, acetic acid, malic acid, fruit juice, Eugenol extract, jujube extract, licorice extract, etc. [Effects of the Invention]

[0047] The features and advantages of the present invention can be summarized as follows: (a) The present invention provides novel pyridoindole derivative compounds and compositions containing the same as active ingredients for preventing or treating degenerative brain diseases. (b) The present invention can achieve fundamental elimination of the cause of neurodegeneration in degenerative brain diseases, specifically, various tauopathies caused by aggregation of Tau protein, by significantly suppressing the interaction between Tau protein and synaptogyrin-3, rather than the conventional symptomatic treatment that focused on controlling peripheral symptoms. [Brief explanation of the drawings]

[0048] [Figure 1] Fluorescence microscopy images of HEK293T cells transfected with EGFP-fused Tau (pTK231:PCMV-Tau-EGFP) and Synaptogyrin3 (pTK233:PCMV-EGFP-Synaptogyrin3) confirm the expression of both proteins 48 hours after transfection. [Figure 2A] This is a schematic diagram of the PCA (Protein Complementary Assay) process using the split luciferase method. Split luciferase is made by dividing luciferase into two pieces, a small bit (sBit) and a large bit (LBit). Each piece is inactive under normal conditions, but when they come close together through interactions with the fused proteins, they are reassembled and become active. When each piece of split luciferase is fused to tau and synaptogyrin3, luciferase activity can be expected due to the interaction between tau and synaptogyrin3. [Figure 2B] All possible combinations of Tau and Synaptogyrin3, sBit and Lbit fusion proteins were co-transfected into HEK293T cells, and luciferase activity was measured 48 hours later. [Figure 3A]Schematic diagram of the phloretin-regulated gene expression regulatory system. This system includes a synthetic transcription activator, TtgA, and a synthetic promoter, PTtgR, based on the flavonoid-regulated TtgR operon of Pseudomonas putida DOT-T1E. In the absence of phloretin, TtgA binds to PTtgR and activates transcription (without phloretin). In the presence of phloretin, TtgA dissociates from DNA and transcription is not activated (with phloretin). [Figure 3B] Phloretin-regulated EGFP expression plasmids (pTK269:PCAG-TtgA and pTK274:PTtgR-EGFP) were co-expressed in HEK293T cells, and EGFP levels were measured 48 hours after treatment with various concentrations of phloretin (0-50 μM). [Figure 4A] Schematic diagram of the phloretin-regulated Tau competition assay. Expression of Tau protein without split luciferase in the stable cell line HEK293T-TK252 expressing Lbit-Tau and sBit-Synaptogyrin3 can lead to competition between Lbit-Tau and Tau for the sBit-Synaptogyrin3 binding site, resulting in a decrease in luciferase signal due to Tau-Synaptogyrin3 interactions that are not encountered by the split luciferase segments. HEK293T-TK252 clones were co-transfected with Tau expression plasmids (pTK269:PCAG-TtgA and pTK285:PTtgR-Tau) and treated with various concentrations of phloretin (0, 10, and 50 μM). [Figure 4B] This shows the luciferase activity of each clone after 48 hours. [Figure 4C] FIG. 1 shows the EGFP measurement values ​​of each clone after 48 hours. DETAILED DESCRIPTION OF THE INVENTION

[0049] The present invention will be described in more detail with reference to the following examples. It will be obvious to those skilled in the art that these examples are merely for the purpose of explaining the present invention in more detail, and that the scope of the present invention is not limited by these examples according to the gist of the present invention. [Example]

[0050] Experimental Method Plasmid design The design and structural characteristics of the plasmids and oligonucleotides used in this invention are summarized in Tables 1 and 2, respectively.

[0051] [Table 1] [Table 2] [Table 3]

[0052] GTA: cyclic-GMP-responsive transcription activator, IRES: internal ribosome entry site, Lbit: large bit (large piece of split luciferase), MCS: multiple cloning site, P CMV : A synthetic mammalian promoter, P, containing the cytomegalovirus early enhancer and chicken beta-actin gene promoter. CMV : Mammalian promoter from human cytomegalovirus, P EF1alpha : Mammalian promoter derived from human EF-1α (elongation factor 1α), P GTA : GTA-induced cyclic GMP-responsive promoter (GTA-specific action site and P CMV Minimal Promoter), P PGK : Mammalian promoter from the phosphoglycerate kinase gene, P PGK [SpeI]:P PGK SpeI restriction site within the promoter is shown, P TtgR: TtgA-induced phloretin-responsive promoter (TtgA-specific actin site and P CMV Minimal promoter), puroR: puromycin-resistance gene, sBit: Small Bit (small fragment of split luciferase), Tau: microtubule-associated protein tau 2N4R isoform (UniProt P10636-8 [Tau-F], GenBank NM_005910), Tau[0N4R]: microtubule-associated protein tau 0N4R subtype (UniProt P10636-6 [Tau-D]), Tau[1N4R]: microtubule-associated protein tau 1N4R subtype (UniProt P10636-7 [Tau-E]), TtgA: phloretin-responsive transcription activator (VP16-fused Peudomonas putida TtgR), VC155: BiFC (Bimolecular fluorescence complementation) fluorescent protein Venus fragment

[0053] [Table 4]

[0054] Cell culture and transfection Human embryonic kidney cells (HEK293T, ATCC: CRL-11268) were cultured in OptiMEM (Cat#51985091 / Gibco. ThermoFisher Korea, Seoul, Korea) supplemented with 8% (v / v) fetal bovine serum (FBS, US origin Cat#16140-089, Lot#2394274P / Gibco. ThermoFisher Korea, Seoul, Korea) in a humidified CO2 (5%) incubator at 37°C. 18 hours before transfection, 10 6Cells were seeded in 10 ml of culture medium in a 100 mm culture dish. 10 μg of DNA was added to 2 ml of OptiMEM, and 30 μg of PEI (1 μg / μl in distilled water, pH 7.4. Cat# 23966-100. Polyscience, PA, USA) was added, followed by immediate vortexing for 3 seconds. After 30 minutes of incubation at room temperature, the DNA-PEI mixture was added to the cells. When a different type of cell culture plate was used, the cell number, DNA, and PEI amounts were adjusted according to the culture volume of the plate.

[0055] measurement SEAP: The production of SEAP (Secreted alkaline phosphatase) in cell culture medium was quantified spectrophotometrically using 4-nitrophenyl phosphate (pNpp. CarboSynth, Berkshire, UK) [1].

[0056] Luciferase assay The activity of luciferase expressed in live cells was measured using the NanoGlo® Live Cell Assay System (Cat# N2012, Promega, WI, USA) according to the manufacturer's manual. All microplate-based measurements were performed using a BioTek Synergy H1 (Agilent, CA, USA).

[0057] cell line To generate a stable cell line for drug screening, HEK293T cells were transfected with pTK252 linearized with BglII restriction enzyme (HEK293T-TK252). 24 hours after transfection, the cells were cultured in culture medium containing 1 μg / ml puromycin (10 mM in DMSO, Cat# J61278 / Alfa Aesar, ThermoFisher Korea, Seoul, Korea) for 9 days. Periodic medium changes with puromycin at the indicated concentrations were performed every 3 days. Sorted cells were trypsinized, diluted to 5 cells / ml, seeded into four 96-well plates (100 μl / well), and cultured in culture medium containing 1 μg / ml puromycin for 11 days. Eighteen wells containing only GFP-positive cells were selected and cultured in culture medium containing 0.1–0.2 μg / ml puromycin for 14 days. Ten clones that showed non-GFP cells were excluded, and the performance of eight clones was evaluated. The selected clone (1E2) was cultured in medium containing 0.5 μg / ml puromycin and used in subsequent experiments.

[0058] Libraries and screening 1,728 compounds (3 μmol each) were dissolved in 300 μl of DMSO (10 mM) and stored at −80°C. 48 hours before compound treatment, 4 × 10 4 HEK293T-TK252-1E2 cells were seeded in 100 μl of culture medium in a 96-well white cell culture plate (Cat# 30196.SPL, Seoul, Korea). For 10 μM compound treatment, 10 mM compound stock was diluted to 50 μM with culture medium, and 25 μl of the diluted compound was added to the designated well of the 96-well plate. For dose-dependent studies, the amount of compound diluted was adjusted to match the volume described above. After 48 hours of compound treatment, the cells were washed once with OptiMEM, and luciferase activity, fluorescence intensity, and fluorescent area were measured.

[0059] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10]

[0060] Production Example 1: Production of 8-phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (intermediate) Production Example 1-1: Production of 8-bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (Intermediate 1-3) [ka]

[0061] (4-Bromophenyl)hydrazine hydrochloride (1 g, 4.47 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (936 mg, 4.7 mmol) were dissolved in 1,4-dioxane. While stirring the reaction mixture at 0°C, H2SO4 (0.56 mL, 8 M) was added. The reaction mixture was stirred at 110°C for 3 hours using a sealed tube. After the reaction was completed, the precipitate was filtered off with 1,4-dioxane. The precipitate was dissolved in distilled water and basified with 1-n aqueous sodium hydroxide solution. Extraction was performed with distilled water and dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure to give 584 mg (65% yield) of the title compound.

[0062] 1H NMR (400 MHz, DMSO) δ 10.94 (s, 1H), 7.49 (d, J = 1.9 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 7.09 (dd, J = 8.5, 2.0 Hz, 1H), 3.82 (t, J = 1.6 Hz, 2H), 3.01 (t, J = 5.7 Hz, 2H), 2.67 (tt, J = 5.7, 1.6 Hz, 2H).

[0063] Preparation Example 1-2: Preparation of tert-butyl 8-bromo-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (Intermediate 1-4) [ka]

[0064] Under nitrogen, 8-bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.13 g, 4.51 mmol) was dissolved in THF, and then BocO (1.14 mL, 4.96 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, the mixture was extracted with distilled water and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the concentrate was subjected to column chromatography to obtain 1.02 g (64% yield) of the title compound.

[0065] 1 H NMR (400 MHz, DMSO) δ 11.14 (s, 1H), 7.60 (d, J = 1.9 Hz, 1H), 7.26 (d, J = 8.6 Hz, 1H), 7.15 (dd, J = 8.6, 2.0 Hz, 1H), 4.51 (s, 2H), 3.70 (t, J = 5.7 Hz, 2H), 2.78 (t, J = 5.8 Hz, 2H), 1.44 (s, 9H).

[0066] Preparation Example 1-3: Preparation of tert-butyl 8-phenyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (Intermediate 1-6) [ka]

[0067] tert-Butyl 8-bromo-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (200 mg, 0.57 mmol), phenylboronic acid (208 mg, 1.71 mmol), and Pd(PPh3)4 (33 mg, 0.028 mmol) were dissolved in a toluene:EtOH (1:1) solution. 1 M Na2CO3 (1.42 mL, 1.42 mmol) was added. The reaction mixture was stirred in a sealed tube at 100 °C for 24 h. After the reaction was completed, the mixture was extracted with distilled water and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to give 79 mg (39% yield) of the title compound.

[0068] 1 H NMR(400 MHz, DMSO) δ10.93(s, 1H), 7.67-7.60(m, 3H), 7.39(dd, J=8.4, 7.1 Hz, 2H), 7.32(t, J=1.0 Hz, 2H), 7.29-7.20(m, 1H), 4.54(s, 2H), 3.68(t, J=5.7 Hz, 2H), 2.75(t, J=5.8 Hz, 2H), 1.41(s, 9H).

[0069] Preparation Example 1-4: Preparation of 8-phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (intermediate 1-7) [ka]

[0070] tert-Butyl 8-phenyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (78 mg, 0.22 mmol) was dissolved in 1,4-dioxane. HCl solution (4 M in dioxane) (1.12 mL, 4.48 mmol) was added. The mixture was stirred at room temperature for 6 hours. After the reaction was completed, the solvent was removed under reduced pressure. The resulting solid was filtered with ethyl acetate to give 38 mg (59% yield) of the title compound.

[0071] 1 H NMR (400 MHz, DMSO) δ 11.25(s, 1H), 7.77(d, J = 1.4 Hz, 1H), 7.69-7.65(m, 2H), 7.44(d, J=7.8 Hz, 4H), 7.32-7.26(m, 1H), 4.34(t, J = 4.3 Hz, 2H), 3.47(d, J=6.6 Hz, 2H), 3.04(t, J = 6.1 Hz, 2H).

[0072] Preparation Example 2: Preparation of (8-phenyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(pyridin-3-yl)methanone (Compound 2) [ka]

[0073] Under nitrogen, 8-phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (22 mg, 0.077 mmol) was dissolved in dimethylformamide. Nicotinic acid (11.41 mg, 0.093 mmol), HATU (58 mg, 0.15 mmol), and DIPEA (0.027 mL, 0.15 mmol) were added. The reaction mixture was stirred at room temperature for 12 hours. Upon completion of the reaction, the mixture was extracted with distilled water and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain 15.7 mg (57% yield) of the title compound.

[0074] 1 H NMR 400 MHz, DMSO) δ11.02(s, 1H), 8.67(s, 2H), 7.95-7.20(m, 12H), 4.86(s, 1H), 4.65(s, 1H), 4.03(s, 1H), 3.66(s, 1H), 2.89(s, 2H).

[0075] Preparation Example 3: Preparation of (8-phenyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(pyridin-4-yl)methanone (Compound 3) [ka]

[0076] Under nitrogen, 8-phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.07 mmol) was dissolved in dimethylformamide. Isonicotinic acid (10.38 mg, 0.084 mmol), HOBt (18.98 mg, 0.14 mmol), EDCI (26.93 mg, 0.14 mmol), and DIPEA (0.049 mL, 0.28 mmol) were added. The reaction mixture was stirred at room temperature for 12 hours. Upon completion of the reaction, the mixture was extracted with distilled water and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was subjected to column chromatography to obtain 5.6 mg (22% yield) of the title compound.

[0077] 1 H NMR (400 MHz, DMSO) δ 11.06 (s, 1H), 8.71 (dd, J = 8.9, 5.1 Hz, 2H), 7.80 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.59 - 7.33 (m, 6H), 7.34 - 7.23 (m, 1H), 4.89 (s, 1H), 4.60 (s, 1H), 4.07 (s, 1H), 3.63 (d, J = 5.9 Hz, 1H), 2.93 (s, 1H), 2.88 (s, 1H).

[0078] Preparation Example 4: Preparation of (5-methylpyridin-3-yl)(8-phenyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)methanone (Compound 4) [ka]

[0079] In the same manner as in Production Example 3, 12.4 mg (yield 48%) of the above-titled compound was obtained using 8-phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.07 mmol), 5-methylnicotinic acid (11.56 mg, 0.084 mmol), HOBt (18.98 mg, 0.14 mmol), EDCI (26.93 mg, 0.14 mmol) and DIPEA (0.049 mL, 0.28 mmol).

[0080] 1 H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 8.50(d, J = 14.1 Hz, 2H), 7.80-7.53 (m, 4H), 7.49-7.22 (m, 5H), 4.87 (s, 1H), 4.65 (s, 1H), 4.03 (s, 1H), 3.68 (s, 1H), 2.89 (d, J = 7.4 Hz, 2H), 2.36(s, 3H).

[0081] Preparation Example 5: Preparation of (6-methylpyridin-3-yl)(8-phenyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)methanone (Compound 5) [ka]

[0082] Under nitrogen, 8-phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.07 mmol) was dissolved in dimethylformamide. 6-Methylnicotinic acid (11.56 mg, 0.084 mmol), EDCI (53.83 mg, 0.28 mmol), and DIPEA (0.049 mL, 0.28 mmol) were added. The reaction mixture was stirred at room temperature for 12 hours. Upon completion of the reaction, the mixture was extracted with distilled water and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was subjected to column chromatography to obtain 12.6 mg (48% yield) of the title compound.

[0083] 1 H NMR(400 MHz, DMSO) δ11.06(s, 1H), 8.58(s, 1H), 7.80(s, 2H), 7.72(s, 1H), 7.61(d, J=16.8 Hz, 1H), 7.44(s, 1H), 7.39(s, 4H), 7.29(s, 1H), 4.86(s, 1H), 4.70(s, 1H), 4.06-4.01(m, 1H), 3.70(s, 1H), 2.92(s, 2H), 2.54(s, 3H).

[0084] Preparation Example 6: Preparation of (5-methylpyrazin-2-yl)(8-phenyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)methanone (Compound 6) [ka]

[0085] In the same manner as in Production Example 3, 9.8 mg (yield 37%) of the title compound was obtained using 8-phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.07 mmol), 5-methylpyrazine-2-carboxylic acid (11.64 mg, 0.084 mmol), HOBt (18.98 mg, 0.14 mmol), EDCI (26.93 mg, 0.14 mmol) and DIPEA (0.049 mL, 0.28 mmol).

[0086] 1 H NMR(400 MHz, DMSO) δ11.03(s, 1H), 8.80-8.70(m, 1H), 8.60(d, J=6.1 Hz, 1H), 7.79(s, 1H), 7.71(d, J=7.8 Hz, 1H), 7.64-7.51(m, 1H), 7.46-7.33(m, 4H), 7.27(dt, J=14.7, 7.4 Hz, 1H), 4.90(s, 1H), 4.72(s, 1H), 4.07(t, J=6.0 Hz, 1H), 3.77 (t, J=5.7 Hz, 1H), 2.95-2.88(m, 2H), 2.57(d, J=8.5 Hz, 3H).

[0087] Preparation Example 7: Preparation of (8-phenyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(pyrazin-2-yl)methanone (Compound 7) [ka]

[0088] In the same manner as in Production Example 2, 9.2 mg (yield 36%) of the title compound was obtained using 8-phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.07 mmol), pyrazine-2-carboxylic acid (10.46 mg, 0.084 mmol), HATU (106.81 mg, 0.28 mmol) and DIPEA (0.049 mL, 0.28 mmol).

[0089] 1H NMR(400 MHz, DMSO) δ 11.03(s, 1H), 8.88 (dd, J=23.3, 1.5 Hz, 1H), 8.77 (dd, J=10.9, 2.6 Hz, 1H), 8.73-8.68(m, 1H), 7.79(s, 1H), 7.74-7.67 (m, 1H), 7.59(d, J=7.7 Hz, 1H), 7.47-7.31(m, 4H), 7.26 (dt, J=15.6, 7.3 Hz, 1H), 4.91(s, 1H), 4.69(s, 1H), 4.07(t, J=5.7 Hz, 1H), 3.75(t, J=5.6 Hz, 1H), 2.96-2.87(m, 2H).

[0090] Preparation Example 8: Preparation of (8-phenyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(pyrimidin-5-yl)methanone (Compound 8) [ka]

[0091] In the same manner as in Production Example 3, 9.1 mg (yield 36%) of the title compound was obtained using 8-phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.07 mmol), pyrimidine-5-carboxylic acid (10.46 mg, 0.084 mmol), HOBt (18.98 mg, 0.14 mmol), EDCI (26.93 mg, 0.14 mmol) and DIPEA (0.049 mL, 0.28 mmol).

[0092] 1H NMR (400 MHz, DMSO) δ 11.06 (s, 1H), 9.31 (d, J = 6.6 Hz, 1H), 8.98 (d, J = 14.3 Hz, 2H), 7.80 (s, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 8.6 Hz, 1H), 7.47-7.34 (m, 4H), 7.32-7.23 (m, 1H), 4.90 (s, 1H), 4.72 (s, 1H), 4.06 (s, 1H), 3.72 (s, 1H), 2.94 (s, 2H).

[0093] Preparation Example 9: Preparation of phenyl(8-phenyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)methanone (Compound 9) [ka]

[0094] In the same manner as in Production Example 5, 7.5 mg (yield 30%) of the title compound was obtained using 8-phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.07 mmol), benzoic acid (10.29 mg, 0.084 mmol), EDCI (53.83 mg, 0.28 mmol) and DIPEA (0.049 mL, 0.28 mmol).

[0095] 1 H NMR(400 MHz, DMSO) δ11.03(s, 1H), 7.69(t, J=35.9 Hz, 3H), 7.43(d, J=41.2 Hz, 10H), 4.84(s, 1H), 4.64(s, 1H), 4.03(s, 1H), 3.67(s, 1H), 2.88(s, 2H).

[0096] Preparation Example 10: Preparation of (1-methyl-1H-indol-4-yl)(8-phenyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)methanone (Compound 10) [ka]

[0097] In the same manner as in Production Example 3, 20.3 mg (yield 71%) of the above-titled compound was obtained using 8-phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.07 mmol), 1-methyl-1H-indole-4-carboxylic acid (14.76 mg, 0.084 mmol), HOBt (18.98 mg, 0.14 mmol), EDCI (26.93 mg, 0.14 mmol) and DIPEA (0.049 mL, 0.28 mmol).

[0098] 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 7.82 - 7.21 (m, 11H), 7.10 (d, J = 7.1 Hz, 1H), 6.35 (s, 1H), 4.95 (s, 1H), 4.56 (s, 1H), 4.11 (s, 1H), 3.84 (s, 3H), 3.62 (s, 1H), 2.86 (d, J = 82.9 Hz, 2H).

[0099] Preparation Example 11: Preparation of (8-phenyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(thiazol-2-yl)methanone (Compound 11) [ka]

[0100] In the same manner as in Production Example 3, 7.5 mg (yield 29%) of the title compound was obtained using 8-phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.07 mmol), thiazole-2-carboxylic acid (10.89 mg, 0.084 mmol), HOBt (18.98 mg, 0.14 mmol), EDCI (26.93 mg, 0.14 mmol) and DIPEA (0.049 mL, 0.28 mmol).

[0101] 1 H NMR (400 MHz, DMSO) δ 11.06 (s, 1H), 8.11-8.02 (m, 2H), 7.80-7.59 (m, 3H), 7.48-7.35 (m, 4H), 7.29 (t, J = 7.4 Hz, 1H), 5.49 (s, 1H), 4.92 (s, 1H), 4.57 (t, J=5.4 Hz, 1H), 4.08 (s, 1H), 2.97 (d, J=17.7 Hz, 2H).

[0102] Preparation Example 12: Preparation of (8-phenyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(4-(trifluoromethyl)phenyl)methanone (Compound 12) [ka]

[0103] In the same manner as in Production Example 3, 16.2 mg (yield 54%) of the above-titled compound was obtained using 8-phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.07 mmol), 4-(trifluoromethyl)benzoic acid (16.03 mg, 0.084 mmol), HOBt (18.98 mg, 0.14 mmol), EDCI (26.93 mg, 0.14 mmol) and DIPEA (0.049 mL, 0.28 mmol).

[0104] 1 H NMR(400 MHz, DMSO) δ11.05(s, 1H), 7.89 - 7.52 (m, 7H), 7.48 - 7.22 (m, 5H), 4.88(s, 1H), 4.62(s, 1H), 4.05(s, 1H), 3.63(s, 1H), 2.90(d, J = 20.3 Hz, 2H).

[0105] Preparation Example 13: Preparation of (3-chlorophenyl)(8-phenyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)methanone (Compound 13) [ka]

[0106] In the same manner as in Production Example 3, 15.8 mg (yield 58%) of the above-titled compound was obtained using 8-phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.07 mmol), 3-chlorobenzoic acid (13.2 mg, 0.084 mmol), HOBt (18.98 mg, 0.14 mmol), EDCI (26.93 mg, 0.14 mmol) and DIPEA (0.049 mL, 0.28 mmol).

[0107] 1 H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 7.79-7.23 (m, 12H), 4.85 (s, 1H), 4.61 (s, 1H), 4.02 (s, 1H), 3.65 (s, 1H), 2.88 (s, 2H).

[0108] Preparation Example 14: Preparation of (8-phenyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(p-tolyl)methanone (Compound 14) [ka]

[0109] In the same manner as in Production Example 3, 13.2 mg (yield 51%) of the above-titled compound was obtained using 8-phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.07 mmol), 4-methylbenzoic acid (11.47 mg, 0.084 mmol), HOBt (18.98 mg, 0.14 mmol), EDCI (26.93 mg, 0.14 mmol) and DIPEA (0.049 mL, 0.28 mmol).

[0110] 1H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 7.69 (s, 3H), 7.37 (d, J = 7.8 Hz, 5H), 7.27 (d, J = 7.4 Hz, 3H), 4.81 (s, 1H), 4.66 (s, 1H), 3.99 (s, 1H), 3.68 (s, 1H), 2.87 (s, 2H), 2.35 (s, 3H).

[0111] Preparation Example 15: Preparation of (8-phenyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(m-tolyl)methanone (Compound 15) [ka]

[0112] In the same manner as in Production Example 5, 10.2 mg (yield 39%) of the above-titled compound was obtained using 8-phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.07 mmol), 3-methylbenzoic acid (11.47 mg, 0.084 mmol), EDCI (53.83 mg, 0.28 mmol) and DIPEA (0.049 mL, 0.28 mmol).

[0113] 1 H NMR (400 MHz, DMSO) δ 11.04 (s, 1H), 7.70 (t, J = 34.9 Hz, 3H), 7.54-7.22 (m, 9H), 4.85 (s, 1H), 4.64 (s, 1H), 4.03 (s, 1H), 3.68 (s, 1H), 2.89 (s, 2H), 2.37 (s, 3H).

[0114] Preparation Example 16: Preparation of (4-ethylphenyl)(8-phenyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)methanone (Compound 16) [ka]

[0115] In the same manner as in Production Example 5, 4.4 mg (yield 16%) of the title compound was obtained using 8-phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.07 mmol), 4-ethylbenzoic acid (12.65 mg, 0.084 mmol), EDCI (53.83 mg, 0.28 mmol) and DIPEA (0.049 mL, 0.28 mmol).

[0116] 1 H NMR(400 MHz, DMSO) δ 11.05(s, 1H), 7.71(t, J=31.6 Hz, 3H), 7.48- 7.36(m, 6H), 7.32(d, J=8.0 Hz, 3H), 4.83(s, 1H), 4.69(s, 1H), 4.04(s, 1H), 3.69(s, 1H), 2.90(s, 2H), 2.67(q, J=7.7 Hz, 2H), 1.22(t, J = 7.6 Hz, 3H).

[0117] Preparation Example 17: Preparation of (4-methoxyphenyl)(8-phenyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)methanone (Compound 17) [ka]

[0118] In the same manner as in Production Example 3, 10.7 mg (yield 39%) of the above-titled compound was obtained using 8-phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.07 mmol), 4-methoxybenzoic acid (12.82 mg, 0.084 mmol), HOBt (18.98 mg, 0.14 mmol), EDCI (26.93 mg, 0.14 mmol) and DIPEA (0.049 mL, 0.28 mmol).

[0119] 1H NMR(400 MHz, DMSO) δ10.99(s, 1H), 7.63(s, 3H), 7.46-7.32(m, 6H), 7.24(t, J=7.3 Hz, 1H), 6.98(d, J=8.4 Hz, 2H), 4.73(s, 2H), 3.78 (s, 5H), 2.86 (s, 2H).

[0120] Preparation Example 18: Preparation of (3-methoxyphenyl)(8-phenyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)methanone (Compound 18) [ka]

[0121] In the same manner as in Production Example 3, 16.3 mg (yield 60%) of the above-titled compound was obtained using 8-phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.07 mmol), 4-methoxybenzoic acid (12.82 mg, 0.084 mmol), HOBt (18.98 mg, 0.14 mmol), EDCI (26.93 mg, 0.14 mmol) and DIPEA (0.049 mL, 0.28 mmol).

[0122] 1 H NMR (400 MHz, DMSO) δ 11.04 (s, 1H), 7.71 (t, J = 33.9 Hz, 3H), 7.34 (d, J = 41.8 Hz, 6H), 7.09 - 6.97 (m, 3H), 4.85 (s, 1H), 4.64 (s, 1H), 4.03 (s, 1H), 3.80 (d, J = 10.9 Hz, 3H), 3.68 (s, 1H), 2.89 (s, 2H).

[0123] Preparation Example 19: Preparation of morpholino(8-phenyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)methanone (Compound 19) [ka]

[0124] Under nitrogen, 8-phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (60 mg, 0.21 mmol) was dissolved in dichloromethane. Morpholine-4-carbonyl chloride (0.03 mL, 0.27 mmol) and TEA (0.12 mL, 0.84 mmol) were added. The reaction mixture was stirred at room temperature for 12 hours. Upon completion of the reaction, the mixture was extracted with distilled water and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was subjected to column chromatography to obtain 9.3 mg (12% yield) of the title compound.

[0125] 1 H NMR(400 MHz, DMSO) δ10.95(s, 1H), 7.72-7.63(m, 3H), 7.42(t, J=7.7 Hz, 2H), 7.35(t, J=1.0 Hz, 2H), 7.32-7.23(m, 1H), 4.46(s, 2H), 3.62-3.59(m, 4H), 3.54(d, J=5.6 Hz, 2H), 3.19(t, J=4.7 Hz, 4H), 2.85(d, J=5.7 Hz, 2H).

[0126] Preparation Example 20: Preparation of Compound 20 Preparation Example 20-1: Preparation of tert-butyl 8-(o-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (Compound 20-2) [ka]

[0127] In the same manner as in Production Example 1-3, 258.2 mg (yield 83%) of the above-titled compound was obtained using tert-butyl 8-bromo-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (300 mg, 0.85 mmol), o-tolylboronic acid (696.74 mg, 5.12 mmol), Pd(PPh3)4 (49.35 mg, 0.043 mmol) and 1 M Na2CO3 (2.14 mL, 2.14 mmol).

[0128] 1 H NMR (400 MHz, DMSO) δ 10.93 (s, 1H), 7.34 - 7.16 (m, 6H), 6.98 (dd, J = 8.3, 1.7 Hz, 1H), 4.51 (s, 2H), 3.69 (t, J = 5.7 Hz, 2H), 2.77 (t, J = 5.8 Hz, 2H), 2.21 (s, 3H), 1.41 (s, 9H).

[0129] Preparation Example 20-2: Preparation of 8-(o-tolyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (Compound 20-3) [ka]

[0130] In the same manner as in Production Example 1-4, 167 mg (yield 78%) of the above-titled compound was obtained using tert-butyl 8-(o-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (258 mg, 0.71 mmol) and HCl solution (4 M in dioxane) (3.56 mL, 14.24 mmol).

[0131] 1H NMR (400 MHz, DMSO) δ 11.19 (s, 1H), 7.38 - 7.31 (m, 2H), 7.25 - 7.16 (m, 4H), 7.01 (dd, J = 8.3, 1.7 Hz, 1H), 4.25 (d, J = 4.6 Hz, 2H), 3.43 (d, J = 6.7 Hz, 2H), 3.02 (t, J = 6.1 Hz, 2H), 2.19 (s, 3H), 1.93(s, 9H).

[0132] Preparation Example 20-3: Preparation of pyridin-3-yl(8-(o-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)methanone (Compound 20) [ka]

[0133] In the same manner as in Production Example 3, 16.2 mg (yield 66%) of the title compound was obtained using 8-(o-tolyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.067 mmol), nicotinic acid (9.88 mg, 0.08 mmol), HOBt (18.08 mg, 0.13 mmol), EDCI (25.65 mg, 0.13 mmol) and DIPEA (0.05 mL, 0.27 mmol).

[0134] 1 H NMR(400 MHz, DMSO) δ11.04(s, 1H), 8.70(s, 2H), 7.92(s, 1H), 7.52(s, 1H), 7.42-7.16(m, 6H), 7.03(d, J=9.1 Hz, 1H), 4.84(s, 1H), 4.63(s, 1H), 4.04 (s, 1H), 3.69 (s, 1H), 2.91(d, J=9.4 Hz, 2H), 2.22(d, J=35.3 Hz, 3H).

[0135] Preparation Example 21: Preparation of pyridin-4-yl(8-(o-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)methanone (Compound 21) [ka]

[0136] In the same manner as in Production Example 3, 4.3 mg (yield 17%) of the title compound was obtained using 8-(o-tolyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.067 mmol), isonicotinic acid (9.88 mg, 0.08 mmol), HOBt (18.08 mg, 0.13 mmol), EDCI (25.65 mg, 0.13 mmol) and DIPEA (0.05 mL, 0.27 mmol).

[0137] 1 H NMR (400 MHz, DMSO) δ 11.04 (s, 1H), 8.68 (dd, J = 21.4, 5.2 Hz, 2H), 7.50-7.46 (m, 1H), 7.44 - 7.12 (m, 7H), 7.00 (dd, J = 20.7, 8.3 Hz, 1H), 4.83 (s, 1H), 4.54 (s, 1H), 4.04 (s, 1H), 3.61 (t, J = 5.5 Hz, 1H), 2.89 (d, J = 20.4 Hz, 2H), 2.21 (d, J = 36.8 Hz, 3H).

[0138] Preparation Example 22: Preparation of (5-methylpyridin-3-yl)(8-(o-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)methanone (Compound 22) [ka]

[0139] In the same manner as in Production Example 3, 13.7 mg (yield 55%) of the above-titled compound was obtained using 8-(o-tolyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.07 mmol), 5-methylnicotinic acid (11.01 mg, 0.08 mmol), HOBt (18.08 mg, 0.13 mmol), EDCI (25.65 mg, 0.13 mmol) and DIPEA (0.05 mL, 0.27 mmol).

[0140] 1 H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 8.50 (d, J = 18.1 Hz, 2H), 7.71 (d, J = 17.9 Hz, 1H), 7.41 - 7.16 (m, 6H), 7.02 (d, J = 9.0 Hz, 1H), 4.82 (s, 1H), 4.61 (s, 1H), 4.03 (s, 1H), 3.67 (s, 1H), 2.90 (s, 2H), 2.34 (d, J = 20.3 Hz, 3H), 2.17 (s, 2H).

[0141] Preparation Example 23: Preparation of phenyl(8-(o-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)methanone (Compound 23) [ka]

[0142] In the same manner as in Production Example 3, 12.9 mg (yield 52%) of the above-titled compound was obtained using 8-(o-tolyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.07 mmol), benzoic acid (9.8 mg, 0.08 mmol), HOBt (18.08 mg, 0.13 mmol), EDCI (25.65 mg, 0.13 mmol) and DIPEA (0.05 mL, 0.27 mmol).

[0143] 1H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 7.47 (s, 5H), 7.35 (s, 1H), 7.23 (s, 5H), 7.01 (s, 1H), 4.80 (s, 1H), 4.60 (s, 1H), 4.03 (s, 1H), 3.67 (s, 1H), 2.89 (s, 2H), 2.22 (d, J = 31.2 Hz, 3H).

[0144] Preparation Example 24: Preparation of (1-methyl-1H-indol-4-yl)(8-(o-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)methanone (Compound 24) [ka]

[0145] In the same manner as in Production Example 3, 14.8 mg (yield 52%) of the above-titled compound was obtained using 8-(o-tolyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.07 mmol), 1-methyl-1H-indole-4-carboxylic acid (14.06 mg, 0.08 mmol), HOBt (18.08 mg, 0.13 mmol), EDCI (25.65 mg, 0.13 mmol) and DIPEA (0.05 mL, 0.27 mmol).

[0146] 1 H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.45 - 6.85 (m, 11H), 6.34 (s, 1H), 4.89 (s, 1H), 4.51 (s, 1H), 4.04 (s, 1H), 3.83 (s, 3H), 3.61 (s, 1H), 2.86 (d, J = 78.4 Hz, 2H), 2.27 (s, 3H).

[0147] Preparation Example 25: Preparation of thiazol-2-yl(8-(o-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)methanone (Compound 25) [ka]

[0148] In the same manner as in Production Example 3, 12.7 mg (yield 50%) of the above-titled compound was obtained using 8-(o-tolyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.07 mmol), thiazole-2-carboxylic acid (10.37 mg, 0.08 mmol), HOBt (18.08 mg, 0.13 mmol), EDCI (25.65 mg, 0.13 mmol) and DIPEA (0.05 mL, 0.27 mmol).

[0149] 1 H NMR(400 MHz, DMSO) δ 11.04(s, 1H), 8.10-7.99(m, 2H), 7.43-7.31(m, 2H), 7.29-7.19(m, 4H), 7.02(d, J=8.3 Hz, 1H), 5.46(s, 1H), 4.87(s, 1H), 4.56(s, 1H), 4.08 (s, 1H), 2.96(d, J=16.6 Hz, 2H), 2.24(d, J=14.1 Hz, 3H).

[0150] Preparation Example 26: Preparation of (3-chlorophenyl)(8-(o-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)methanone (Compound 26) [ka]

[0151] In the same manner as in Production Example 3, 19.9 mg (yield 74%) of the above-titled compound was obtained using 8-(o-tolyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.07 mmol), 3-chlorobenzoic acid (12.57 mg, 0.08 mmol), HOBt (18.08 mg, 0.13 mmol), EDCI (25.65 mg, 0.13 mmol) and DIPEA (0.05 mL, 0.27 mmol).

[0152] 1 H NMR(400 MHz, DMSO) δ11.04(s, 1H), 7.61-7.14(m, 10H), 7.02(s, 1H), 4.82(s, 1H), 4.58(s, 1H), 4.03(s, 1H), 3.66(s, 1H), 2.89(s, 2H), 2.27(s, 3H).

[0153] Preparation Example 27: Preparation of Compound 27 Preparation Example 27-1: Preparation of tert-butyl 8-(m-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (Compound 27-2) [ka]

[0154] In the same manner as in Production Example 1-3, 137 mg (yield 66%) of the above-titled compound was obtained using tert-butyl 8-bromo-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (200 mg, 0.75 mmol), m-tolylboronic acid (464.49 mg, 3.42 mmol), Pd(PPh3)4 (32.9 mg, 0.028 mmol) and 1 M Na2CO3 (1.42 mL, 1.42 mmol).

[0155] 1H NMR (400 MHz, DMSO) δ 10.96(s, 1H), 7.66(s, 1H), 7.53-7.43(m, 2H), 7.40-7.27(m, 3H), 7.10(d, J = 7.5 Hz, 1H), 4.59(s, 2H), 3.72(t, J=5.8 Hz, 2H), 2.78 (d, J=6.1 Hz, 2H), 2.38(s, 3H), 1.45(d, J=1.2 Hz, 9H).

[0156] Preparation Example 27-2: Preparation of 8-(m-tolyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (Compound 27-3) [ka]

[0157] In a similar manner to Preparation Example 1-4, 91.3 mg (80% yield) of the title compound was obtained using tert-butyl 8-(m-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (137 mg, 0.38 mmol) and HCl solution (4 M in dioxane) (1.89 mL, 7.56 mmol).

[0158] 1 H NMR(400 MHz, DMSO) δ11.22(s, 1H), 7.76(s, 1H), 7.50(s, 1H), 7.47(d, J=7.9 Hz, 1H), 7.42(d, J=1.2 Hz, 2H), 7.33(t, J=7.6 Hz, 1H), 7.12(d, J=7.5 Hz, 1H), 4.37(s, 2H), 3.48(s, 2H), 3.05(t, J=6.1 Hz, 2H), 2.39(s, 3H).

[0159] Preparation Example 27-3: Preparation of pyridin-3-yl(8-(m-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)methanone (Compound 27) [ka]

[0160] In the same manner as in Production Example 5, 3.2 mg (yield 13%) of the title compound was obtained using 8-(m-tolyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.07 mmol), nicotinic acid (9.88 mg, 0.08 mmol), EDCI (51.3 mg, 0.27 mmol) and DIPEA (0.047 mL, 0.27 mmol).

[0161] 1 H NMR(400 MHz, DMSO) δ11.05(s, 1H), 8.70(s, 2H), 7.94(s, 1H), 7.53(d, J=13.6 Hz, 3H), 7.36(d, J=19.3 Hz, 4H), 7.11(d, J=7.2 Hz, 1H), 4.89(s, 1H), 4.68(s, 1H), 4.06(s, 1H), 3.69(s, 2H), 2.92(s, 2H), 2.37(d, J=19.4 Hz, 3H).

[0162] Preparation Example 28: Preparation of phenyl(8-(m-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)methanone (Compound 28) [ka]

[0163] In the same manner as in Production Example 5, 9.7 mg (yield 39%) of the title compound was obtained using 8-(m-tolyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.07 mmol), benzoic acid (9.8 mg, 0.08 mmol), EDCI (51.3 mg, 0.27 mmol) and DIPEA (0.047 mL, 0.27 mmol).

[0164] 1H NMR (400 MHz, DMSO) δ 11.04 (s, 1H), 7.78 (s, 1H), 7.44 (d, J = 46.5 Hz, 10H), 7.10 (s, 1H), 4.86 (s, 1H), 4.65 (s, 1H), 4.04 (s, 1H), 3.68 (s, 1H), 2.89 (s, 2H), 2.37 (d, J = 16.5 Hz, 3H).

[0165] Preparation Example 29: Preparation of Compound 29 Preparation Example 29-1: Preparation of tert-butyl 8-(p-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (Compound 29-2) [ka]

[0166] In the same manner as in Production Example 1-3, 120 mg (yield 58%) of the above-titled compound was obtained using tert-butyl 8-bromo-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (200 mg, 0.75 mmol), p-tolylboronic acid (464.49 mg, 3.42 mmol), Pd(PPh3)4 (32.9 mg, 0.028 mmol) and 1 M Na2CO3 (1.42 mL, 1.42 mmol).

[0167] 1 H NMR (400 MHz, DMSO) δ 10.95(s, 1H), 7.64(s, 1H), 7.62-7.54(m, 2H), 7.39-7.30(m, 2H), 7.24(d, J=7.9 Hz, 2H), 4.58(s, 2H), 3.72(t, J=5.6 Hz, 2H), 2.79(t, J=5.6 Hz, 2H), 2.34(s, 3H), 2.08(s, 12H), 1.45(s, 9H).

[0168] Preparation Example 29-2: Preparation of 8-(p-tolyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (Compound 29-3) [ka]

[0169] In a similar manner to Preparation Example 1-4, 86.2 mg (87% yield) of the title compound was obtained using tert-butyl 8-(p-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (120 mg, 0.31 mmol) and HCl solution (4 M in dioxane) (1.66 mL, 6.62 mmol).

[0170] 1 H NMR (400 MHz, DMSO) δ 11.22 (s, 1H), 7.75 (s, 1H), 7.61 - 7.54 (m, 2H), 7.40(d, J = 1.2 Hz, 2H), 7.25 (d, J = 7.9 Hz, 2H), 4.36 (s, 2H), 3.49 (d, J = 5.4 Hz, 2H), 3.05 (t, J = 6.0 Hz, 2H), 2.34 (s, 3H).

[0171] Preparation Example 29-3: Preparation of pyridin-3-yl(8-(p-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-B]indol-2-yl)methanone (Compound 29) [ka]

[0172] In the same manner as in Production Example 5, 10.7 mg (yield 43%) of the title compound was obtained using 8-(p-tolyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.067 mmol), nicotinic acid (9.88 mg, 0.08 mmol), EDCI (51.3 mg, 0.27 mmol) and DIPEA (0.047 mL, 0.27 mmol).

[0173] 1 H NMR (400 MHz, DMSO) δ 11.04 (s, 1H), 8.70 (s, 2H), 7.95 (d, J = 8.5 Hz, 1H), 7.77 (s, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.52 (d, J = 7.2 Hz, 2H), 7.35 (d, J = 16.2 Hz, 2H), 7.28 - 7.18 (m, 2H), 4.88 (s, 1H), 4.67 (s, 1H), 4.05 (s, 1H), 3.69 (s, 1H), 2.92 (s, 2H), 2.33 (d, J = 13.0 Hz, 3H).

[0174] Preparation Example 30: Preparation of phenyl(8-(p-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)methanone (Compound 30) [ka]

[0175] In the same manner as in Production Example 5, 9.7 mg (yield 39%) of the title compound was obtained using 8-(p-tolyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.07 mmol), benzoic acid (9.8 mg, 0.08 mmol), EDCI (51.3 mg, 0.27 mmol) and DIPEA (0.047 mL, 0.27 mmol).

[0176] 1 H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 7.76 (s, 1H), 7.61 (s, 1H), 7.50 (s, 6H), 7.37 (s, 2H), 7.24 (s, 1H), 7.20 (s, 1H), 4.85 (s, 1H), 4.65 (s, 1H), 4.05 (s, 1H), 3.68 (s, 1H), 2.89 (s, 2H), 2.37-2.23 (m, 3H).

[0177] Preparation Example 31: Preparation of Compound 31 Preparation Example 31-1: Preparation of tert-butyl 8-(pyridin-3-yl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (Compound 31-2) [ka]

[0178] In the same manner as in Production Example 1-3, 104.4 mg (yield 52%) of the above-titled compound was obtained using tert-butyl 8-bromo-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (200 mg, 0.57 mmol), pyridin-3-ylboronic acid (209.97 mg, 1.71 mmol), Pd(PPh3)4 (32.9 mg, 0.028 mmol) and 1 M Na2CO3 (1.42 mL, 1.42 mmol).

[0179] 1 H NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 8.55 (d, J = 4.7 Hz, 1H), 7.93 (s, 1H), 7.64 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 8.3 Hz, 2H), 4.70 (s, 2H), 3.84 (t, J = 5.8 Hz, 2H), 2.90 - 2.82 (m, 2H), 1.53 (s, 9H).

[0180] Preparation Example 31-2: Preparation of 8-phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (compound 31-3) [ka]

[0181] In a similar manner to Preparation Example 1-4, 76.1 mg (89% yield) of the title compound was obtained using tert-butyl 8-(pyridin-3-yl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (104.4 mg, 0.3 mmol) and HCl solution (4 M in dioxane) (1.49 mL, 5.98 mmol).

[0182] 1 H NMR (400 MHz, DMSO) δ 11.50 (s, 1H), 9.21 (d, J = 2.1 Hz, 1H), 8.85 - 8.75 (m, 2H), 8.09 (d, J = 1.8 Hz, 1H), 8.03 (dd, J = 8.3, 5.5 Hz, 1H), 7.61 (dd, J = 8.5, 1.8 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 4.34 (d, J = 4.5 Hz, 2H), 3.48 (d, J = 6.7 Hz, 2H), 3.07(t, J = 6.1 Hz, 2H).

[0183] Preparation Example 31-3: Preparation of pyridin-3-yl (8-(pyridin-3-yl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)methanone (Compound 31) [ka]

[0184] In the same manner as in Production Example 2, 8.5 mg (yield 27%) of the title compound was obtained using 8-phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (25 mg, 0.088 mmol), nicotinic acid (12.93 mg, 0.11 mmol), HATU (66.54 mg, 0.18 mmol) and DIPEA (0.031 mL, 0.18 mmol).

[0185] 1H NMR (400 MHz, MeOD) δ 8.85 - 8.64 (m, 3H), 8.41 (d, J = 16.6 Hz, 1H), 8.14 - 7.94 (m, 2H), 7.76 - 7.32 (m, 5H), 4.97 (s, 1H), 4.72 (s, 1H), 4.17 (s, 1H), 3.78 (s, 1H), 3.00 (s, 1H), 2.94 (s, 1H).

[0186] Preparation Example 32: Preparation of Compound 32 Preparation Example 32-1: Preparation of tert-butyl 8-((4-chlorophenyl)amino)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (Compound 32-2) [ka]

[0187] tert-Butyl 8-bromo-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (200 mg, 0.57 mmol), 4-chloroaniline (290.55 mg, 2.28 mmol), Pd(dba)a (52.14 mg, 0.057 mmol), Xphos (27.14 mg, 0.057 mmol), and KCO (314.78 mg, 2.28 mmol) were dissolved in toluene. The reaction mixture was stirred at 100 °C in a sealed tube for 12 hours. After the reaction was completed, the mixture was extracted with distilled water and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure to give 95 mg of the title compound (41% yield).

[0188] 1H NMR (400 MHz, DMSO) δ 10.78 (s, 1H), 7.88 (s, 1H), 7.22 (d, J = 8.5 Hz, 1H), 7.16-7.09 (m, 2H), 7.07 (s, 1H), 6.89-6.79 (m, 3H), 4.45 (s, 2H), 3.67 (t, J = 5.7 Hz, 2H), 2.73 (t, J = 5.6 Hz, 2H), 1.41 (s, 9H).

[0189] Preparation Example 32-2: Preparation of N-(4-chlorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-B]indol-8-amine hydrochloride (Compound 32-3) [ka]

[0190] In the same manner as in Production Example 1-4, 73 mg (yield 91%) of the above-titled compound was obtained using tert-butyl 8-((4-chlorophenyl)amino)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (95 mg, 0.24 mmol) and HCl solution (4 M in dioxane) (1.19 mL, 4.78 mmol).

[0191] 1 H NMR (400 MHz, DMSO) δ 11.07(s, 1H), 9.26(s, 1H), 7.30(d, J=8.5 Hz, 1H), 7.21(d, J=2.1 Hz, 1H), 7.18-7.11 (m, 2H), 6.89 (dd, J=8.8, 2.4 Hz, 3H), 4.27 (s, 2H), 3.57(s, 2H), 3.02(t, J=6.1 Hz, 2H), 1.18(t, J=7.1 Hz, 1H).

[0192] Preparation Example 32-3: Preparation of (8-((4-chlorophenyl)amino)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(pyridin-3-yl)methanone (Compound 32) [ka]

[0193] In the same manner as in Production Example 5, 14.1 mg (yield 35%) of the above-titled compound was obtained using N-(4-chlorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-B]indol-8-amine hydrochloride (33 mg, 0.099 mmol), nicotinic acid (14.59 mg, 0.12 mmol), EDCI (75.7 mg, 0.39 mmol) and DIPEA (0.069 mL, 0.39 mmol).

[0194] 1 H NMR (400 MHz, DMSO) δ 10.89 (s, 1H), 8.68 (s, 2H), 7.93 (s, 2H), 7.50 (s, 1H), 7.29 - 7.06 (m, 4H), 6.86 (dd, J = 27.9, 14.2 Hz, 3H), 4.76 (s, 1H), 4.54 (s, 1H), 4.02 (s, 1H), 3.65 (s, 1H), 2.87 (s, 2H).

[0195] Preparation Example 33: Preparation of (8-((4-chlorophenyl)amino)-1,3,4,5-tetrahydro-2H-pyrido[4,3-B]indol-2-yl)(phenyl)methanone (Compound 33) [ka]

[0196] In the same manner as in Production Example 5, 4.9 mg (yield 20%) of the title compound was obtained using N-(4-chlorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-B]indol-8-amine hydrochloride (20 mg, 0.06 mmol), benzoic acid (8.77 mg, 0.072 mmol), EDCI (45.89 mg, 0.24 mmol) and DIPEA (0.042 mL, 0.24 mmol).

[0197] 1 H NMR(400 MHz, DMSO) δ10.88(s, 1H), 7.94(s, 1H), 7.48(s, 4H), 7.21 (d, J=41.7 Hz, 4H), 6.88(s, 4H), 4.75(s, 2H), 4.03(s, 1H), 3.65 (s, 1H), 2.86 (s, 2H).

[0198] Preparation Example 34: Preparation of Compound 34 Preparation Example 34-1: Preparation of 7-bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole / 9-bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (Compounds 34-2 / 34-3) [ka]

[0199] (3-Bromophenyl)hydrazine hydrochloride (2 g, 8.95 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (1.87 g, 9.4 mmol) were dissolved in 1,4-dioxane. While stirring the reaction mixture at 0 °C, H2SO4 (1.12 mL, 8 M) was added. The reaction mixture was stirred at 110 °C for 3 hours using a sealed tube. After the reaction was completed, the precipitate was filtered off with 1,4-dioxane. The precipitate was dissolved in distilled water and basified with 1-n aqueous sodium hydroxide solution. Extraction was performed with distilled water and dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure to give 552 mg of a mixture of regioisomers.

[0200] Preparation Example 34-2: Preparation of tert-butyl 7-bromo-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (Compound 34-4) [ka]

[0201] Under nitrogen, the regioisomers (33-2 and 33-3) (1.13 g, 4.51 mmol) were dissolved in THF, and then BocO (0.56 mL, 2.42 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, the mixture was extracted with distilled water and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the concentrate was subjected to column chromatography to obtain 354.1 mg (45% yield) of the title compound (34-4).

[0202] 1 H NMR (400 MHz, DMSO) δ 11.38 (s, 1H), 7.76 (d, J = 1.7 Hz, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.38 (dd, J = 8.4, 1.8 Hz, 1H), 4.80 (s, 2H), 3.99 (t, J = 5.7 Hz, 2H), 3.05 (t, J = 5.8 Hz, 2H), 1.73 (s, 9H).

[0203] Preparation Example 34-3: Preparation of tert-butyl 7-phenyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (Compound 34-6) [ka]

[0204] In the same manner as in Production Example 1-3, 105.4 mg (yield 53%) of the above-titled compound was obtained using tert-butyl 7-bromo-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (200 mg, 0.57 mmol), phenylboronic acid (208.28 mg, 1.71 mmol), Pd(PPh3)4 (33 mg, 0.028 mmol) and 1 M Na2CO3 (1.42 mL, 1.42 mmol).

[0205] 1H NMR(400 MHz, DMSO) δ 11.01(s, 1H), 7.70-7.64(m, 2H), 7.55(d, J = 1.6 Hz, 1H), 7.45(td, J=7.8, 2.9 Hz, 3H), 7.35-7.25(m, 2H), 4.56(s, 2H), 3.73(t, J=5.7 Hz, 2H), 2.81(t, J=5.8 Hz, 2H), 1.46(s, 9H), 1.30(s, 1H).

[0206] Preparation Example 34-4: Preparation of 7-phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (compound 34-7) [ka]

[0207] In the same manner as in Preparation Example 1-4, 65 mg (yield 75%) of the above-titled compound was obtained using tert-butyl 7-phenyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (105.4 mg, 0.3 mmol) and HCl solution (4 M in dioxane) (1.51 mL, 6.05 mmol).

[0208] 1 H NMR(400 MHz, DMSO) δ11.27(s, 1H), 9.33(s, 2H), 7.70-7.66(m, 2H), 7.61(d, J=1.6 Hz, 1H), 7.56-7.53(m, 1H), 7.46(t, J=7.7 Hz, 3H), 7.37-7.31(m, 2H), 4.34(s, 2H), 3.49(d, J = 6.6 Hz, 2H), 3.07(t, J = 6.0 Hz, 2H).

[0209] Preparation Example 34-5: Preparation of 7-phenyl-2-(pyridin-3-ylsulfonyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (Compound 34) [ka]

[0210] Under nitrogen, 7-phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (30 mg, 0.11 mmol) was dissolved in dichloromethane, and then pyridine-3-sulfonyl chloride (0.01 mL, 0.1 mmol) and triethylamine (0.029 mL, 0.2 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 3 hours. Upon completion of the reaction, the mixture was extracted with distilled water and dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain 5.7 mg (14% yield) of the title compound.

[0211] 1 H NMR(400 MHz, DMSO) δ11.01(s, 1H), 9.03(dd, J=2.3, 0.8 Hz, 1H), 8.85(dd, J=4.8, 1.6 Hz, 1H), 8.28(ddd, J=8.1, 2.4, 1.6 Hz, 1H), 7.66(ddd, J= 8.1, 2.9, 1.6 Hz, 3H), 7.55-7.48(m, 2H), 7.47-7.41(m, 2H), 7.31(ddd, J=8.3, 6.8, 1.3 Hz, 2H), 4.41(s, 2H), 3.56(t, J=5.8 Hz, 2H), 2.85(t, J = 5.7 Hz, 2H).

[0212] Preparation Example 35: Preparation of (7-phenyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(pyridin-3-yl)methanone (Compound 35) [ka]

[0213] In the same manner as in Production Example 2, 13.3 mg (yield 42%) of the title compound was obtained using 7-phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (25 mg, 0.088 mmol), nicotinic acid (12.97 mg, 0.11 mmol), HATU (66.77 mg, 0.18 mmol) and DIPEA (0.031 mL, 0.18 mmol).

[0214] 1 H NMR(400 MHz, DMSO) δ 11.08(s, 1H), 8.69(d, J=4.7 Hz, 2H), 7.94(d, J=8.5 Hz, 1H), 7.70-7.61(m, 2H), 7.59-7.49(m, 3H), 7.44(t, J=7.4 Hz, 3H), 7.31(d, J=6.6 Hz, 2H), 4.84(s, 1H), 4.62(s, 1H), 4.05(s, 1H), 3.68(s, 1H), 2.92 (s, 2H).

[0215] Preparation Example 36: Preparation of cyclohexyl(8-(p-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)methanone (Compound 36) [ka]

[0216] In the same manner as in Production Example 5, 6.8 mg (yield 18%) of the title compound was obtained using 8-(p-tolyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (30 mg, 0.10 mmol), cyclohexanecarboxylic acid (15.44 mg, 0.12 mmol), EDCI (76.99 mg, 0.40 mmol) and DIPEA (0.07 mL, 0.40 mmol).

[0217] 1H NMR (400 MHz, DMSO) δ 10.93 (s, 1H), 7.70 (d, J = 40.7 Hz, 1H), 7.56 (d, J = 7.2 Hz, 2H), 7.33 (s, 2H), 7.23 (s, 2H), 4.70 (d, J = 38.8 Hz, 2H), 3.84 (s, 2H), 2.86 (s, 1H), 2.76 - 2.70 (m, 2H), 2.33 (s, 3H), 1.98 (s, 1H), 1.66 (d, J = 21.3 Hz, 6H), 1.35 (s, 4H).

[0218] Preparation Example 37: Preparation of p-tolyl(8-(p-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)methanone (Compound 37) [ka]

[0219] In the same manner as in Production Example 5, 13.7 mg (yield 53%) of the above-titled compound was obtained using 8-(p-tolyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.07 mmol), 4-methylbenzoic acid (10.94 mg, 0.08 mmol), EDCI (51.3 mg, 0.27 mmol) and DIPEA (0.047 mL, 0.27 mmol).

[0220] 1 H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 7.65 - 7.19 (m, 11H), 4.73 (d, J = 60.4 Hz, 2H), 3.67 (s, 2H), 2.87 (s, 2H), 2.34 (d, J = 14.5 Hz, 6H).

[0221] Preparation Example 38: Preparation of m-tolyl(8-(p-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)methanone (Compound 38) [ka]

[0222] In the same manner as in Production Example 5, 10 mg (yield 39%) of the above-titled compound was obtained using 8-(p-tolyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.07 mmol), 3-methylbenzoic acid (10.94 mg, 0.08 mmol), EDCI (51.3 mg, 0.27 mmol) and DIPEA (0.047 mL, 0.27 mmol).

[0223] 1 H NMR (400 MHz, DMSO) δ 11.00(s, 1H), 7.76 - 7.15(m, 11H), 4.72(d, J = 82.2 Hz, 2H), 4.02(d, J=8.4 Hz, 1H), 3.66(s, 1H), 2.87(s, 2H), 2.44 - 2.24(m, 6H).

[0224] Preparation Example 39: Preparation of (4-methoxyphenyl)(8-(p-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)methanone (Compound 39) [ka]

[0225] In the same manner as in Production Example 5, 11.7 mg (yield 44%) of the above-titled compound was obtained using 8-(p-tolyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.07 mmol), 4-methoxybenzoic acid (12.22 mg, 0.08 mmol), EDCI (51.3 mg, 0.27 mmol) and DIPEA (0.047 mL, 0.27 mmol).

[0226] 1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.55 (s, 2H), 7.46 (d, J = 8.2 Hz, 3H), 7.34 (s, 2H), 7.21 (s, 2H), 7.01 (d, J = 8.3 Hz, 2H), 4.75 (s, 2H), 3.81 (s, 5H), 2.88 (s, 2H), 2.32 (s, 3H).

[0227] Preparation Example 40: Preparation of (6-methylpyridin-3-yl)(8-(p-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)methanone (Compound 40) [ka]

[0228] In the same manner as in Production Example 5, 8.4 mg (yield 32%) of the title compound was obtained using 8-(p-tolyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.07 mmol), 6-methylnicotinic acid (11.015 mg, 0.08 mmol), EDCI (51.3 mg, 0.27 mmol) and DIPEA (0.047 mL, 0.27 mmol).

[0229] 1 H NMR (400 MHz, DMSO) δ 11.03(s, 1H), 8.58(s, 1H), 7.83(s, 2H), 7.58(d, J=25.9 Hz, 2H), 7.37(s, 3H), 7.24(s, 2H), 4.86(s, 1H), 4.69(s, 1H), 4.04(d, J=6.6 Hz, 1H), 3.70(s, 1H), 2.92(s, 2H), 2.55(s, 3H), 2.34(s, 3H).

[0230] Preparation Example 41: Preparation of (2-methylpyridin-4-yl)(8-(p-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)methanone (Compound 41) [ka]

[0231] In the same manner as in Production Example 5, 5.1 mg (yield 19%) of the title compound was obtained using 8-(p-tolyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.07 mmol), 2-methylisonicotinic acid (11.015 mg, 0.08 mmol), EDCI (51.3 mg, 0.27 mmol) and DIPEA (0.047 mL, 0.27 mmol).

[0232] 1 H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 8.54 (s, 1H), 7.74 (s, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.36 - 7.17 (m, 6H), 4.85 (s, 1H), 4.55 (s, 1H), 4.02 (s, 1H), 3.60 (s, 1H), 2.87 (d, J = 18.6 Hz, 2H), 2.52 (s, 3H), 2.31 (d, J = 13.7 Hz, 3H).

[0233] Preparation Example 42: Preparation of phenyl(8-(pyridin-3-yl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)methanone (Compound 42) [ka]

[0234] In the same manner as in Production Example 5, 13.9 mg (yield 37%) of the above-titled compound was obtained using 8-phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (30 mg, 0.11 mmol), benzoic acid (15.39 mg, 0.13 mmol), EDCI (80.51 mg, 0.42 mmol) and DIPEA (0.073 mL, 0.42 mmol).

[0235] 1 H NMR (400 MHz, DMSO) δ 11.11 (s, 1H), 8.88 (d, J = 40.9 Hz, 1H), 8.48 (s, 1H), 8.05 (d, J = 40.5 Hz, 1H), 7.87 (s, 1H), 7.44 (d, J = 24.4 Hz, 8H), 4.85 (s, 1H), 4.65 (s, 1H), 4.02 (s, 1H), 3.66 (s, 1H), 2.88 (s, 2H).

[0236] Preparation Example 43: Preparation of Compound 43 Preparation Example 43-1: Preparation of tert-butyl 5-methyl-8-(p-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (Compound 43-1) [ka]

[0237] Under nitrogen, tert-butyl 8-(p-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (100 mg, 0.28 mmol) was dissolved in THF. At 0 °C, NaH (22.07 mg, 0.55 mmol) and CHCl (0.018 mL, 0.28 mmol) were added. The reaction mixture was stirred at room temperature for 6 hours. Upon completion of the reaction, the mixture was extracted with distilled water and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was subjected to column chromatography to obtain 68.3 mg (65% yield) of the title compound.

[0238] 1H NMR (400 MHz, CDCl3) δ7.63(d, J=1.7Hz, 1H), 7.54(d, J=7.7Hz, 2H), 7.41(dd, J=8.6, 1.7Hz, 1H), 7.26(dd, J=21.2, 8.1Hz, 3H), 4.67(s, 2H), 3.83(s, 2H), 3.60(s, 3H), 2.78(t, J=5.9Hz, 2H), 2.38(s, 3H), 1.50(s, 9H), 1.30(d, J=13.9Hz, 9H).

[0239] Preparation Example 43-2: Preparation of 5-methyl-8-(p-tolyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (compound 43-2) [ka]

[0240] In the same manner as in Production Example 1-4, 48.7 mg (yield 85%) of the above-titled compound was obtained using tert-butyl 5-methyl-8-(p-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (68.3 mg, 0.18 mmol) and HCl solution (4 M in dioxane) (0.91 mL, 3.63 mmol).

[0241] 1 H NMR (400 MHz, DMSO) δ 9.19 (s, 1H), 7.78 (s, 1H), 7.59 (d, J = 7.8 Hz, 2H), 7.56 - 7.43 (m, 2H), 7.25 (d, J = 7.8 Hz, 2H), 4.37 (s, 2H), 3.69 (s, 3H), 3.53 (s, 2H), 3.07 (s, 2H), 2.34 (s, 3H).

[0242] Preparation Example 43-3: Preparation of (5-methyl-8-(p-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(phenyl)methanone (Compound 43) [ka]

[0243] In the same manner as in Production Example 5, 12.4 mg (yield 45%) of the above-titled compound was obtained using 5-methyl-8-(p-tolyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (22.5 mg, 0.072 mmol), benzoic acid (10.54 mg, 0.086 mmol), EDCI (55.15 mg, 0.29 mmol) and DIPEA (0.05 mL, 0.29 mmol).

[0244] 1 H NMR (400 MHz, DMSO) δ 7.78 (s, 1H), 7.54 (d, J = 52.7 Hz, 9H), 7.23 (s, 2H), 4.84 (s, 1H), 4.64 (s, 1H), 4.02 (d, J = 11.0 Hz, 1H), 3.65 (s, 4H), 2.91 (s, 2H), 2.32 (s, 3H).

[0245] Preparation Example 44: Preparation of (5-methyl-8-(p-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(pyridin-3-yl)methanone (Compound 44) [ka]

[0246] In the same manner as in Production Example 5, 7.4 mg (yield 23%) of the title compound was obtained using 5-methyl-8-(p-tolyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (26.2 mg, 0.084 mmol), nicotinic acid (12.37 mg, 0.1 mmol), EDCI (64.22 mg, 0.34 mmol) and DIPEA (0.058 mL, 0.34 mmol).

[0247] 1H NMR (400 MHz, DMSO) δ 8.70 (s, 2H), 7.93 (s, 1H), 7.48 (d, J = 29.6 Hz, 6H), 7.26 - 7.18 (m, 2H), 4.88 (s, 1H), 4.67 (s, 1H), 4.07 (s, 1H), 3.67 (s, 4H), 2.94 (s, 2H), 2.34 (s, 3H).

[0248] Preparation Example 45: Preparation of Compound 45 Preparation Example 45-1: Preparation of tert-butyl 5-ethyl-8-(p-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (Compound 45-1) [ka]

[0249] Under nitrogen, tert-butyl 8-(p-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (200 mg, 0.55 mmol) was dissolved in THF. At 0 °C, NaH (44.14 mg, 1.1 mmol) and ethyl iodide (0.045 mL, 0.56 mmol) were added. The reaction mixture was stirred at room temperature for 4 hours. Upon completion of the reaction, the mixture was extracted with distilled water and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was subjected to column chromatography to obtain 75.9 mg (35% yield) of the title compound.

[0250] 1H NMR (400 MHz, DMSO) δ 7.68 (s, 1H), 7.59 (d, J = 7.8 Hz, 2H), 7.49 (d, J = 8.6 Hz, 1H), 7.44 - 7.37 (m, 1H), 7.25 (d, J = 7.8 Hz, 2H), 4.60 (s, 2H), 4.15 (q, J = 7.1 Hz, 2H), 3.76 (t, J = 5.6 Hz, 2H), 2.83 (s, 2H), 2.35 (s, 3H), 1.46 (s, 9H), 1.25 (t, J = 7.1 Hz, 3H).

[0251] Preparation Example 45-2: Preparation of 5-ethyl-8-(p-tolyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (compound 45-2) [ka]

[0252] In the same manner as in Production Example 1-4, 40.5 mg (yield 63%) of the above-titled compound was obtained using tert-butyl 5-ethyl-8-(p-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (75.9 mg, 0.19 mmol) and HCl solution (4 M in dioxane) (0.97 mL, 3.89 mmol).

[0253] 1 H NMR (400 MHz, DMSO) δ 9.31 (s, 1H), 7.79 (d, J = 1.8 Hz, 1H), 7.58 (dd, J = 16.5, 8.2 Hz, 3H), 7.47 (dd, J = 8.7, 1.8 Hz, 1H), 7.27 (d, J = 7.8 Hz, 2H), 4.38 (s, 2H), 4.19 (d, J = 7.4 Hz, 2H), 3.54 (s, 2H), 3.11 (d, J = 6.6 Hz, 2H), 2.35 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H).

[0254] Preparation Example 45-3: Preparation of (5-ethyl-8-(p-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(phenyl)methanone (Compound 45) [ka]

[0255] In the same manner as in Production Example 5, 15.3 mg (yield 63%) of the title compound was obtained using 5-ethyl-8-(p-tolyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.061 mmol), benzoic acid (8.97 mg, 0.073 mmol), EDCI (46.93 mg, 0.24 mmol) and DIPEA (0.043 mL, 0.24 mmol).

[0256] 1 H NMR (400 MHz, CDCl3) δ 7.64 - 7.20 (m, 13H), 5.04 (s, 1H), 4.73 (s, 1H), 4.23 (s, 1H), 3.83 (s, 1H), 2.95 (d, J = 43.6 Hz, 2H), 2.41 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H).

[0257] Preparation Example 46: Preparation of (5-ethyl-8-(p-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(pyridin-3-yl)methanone (Compound 46) [ka]

[0258] In the same manner as in Production Example 5, 14.5 mg (yield 59%) of the title compound was obtained using 5-ethyl-8-(p-tolyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.061 mmol), nicotinic acid (9.004 mg, 0.073 mmol), EDCI (46.93 mg, 0.24 mmol) and DIPEA (0.043 mL, 0.24 mmol).

[0259] 1 H NMR (400 MHz, CDCl3)δ8.80(s, 1H), 8.73(s, 1H), 7.86(s, 1H), 7.59-7.39(m, 6H), 7.24(d, J=8.1Hz, 2H), 5.05(s, 1H), 4.76(s, 1H), 4.24(s, 1H), 4.16(t, J=7.2Hz, 2H), 3.84(s, 1H), 2.97(d, J=33.3Hz, 2H), 2.42(d, J=9.3Hz, 3H), 1.41(t, J=7.2Hz, 3H).

[0260] Preparation Example 47: Preparation of Compound 47 Preparation Example 47-1: Preparation of tert-butyl 8-(6-methylpyridin-3-yl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (Compound 47-2) [ka]

[0261] In the same manner as in Production Example 1-3, 216.2 mg (yield 68%) of the above-titled compound was obtained using tert-butyl 8-bromo-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (304.5 mg, 0.87 mmol), (6-methylpyridin-3-yl)boronic acid (356.14 mg, 2.6 mmol), Pd(PPh3)4 (50.094 mg, 0.043 mmol) and 1 M Na2CO3 (2.17 mL, 2.17 mmol).

[0262] 1 H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 8.76 (d, J = 2.5 Hz, 1H), 7.96 (dd, J = 8.1, 2.4 Hz, 1H), 7.72 (s, 1H), 7.37 (d, J = 2.5 Hz, 2H), 7.29 (d, J = 8.0 Hz, 1H), 4.58 (s, 2H), 3.71 (d, J = 6.0 Hz, 2H), 3.16 (d, J = 5.2 Hz, 3H), 2.78 (s, 2H), 1.44 (s, 9H).

[0263] Preparation Example 47-2: Preparation of 8-(6-methylpyridin-3-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (compound 47-3) [ka]

[0264] In the same manner as in Production Example 1-4, 178.32 mg (yield 100%) of the above-titled compound was obtained using tert-butyl 8-(6-methylpyridin-3-yl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (216.2 mg, 0.59 mmol) and HCl solution (4 M in dioxane) (2.97 mL, 11.896 mmol).

[0265] 1 H NMR (400 MHz, DMSO) δ 11.44 (s, 1H), 9.34 (s, 1H), 9.05 (s, 1H), 8.69 (s, 1H), 8.05 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.7 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 4.36 (s, 2H), 3.51 (s, 2H), 3.07 (t, J = 5.9 Hz, 2H), 2.73 (s, 2H).

[0266] Preparation Example 47-3: Preparation of (8-(6-methylpyridin-3-yl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(phenyl)methanone (Compound 47) [ka]

[0267] In the same manner as in Production Example 5, 18.4 mg (yield 50%) of the above-mentioned title compound was obtained using 8-(6-methylpyridin-3-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (30 mg, 0.1 mmol), benzoic acid (14.67 mg, 0.12 mmol), EDCI (76.76 mg, 0.4 mmol) and DIPEA (0.07 mL, 0.4 mmol).

[0268] 1 H NMR (400 MHz, DMSO) δ 11.07 (s, 1H), 8.72 (d, J = 40.7 Hz, 1H), 7.98 (s, 1H), 7.82 (s, 1H), 7.42 (d, J = 36.0 Hz, 8H), 4.83 (s, 1H), 4.63 (s, 1H), 4.00 (t, J = 7.2 Hz, 1H), 3.65 (s, 1H), 2.87 (s, 2H).

[0269] Preparation Example 48: Preparation of (8-(6-methylpyridin-3-yl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(pyridin-3-yl)methanone (Compound 48) [ka]

[0270] In the same manner as in Production Example 5, 14.1 mg (yield 38%) of the title compound was obtained using 8-(6-methylpyridin-3-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (30 mg, 0.1 mmol), nicotinic acid (14.79 mg, 0.12 mmol), EDCI (76.76 mg, 0.4 mmol) and DIPEA (0.07 mL, 0.4 mmol).

[0271] 1 H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 8.75 (d, J = 40.5 Hz, 3H), 8.02 - 7.84 (m, 2H), 7.65 - 7.20 (m, 5H), 4.88 (s, 1H), 4.67 (s, 1H), 4.07 - 4.00 (m, 1H), 3.68 (s, 1H), 2.92 (s, 2H), 2.46 (s, 3H).

[0272] Preparation Example 49: Preparation of (6-methylpyridin-3-yl)(8-(6-methylpyridin-3-yl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)methanone (Compound 49) [ka]

[0273] In the same manner as in Production Example 5, 17.1 mg (yield 44%) of the above-mentioned title compound was obtained using 8-(6-methylpyridin-3-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (30 mg, 0.1 mmol), 6-methylnicotinic acid (16.47 mg, 0.12 mmol), EDCI (76.76 mg, 0.4 mmol) and DIPEA (0.07 mL, 0.4 mmol).

[0274] 1H NMR (400 MHz, DMSO) δ 11.10(s, 1H), 8.76(d, J = 33.2 Hz, 1H), 8.58 (s, 1H), 7.88(d, J=31.4 Hz, 3H), 7.43 - 7.25(m, 4H), 4.87(s, 1H), 4.70 (s, 1H), 4.03 (t, J=7.1 Hz, 1H), 3.70(s, 1H), 2.92(s, 2H), 2.54(s, 6H).

[0275] Preparation Example 50: Preparation of Compound 50 Preparation Example 50-1: Preparation of tert-butyl 8-(4-cyanophenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (Compound 50-2) [ka]

[0276] In the same manner as in Production Example 1-3, 427.9 mg (yield 40%) of the above-titled compound was obtained using tert-butyl 8-bromo-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (1 g, 2.85 mmol), (4-cyanophenyl)boronic acid (1.26 g, 8.54 mmol), Pd(PPh3)4 (164.55 mg, 0.14 mmol) and 1 M Na2CO3 (7.12 mL, 7.12 mmol).

[0277] 1 H NMR(400 MHz, DMSO) δ 11.09(s, 1H), 7.93-7.82(m, 5H), 7.48-7.37(m, 2H), 4.59(s, 2H), 3.71(t, J=5.7Hz, 2H), 2.79(d, J=6.1 Hz, 2H), 1.44(s, 9H).

[0278] Preparation Example 50-2: Preparation of 4-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)benzonitrile hydrochloride (Compound 50-3) [ka]

[0279] In the same manner as in Production Example 1-4, 315.1 mg (yield 88%) of the above-titled compound was obtained using tert-butyl 8-(4-cyanophenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (427.9 mg, 1.15 mmol) and HCl solution (4 M in dioxane) (5.73 mL, 22.92 mmol).

[0280] 1 H NMR (400 MHz, DMSO) δ 11.38(s, 1H), 9.37(s, 1H), 7.93(d, J=13.5 Hz, 5H), 7.56-7.44(m, 2H), 4.37(s, 2H), 3.50(s, 2H), 3.07(d, J=6.0 Hz, 2H).

[0281] Preparation Example 50-3: Preparation of (8-(4-isocyanophenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(phenyl)methanone (Compound 50) [ka]

[0282] In the same manner as in Production Example 5, 8.8 mg (yield 31%) of the title compound was obtained using 4-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)benzonitrile hydrochloride (22.7 mg, 0.073 mmol), benzoic acid (10.74 mg, 0.088 mmol), EDCI (56.21 mg, 0.29 mmol) and DIPEA (0.051 mL, 0.29 mmol).

[0283] 1H NMR (400 MHz, DMSO) δ 11.19 (s, 1H), 7.99 - 7.83 (m, 4H), 7.68 (s, 1H), 7.50 (s, 7H), 4.87 (s, 1H), 4.67 (s, 1H), 3.68 (s, 2H), 2.90 (s, 2H).

[0284] Preparation Example 51: Preparation of ((8-(4-isocyanophenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(pyridin-3-yl)methanone (Compound 51) [ka]

[0285] In the same manner as in Production Example 5, 11.3 mg (yield 40%) of the above-mentioned title compound was obtained using 4-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)benzonitrile hydrochloride (22.7 mg, 0.073 mmol), nicotinic acid (10.82 mg, 0.088 mmol), EDCI (56.19 mg, 0.29 mmol) and DIPEA (0.051 mL, 0.29 mmol).

[0286] 1 H NMR (400 MHz, DMSO) δ 11.20 (s, 1H), 8.70 (s, 2H), 7.97 (d, J = 9.0 Hz, 2H), 7.92 - 7.72 (m, 4H), 7.55 - 7.40 (m, 3H), 4.90 (s, 1H), 4.69 (s, 1H), 4.06 (s, 1H), 3.69 (s, 1H), 2.93 (s, 2H).

[0287] Preparation Example 52: Preparation of (8-(4-isocyanophenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(p-tolyl)methanone (Compound 52) [ka]

[0288] In the same manner as in Production Example 5, 10 mg (yield 39%) of the above-titled compound was obtained using 4-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)benzonitrile hydrochloride (20 mg, 0.065 mmol), 4-methylbenzoic acid (10.55 mg, 0.077 mmol), EDCI (49.5 mg, 0.26 mmol) and DIPEA (0.045 mL, 0.26 mmol).

[0289] 1 H NMR (400 MHz, DMSO) δ 11.14 (s, 1H), 7.88 (d, J = 33.4 Hz, 5H), 7.43 - 7.34 (m, 4H), 7.27 (d, J = 7.7 Hz, 2H), 4.81 (s, 1H), 4.68 (s, 1H), 4.00 (s, 1H), 3.67 (s, 1H), 2.87 (s, 2H), 2.35 (s, 3H).

[0290] Preparation Example 53: Preparation of (8-(4-isocyanophenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(m-tolyl)methanone (Compound 53) [ka]

[0291] In the same manner as in Production Example 5, 11.7 mg (yield 46%) of the above-mentioned title compound was obtained using 4-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)benzonitrile hydrochloride (20 mg, 0.065 mmol), 3-methylbenzoic acid (10.55 mg, 0.077 mmol), EDCI (49.5 mg, 0.26 mmol) and DIPEA (0.045 mL, 0.26 mmol).

[0292] 1H NMR (400 MHz, DMSO) δ 11.16(s, 1H), 7.95(s, 2H), 7.85(s, 2H), 7.67 (s, 1H), 7.42(s, 2H), 7.36(s, 1H), 7.29(d, J=11.7 Hz, 3H), 4.85(s, 1H), 4.64(s, 1H), 4.02(d, J=7.7 Hz, 1H), 3.67(s, 1H), 2.88(s, 2H), 2.36(s, 3H).

[0293] Preparation Example 54: Preparation of (8-(4-isocyanophenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(6-methylpyridin-3-yl)methanone (Compound 54) [ka]

[0294] In the same manner as in Production Example 5, 10.8 mg (yield 42%) of the above-titled compound was obtained using 4-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)benzonitrile hydrochloride (20 mg, 0.065 mmol), 6-methylnicotinic acid (10.62 mg, 0.077 mmol), EDCI (49.5 mg, 0.26 mmol) and DIPEA (0.045 mL, 0.26 mmol).

[0295] 1 H NMR (400 MHz, DMSO) δ 11.16 (s, 1H), 8.57 (s, 1H), 7.90 (d, J = 40.3 Hz, 6H), 7.40 (d, J = 19.9 Hz, 3H), 4.78 (d, J = 66.6 Hz, 2H), 4.03 (s, 1H), 3.69 (s, 1H), 2.91 (s, 2H), 2.53 (s, 3H).

[0296] Preparation Example 55: Preparation of 3-(8-(4-isocyanophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-2-carbonyl)benzonitrile (Compound 55) [ka]

[0297] In the same manner as in Production Example 5, 12.2 mg (yield 46%) of the above-mentioned title compound was obtained using 4-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)benzonitrile hydrochloride (20 mg, 0.065 mmol), 3-cyanobenzoic acid (11.4 mg, 0.077 mmol), EDCI (49.5 mg, 0.26 mmol) and DIPEA (0.045 mL, 0.26 mmol).

[0298] 1 H NMR (400 MHz, DMSO) δ 11.17 (s, 1H), 7.95 (s, 4H), 7.85 (d, J = 20.0 Hz, 4H), 7.69 (s, 1H), 7.46 (s, 1H), 7.41 (s, 1H), 4.87 (s, 1H), 4.61 (s, 1H), 3.63 (s, 2H), 2.89 (s, 2H).

[0299] Preparation Example 56: Preparation of Compound 56 Preparation Example 56-1: Preparation of tert-butyl 8-(3-cyanophenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (Compound 56-2) [ka]

[0300] In the same manner as in Production Example 1-3, 278.3 mg (yield 26%) of the above-titled compound was obtained using tert-butyl 8-bromo-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (1 g, 2.85 mmol), (3-cyanophenyl)boronic acid (1.26 g, 8.54 mmol), Pd(PPh3)4 (164.55 mg, 0.14 mmol) and 1 M Na2CO3 (7.12 mL, 7.12 mmol).

[0301] 1 H NMR (400 MHz, DMSO) δ 11.06 (s, 1H), 8.19(s, 1H), 8.06(d, J=7.6 Hz, 1H), 7.85(s, 1H), 7.74(d, J=7.6Hz, 1H), 7.64(d, J=8.1 Hz, 1H), 7.46-7.36(m, 2H), 4.60(s, 2H), 3.73(s, 2H), 2.80(s, 2H), 1.45(d, J=3.6 Hz, 9H).

[0302] Preparation Example 56-2: Preparation of 3-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)benzonitrile hydrochloride (Compound 56-3) [ka]

[0303] In the same manner as in Production Example 1-4, 198.8 mg (yield 86%) of the above-titled compound was obtained using tert-butyl 8-(3-cyanophenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (278.3 mg, 0.75 mmol) and HCl solution (4 M in dioxane) (3.73 mL, 14.9 mmol).

[0304] 1H NMR (400 MHz, DMSO) δ 11.32(s, 1H), 9.34(s, 2H), 8.16(d, J=1.8 Hz, 1H), 8.05(dt, J = 7.9, 1.5 Hz, 1H), 7.93(d, J=1.8 Hz, 1H), 7.75(dt, J = 7.7, 1.3 Hz, 1H), 7.65(t, J = 7.8 Hz, 1H), 7.51(dd, J = 8.5, 1.8 Hz, 1H), 7.45(d, J=8.4 Hz, 1H), 4.36(s, 2H), 3.49(d, J=6.5 Hz, 2H), 3.05(t, J = 6.0 Hz, 2H).

[0305] Preparation Example 56-3: Preparation of 3-(2-(4-methylbenzoyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)benzonitrile (Compound 56) [ka]

[0306] Under nitrogen, 3-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)benzonitrile hydrochloride (20 mg, 0.065 mmol) was dissolved in dimethylformamide. 4-Methylbenzoic acid (10.55 mg, 0.077 mmol), DMAP (31.54 mg, 0.26 mmol), EDCI (49.5 mg, 0.26 mmol), and DIPEA (0.045 mL, 0.26 mmol) were added. The reaction mixture was stirred at room temperature for 12 hours. Upon completion of the reaction, the mixture was extracted with distilled water and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain 10.9 mg (43% yield) of the title compound.

[0307] 1H NMR (400 MHz, DMSO) δ 11.11(s, 1H), 8.23-7.93(m, 3H), 7.66(d, J = 40.0 Hz, 3H), 7.33(dd, J = 41.3, 8.0 Hz, 6H), 4.83(s, 1H), 4.68(s, 1H), 4.02 (d, J = 7.0 Hz, 1H), 3.68 (s, 1H), 2.88(s, 2H), 2.36(s, 3H).

[0308] Preparation Example 57: Preparation of 3-(2-(6-methylnicotinoyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)benzonitrile (Compound 57) [ka]

[0309] In the same manner as in Production Example 56-3, 3-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)benzonitrile hydrochloride (20 mg, 0.065 mmol), 6-methylnicotinic acid (10.62 mg, 0.077 mmol), DMAP (31.54 mg, 0.26 mmol), EDCI (49.5 mg, 0.26 mmol) and DIPEA (0.045 mL, 0.26 mmol) were used to obtain 6 mg of the above-mentioned title compound (yield 23%).

[0310] 1 H NMR (400 MHz, DMSO) δ 11.12 (s, 1H), 8.57 (s, 1H), 8.21 (s, 1H), 8.10 (s, 1H), 7.97 (s, 1H), 7.81 (s, 1H), 7.73 (d, J = 8.5 Hz, 2H), 7.61 (s, 1H), 7.36 (d, J = 8.0 Hz, 2H), 4.86 (s, 1H), 4.70 (s, 1H), 4.03 (d, J = 5.0 Hz, 1H), 3.69 (s, 1H), 2.91 (s, 2H), 2.53 (s, 3H).

[0311] Preparation Example 58: Preparation of 3-(2-benzoyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)benzonitrile (Compound 58) [ka]

[0312] In the same manner as in Production Example 56-3, 9.8 mg (yield 40%) of the above-mentioned title compound was obtained using 3-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)benzonitrile hydrochloride (20 mg, 0.065 mmol), benzoic acid (9.46 mg, 0.077 mmol), DMAP (31.54 mg, 0.26 mmol), EDCI (49.5 mg, 0.26 mmol) and DIPEA (0.045 mL, 0.26 mmol).

[0313] 1 H NMR (400 MHz, DMSO) δ 11.12 (s, 1H), 8.22 (s, 1H), 8.09 (s, 1H), 7.97 (s, 1H), 7.72 (s, 1H), 7.63 (s, 1H), 7.49 (s, 5H), 7.41 (s, 2H), 4.86 (s, 1H), 4.66 (s, 1H), 4.03 (s, 1H), 3.68 (s, 1H), 2.90 (s, 2H).

[0314] Preparation Example 59: Preparation of Compound 59 Preparation Example 59-1: Preparation of tert-butyl 8-(2-cyanophenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (Compound 59-2) [ka]

[0315] In the same manner as in Production Example 1-3, 798 mg (yield 75%) of the above-titled compound was obtained using tert-butyl 8-bromo-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (1 g, 2.85 mmol), (2-cyanophenyl)boronic acid (1.26 g, 8.54 mmol), Pd(PPh3)4 (164.55 mg, 0.14 mmol) and 1 M Na2CO3 (7.12 mL, 7.12 mmol).

[0316] 1 H NMR (400 MHz, DMSO) δ 11.14 (s, 1H), 7.90 (dd, J = 7.8, 1.4 Hz, 1H), 7.75 (td, J = 7.6, 1.4 Hz, 1H), 7.68 - 7.57 (m, 2H), 7.51 (td, J = 7.6, 1.3 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.25 (dd, J = 8.4, 1.8 Hz, 1H), 4.57 (s, 2H), 3.72 (t, J = 5.7 Hz, 2H), 2.80 (t, J = 5.8 Hz, 2H), 1.43 (s, 9H).

[0317] Preparation Example 59-2: Preparation of 2-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)benzonitrile hydrochloride (Compound 59-3) [ka]

[0318] In the same manner as in Production Example 1-4, 465.2 mg (yield 70%) of the above-titled compound was obtained using tert-butyl 8-(2-cyanophenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (798 mg, 2.14 mmol) and HCl solution (4 M in dioxane) (10.68 mL, 42.74 mmol).

[0319] 1H NMR (400 MHz, DMSO) δ 11.40 (s, 1H), 9.36 (s, 1H), 7.91 (dd, J = 7.7, 1.3 Hz, 1H), 7.76 (td, J = 7.7, 1.4 Hz, 1H), 7.68 (d, J = 1.7 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.59 - 7.45 (m, 2H), 7.30 (dd, J = 8.4, 1.8 Hz, 1H), 4.33 (s, 2H), 3.48 (d, J = 6.4 Hz, 2H), 3.06 (t, J = 6.0Hz, 2H).

[0320] Preparation Example 59: Preparation of 2-(2-(4-methylbenzoyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)benzonitrile (Compound 59) [ka]

[0321] In the same manner as in Production Example 56-3, 2-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)benzonitrile hydrochloride (20 mg, 0.065 mmol), 4-methylbenzoic acid (10.55 mg, 0.077 mmol), DMAP (31.54 mg, 0.26 mmol), EDCI (49.5 mg, 0.26 mmol) and DIPEA (0.045 mL, 0.26 mmol) were used to obtain 16.5 mg (yield 65%) of the above-mentioned title compound.

[0322] 1 H NMR (400 MHz, DMSO) δ 11.20 (s, 1H), 7.89 (s, 1H), 7.73 (s, 3H), 7.50 (s, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.37 (d, J = 7.5 Hz, 2H), 7.27 (s, 3H), 4.79 (s, 1H), 4.66 (s, 1H), 3.69 (s, 2H), 2.90 (s, 2H), 2.35 (s, 3H).

[0323] Preparation Example 60: Preparation of 2-(2-(6-methylnicotinoyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)benzonitrile (Compound 60) [ka]

[0324] In the same manner as in Production Example 56-3, 2-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)benzonitrile hydrochloride (20 mg, 0.065 mmol), 6-methylnicotinic acid (10.62 mg, 0.077 mmol), DMAP (31.54 mg, 0.26 mmol), EDCI (49.5 mg, 0.26 mmol) and DIPEA (0.045 mL, 0.26 mmol) were used to obtain 15.3 mg (yield 60%) of the above-mentioned title compound.

[0325] 1 H NMR (400 MHz, DMSO) δ 11.21 (s, 1H), 8.56 (s, 1H), 7.90 - 7.68 (m, 4H), 7.39 (dd, J = 63.4, 30.2 Hz, 5H), 4.83 (s, 1H), 4.67 (s, 1H), 4.03 (s, 1H), 3.69 (s, 1H), 2.92 (s, 2H), 2.52 (s, 3H).

[0326] Preparation Example 61: Preparation of 2-(2-benzoyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)benzonitrile (Compound 61) [ka]

[0327] In the same manner as in Production Example 56-3, 2-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)benzonitrile hydrochloride (20 mg, 0.065 mmol), benzoic acid (9.46 mg, 0.077 mmol), DMAP (31.54 mg, 0.26 mmol), EDCI (49.5 mg, 0.26 mmol) and DIPEA (0.045 mL, 0.26 mmol) were used to obtain 13.7 mg (yield 56%) of the above-mentioned title compound.

[0328] 1 H NMR (400 MHz, DMSO) δ 11.21 (s, 1H), 7.90 (s, 1H), 7.71 (s, 3H), 7.52 - 7.43 (m, 7H), 7.27 (s, 1H), 4.83 (s, 1H), 4.63 (s, 1H), 3.85 (d, J = 136.5 Hz, 2H), 2.91 (s, 2H).

[0329] Preparation Example 62: Preparation of Compound 62 Preparation Example 62-1: Preparation of tert-butyl 8-(4-methoxyphenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (Compound 62-2) [ka]

[0330] In the same manner as in Production Example 1-3, 160.6 mg (yield 74%) of the above-titled compound was obtained using tert-butyl 8-bromo-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (200 mg, 0.57 mmol), (4-methoxyphenyl)boronic acid (450 mg, 2.96 mmol), Pd(PPh3)4 (32.9 mg, 0.028 mmol) and 1 M Na2CO3 (1.42 mL, 1.42 mmol).

[0331] 1H NMR (400 MHz, DMSO) δ 10.91 (s, 1H), 7.62 - 7.55 (m, 3H), 7.36 - 7.25 (m, 2H), 6.98 (d, J = 8.7 Hz, 2H), 4.56 (s, 2H), 3.78 (s, 3H), 3.70 (t, J = 5.7 Hz, 2H), 2.77 (s, 2H), 1.44 (s, 9H).

[0332] Preparation Example 62-2: Preparation of 8-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (Compound 62-3) [ka]

[0333] In the same manner as in Production Example 1-4, 116.4 mg (yield 87%) of the above-titled compound was obtained using tert-butyl 8-(4-methoxyphenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (160.6 mg, 0.42 mmol) and HCl solution (4 M in dioxane) (2.12 mL, 8.486 mmol).

[0334] 1 H NMR (400 MHz, DMSO) δ 11.18 (s, 1H), 9.28 (s, 1H), 7.70 (s, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.41 - 7.34 (m, 2H), 7.01 (d, J = 8.4 Hz, 2H), 4.35 (s, 2H), 3.79 (s, 3H), 3.49 (s, 2H), 3.03 (d, J = 8.3 Hz, 2H).

[0335] Preparation Example 62-3: Preparation of (8-(4-methoxyphenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(phenyl)methanone (Compound 62) [ka]

[0336] In the same manner as in Production Example 5, 8.2 mg (yield 27%) of the title compound was obtained using 8-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (30 mg, 0.079 mmol), benzoic acid (11.62 mg, 0.095 mmol), EDCI (60.79 mg, 0.32 mmol) and DIPEA (0.055 mL, 0.32 mmol).

[0337] 1 H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 7.65 (d, J = 31.6 Hz, 2H), 7.47 (s, 5H), 7.30 (d, J = 17.7 Hz, 3H), 6.98 (s, 2H), 4.83 (s, 1H), 4.62 (s, 1H), 3.77 (s, 4H), 3.65 (s, 1H), 2.87 (s, 2H).

[0338] Preparation Example 63: Preparation of (8-(4-methoxyphenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(pyridin-3-yl)methanone (Compound 63) [ka]

[0339] In the same manner as in Production Example 5, 8.9 mg (yield 29%) of the title compound was obtained using 8-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (30 mg, 0.079 mmol), nicotinic acid (11.71 mg, 0.095 mmol), EDCI (60.79 mg, 0.32 mmol) and DIPEA (0.055 mL, 0.32 mmol).

[0340] 1H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 8.68 (s, 2H), 7.93 (s, 1H), 7.70 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.50 (s, 2H), 7.32 (s, 2H), 6.98 (d, J = 8.4 Hz, 2H), 4.85 (s, 1H), 4.64 (s, 1H), 3.76 (d, J = 11.7 Hz, 4H), 3.66 (s, 1H), 2.88 (d, J = 7.2 Hz, 2H).

[0341] Preparation Example 64: Preparation of Compound 64 Preparation Example 64-1: Preparation of tert-butyl 8-(4-fluorophenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (Compound 64-2) [ka]

[0342] In the same manner as in Production Example 1-3, 119.4 mg (yield 57%) of the above-titled compound was obtained using tert-butyl 8-bromo-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (200 mg, 0.57 mmol), (4-fluorophenyl)boronic acid (478 mg, 3.42 mmol), Pd(PPh3)4 (32.9 mg, 0.028 mmol) and 1 M Na2CO3 (1.42 mL, 1.42 mmol).

[0343] 1 H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 7.68 (dd, J = 16.5, 9.5 Hz, 3H), 7.33 (q, J = 8.1 Hz, 2H), 7.24 (t, J = 8.6 Hz, 2H), 4.57 (s, 2H), 3.70 (d, J = 6.0 Hz, 2H), 2.77 (s, 2H), 1.44 (s, 9H).

[0344] Preparation Example 64-2: Preparation of 8-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (Compound 64-3) [ka]

[0345] In the same manner as in Production Example 1-4, 71.8 mg (72% yield) of the above-titled compound was obtained using tert-butyl 8-(4-fluorophenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (119.4 mg, 0.33 mmol) and HCl solution (4 M in dioxane) (1.63 mL, 6.52 mmol).

[0346] 1 H NMR (400 MHz, DMSO) δ 11.23 (s, 1H), 9.29 (s, 1H), 7.77 - 7.65 (m, 3H), 7.40 (t, J = 6.6 Hz, 2H), 7.26 (t, J = 8.8 Hz, 2H), 4.33 (s, 2H), 3.47 (s, 2H), 3.04 (d, J = 6.2 Hz, 2H).

[0347] Preparation Example 64-3: Preparation of (8-(4-fluorophenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(phenyl)methanone (Compound 64) [ka]

[0348] In the same manner as in Production Example 5, 18.6 mg (yield 50%) of the title compound was obtained using 8-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (30 mg, 0.099 mmol), benzoic acid (14.52 mg, 0.12 mmol), EDCI (75.97 mg, 0.4 mmol) and DIPEA (0.069 mL, 0.4 mmol).

[0349] 1 H NMR (400 MHz, DMSO) δ 11.05 (s, 1H), 7.74 (s, 1H), 7.63 (s, 1H), 7.49 (s, 5H), 7.36(s, 2H), 7.25 (s, 3H), 4.85 (s, 1H), 4.64 (s, 1H), 3.67 (s, 2H), 2.89 (s, 2H).

[0350] Preparation Example 65: Preparation of (8-(4-fluorophenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(pyridin-3-yl)methanone (Compound 65) [ka]

[0351] In the same manner as in Production Example 5, 19.2 mg (yield 52%) of the above-mentioned title compound was obtained using 8-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (30 mg, 0.099 mmol), nicotinic acid (14.64 mg, 0.12 mmol), EDCI (75.97 mg, 0.4 mmol) and DIPEA (0.069 mL, 0.4 mmol).

[0352] 1 H NMR (400 MHz, DMSO) δ 11.06 (s, 1H), 8.69 (s, 2H), 7.92 (s, 1H), 7.75 (d, J = 17.1 Hz, 2H), 7.63 (s, 1H), 7.52 (s, 1H), 7.36 (s, 2H), 7.24 (s, 2H), 4.87 (s, 1H), 4.66 (s, 1H), 4.03 (s, 1H), 3.67 (s, 1H), 2.90 (s, 2H).

[0353] Preparation Example 66: Preparation of Compound 66 Preparation Example 66-1: Preparation of tert-butyl 8-(4-cyclohexylphenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (Compound 66-2) [ka]

[0354] In the same manner as in Production Example 1-3, 288.7 mg (yield 78%) of the above-titled compound was obtained using tert-butyl 8-bromo-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (300 mg, 0.85 mmol), (4-cyclohexylphenyl)boronic acid (522.91 mg, 2.56 mmol), Pd(PPh3)4 (49.35 mg, 0.043 mmol) and 1 M Na2CO3 (2.14 mL, 2.14 mmol).

[0355] 1 H NMR (400 MHz, DMSO) δ 10.94 (s, 1H), 7.65 - 7.54 (m, 3H), 7.33 (s, 2H), 7.27 (d, J = 7.8 Hz, 2H), 4.57 (s, 2H), 3.71 (d, J = 7.1 Hz, 2H), 2.78 (s, 2H), 2.49 (s, 1H), 1.81 (d, J = 9.2 Hz, 4H), 1.72 (d, J = 12.8 Hz, 1H), 1.51 - 1.35 (m, 15H).

[0356] Preparation Example 66-2: Preparation of 8-(4-cyclohexylphenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (Compound 66-3) [ka]

[0357] In the same manner as in Production Example 1-4, 220.6 mg (yield 89%) of the above-titled compound was obtained using 8-(4-cyclohexylphenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (288.7 mg, 0.67 mmol) and HCl solution (4 M in dioxane) (3.35 mL, 13.41 mmol).

[0358] 1 H NMR (400 MHz, DMSO) δ 11.20 (s, 1H), 9.26 (s, 2H), 7.73 (s, 1H), 7.58 (d, J = 7.9 Hz, 2H), 7.39 (s, 2H), 7.28 (d, J = 7.9 Hz, 2H), 4.35 (s, 2H), 3.48 (s, 2H), 3.04 (s, 2H), 2.49 (s, 1H), 1.81 (d, J = 9.7 Hz, 5H), 1.41 (q, J = 12.1 Hz, 5H).

[0359] Preparation Example 66-3: Preparation of (8-(4-cyclohexylphenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(phenyl)methanone (Compound 66) [ka]

[0360] In the same manner as in Production Example 56-3, 9.3 mg (yield 39%) of the above-mentioned title compound was obtained using 8-(4-cyclohexylphenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.055 mmol), benzoic acid (7.99 mg, 0.065 mmol), DMAP (26.63 mg, 0.22 mmol), EDCI (41.79 mg, 0.22 mmol) and DIPEA (0.038 mL, 0.22 mmol).

[0361] 1H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 7.75 (s, 1H), 7.62 (s, 2H), 7.50 (s, 5H), 7.37 (s, 2H), 7.28 (s, 2H), 4.85 (s, 1H), 4.64 (s, 1H), 4.04 (s, 1H), 3.68 (s, 1H), 2.89 (s, 2H), 1.82 (s, 4H), 1.73 (d, J = 12.6 Hz, 1H), 1.42 (s, 4H), 1.26 (d, J = 10.9 Hz, 1H).

[0362] Preparation Example 67: Preparation of (8-(4-cyclohexylphenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(6-methylpyridin-3-yl)methanone (Compound 67) [ka]

[0363] In the same manner as in Production Example 56-3, 8-(4-cyclohexylphenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.055 mmol), 6-methylnicotinic acid (8.97 mg, 0.077 mmol), DMAP (26.63 mg, 0.2265 mmol), EDCI (41.79 mg, 0.22 mmol) and DIPEA (0.038 mL, 0.22 mmol) were used to obtain 7.3 mg (yield 29%) of the above-mentioned title compound.

[0364] 1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 8.56 (s, 1H), 7.80 (s, 2H), 7.60 (s, 1H), 7.52 (s, 1H), 7.35 (s, 3H), 7.26 (s, 2H), 4.84 (s, 1H), 4.67 (s, 1H), 3.68 (s, 2H), 2.90 (s, 2H), 2.53 (s, 3H), 1.80 (s, 4H), 1.71 (d, J = 12.5 Hz, 1H), 1.40 (s, 4H), 1.24 (d, J = 11.6Hz, 1H).

[0365] Preparation Example 68: Preparation of Compound 68 Preparation Example 68-1: Preparation of 8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (Compound 68-2) [ka]

[0366] In the same manner as in Production Example 1-1, 95.3 mg (yield 40%) of the above-titled compound was obtained using p-tolylhydrazine hydrochloride (200 mg, 1.26 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (263.83 mg, 1.32 mmol) and H2SO4 (0.16 mL, 8 M).

[0367] 1 H NMR (400 MHz, DMSO) δ 10.55 (s, 1H), 7.13 (d, J = 8.1 Hz, 1H), 7.08 (s, 1H), 6.81 (dd, J = 8.2, 1.7 Hz, 1H), 3.81 (s, 2H), 3.57 (s, 1H), 3.00 (t, J = 5.6 Hz, 2H), 2.65 (d, J = 5.7 Hz, 2H), 2.34 (s, 3H).

[0368] Preparation Example 68-2: Preparation of (8-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(phenyl)methanone (Compound 68) [ka]

[0369] In the same manner as in Production Example 5, 11.6 mg (yield 37%) of the title compound was obtained using 8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (20 mg, 0.11 mmol), benzoic acid (15.74 mg, 0.13 mmol), EDCI (82.35 mg, 0.43 mmol) and DIPEA (0.075 mL, 0.43 mmol).

[0370] 1 H NMR (400 MHz, DMSO) δ 10.83 (s, 1H), 7.49 (s, 5H), 7.25 (s, 1H), 7.18 (s, 1H), 6.92 - 6.82 (m, 1H), 4.76 (s, 1H), 4.55 (s, 1H), 4.01 (s, 1H), 3.64 (s, 1H), 2.85 (s, 2H), 2.33 (d, J = 40.9 Hz, 3H).

[0371] Preparation Example 69: Preparation of (4-(dimethylamino)phenyl)(8-(p-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)methanone (Compound 69) [ka]

[0372] In the same manner as in Production Example 5, 13.1 mg (yield 47%) of the title compound was obtained using 8-(p-tolyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.07 mmol), 4-(dimethylamino)benzoic acid (22.12 mg, 0.13 mmol), EDCI (51.3 mg, 0.27 mmol) and DIPEA (0.047 mL, 0.27 mmol).

[0373] 1 H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 7.70 - 7.53 (m, 3H), 7.42 - 7.30 (m, 4H), 7.22 (d, J = 7.9 Hz, 2H), 6.75 (d, J = 8.8 Hz, 2H), 4.76 (s, 2H), 3.85 (s, 2H), 2.97 (s, 6H), 2.90 (s, 2H), 2.33 (s, 3H).

[0374] Preparation Example 70: Preparation of Compound 70 Preparation Example 70-1: Preparation of tert-butyl 8-(4-chlorophenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (Compound 70-2) [ka]

[0375] In the same manner as in Production Example 1-3, 66.7 mg (yield 61%) of the above-titled compound was obtained using tert-butyl 8-bromo-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (100 mg, 0.28 mmol), (4-chlorophenyl)boronic acid (66.79 mg, 0.43 mmol), Pd(PPh3)4 (16.46 mg, 0.014 mmol) and 1 M Na2CO3 (0.71 mL, 0.71 mmol).

[0376] 1H NMR (400 MHz, DMSO) δ 11.03 (s, 1H), 7.75 - 7.65 (m, 3H), 7.52 - 7.44 (m, 2H), 7.37 (t, J = 1.4 Hz, 2H), 4.59 (s, 2H), 3.72 (t, J = 5.9 Hz, 2H), 2.80 (d, J = 5.4 Hz, 2H), 1.45 (s, 9H).

[0377] Preparation Example 70-2: Preparation of 8-(4-chlorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (Compound 70-3) [ka]

[0378] In the same manner as in Production Example 1-4, 41.7 mg (74% yield) of the above-titled compound was obtained using tert-butyl 8-(4-chlorophenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (66.7 mg, 0.17 mmol) and HCl solution (4 M in dioxane) (0.87 mL, 3.48 mmol).

[0379] 1 H NMR (400 MHz, DMSO) δ 11.31 (s, 1H), 9.45 (s, 1H), 7.81 (s, 1H), 7.75 - 7.65 (m, 2H), 7.53 - 7.44 (m, 2H), 7.43 (s, 2H), 4.35 (s, 2H), 3.51 - 3.44 (m, 2H), 3.05 (t, J = 6.4 Hz, 2H).

[0380] Preparation Example 70-3: Preparation of (8-(4-chlorophenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(phenyl)methanone (Compound 70) [ka]

[0381] In the same manner as in Production Example 5, 12.3 mg (yield 50%) of the title compound was obtained using 8-(4-chlorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (20 mg, 0.063 mmol), benzoic acid (9.18 mg, 0.075 mmol), EDCI (48.04 mg, 0.25 mmol) and DIPEA (0.044 mL, 0.25 mmol).

[0382] 1 H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 7.83 (s, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.65 (s, 1H), 7.50 (s, 6H), 7.39 (s, 3H), 4.86 (s, 1H), 4.65 (s, 1H), 4.04 (q, J = 7.1 Hz, 1H), 3.67 (s, 1H), 2.89 (s, 2H).

[0383] Preparation Example 71: Preparation of Compound 71 Preparation Example 71-1: Preparation of tert-butyl 8-(4-nitrophenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (Compound 71-2) [ka]

[0384] In the same manner as in Production Example 1-3, 33.7 mg (yield 30%) of the above-titled compound was obtained using tert-butyl 8-bromo-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (100 mg, 0.28 mmol), (4-nitrophenyl)boronic acid (142.57 mg, 0.85 mmol), Pd(PPh3)4 (16.46 mg, 0.014 mmol) and 1 M Na2CO3 (0.71 mL, 0.71 mmol).

[0385] 1H NMR (400 MHz, DMSO) δ 11.16(s, 1H), 8.27(d, J = 8.4 Hz, 2H), 8.01 (d, J=8.5 Hz, 2H), 7.91(s, 1H), 7.51 (d, J=8.6 Hz, 1H), 7.43(d, J=8.4 Hz, 1H), 4.61(s, 2H), 3.73 (t, J = 5.7 Hz, 2H), 2.84-2.77(m, 2H), 1.45(s, 9H).

[0386] Preparation Example 71-2: Preparation of 8-(4-nitrophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (Compound 71-3) [ka]

[0387] In the same manner as in Production Example 1-4, 23.8 mg (yield 84%) of the above-titled compound was obtained using tert-butyl 8-(4-nitrophenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (33.7 mg, 0.086 mmol) and HCl solution (4 M in dioxane) (0.43 mL, 1.71 mmol).

[0388] 1 H NMR (400 MHz, DMSO) δ 11.40 (s, 1H), 9.18 (s, 1H), 8.31 (d, J = 8.6 Hz, 2H), 8.00 (d, J = 7.5 Hz, 3H), 7.58 (d, J = 8.5 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 4.39 (s, 2H), 3.52 (d, J = 6.1 Hz, 2H), 3.07 (d, J = 6.2 Hz, 2H).

[0389] Preparation Example 71-3: Preparation of (8-(4-nitrophenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(phenyl)methanone (Compound 71) [ka]

[0390] In the same manner as in Production Example 5, 25.7 mg (yield 89%) of the title compound was obtained using 8-(4-nitrophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (23.8 mg, 0.072 mmol), benzoic acid (10.58 mg, 0.087 mmol), EDCI (55.34 mg, 0.29 mmol) and DIPEA (0.05 mL, 0.29 mmol).

[0391] 1 H NMR (400 MHz, DMSO) δ 11.24 (s, 1H), 8.28 (s, 1H), 8.23 ​​(s, 1H), 8.04 (s, 2H), 7.95 (s, 1H), 7.74 (s, 1H), 7.50 (s, 6H), 4.88 (s, 1H), 4.68 (s, 1H), 4.04 (s, 1H), 3.69 (s, 1H), 2.90 (s, 2H).

[0392] Preparation Example 72: Preparation of (8-(4-aminophenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(phenyl)methanone (Compound 72) [ka] (8-(4-Nitrophenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(phenyl)methanone (20 mg, 0.05 mmol) and 10% Pd / C (5.32 mg, 0.005 mmol) were dissolved in ethyl acetate. The reaction mixture was stirred at room temperature under hydrogen for 3 hours. After the reaction was completed, the mixture was filtered using ethyl acetate, and the filtrate was concentrated under reduced pressure. The solid was then solidified with ether and filtered to give 6.3 mg (34% yield) of the title compound.

[0393] 1H NMR (400 MHz, DMSO) δ 10.91 (s, 1H), 7.61 (s, 1H), 7.49 (s, 5H), 7.38 (s, 1H), 7.29 (d, J = 10.9 Hz, 3H), 6.63 (s, 1H), 6.59 (s, 1H), 5.06 (s, 2H), 4.83 (s, 1H), 4.62 (s, 1H), 4.03 (s, 1H), 3.67 (s, 1H), 2.87 (s, 2H).

[0394] Preparation Example 73: Preparation of Compound 73 Preparation Example 73-1: Preparation of tert-butyl 8-(4-(dimethylamino)phenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (Compound 73-2) [ka]

[0395] In a similar manner to that in Production Example 1-3, 25.7 mg (yield 23%) of the above-titled compound was obtained using tert-butyl 8-bromo-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (100 mg, 0.28 mmol), N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (211.08 mg, 0.85 mmol), Pd(PPh3)4 (16.46 mg, 0.014 mmol) and 1 M Na2CO3 (0.71 mL, 0.71 mmol).

[0396] 1 H NMR (400 MHz, DMSO) δ 10.85 (s, 1H), 7.55 - 7.46 (m, 3H), 7.28 (t, J = 7.0 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H), 4.55 (s, 2H), 3.70 (t, J = 5.6 Hz, 2H), 2.91 (s, 6H), 2.74 (d, J = 15.5 Hz, 2H), 1.43 (s, 9H).

[0397] Preparation Example 73-2: Preparation of N,N-dimethyl-4-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)aniline hydrochloride (Compound 73-3) [ka]

[0398] In the same manner as in Production Example 1-4, 16.4 mg (yield 76%) of the above-titled compound was obtained using tert-butyl 8-(4-(dimethylamino)phenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (25.7 mg, 0.065 mmol) and HCl solution (4 M in dioxane) (0.33 mL, 1.31 mmol).

[0399] 1 H NMR (400 MHz, DMSO) δ 11.22 (s, 1H), 9.31 (s, 2H), 7.74 (s, 1H), 7.67 (s, 3H), 7.40 (s, 3H), 4.35 (s, 2H), 3.50 (s, 2H), 3.04 (s, 8H).

[0400] Preparation Example 73-3: Preparation of (8-(4-(dimethylamino)phenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)(phenyl)methanone (Compound 73) [ka]

[0401] In the same manner as in Production Example 5, 10 mg (yield 55%) of the above-mentioned title compound was obtained using N,N-dimethyl-4-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)aniline hydrochloride (15 mg, 0.046 mmol), benzoic acid (6.7 mg, 0.055 mmol), EDCI (35.08 mg, 0.18 mmol) and DIPEA (0.032 mL, 0.18 mmol).

[0402] 1 H NMR (400 MHz, DMSO) δ 10.95 (s, 1H), 7.67 (s, 1H), 7.50 (s, 6H), 7.32 (s, 3H), 6.78 (d, J = 20.1 Hz, 2H), 4.84 (s, 1H), 4.63 (s, 1H), 4.04 (d, J = 7.3 Hz, 1H), 3.67 (s, 1H), 2.93 (s, 8H).

[0403] Preparation Example 74: Preparation of N-phenyl-8-(p-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carbothioamide (Compound 74) [ka]

[0404] Under nitrogen, 8-(p-tolyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (40 mg, 0.13 mmol) was dissolved in dichloromethane. Isothiocyanatobenzene (0.019 mL, 0.16 mmol) and TEA (0.072 mL, 0.52 mmol) were added. The reaction mixture was stirred at room temperature for 18 hours. Upon completion of the reaction, the mixture was extracted with distilled water and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography. The precipitate was filtered off with diethyl ether to obtain 23 mg (45% yield) of the title compound.

[0405] 1H NMR (400 MHz, DMSO) δ 11.04(s, 1H), 9.44(s, 1H), 7.62(d, J=1.5 Hz, 1H), 7.56(d, J=8.1 Hz, 2H), 7.42 - 7.27(m, 6H), 7.24(d, J=8.0 Hz, 2H), 7.13 (s, 1H), 5.10(s, 2H), 4.35(t, J=5.7 Hz, 2H), 2.96(s, 2H), 2.34(s, 3H).

[0406] Preparation Example 75: Preparation of N-phenyl-8-(p-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxamide (Compound 75) [ka]

[0407] In the same manner as in Production Example 74, 28 mg (yield 73%) of the above-titled compound was obtained using 8-(p-tolyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (30 mg, 0.1 mmol), isocyanatobenzene (0.013 mL, 0.12 mmol), and TEA (0.056 mL, 0.04 mmol).

[0408] 1 H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 8.62 (s, 1H), 7.66 (s, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 7.39 - 7.34 (m, 2H), 7.28 - 7.22 (m, 4H), 6.95 (t, J = 7.4 Hz, 1H), 4.74 (s, 2H), 3.87 (t, J = 5.6 Hz, 2H), 2.87 (s, 2H), 2.35 (s, 3H).

[0409] Preparation Example 76: Preparation of N,8-di-p-tolyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carbothioamide (Compound 76) [ka]

[0410] In the same manner as in Production Example 74, 18 mg (yield 36%) of the above-titled compound was obtained using 8-(p-tolyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (35 mg, 0.12 mmol), 1-isothiocyanato-4-methylbenzene (27 mg, 0.18 mmol), and TEA (0.067 mL, 0.48 mmol).

[0411] 1 H NMR (400 MHz, DMSO) δ 11.05 (s, 1H), 9.37 (s, 1H), 7.61 (s, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.42 - 7.32 (m, 2H), 7.24 (d, J = 7.8 Hz, 2H), 7.20 (d, J = 8.2 Hz, 2H), 7.12 (d, J = 8.2 Hz, 2H), 5.09 (s, 2H), 4.34 (s, 2H), 2.95 (s, 2H), 2.34 (s, 3H), 2.29 (s, 3H).

[0412] Preparation Example 77: Preparation of N-(4-cyanophenyl)-8-(p-tolyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carbothioamide (Compound 77) [ka]

[0413] Using H-pyrido[4,3-b]indole hydrochloride (35 mg, 0.12 mmol), 4-isothiocyanatobenzonitrile (29 mg, 0.18 mmol), and TEA (0.067 mL, 0.48 mmol), 32 mg of the above-titled compound was obtained (yield 63%).

[0414] 1 H NMR (400 MHz, DMSO) δ 11.07(s, 1H), 9.79(s, 1H), 7.75(d, J = 8.4 Hz, 2H), 7.63(s, 1H), 7.58(dd, J = 11.5, 8.1 Hz, 4H), 7.42-7.32(m, 2H), 7.24 (d, J=7.8 Hz, 2H), 5.12(s, 2H), 4.35(s, 2H), 3.00(s, 2H), 2.33(s, 3H).

[0415] Experimental results Tau-Synaptogyrin-3 Interaction Cell-Based Assay Because Synaptogyrin3 is a four-membrane-spanning neuronal vesicle protein, the development of an in vitro assay method for detecting the interaction between Tau and Synaptogyrin3 requires the expression and purification of recombinant protein. Therefore, to avoid interference between endogenous Synaptogyrin3 and Tau expression and to facilitate the manipulation of large samples, we designed a cell-based assay using HEK293T cells. Tau fused to EGFP (pTK231:P CMV -Tau-EGFP) and Synaptogyrin3 (pTK233:P CMV We confirmed the expression of both proteins in HEK293T cells by transfecting them with Tau-EGFP-Synaptogyrin3. Both proteins were well expressed in HEK293T cells, and while Tau-EGFP was localized in the cytoplasm, EGFP-Synaptogyrin3 was distributed mostly in granules (Fig. 1). This confirmed that the Tau-Synaptogyrin3 interaction could be captured in HEK293T cells.

[0416] Protein complementary assays (PCA) are widely used to detect protein-protein interactions, and bimolecular fluorescence complementation and split luciferase methods have been actively used to develop assays for monitoring Tau protein-protein interactions [2, 3]. The split luciferase system, called NanoBit, contains a small bit (sBit) and a large bit (Lbit), and is small enough to prevent oligomerization and is used to analyze the functionality and usefulness of nanoBit in living cells. All combinations of sBit / Lbit and Synaptogyrin3 / Tau fusion proteins (Table 1: pTK225:Tau-sBit, pTK226:Tau-Lbit, pTK227:sBit-Tau, pTK228:Lbit-Tau, pTK245:Synaptogyrin3-sBit, pTK246:Synaptogyrin3-Lbit, pTK247:sBit-Synaptogyrin3, and pTK248:Lbit-Synaptogyrin3) were cloned under the CMV promoter for expression in mammalian cells. Co-transfection of all possible combinations in HEK293T cells confirmed that the combination of Lbit-Synaptogyrin3 and sBit-Tau showed the highest signal increase (Figure 2). Therefore, the combination of Lbit-Synaptogyrin3 and sBit-Tau was selected.

[0417] Generation and validation of stable cell lines To improve the efficiency of stable cell line generation, we applied a dual-promoter and multi-cistronic construct in which all essential components were contained in a single plasmid. The constructs for the Tau-Synaptogyrin3 interaction assay, including the fluorescent protein and puromycin resistance gene, were cloned into a single plasmid (Table 1: pTK252:P EF1alpha -sBit-Tau-IRES-EGFP / P PGKTwo GFPs (EGFP and copGFP) were inserted into each expression unit of the vector, and eight GFP-positive clones (1E2, 1D6, 2B5, 2C9, 2C10, 3B5, 4D7, and 4F2) were selected after selection of pTK252-transfected HEK293T cells with puromycin.

[0418] The reliability of the Tau-Synaptogyrin3 interaction assay in HEK293T-TK252 clones was indirectly confirmed by competitive expression of native Tau using phloretin-regulated gene expression (Figures 3 and 4). Native Tau competitively binds to Synaptogyrin3 with sBit-Tau, and the co-expression of more native Tau predicted lower luciferase activity (Figure 4A). The expression of native Tau was dose-dependently regulated using a phloretin-regulated gene expression system. The phloretin-regulated gene expression system was composed of a synthetic transcriptional activator, TtgA, derived from the flavonoid-regulated TtgRoperon of Pseudomonas putida DOT-T1E strain, and a synthetic promoter, P. TtgR (Figure 3A) [5]. The TtgR activation site (O) on DNA TtgR ) and is dissociated from DNA as soon as phloretin binds to TtgR. The synthetic transcription factor is a fusion protein of TtgR and the herpes simplex-derived transactivation domain VP16, and the synthetic promoter is O 5' upstream of the CMV minimal promoter. TtgR In the absence of phloretin, TtgA is composed of P TtgR In the presence of phloretin, TtgA dissociates from DNA and transcription is not activated. CAG -TtgA and pTK274:P TtgRCo-expression of phloretin-EGFP showed a dose-dependent EGFP signal (0-50 μM phloretin), with a 4-fold difference between the 0 and 50 μM treatments (Figure 3B). CAG -TtgA and pTK285:P TtgR HEK293T-TK252 clones were co-transfected with phloretin (-Tau) and treated with different concentrations (0, 10, and 50 μM). The expected competitive binding was observed in clones 1E2, 2C9, and 2C10. Among these, 1E2 showed the lowest maximum signal but the highest dose-dependence, with a two-fold difference in efficacy between 0 and 50 μM treatments, and was selected for screening (Figure 4B). The other clones either did not respond to phloretin (1D6, 4F2, and 4D7) or responded in a reversed manner (3B5 and 2B5). Phloretin treatment did not significantly alter EGFP signals, confirming that phloretin had no effect on cell viability or protein expression.

[0419] Derivative screening of hit compounds HEK293T-TK252-1E2 cells were treated with 1,728 compounds at a concentration of 10 μM each and then cultured for 48 hours. Because phenol red significantly affects assay results, phenol red-free medium was used throughout the entire process, from cell culture to measurement. Before measurement, dead cells were removed and a single wash with FBS-free medium was performed to remove FBS, which may affect the luciferase assay. Luciferase activity and fluorescence intensity were measured at a single time point. Because fluorescence intensity is expected to be proportional to the cell number at the measurement time point, luciferase activity was normalized using fluorescence intensity. The L / F value (luciferase activity / fluorescence intensity), which represents luciferase activity normalized to fluorescence intensity, was calculated for all measurements and compared with the L / F value of the DMSO control group to evaluate inhibitory effects. The average coefficient of variation (CV) calculated from the L / F values ​​for triplicates of all measurements was 0.116, confirming the robustness of the cell-based assay. Immediately after measuring luciferase activity and fluorescence intensity, cytotoxicity was assessed by scanning the fluorescent area (FA) to identify residual fluorescent cells in the wells. FA values ​​were proportional to WST assay results (data not shown), and the average CV for all triplicate measurements was 0.04.

[0420] Dose-dependence of 61 compounds was examined by measuring the inhibitory effect measured by L / F values ​​(<60%) and FA-based cell viability (>90%) compared to the DMSO control at a concentration of 10 μM. Of these, 10 compounds were considered hit compounds after triplicate experiments. The IC of the derivatives (indicated by chemical formula number) was 50 The values ​​are shown in Table 4 below.

[0421] [Table 11]

[0422] Although certain parts of the present invention have been described in detail above, it will be apparent to those skilled in the art that such specific descriptions are merely preferred embodiments and do not limit the scope of the present invention. Therefore, the true scope of the present invention is defined by the appended claims and their equivalents.

[0423] References 1. Schlatter, S., et al., Gene, 282(1-2): 19-31(2002). 2. Wegmann, S., et al., J Neurochem, 2016. 139(6): 1163-1174(2016). 3. Tak, H., et al., PLoS One, 2013. 8(12): e81682. 4. Dixon, AS, et al., ACS Chem Biol, 11(2): 400-408(2016). 5. Gitzinger, M., et al., Proc Natl Acad Sci USA, 106(26): 10638-10643 (2009).

Claims

1. A compound represented by the following chemical formula 1: 【Chemistry 1】 [wherein R １ is C １ -C ３ alkyl; or unsubstituted or C １ -C ３ Alkyl, C ３ -C ７ Cycloalkyl, C １ -C ３ Alkoxy, halogen, -CN, -NO ２ or -NR ３ R ４ (R ３ and R ４ are each independently hydrogen or C １ -C ３ C substituted with alkyl ６ -C １０ aryl, or 5- to 12-membered heteroaryl; R ２ is unsubstituted or C １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C １ -C ３ Alkoxy, halogen, -CN, -NO ２ or NR ５ R ６ (R ５ and R ６ are each independently hydrogen, C １ -C ３ C substituted with alkyl ６ -C １０ Aryl, 5- to 12-membered heteroaryl, C ３ -C ７ cycloalkyl, or a 6-membered heterocycloalkyl; R ３ is hydrogen, or C １ -C ３ is alkyl; L １ is a direct bond or —NH—; L ２ is a direct bond, —C(O)—, —C(S)—, —C(O)NH—, —C(S)NH—, or —S(O ２ )-is.

2. The R １ But C １ -C ２ alkyl; or unsubstituted or C １ -C ３ Alkyl, C ５ -C ６ Cycloalkyl, C １ -C ３ Alkoxy, halogen, -CN, -NO ２ , -NH ２ or -N(CH ３ ) ２ The compound according to claim 1, wherein the compound is a phenyl substituted with , or a 5- to 9-membered heteroaryl.

3. The compound of claim 2, wherein the heteroaryl is pyridine.

4. The R ２ is unsubstituted or C １ -C ３ Alkyl, trihalomethyl, C １ -C ３ Alkoxy, —N(CH ３ ) ２ phenyl substituted with —CN or halogen, 5- to 9-membered heteroaryl, C ５ -C ６ 2. The compound according to claim 1, characterized in that it is a cycloalkyl or morpholine.

5. 5. The compound of claim 4, wherein said heteroaryl is selected from the group consisting of pyridine, pyrimidine, pyrazine, thiazole and indole.

6. Said L ２ When is —C(O)NH— or —C(S)NH—, the R ２ is unsubstituted or C １ -C ２ The compound according to claim 1, characterized in that it is a phenyl substituted with alkyl or -CN.

7. The compound according to claim 1, wherein the compound represented by Chemical Formula 1 is selected from the group consisting of compounds represented by the following Chemical Formulas 2 to 77: 【Chemistry 2】 【Transformation 3】 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】

8. A composition for preventing or treating a degenerative brain disease, comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient.

9. The degenerative brain disease may be Alzheimer's disease, argyrophilic grain disease (AGD), dementia with Lewy bodies, frontotemporal dementia, progressive supranuclear palsy (PSP), progressive supranuclear palsy-parkinsonism syndrome (PSP-P), Richardson's syndrome, Pick's disease, Niemann-Pick disease, Rasmussen's syndrome, Parkinson's disease, atypical parkinsonism in Guadeloupe, or atypical parkinsonism in Guadeloupe. Guadeloupe, FTDP-17 (Frontotemporal dementia with parkinsonism associated with chromosome 17), progressive subcortical gliosis, primary progressive aphasia, global gliopathy, Lytico-Bodig disease, neurodegeneration with brain iron accumulation, pantothenate kinase-associated neurodegeneration kinase-associated neurodegeneration (PKAN), postencephalitic parkinsonism, chronic traumatic encephalopathy;CTE), Familial British dementia, Familial Danish dementia, Huntington's disease, Down's syndrome, Gerstmann-Straussler-Scheinker disease, myotonic dystrophy, leukotauopathy, amyotrophic lateral sclerosis (ALS), cerebral amyloid angiopathy, and neurofibrillary tangle dementia.

9. The composition according to claim 8, characterized in that the neurofibrillary tangle type is selected from the group consisting of neurofibrillary tangle type, motor neuron disease with neurofibrillary tangles, diffuse neurofibrillary tangles with calcification, corticobasal degeneration, primary age-related tauopathy and traumatic brain injury.

10. The composition according to claim 8, wherein the composition inhibits the interaction between Tau and synaptogrynin 3.

11. A functional food composition for improving or preventing degenerative brain diseases, comprising the compound according to any one of claims 1 to 7 or a nutritively acceptable salt thereof as an active ingredient.

12. A functional food composition for inhibiting the interaction between tau and synaptogrynin 3, comprising the compound according to any one of claims 1 to 7 or a nutritively acceptable salt thereof as an active ingredient.

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